Textbook of Pathology, 6th Edition

785
























Figure 26.27 Solid basal cell carcinoma. The dermis is invaded by irregular masses of basaloid cells with characteristic peripheral palisaded
appearance. The masses of tumour cells are separated from dermal collagen by a space called shrinkage artefact.



name ‘rodent ulcer’. However, less frequently non- 1. TRICHOEPITHELIOMA (BROOKE’S TUMOUR). This
ulcerated nodular pattern, pigmented basal cell carcinoma tumour may occur as a solitary lesion or as multiple inherited
and fibrosing variants are also encountered. lesions, predominantly on the face, scalp and neck.
Histologically, the most characteristic feature is the Histologically, the tumour is often circumscribed. The
proliferation of basaloid cells (resembling basal layer of most characteristic histologic feature is the presence of CHAPTER 26
epidermis). A variety of patterns of these cells may be seen: multiple horn cysts having keratinised centre and
solid masses, masses of pigmented cells, strands and nests surrounded by basophilic cells resembling basal cells.
of tumour cells in morphea pattern, keratotic masses, These horn cysts simulate abortive pilar structures which
cystic change with sebaceous differentiation, and adenoid are interconnected by epithelial tracts.
pattern with apocrine or eccrine differentiation. The most
common pattern is solid basal cell carcinoma in which the 2. PILOMATRICOMA (CALCIFYING EPITHELIOMA
dermis contains irregular masses of basaloid cells having OF MALHERBE). Pilomatricoma usually occurs as a solitary The Skin
characteristic peripheral palisaded appearance of the lesion, more often on the face and upper extremities. It may
nuclei (Fig. 26.27). A superficial multicentric variant be seen at any age. The lesions vary in size from 0.5-5 cm
composed of multiple foci of tumour cells present in the and appear as well-demarcated dark red nodules.
dermis, especially in the trunk, has also been described.
Histologically, the circumscribed tumour is located in
deeper dermis and subcutis. The masses of tumour cells
3. METATYPICAL CARCINOMA (BASOSQUAMOUS
CELL CARCINOMA). Metatypical or basosquamous cell embedded in cellular stroma characteristically consist of
carcinoma is the term used for a tumour in which the cell 2 types of cells: the peripheral basophilic cells resembling
type and arrangement of cells cause difficulty in deciding hair matrix cells, and the inner shadow cells having central
between basal cell carcinoma and squamous cell carcinoma. unstained shadow in place of the lost nucleus. Areas of
The tumour masses are composed of malignant squamous calcification are present within lobules of shadow cells in
cells with horn pearls and the outer row of dark-staining basal three-fourth of the tumours (Fig. 26.28).
cells. These tumours have a high malignant potential and B. Tumours of Sebaceous Glands
may occasionally metastasise.
Tumours originating from sebaceous glands are commonly
II. ADNEXAL (APPENDAGEAL) TUMOURS benign (e.g. naevus sebaceus and sebaceous adenoma) but
sebaceous carcinoma may occasionally occur.
Tumours arising from epidermal adnexa or appendages can 1. NAEVUS SEBACEUS. Naevus sebaceus of Jadassohn
differentiate towards hair follicles, sebaceous glands and occurs mainly on the scalp or face as a solitary lesion that
sweat glands (apocrine and eccrine glands). Most of the may be present at birth. Initially, the lesion appears as a
adnexal tumours are benign but a few malignant variants hairless plaque, but later it becomes verrucous and nodular.
also exist.
Histologically, naevus sebaceus is characterised by
A. Tumours of Hair Follicle hyperplasia of immature sebaceous glands and pilar
structures. The overlying epidermis shows papillary
These are uncommon benign tumours. Two important
examples are trichoepithelioma and pilomatricoma. acanthosis.

786 Histologically, it consists of tumour cells arising from the
lower portion of the epidermis and extending downward
into dermis as broad anastomosing bands. The tumour
cells are, however, different from squamous cells. They
are smaller in size, cuboidal in shape and have deeply
basophilic nucleus.

Eccrine hidradenoma. Hidradenoma originates from the
intradermal portion of the eccrine sweat duct. The tumour
may occur anywhere in the body.
Histologically, hidradenoma consists of solid masses and
cords of tumour cells which may have an occasional duct-
like structure containing mucin. The tumour cells are
round to polygonal and may have clear or eosinophilic
cytoplasm.
Eccrine spiradenoma. This is found as a solitary, painful,
circumscribed nodule in the dermis.
Figure 26.28 Pilomatricoma (calcifying epithelioma of Malherbe). Histologically, the tumour consists of lobules which are
The tumour shows islands and lobules within the dermis which are surrounded by a thin capsule. The tumour lobules contain
composed of two types of cells: outer basophilic cells and inner shadow
cells. Areas of calcification are also seen. 2 types of epithelial cells like in the secretory coils of the
eccrine sweat gland. Peripheral cells are small with dark
2. SEBACEOUS ADENOMA. Sebaceous adenoma occurs nuclei, while the centre of lobules contains large cells with
in middle-aged persons, most commonly on the face. pale nuclei. An occasional area may show glandular
structures.
Histologically, it is sharply demarcated from the
surrounding tissue. The tumour is composed of irregular 2. APOCRINE TUMOURS. Apocrine sweat glands may
lobules of incompletely differentiated sebaceous glands. give rise to tumours; the two common examples being
SECTION III
papillary hidradenoma and cylindroma.
3. SEBACEOUS CARCINOMA. Sebaceous carcinoma is a Papillary hidradenoma. Papillary hidradenoma or hidra-
rare tumour that may occur anywhere in the body except denoma papilliferrum is usually located as a small lesion
the palms and soles. Variants of sebaceous carcinoma are commonly in women in the skin of the anogenital area.
carcinoma of the Meibomian glands of the eyelids (page 511)
and carcinoma of the ceruminous glands in the external Histologically, it is a circumscribed tumour in the dermis
meatus. under a normal epidermis. Papillary hidradenoma
represents an adenoma with apocrine differentiation and
Histologically, the tumour is composed of variable-sized
lobules of poorly-differentiated cells containing some containing papillary, tubular and cystic structures. The
sebaceous cells. The tumour cells show marked cytologic tumour cells lining these structures resemble apocrine
Systemic Pathology
atypia such as pleomorphism and hyperchromasia. epithelium with features of decapitation secretions.
Cylindroma. Also called as ‘turban tumour’ due to its
C. Tumours of Sweat Glands common location on the scalp, cylindroma may occur as both

A large number of lesions develop from sweat gland solitary and multiple lesions.
structures, either from apocrine or eccrine glands. These are
more commonly benign but sweat gland carcinoma may also Histologically, the tumour is composed of irregular
occur. islands of tumour cells creating a pattern resembling
jigsaw puzzle. The islands are surrounded by a hyaline
1. ECCRINE TUMOURS. Depending upon the portion of sheath. The tumour cells comprising the islands consist
eccrine sweat gland from which the tumour takes origin, the of 2 types of epithelial cells: peripheral small cells with dark
eccrine tumours are of 3 types: nuclei, and inner large cells with light staining nuclei. Some
i) arising from intraepidermal portion of the duct e.g. eccrine of the islands may contain tubular lumina containing
poroma; amorphous material.
ii) arising from intradermal portion of the duct e.g.
hidradenoma; and 3. SWEAT GLAND CARCINOMA. Rarely, the eccrine and
iii) arising from secretory coils e.g. eccrine spiradenoma. apocrine gland tumours described above may turn
Eccrine poroma. This tumour arises from intraepidermal malignant. All these carcinomas are adenocarcinomas and
portion of the sweat gland duct. The tumour is found more must be distinguished from metastatic adenocarcinoma in
commonly on the sole and hands. the skin.

III. MELANOCYTIC TUMOURS 787
Melanocytic tumours may arise from one of the three cell
types: naevus cells, epidermal melanocytes and dermal
melanocytes.
Benign tumours originating from naevus cells are called
naevocellular naevi.
The examples of benign tumours arising from epidermal
melanocytes are lentigo, freckles, pigmentation associated with
Albright’s syndrome and cafe-au-lait spots of neuro-
fibromatosis (page 838).
Benign tumours derived from dermal melanocytes are
Mongolian spots, naevi of Ota and of Ito and the blue naevus.
Malignant melanoma is the malignant counterpart of
melanocytic tumours.
The important examples amongst these are described
below.
1. NAEVOCELLULAR NAEVI. Pigmented naevi or moles Figure 26.29 Intradermal naevus showing nests of naevus cells
are extremely common lesions on the skin of most which are typically uniform and present in the dermis. Melanin pigment
individuals. They are often flat or slightly elevated lesions; in naevus cells is coarse and irregular.
rarely they may be papillomatous or pedunculated. Most
naevi appear in adolescence and in early adulthood due to vii) Dysplastic naevi are certain atypical naevi which have
hormonal influence but rarely may be present at birth. They increased risk of progression to malignant melanoma. These
are mostly tan to brown and less than 1 cm in size. lesions are larger than the usual acquired naevi, are often
multiple, and appear as flat macules to slightly elevated
Histologically, irrespective of the histologic types, all plaques with irregular borders and variable pigmentation. CHAPTER 26
naevocellular naevi are composed of ‘naevus cells’ which Many of the cases are familial and inheritable. Dysplastic
are actually identical to melanocytes but differ from naevi have melanocytic proliferation at the epidermo-dermal
melanocytes in being arranged in clusters or nests. Naevus junction with some cytologic atypia.
cells are cuboidal or oval in shape with homogeneous
cytoplasm and contain large round or oval nucleus. 2. MALIGNANT MELANOMA. Malignant melanoma or
Melanin pigment is abundant in the naevus cells present melanocarcinoma arising from melanocytes is one of the most
in the lower epidermis and upper dermis, but the cells in rapidly spreading malignant tumour of the skin that can The Skin
the mid-dermis and lower dermis hardly contain any occur at all ages but is rare before puberty. The tumour
melanin (Fig. 26.29). spreads locally as well as to distant sites by lymphatics and
by blood. The etiology is unknown but there is role of
The important histological variants of naevi are as under: excessive exposure of white skin to sunlight e.g. higher
i) Lentigo is the replacement of the basal layer of the incidence in New Zealand and Australia where sun exposure
epidermis by melanocytes. in high. Besides the skin, melanomas may occur at various
ii) Junctional naevus is the one in which the naevus cells other sites such as oral and anogenital mucosa, oesophagus,
conjunctiva, orbit (page 512) and leptomeninges. The
lie at the epidermal-dermal junction. The naevus cells form
well-circumscribed nests. common sites on the skin are the trunk (in men), legs (in
women); other locations are face, soles, palms and nail-beds.
iii) Compound naevus is the commonest type of pigmented Some high risk factors associated with increased
naevus. These lesions, in addition to the junctional activity incidence of malignant melanoma are as under:
as in junctional naevi, show nests of naevus cells in the dermis i) Persistent change in appearance of a mole.
to a variable depth. ii) Presence of pre-existing naevus (especially dysplastic
iv) Intradermal naevus shows slight or no junctional activity. naevus).
The lesion is mainly located in the upper dermis as nests iii) Family history of melanoma in a patient of atypical mole.
and cords of naevus cells. Multinucleate naevus cells are iii) Higher age of the patient.
common. iv) More than 50 moles 2 mm or more in diameter.
v) Spindle cell (epithelioid) naevus or juvenile melanoma Molecular studies in familial and hereditary cases have
is a compound naevus with junctional activity. The naevus revealed germline mutation in CDKN2A gene which encodes
cells are, however, elongated and epithelioid in appearance for cyclin-dependent kinase inhibitor, mutational loss of
which may or may not contain melanin. Juvenile melanoma PTEN gene and mutation in several other tumour suppressor
is important since it is frequently confused with malignant genes but not p53.
melanoma histologically. Clinically, melanoma often appears as a flat or slightly
vi) Blue naevus is characterised by dendritic spindle naevus elevated naevus which has variegated pigmentation,
cells rather than the usual rounded or cuboidal naevus cells. irregular borders and, of late, has undergone secondary
These cells are often quite rich in melanin pigment. changes of ulceration, bleeding and increase in size. Many

788
  TABLE 26.3: Distinguishing Features of Benign Mole and Malignant Melanoma.
Feature Benign Mole Malignant Melanoma
1. Clinical features
i) Symmetry Symmetrical A = Asymmetry
ii) Border Well-demarcated B = Border irregularity
iii) Colour Uniformly pigmented C = Colour change
iv) Diameter Small, less than 6 mm D = Diameter more than 6 mm
2. Common locations Skin of face, mucosa Skin; mucosa of nose, bowel, anal region
3. Histopathology
i) Architecture Nests of cells Various patterns: solid sheets, alveoli, nests, islands
ii) Cell morphology Uniform looking naevus cells Malignant cells, atypia, mitoses, nucleoli
iii) Melanin pigment Irregular, coarse clumps Fine granules, uniformly distributed
iv) Inflammation May or may not be present Often present
4. Spread Remains confined, poses cosmetic Haematogenous and/or lymphatic spread early
problem only



of the malignant melanomas, however, arise de novo rather epithelioid or spindle-shaped, the former being more
than from a pre-existing naevus. Malignant melanoma can common. The tumour cells have amphophilic cytoplasm
be differentiated from benign pigmented lesions by subtle and large, pleomorphic nuclei with conspicuous nucleoli.
features as summed up in Table 26.3; the dermatologists term Mitotic figures are often present and multinucleate giant
this as ABCD of melanoma (acronym for Asymmetry, Border cells may occur. These tumour cells may be arranged in
irregularity, Colour change and Diameter >6mm). various patterns such as solid masses, sheets, island,
alveoli etc.
MORPHOLOGIC FEATURES. Grossly, depending upon iii) Melanin. Melanin pigment may be present (melanotic)
the clinical course and prognosis, cutaneous malignant or absent (amelanotic melanoma) without any prognostic
melanomas are of the following 4 types: influence. The pigment, if present, tends to be in the form
SECTION III
i) Lentigo maligna melanoma. This often develops from of uniform fine granules (unlike the benign naevi in which
a pre-existing lentigo (a flat naevus characterised by coarse irregular clumps of melanin are present). At times,
replacement of basal layer of epidermis by naevus cells). there may be no evidence of melanin in H&E stained
It is essentially a malignant melanoma in situ. It is slow- sections but Fontana-Masson stain or dopa reaction reveals
growing and has good prognosis. melanin granules in the cytoplasm of tumour cells.
ii) Superficial spreading melanoma. This is a slightly Immunohistochemically, melnoma cells are positive for
elevated lesion with variegated colour and ulcerated HMB-45 (most specific), S-100 and Melan-A.
surface. It often develops from a superficial spreading iv) Inflammatory infiltrate. Some amount of inflam-
melanoma in situ (pagetoid melanoma) in 5 to 7 years. matory infiltrate is present in the invasive melanomas.
The prognosis is worse than for lentigo maligna Infrequently, partial spontaneous regression of the tumour
melanoma. occurs due to destructive effect of dense inflammatory
Systemic Pathology
infiltrate.
iii) Acral lentigenous melanoma. This occurs more
commonly on the soles, palms and mucosal surfaces
(Fig. 26.30). The tumour often undergoes ulceration and
early metastases. The prognosis is worse than that of
superficial spreading melanoma.
iv) Nodular melanoma. This often appears as an elevated
and deeply pigmented nodule that grows rapidly and
undergoes ulceration. This variant carries the worst
prognosis.
Histologically, irrespective of the type of malignant
melanoma, the following characteristics are observed (Fig.
26.31):
i) Origin. The malignant melanoma, whether arising
from a pre-existing naevus or starting de novo, has marked
junctional activity at the epidermo-dermal junction and
grows downward into the dermis.
ii) Tumour cells. The malignant melanoma cells are Figure 26.30 Malignant melanoma of the oral cavity. The hemi-
usually larger than the naevus cells. They may be maxillectomy specimen shows an elevated blackish ulcerated area with
irregular outlines.

789
























Figure 26.31 Malignant melanoma shows junctional activity at the dermal-epidermal junction. Tumour cells resembling epithelioid cells with
pleomorphic nuclei and prominent nucleoli are seen as solid masses in the dermis. Many of the tumour cells contain fine granular melanin pigment.
Photomicrograph shows a prominent atypical mitotic figure (arrow).

The prognosis for patients with malignant melanoma is benign variant is also known by various synonyms like
related to the depth of invasion of the tumour in the dermis. dermatofibroma, histiocytoma, sclerosing haemangioma,
Depending upon the depth of invasion below the granular fibroxanthoma and xanthogranuloma. Benign histiocytomas
cell layer in millimeters, Clark has described 5 levels: are often small but malignant fibrous histiocytomas may be
Level I: Malignant melanoma cells confined to the epidermis of enormous size. They are circumscribed but unencapsu- CHAPTER 26
and its appendages. lated.
Level II: Extension into the papillary dermis. Histologically, the tumours are composed of spindle-
Level III: Extension of tumour cells upto the interface shaped fibrohistiocytoid cells which are characteristically
between papillary and reticular dermis. arranged in cartwheel or storiform pattern. The benign
Level IV: Invasion of reticular dermis. variety contains uniform spindle-shaped cells with
admixture of numerous foamy histiocytes. The malignant The Skin
Level V: Invasion of the subcutaneous fat.
fibrous histiocytoma shows pleomorphic tumour cells and
Metastatic spread of malignant melanoma is very some multinucleate giant cells in a stroma that may show
common and takes place via lymphatics to the regional myxoid change and inflammatory infiltrate.
lymph nodes and through blood to distant sites like lungs,
liver, brain, spinal cord, and adrenals. Rarely, the primary 2. DERMATOFIBROSARCOMA PROTUBERANS. This
lesion regresses spontaneously but metastases are present is a low-grade fibrosarcoma that rarely metastasises but is
widely distributed. locally recurrent. The tumour usually forms a solid nodule,
within the dermis and subcutaneous fat, protruding the
IV.TUMOURS OF THE DERMIS epidermis outwards. Sometimes multiple nodules may form.
All the tissue elements of the dermis such as fibrous tissue, Histologically, the tumour is very cellular and is
adipose tissue, neural tissue, endothelium and smooth composed of uniform fibroblasts arranged in a cartwheel
muscle are capable of transforming into benign and or storiform pattern. A few mitoses are often present. The
malignant tumours. Many of the examples of these tumours overlying epidermis is generally thinned and may be
are discussed in Chapter 29 but a few representative dermal ulcerated (Fig. 26.32). The subcutaneous fat is frequently
neoplasms are described below. invaded by the tumour cells.
1. DERMATOFIBROMA AND MALIGNANT FIBROUS
HISTIOCYTOMA. These soft tissue tumours are composed 3. XANTHOMAS. These are solitary or multiple tumour-
of cells having mixed features of fibroblasts, myofibroblasts, like lesions, often associated with high levels of serum
histiocytes and primitive mesenchymal cells. The cholesterol and phospholipids. Many of the cases result from
histogenesis of these tumours is not quite clear but probably familial hyperlipidaemia. They may occur at different sites
they arise from multi-directional differentiation of the such as buttocks, knees, elbows, tendo-Achilles, palmar
primitive mesenchymal cells. The tumours appear at any age creases and on the eyelids (referred to as xanthelasma).
but are more common in advanced age. The commonest sites Histologically, xanthomas are composed of dermal collec-
are the lower and upper extremities, followed in decreasing tions of benign-appearing foamy histiocytes. Multi-
frequency, by abdominal cavity and retroperitoneum. The

790 stage, mycosis fungoides may disseminate to the lymph
nodes and other organs. Clinically, mycosis fungoides may
manifest in 3 stages:
i) Premycotic stage in which the lesions are erythematous,
red-brown, scaly and pruritic, resembling eczema or
psoriasis.
ii) Infiltrative stage has slightly elevated, bluish-red, firm
plaques.
iii) Fungoid (Tumour) stage is characterised by red-brown
nodules of tumour which often undergo ulceration.
The etiology of mycosis fungoides or CTCL has been
found to be the same as for adult T cell lymphoma-leukaemia
syndrome which is human T cell-leukaemia virus-I (HTLV-
I) as discussed on page 227.
Sézary syndrome is a variant of CTCL, often due to
dissemination of underlying CTCL to the blood and infil-
tration into the skin causing generalised erythroderma,
Figure 26.32 Dermatofibrosarcoma protuberans. The tumour cells lymphadenopathy and hepatosplenomegaly.
are arranged in storiform or cartwheel pattern. The tumour cells are
spindled admixed with histiocytes and show moderate anisocytosis and The condition is found more frequently beyond 4th
anisonucleosis. decade of life. Lesions may affect different body surfaces but
often involve the trunk, extremities, face and scalp.
nucleate tumour giant cells surrounded by lipid-laden Histologically, the condition has the following charac-
cytoplasm are often present.
teristics:
i) Initially, lower portion of the epidermis contains
V. CELLULAR MIGRANT TUMOURS
hyperchromatic enlarged lymphocytes. In about half the
All the tumours described above arise from progenitor cells cases, there is formation of intraepidermal clusters of
in the skin only. However, there are some tumours which atypical lymphoid cells forming Darier-Pautrier’s
have their precursor cells elsewhere in the body, but are microabscesses which is a misnomer as it does not contain
SECTION III
cellular immigrants to the skin. The examples are pus cells.
Langerhans’ cell histiocytosis (page 385), mycosis fungoides, ii) Later, there are band-like sharply demarcated
mastocytosis, lymphomas and leukaemias (Chapter 14). aggregates of polymorphous cellular infiltrate in the
Mycosis fungoides is considered here. dermis including atypical lymphoid cells (Sézary-Lutzner
cells) and multinucleated cells.
MYCOSIS FUNGOIDES (CUTANEOUS T-CELL iii) The individual mycosis cells are malignant T lympho-
LYMPHOMA) AND SEZARY SYNDROME. Mycosis cytes which have hyperchromatic and cerebriform nuclei
fungoides or cutaneous T-cell lymphoma (CTCL) is the and express CD4 and HLA-DR antigen.
commonest form of lymphoma in the skin but in advanced

❑
Systemic Pathology

791


Chapter 27 The Endocrine System
Chapter 27








ENDOCRINES: THE BASIC CONCEPT Group I: Those interacting with cell-surface membrane
receptors:
The development, structure and functions of human body 1. Amino acid derivatives: thyroid hormone, catecholamines.
are governed and maintained by 2 mutually interlinked 2. Small neuropeptides: gonadotropin-releasing hormone
systems—the endocrine system and the nervous system (Chapter (GnRH), thyrotropin-releasing hormone (TRH), somatostatin,
30); a third system combining features of both these systems vasopressin.
is appropriately called neuroendocrine system.
Group II: Those interacting with intracellular nuclear
receptors:
NEUROENDOCRINE SYSTEM
3. Large proteins: insulin, luteinising hormone (LH), para-
This system forms a link between the endocrine and nervous thormone hormone.
systems. The cells of this system elaborate polypeptide 4. Steroid hormones: cortisol, estrogen.
hormones; owing to these biochemical properties, it has also 5. Vitamin derivatives: retinol (vitamin A) and vitamin D.
been called as APUD cell system (acronym for Amine The synthesis of these hormones and their precursors takes
Precursor Uptake and Decarboxylation properties). place through a prescribed genetic pathway that involves:
However, though having common biochemical properties, transcription → mRNA → protein synthesis → post- CHAPTER 27
the cells of this system are widely distributed in the body in translational protein processing → intracellular sorting/
different anatomic areas and hence is currently called membrane integration → secretion.
dispersed neuroendocrine system. Cells comprising this system Major functions of hormones are as under:
are as under: i) Growth and differentiation of cells: by pituitary hormones,
1. Neuroendocrine cells are present in the gastric and intestinal thyroid, parathyroid, steroid hormones.
mucosa and elaborate peptide hormones. ii) Maintenance of homeostasis: thyroid (by regulating BMR),
2. Neuroganglia cells lie in the ganglia cells in the sympathetic parathormone, mineralocorticoids, vasopressin, insulin.
chain and elaborate amines. iii) Reproduction: sexual development and activity, pregnancy,
3. Adrenal medulla elaborates epinephrine and norepinephrine. foetal development, menopause etc.
4. Parafollicular C cells of the thyroid secrete calcitonin. A basic feature of all endocrine glands is the existence of The Endocrine System
5. Islets of Langerhans in the pancreas (included in both both negative and positive feedback control system that
endocrine and neuroendocrine systems) secrete insulin. stimulates or regulates hormone production in a way that levels
6. Isolated cells in the left atrium of the heart secrete atrial remain within the normal range (abbreviated as S or R
natriuretic (salt-losing) peptide hormone. respectively with the corresponding hormone e.g. TSH-TRH
In addition to above, other non-endocrine secretions pathway, GnRH-LH/FSH pathway etc). This system is
include neurotransmitter substances such as acetylcholine and commonly termed hypothalamic-pituitary hormone axis for
dopamine released from neural synapses, and erythropoietin different hormones schematically illustrated in Fig. 27.1. The
and vitamin D elaborated from the kidney. stimulatory or regulatory action by endocrine hormonal
3
secretions may follow paracrine or autocrine pathways:
Paracrine regulation means that the stimulatory/
THE ENDOCRINE SYSTEM
regulatory factors are released by one type of cells but act on
Anatomically, the endocrine system consists of 6 distinct another adjacent cell of the system.
organs: pituitary, adrenals, thyroid, parathyroids, gonads, Autocrine regulation refers to action of the factor on the
and pancreatic islets; the last one is included in neuro- same cell that produced it.
endocrine system also). Understanding the patholgy of these With this brief overview of principles of physiology of
endocrine organs requires the knowledge of overall frame- hormones, we now turn to the study of diseases of the
work of hormone secretions, their actions and broad endocrine organs. In general, pathologic processes affecting
principles of feedback mechanisms. endocrine glands with resultant hormonal abnormalities may
Broadly speaking, human hormones are divided into 5 occur from following processes:
major classes which are further grouped under two headings Hyperfunction: This results from excess of hormone secreting
depending upon their site of interactions on the target cell tissues e.g. hyperplasia, tumours (adenoma, carcinoma),
receptors (whether cell membrane or nuclear receptor): ectopic hormone production, excessive stimulation from

792









































SECTION III














Systemic Pathology
Figure 27.1 Endocrine organs and the presence of feedback controls. Both positive and negative feedback controls exist for each endocrine
gland having a regulating (R) and stimulating (S) hormone. Those acting through hypothalamic-pituitary axis include: thyroid hormones on TRH-
TSH axis, cortisol on CRH-ACTH axis, gonadal steroids on GnRH-LH/FSH axis and insulin-like GH on GHRH-GH axis. Those independent of
pituitary control (shown by interrupted arrows) have also feedback controls by calcium on PTH, and hypoglycaemia on insulin release by pancreatic
islets.


inflammation (often autoimmune), infections, iatrogenic membrane receptors, nuclear receptors or receptor for signal
(drugs-induced, hormonal administration). transduction).
Hypofunction: Deficiency of hormones occurs from
destruction of hormone-forming tissues from inflammations PITUITARY GLAND
(often autoimmune), infections, iatrogenic (e.g. surgical
removal, radiation damage), developmental defects (e.g. NORMAL STRUCTURE
Turner’s syndrome, hypoplasia), enzyme deficiency, ANATOMY. The pituitary gland or hypophysis in an adult
haemorrhage and infarction (e.g. Sheehan’s syndrome), weighs about 500 mg and is slightly heavier in females. It is
nutritional deficiency (e.g. iodine deficiency).
situated at the base of the brain in a hollow called sella turcica
Hormone resistance: There may be adequate or excessive formed out of the sphenoid bone. The gland is composed of
production of a hormone but there is peripheral resistance, 2 major anatomic divisions: anterior lobe (adenohypophysis)
often from inherited mutations in receptors (e.g. defect in and posterior lobe (neurohypophysis).

1. The anterior lobe or adenohypophysis is an ectodermal of the hypothalamus but are stored in the cells of posterior 793
derivative formed from Rathke’s pouch which is an upward pituitary.
diverticulum from the primitive buccal cavity. The 1. ADH causes reabsorption of water from the renal tubules
adenohypophysis has no direct neural connection but has and is essential for maintenance of osmolality of the plasma.
indirect connection through capillary portal circulation by Its deficiency results in diabetes insipidus characterised by
which the anterior pituitary receives the blood which has uncontrolled diuresis and polydipsia.
already passed through the hypothalamus.
2. The posterior lobe or neurohypophysis is a downgrowth 2. Oxytocin causes contraction of mammary myoepithelial
from the primitive neural tissue. The neurohypophysis, cells resulting in ejection of milk from the lactating breast
therefore, has direct neural connection superiorly with the and causes contraction of myometrium of the uterus at term.
hypothalamus. It is obvious from the description above that pituitary,
though a tiny organ, is concerned with a variety of diverse
HISTOLOGY AND FUNCTIONS. The histology and functions in the body. The pituitary gland and hypothalamus
functions of the anterior and posterior lobes of the pituitary are so closely interlinked that diseases of the pituitary gland
gland are quite distinct. involve the hypothalamus, and dysfunctions of the
hypothalamus cause secondary changes in the pituitary. The
A. ANTERIOR LOBE (ADENOHYPOPHYSIS). It is com- pituitary gland is involved in several diseases which include:
posed of round to polygonal epithelial cells arranged in cords non-neoplastic (e.g. inflammations, haemorrhage, trauma,
and islands having fibrovascular stroma. These epithelial
cells, depending upon their staining characteristics and infarction and many other endocrine diseases) and neoplastic
diseases. However, functionally and morphologically,
functions, are divided into 3 types, each of which performs diseases of the pituitary can be classified as below, each of
separate functions:
which includes diseases of the anterior and posterior
1. Chromophil cells with acidophilic granules: These cells pituitary and the hypothalamus, separately:
comprise about 40% of the anterior lobe and are chiefly i) Hyperpituitarism
located in the lateral wings. The acidophils are further of 2 ii) Hypopituitarism
types: iii) Pituitary tumours CHAPTER 27
i) Somatotrophs (GH cells) which produce growth hormone
(GH).
ii) Lactotrophs (PRL cells) which produce prolactin (PRL). HYPERPITUITARISM
Cells containing both GH and PRL called mammo- Hyperpituitarism is characterised by oversecretion of one or
somatotrophs are also present. more of the pituitary hormones. Such hypersecretion may

2. Chromophil cells with basophilic granules: These cells be due to diseases of the anterior pituitary, posterior pituitary
constitute about 10% of the anterior lobe and are mainly or hypothalamus. For all practical purposes, however,
found in the region of median wedge. The chromatophils hyperfunction of the anterior pituitary is due to the
include 3 types of cells: development of a hormone-secreting pituitary adenoma
i) Gonadotrophs (FSH-LH cells) which are the source of the (discussed later), and rarely, a carcinoma. For each of the The Endocrine System
FSH and LH or interstitial cell stimulating hormone (ICSH). hormonal hyperfunction of the anterior pituitary, posterior
ii) Thyrotrophs (TSH cells) are the cells producing TSH. pituitary and hypothalamus, a clinical syndrome is described.
iii) Corticotrophs (ACTH-MSH cells) produce ACTH, A few important syndromes are as follows:
melanocyte stimulating hormone (MSH), β-lipoprotein and
β-endorphin. A. Hyperfunction of Anterior Pituitary
Three common syndromes of adenohypophyseal hyper-
3. Chromophobe cells without visible granules: These cells
comprise the remainder 50% of the adenohypophysis. These function are: gigantism and acromegaly, hyperprolacti-
cells by light microscopy contain no visible granules, but on naemia and Cushing’s syndrome.
electron microscopy reveal sparsely granulated cortico- GIGANTISM AND ACROMEGALY. Both these clinical
trophs, thyrotrophs and gonadotrophs. syndromes result from sustained excess of growth hormone
All these functions of the adenohypophysis are under the (GH), most commonly by somatotroph (GH-secreting)
indirect control of the hypothalamus through stimulatory and adenoma.
inhibitory factors synthesised by the hypothalamus which Gigantism. When GH excess occurs prior to epiphyseal
reach the anterior lobe through capillary portal blood. closure, gigantism is produced. Gigantism, therefore, occurs
B. POSTERIOR LOBE (NEUROHYPOPHYSIS). The in prepubertal boys and girls and is much less frequent than
neurohypophysis is composed mainly of interlacing nerve acromegaly. The main clinical feature in gigantism is the
fibres in which are scattered specialised glial cells called excessive and proportionate growth of the child. There is
pituicytes. These nerve fibres on electron microscopy contain enlargement as well as thickening of the bones resulting in
granules of neurosecretory material made up of 2 considerable increase in height and enlarged thoracic cage.
octapeptides—vasopressin or antidiuretic hormone (ADH), and Acromegaly. Acromegaly results when there is overproduc-
oxytocin, both of which are produced by neurosecretory cells tion of GH in adults following cessation of bone growth and

794 is more common than gigantism. The term ‘acromegaly’ the female, growth of pubic hair and axillary hair. In the
means increased growth of extremities (acro=extremity). female, there is breast growth and onset of menstruation.
There is enlargement of hands and feet, coarseness of facial
features with increase in soft tissues, prominent supraorbital HYPOPITUITARISM
ridges and a more prominent lower jaw which when clenched In hypopituitarism, there is usually deficiency of one or more
results in protrusion of the lower teeth in front of upper teeth of the pituitary hormones affecting either anterior pituitary,
(prognathism). Other features include enlargement of the or posterior pituitary and hypothalamus.
tongue and lips, thickening of the skin and kyphosis.
Sometimes, a few associated features such as TSH excess A. Hypofunction of Anterior Pituitary
resulting in thyrotoxicosis, and gonadotropin insufficiency
causing amenorrhoea in the females and impotence in the Adenohypophyseal hypofunction is invariably due to
male, are found. destruction of the anterior lobe of more than 75% because
the anterior pituitary possesses a large functional reserve.
HYPERPROLACTINAEMIA. Hyperprolactinaemia is the This may result from anterior pituitary lesions or pressure
excessive production of prolactin (PRL), most commonly by and destruction from adjacent lesions. Lesions of the anterior
lactotroph (PRL-secreting) adenoma, also called prolac- pituitary include nonsecretory (chromophobe) adenoma,
tinoma. Occasionally, hyperprolactinaemia results from metastatic carcinoma, craniopharyngioma, trauma,
hypothalamic inhibition of PRL secretion by certain drugs postpartum ischaemic necrosis (Sheehan’s syndrome),
(e.g. chlorpromazine, reserpine and methyl-dopa). In the empty-sella syndrome, and rarely, tuberculosis. Though a
female, hyperprolactinaemia causes amenorrhoea-galactorrhoea number of syndromes associated with deficiency of anterior
syndrome characterised clinically by infertility and expression pituitary hormones have been described, two important
of a drop or two of milk from breast, not related to pregnancy syndromes are panhypopituitarism and dwarfism.
or puerperium. In the male, it may cause impotence or reduced
libido. These features result either from associated inhibition PANHYPOPITUITARISM. The classical clinical condition
of gonadotropin secretion or interference in gonadotropin of major anterior pituitary insufficiency is called
effects. panhypopituitarism. Three most common causes of
panhypopituitarism are: non-secretory (chromophobe)
CUSHING’S SYNDROME. Pituitary-dependent Cushing’s adenoma (discussed later), Sheehan’s syndrome and
syndrome results from ACTH excess. Most frequently, it is Simmond’s disease, and empty-sella syndrome.
caused by corticotroph (ACTH-secreting) adenoma.
SECTION III
Cushing’s syndrome is discussed under diseases of the Sheehan’s syndrome and Simmond’s disease. Pituitary
adrenal gland on page 797. insufficiency occurring due to postpartum pituitary
(Sheehan’s) necrosis is called Sheehan’s syndrome, whereas
B. Hyperfunction of Posterior Pituitary and occurrence of similar process without preceding pregnancy
Hypothalamus as well as its occurrence in males is termed Simmond’s
disease. The main pathogenetic mechanism underlying
Lesions of posterior pituitary and hypothalamus are Sheehan’s necrosis is the enlargement of the pituitary
uncommon. Two of the syndromes associated with hyper- occurring during pregnancy which may be followed by
function of the posterior pituitary and hypothalamus are: hypotensive shock precipitating ischaemic necrosis of the
inappropriate release of ADH and precocious puberty.
pituitary. Other mechanisms hypothesised are: DIC
INAPPROPRIATE RELEASE OF ADH. Inappropriate following delivery, traumatic injury to vessels, and excessive
Systemic Pathology
release of ADH results in its excessive secretion which haemorrhage. Patients with long-standing diabetes mellitus
manifests clinically by passage of concentrated urine due to appear to be at greater risk of developing this complication.
increased reabsorption of water and loss of sodium in the The first clinical manifestation of Sheehan’s syndrome is
urine, consequent hyponatraemia, haemodilution and failure of lactation following delivery which is due to
expansion of intra- and extracellular fluid volume. deficiency of prolactin. Subsequently, other symptoms
Inappropriate release of ADH occurs most often in develop which include loss of axillary and pubic hair,
paraneoplastic syndrome e.g. in oat cell carcinoma of the amenorrhoea, sterility and loss of libido. Concomitant defi-
lung, carcinoma of the pancreas, lymphoma and thymoma. ciency of TSH and ACTH may result in hypothyroidism and
Infrequently, lesions of the hypothalamus such as trauma, adrenocortical insufficiency.
haemorrhage and meningitis may produce ADH
hypersecretion. Rarely, pulmonary diseases such as The morphologic features in the anterior pituitary in
tuberculosis, lung abscess, pneumoconiosis, empyema and Sheehan’s syndrome during early stage are ischaemic
pneumonia may cause overproduction of ADH. necrosis and haemorrhage, while later necrotic tissue is
replaced by fibrous tissue.
PRECOCIOUS PUBERTY. A tumour in the region of
hypothalamus or the pineal gland may result in premature Empty-sella syndrome. Empty-sella syndrome is charac-
release of gonadotropins causing the onset of pubertal terised by the appearance of an empty sella and features of
changes prior to the age of 9 years. The features include panhypopituitarism. Most commonly, it results from
premature development of genitalia both in the male and in herniation of subarachnoid space into the sella turcica due

to an incomplete diaphragma sella creating an empty sella. pharyngioma and granular cell tumour (choristoma) are the 795
Other less common causes are Sheehan’s syndrome, other benign pituitary tumours found occasionally.
infarction and scarring in an adenoma, irradiation damage, All pituitary tumours, whether benign or malignant,
or surgical removal of the gland. cause symptoms by following 2 ways:
PITUITARY DWARFISM. Severe deficiency of GH in 1. Pressure effects. These are caused by expansion of the
children before growth is completed results in retarded lesion resulting in destruction of the surrounding glandular
growth and pituitary dwarfism. Most commonly, isolated tissue by pressure atrophy. This causes erosion and
GH deficiency is the result of an inherited autosomal enlargement of sella turcica, upward extension of the tumour
recessive disorder. Less often it may be due to a pituitary damaging the optic chiasma, optic nerves, neurohypophysis
adenoma or craniopharyngioma, infarction and trauma to and adjacent cranial nerves, and rarely, downward extension
the pituitary. The clinical features of inherited cases of into the nasopharynx.
pituitary dwarfism appear after one year of age. These 2. Hormonal effects. Depending upon their cell types,
include proportionate retardation in growth of bones, normal pituitary adenomas produce excess of pituitary hormones
mental state for age, poorly-developed genitalia, delayed and the corresponding clinical syndromes of hyper-
puberty and episodes of hypoglycaemia. Pituitary dwarf pituitarism. Infarction and destruction of adenoma may cause
must be distinguished from hypothyroid dwarf (cretinism) symptoms of hypopituitarism.
in which there is achondroplasia and mental retardation
(page 803).
Pituitary Adenomas
B. Hypofunction of Posterior Pituitary and Adenomas are the most common pituitary tumours. They
Hypothalamus are conventionally classified according to their H & E staining
characteristics of granules into acidophil, basophil and
Insufficiency of the posterior pituitary and hypothalamus is chromophobe adenomas. However, this morphologic
uncommon. The only significant clinical syndrome due to classification is considered quite inadequate because of the
hypofunction of the neurohypophysis and hypothalamus is significant functional characteristics of each type of adenoma
diabetes insipidus. including the chromophobe adenoma, which on H & E CHAPTER 27
DIABETES INSIPIDUS. Deficient secretion of ADH causes staining does not show visible granules. As a result of
diabetes insipidus. The causes of ADH deficiency are: advances in the ultrastructural and immunocytochemical
inflammatory and neoplastic lesions of the hypothalamo- studies, a functional classification of pituitary adenoma has
hypophyseal axis, destruction of neurohypophysis due to emerged. Table 27.1 presents a classification of pituitary
surgery, radiation, head injury, and lastly, are those cases adenomas based on functional features as correlated with
where no definite cause is known and are labelled as morphologic features of older classification. The syndromes
idiopathic. The main features of diabetes insipidus are produced by the tumours have been described already.
excretion of a very large volume of dilute urine of low specific
gravity (below 1.010), polyuria and polydipsia. MORPHOLOGIC FEATURES. Grossly, pituitary
adenomas range in size from small foci of less than 10 The Endocrine System
mm in size (termed microadenoma) to large adenomas
PITUITARY TUMOURS several centimeters in diameter. They are spherical, soft

Tumours of the anterior pituitary are more common than and encapsulated.
those of the posterior pituitary and hypothalamus. The most Histologically, by light microscopy of H & E stained
common of the anterior pituitary tumours are adenomas; sections, an adenoma is composed predominantly of one
primary and metastatic carcinomas being rare. Cranio- of the normal cell types of the anterior pituitary i.e.



  TABLE 27.1: Morphologic and Functional Classification of Pituitary Adenomas.
Functional Type Frequency Hormones Produced Clinical Syndrome
1. Lactotroph adenoma (Prolactinoma) 20-30% PRL Hypogonadism, galactorrhoea
2. Somatotroph adenoma 5% GH Acromegaly/gigantism
3. Mixed somatotroph-lactotroph adenoma 5% PRL, GH Acromegaly, hypogonadism,
galactorrhoea
4. Corticotroph adenoma 10-15% ACTH Cushing’s syndrome
5. Gonadotroph adenoma 10-15% FSH-LH Inactive or hypogonadism
6. Thyrotroph adenoma 1% TSH Thyrotoxicosis
7. Null cell adenoma/ oncocytoma 20% Nil Pituitary failure
8. Pleurihormonal adenoma 15% Multiple hormones Mixed

796 Histologically, craniopharyngioma closely resembles
ameloblastoma of the jaw (page 530). There are 2 distinct
histologic features:
1. Stratified squamous epithelium frequently lining, a
cyst and containing loose stellate cells in the centre; and
2. Solid ameloblastous areas.

Granular Cell Tumour (Choristoma)
Though tumours of the posterior pituitary are rare, granular
cell tumour or choristoma is the most common tumour of
the neurohypophysis. It is composed of a mass of cells having
granular eosinophilic cytoplasm similar to the cells of the
posterior pituitary. It arises as a result of developmental
anomaly and hence the name choristoma. Generally, it
remains asymptomatic and is discovered as an incidental
autopsy finding.

ADRENAL GLAND
Figure 27.2 Pituitary adenoma, sinusoidal pattern.
NORMAL STRUCTURE
acidophil, basophil or chromophobe cells. These cells may ANATOMY. The adrenal glands lie at the upper pole of each
have following 3 types of patterns: kidney. Each gland weighs approximately 4 gm in the adult
1. Diffuse pattern is composed of polygonal cells arranged but in children the adrenals are proportionately larger. On
in sheets with scanty stroma. sectioning, the adrenal is composed of 2 distinct parts: an
2. Sinusoidal pattern consists of columnar or fusiform cells outer yellow-brown cortex and an inner grey medulla. The
with fibrovascular stroma around which the tumour cells anatomic and functional integrity of adrenal cortices are
are arranged (Fig. 27.2). essential for life, while it does not hold true for adrenal
SECTION III
3. Papillary pattern is composed of columnar or fusiform medulla.
cells arranged about fibrovascular papillae.
HISTOLOGY AND PHYSIOLOGY. Microscopically and
Functionally, most common pituitary adenomas, in functionally, cortex and medulla are quite distinct.
decreasing order of frequency, are: lactotroph (PRL-secreting)
adenoma, somatotroph (GH-secreting) adenoma and ADRENAL CORTEX. It is composed of 3 layers:
corticotroph (ACTH-secreting) adenoma. Infrequently, 1. Zona glomerulosa is the outer layer and comprises about
mixed somatotroph-lactotroph (GH-PRL-secreting) 10% of the cortex. It consists of cords or columns of
adenoma, gonadotroph (FSH-LH-secreting) adenomas and polyhedral cells just under the capsule. This layer is
null-cell (endocrinologically inactive) adenomas or responsible for the synthesis of mineralocorticoids, the most
oncocytoma are found. Pleurihormonal-pituitary adenoma, important of which is aldosterone, the salt and water
on the other hand, may have multiple hormone elaborations. regulating hormone.
Systemic Pathology
Functional classification of pituitary adenoma can be done 2. Zona fasciculata is the middle layer and constitutes
by carrying out specific immunostains against the hormone approximately 70% of the cortex. It is composed of columns
products. of lipid-rich cells which are precursors of various steroid
Pituitary adenoma may also occur as a part of multiple hormones manufactured in the adrenal cortex such as
endocrine neoplasia type I (MEN-I) in which adenomas of glucocorticoids (e.g. cortisol) and sex steroids (e.g.
pancreatic islets, parathyroids and the pituitary are found testosterone).
(page 829). Clinically, the patients are characterised by 3. Zona reticularis is the inner layer which makes up the
combination of features of Zollinger-Ellison’s syndrome, remainder of the adrenal cortex. It consists of cords of more
hyperparathyroidism and hyperpituitarism.
compact cells than those of zona fasciculata but has similar
Craniopharyngioma functional characteristics of synthesis and secretion of
glucocorticoids and androgens.
Craniopharyngioma is a benign tumour arising from The synthesis of glucocorticoids and adrenal androgens
remnants of Rathke’s pouch. It is more common in children is under the control of ACTH from hypothalamus-anterior
and young adults. The tumour, though benign, compresses pituitary. In turn, ACTH release is under the control of a
as well as invades the adjacent structures extensively. hypothalamic releasing factor called corticotropin-releasing

MORPHOLOGIC FEATURES. Grossly, the tumour is factor. Release of aldosterone, on the other hand, is
encapsulated, adherent to surrounding structures and is independent of ACTH control and is largely regulated by
typically cystic, reddish-grey mass. the serum levels of potassium and renin-angiotensin
mechanism (page 98).

ADRENAL MEDULLA. The adrenal medulla is a component doses of dexamethasone which suppresses ACTH secretion 797
of the dispersed neuroendocrine system derived from and causes fall in plasma cortisol level.
primitive neuroectoderm; the other components of this 2. Adrenal Cushing’s syndrome. Approximately 20-25%
system being paraganglia distributed in the vagi, cases of Cushing’s syndrome are caused by disease in one or
paravertebral and visceral autonomic ganglia. The cells both the adrenal glands. These include adrenal cortical
comprising this system are neuroendocrine cells, the major adenoma, carcinoma, and less often, cortical hyperplasia.
function of which is synthesis and secretion of catecholamines This group of cases is characterised by low serum ACTH
(epinephrine and norepinephrine). Various other peptides levels and absence of therapeutic response to administration
such as calcitonin, somatostatin and vasoactive intestinal of high doses of glucocorticoid.
polypeptide (VIP) are also secreted by these cells. The major 3. Ectopic Cushing’s syndrome. About 10-15% cases of
metabolites of catecholamines are metanephrine, nor-me- Cushing’s syndrome have an origin in ectopic ACTH elabo-
tanephrine, vanillyl mandelic acid (VMA) and homovanillic ration by non-endocrine tumours. Most often, the tumour is
acid (HVA). In case of damage to the adrenal medulla, its an oat cell carcinoma of the lung but other lung cancers,
function is taken over by other paraganglia. malignant thymoma and pancreatic tumours have also been
Diseases affecting the two parts of adrenal glands are
quite distinctive in view of distinct morphology, and function implicated. The plasma ACTH level is high in these cases
and cortisol secretion is not suppressed by dexamethasone
of the adrenal cortex and medulla. While the disorders of administration.
the adrenal cortex include adrenocortical hyperfunction
(hyperadrenalism), adrenocortical insufficiency (hypo- 4. Iatrogenic Cushing’s syndrome. Prolonged therapeutic
adrenalism) and adrenocortical tumours, the main lesions administration of high doses of glucocorticoids or ACTH may
affecting the adrenal medulla are the medullary tumours. result in Cushing’s syndrome e.g. in organ transplant
recipients and in autoimmune diseases. These cases are
ADRENOCORTICAL HYPERFUNCTION generally associated with bilateral adrenocortical
(HYPERADRENALISM) insufficiency.
Hypersecretion of each of the three types of corticosteroids CLINICAL FEATURES. Cushing’s syndrome occurs more
elaborated by the adrenal cortex causes distinct often in patients between the age of 20-40 years with three CHAPTER 27
corresponding hyperadrenal clinical syndromes: times higher frequency in women than in men. The severity
1. Cushing’s syndrome caused by excess of glucocorticoids of the syndrome varies considerably, but in general the
(i.e. cortisol); also called chronic hypercortisolism. following features characterise a case of Cushing’s syndrome:
2. Conn’s syndrome caused by oversecretion of mineralo- 1. Central or truncal obesity contrasted with relatively thin
corticoids (i.e. aldosterone); also called primary hyper- arms and legs, buffalo hump due to prominence of fat over
the shoulders, and rounded oedematous moon-face.
aldosteronism.
3. Adrenogenital syndrome characterised by excessive produc- 2. Increased protein breakdown resulting in wasting and
tion of adrenal sex steroids (i.e. androgens); also called adrenal thinning of the skeletal muscles, atrophy of the skin and
subcutaneous tissue with formation of purple striae on the
virilism.
Mixed forms of these clinical syndromes may also occur. abdominal wall, osteoporosis and easy bruisability of the thin The Endocrine System
skin to minor trauma.
Cushing’s Syndrome (Chronic Hypercortisolism) 3. Systemic hypertension is present in 80% of cases because
of associated retention of sodium and water.
Cushing’s syndrome is caused by excessive production of 4. Impaired glucose tolerance and diabetes mellitus are found
cortisol of whatever cause. The full clinical expression of the in about 20% cases.
syndrome, however, includes contribution of the secondary 5. Amenorrhoea, hirsutism and infertility in many women.
derangements. 6. Insomnia, depression, confusion and psychosis.

ETIOPATHOGENESIS. There are 4 major etiologic types Conn’s Syndrome (Primary Hyperaldosteronism)
of Cushing’s syndrome which should be distinguished for
effective treatment. This is an uncommon syndrome occurring due to overpro-
duction of aldosterone, the potent salt-retaining hormone.
1. Pituitary Cushing’s syndrome. About 60-70% cases of
Cushing’s syndrome are caused by excessive secretion of ETIOPATHOGENESIS. The condition results primarily due
ACTH due to a lesion in the pituitary gland, most commonly to adrenocortical diseases as follows:
a corticotroph adenoma or multiple corticotroph 1. Adrenocortical adenoma, producing aldosterone.
microadenomas. This group of cases was first described by 2. Bilateral adrenal hyperplasia, especially in children
Harvey Cushing, an American neurosurgeon, who termed (congenital hyperaldosteronism).
the condition as Cushing’s disease. Also included in this 3. Rarely, adrenal carcinoma.
group are cases with hypothalamic origin of excessive ACTH Primary hyperaldosteronism from any of the above causes
levels without apparent pituitary lesion. All cases with is associated with low plasma renin levels. Secondary
pituitary Cushing’s syndrome are characterised by bilateral hyperaldosteronism, on the contrary, occurs in response to high
adrenal cortical hyperplasia and elevated ACTH levels. These plasma renin level due to overproduction of renin by the
cases show therapeutic response on administration of high kidneys such as in renal ischaemia, reninoma or oedema.

798 CLINICAL FEATURES. Conn’s syndrome is more frequent ETIOPATHOGENESIS. Causes of acute insufficiency are
in adult females. Its principal features are as under: as under:
1. Hypertension, usually mild to moderate diastolic 1. Bilateral adrenalectomy e.g. in the treatment of cortical
hypertension. hyperfunction, hypertension and in selected cases of breast
2. Hypokalaemia and associated muscular weakness, cancer.
peripheral neuropathy and cardiac arrhythmias. 2. Septicaemia e.g. in endotoxic shock and meningococcal
3. Retention of sodium and water. infection producing grossly haemorrhagic and necrotic
4. Polyuria and polydipsia due to reduced concentrating adrenal cortex termed adrenal apoplexy. The acute condition
power of the renal tubules. so produced is called Waterhouse-Friderichsen’s syndrome.
3. Rapid withdrawal of steroids.
Adrenogenital Syndrome (Adrenal Virilism) 4. Any form of acute stress in a case of chronic insufficiency
i.e. in Addison’s disease.
Adrenal cortex secretes a smaller amount of sex steroids than
the gonads. However, adrenocortical hyperfunction may CLINICAL FEATURES. Clinical features of acute adreno-
occasionally cause sexual disturbances. cortical insufficiency are due to deficiency of mineralo-
ETIOPATHOGENESIS. Hypersecretion of sex steroids, corticoids and glucocorticoids. These are as follows:
mainly androgens, may occur in children or in adults: 1. Deficiency of mineralocorticoids (i.e. aldosterone
1. In children, it is due to congenital adrenal hyperplasia in deficiency) result in salt deficiency, hyperkalaemia and
which there is congenital deficiency of a specific enzyme. dehydration.
2. In adults, it is caused by an adrenocortical adenoma or a 2. Deficiency of glucocorticoids (i.e. cortisol deficiency)
carcinoma. Cushing’s syndrome is often present as well. leads to hypoglycaemia, increased insulin sensitivity and
vomitings.
CLINICAL FEATURES. The clinical features depend upon
the age and sex of the patient. B. Primary Chronic Adrenocortical Insufficiency
1. In children, there is distortion of the external genitalia in (Addison’s Disease)
girls, and precocious puberty in boys.
2. In adults, the features in females show virilisation (e.g. Progressive chronic destruction of more than 90% of adrenal
hirsutism, oligomenorrhoea, deepening of voice, hyper- cortex on both sides results in an uncommon clinical
trophy of the clitoris); and in males may rarely cause condition called Addison’s disease.
feminisation. ETIOPATHOGENESIS. Any condition which causes
SECTION III
3. There is generally increased excretion of 17-ketosteroids marked chronic adrenal destruction may produce Addison’s
in the urine. disease. These include: tuberculosis, autoimmune or
idiopathic adrenalitis, histoplasmosis, amyloidosis,
ADRENOCORTICAL INSUFFICIENCY
(HYPOADRENALISM) metastatic cancer, sarcoidosis and haemochromatosis.
However, currently the first two causes—tuberculosis and
Adrenocortical insufficiency may result from deficient autoimmune chronic destruction of adrenal glands, are
synthesis of cortical steroids from the adrenal cortex or may implicated in majority of cases of Addison’s disease.
be secondary to ACTH deficiency. Three types of Irrespective of the cause, the adrenal glands are bilaterally
adrenocortical hypofunction are distinguished: small and irregularly shrunken. Histologic changes,
1. Primary adrenocortical insufficiency caused primarily by the depending upon the cause, may reveal specific features as
disease of the adrenal glands. Two forms are described: acute in tuberculosis and histoplasmosis, or the changes may be
Systemic Pathology
or ‘adrenal crisis’, and chronic or ‘Addison’s disease’. in the form of nonspecific lymphocytic infiltrate as in
2. Secondary adrenocortical insufficiency resulting from idiopathic (autoimmune) adrenalitis.
diminished secretion of ACTH.
3. Hypoaldosteronism characterised by deficient secretion of CLINICAL FEATURES. Clinical manifestations develop
aldosterone. slowly and insidiously. The usual features are as under:
1. Asthenia i.e. progressive weakness, weight loss and
PRIMARY ADRENOCORTICAL INSUFFICIENCY lethargy as the cardinal symptoms.
Primary adrenal hypofunction occurs due to defect in the 2. Hyperpigmentation, initially most marked on exposed
adrenal glands and normal pituitary function. It may develop areas, but later involves unexposed parts and mucous
in 2 ways: membranes as well.
A. Acute primary adrenocortical insufficiency or ‘adrenal 3. Arterial hypotension.
crisis’. 4. Vague upper gastrointestinal symptoms such as mild loss
B. Chronic primary adrenocortical insufficiency or of appetite, nausea, vomiting and upper abdominal pain.
‘Addison’s disease’.
5. Lack of androgen causing loss of hair in women.
A. Primary Acute Adrenocortical Insufficiency 6. Episodes of hypoglycaemia.
(Adrenal Crisis)
7. Biochemical changes include reduced GFR, acidosis,
Sudden loss of adrenocortical function may result in an acute hyperkalaemia and low levels of serum sodium, chloride and
condition called adrenal crisis. bicarbonate.

SECONDARY ADRENOCORTICAL INSUFFICIENCY workers. Occasionally, a cortical adenoma may be a part of 799
multiple endocrine neoplasia type I (MEN-I) in which
Adrenocortical insufficiency resulting from deficiency of patients have associated adenomas of parathyroid, islet cells
ACTH is called secondary adrenocortical insufficiency.
and anterior pituitary (page 829).
ETIOPATHOGENESIS. ACTH deficiency may appear in
2 settings : MORPHOLOGIC FEATURES. Grossly, an adenoma is
1. Selective ACTH deficiency due to prolonged administration usually a small, solitary, spherical and encapsulated
of high doses of glucocorticoids. This leads to suppression tumour which is well-delineated from the surrounding
of ACTH release from the pituitary gland and selective normal adrenal gland. Cut section is typically bright
deficiency. yellow.
2. Panhypopituitarism due to hypothalamus-pituitary Microscopically, the tumour cells are arranged in
diseases is associated with deficiency of multiple trophic trabeculae and generally resemble the cells of zona
hormones (page 794). fasciculata. Less frequently, the cells of adenoma are like
those of zona glomerulosa or zona reticularis.
CLINICAL FEATURES. The clinical features of secondary
adrenocortical insufficiency are like those of Addison’s Cortical Carcinoma
disease except the following:
1. These cases lack hyperpigmentation because of Carcinoma of the adrenal cortex is an uncommon tumour
suppressed production of melanocyte-stimulating hormone occurring mostly in adults. It invades locally as well as
(MSH) from the pituitary. spreads to distant sites. Most cortical carcinomas secrete one
2. Plasma ACTH levels are low-to-absent in secondary of the adrenocortical hormones excessively.
insufficiency but are elevated in Addison’s disease.
3. Aldosterone levels are normal due to stimulation by MORPHOLOGIC FEATURES. Grossly, an adrenal
renin. carcinoma is generally large, spherical and well-
demarcated tumour. On cut section, it is predominantly
HYPOALDOSTERONISM yellow with intermixed areas of haemorrhages, necrosis
and calcification. CHAPTER 27
Isolated deficiency of aldosterone with normal cortisol level Microscopically, the cortical carcinoma may vary from
may occur in association with reduced renin secretion. well-differentiated to anaplastic growth. Well-
ETIOPATHOGENESIS. The causes of such hyporeninism differentiated carcinoma consists of foci of atypia in an
are as follows: adenoma, while anaplastic carcinoma shows large,
1. Congenital defect due to deficiency of an enzyme required pleomorphic and bizarre cells with high mitotic activity.
for its synthesis.
2. Prolonged administration of heparin. MEDULLARY TUMOURS
3. Certain diseases of the brain. The most significant lesions of the adrenal medulla are
4. Excision of an aldosterone-secreting tumour.
neoplasms. These include the following: The Endocrine System
CLINICAL FEATURES. The patients of isolated hypo- Benign tumours: These are less common and include
aldosteronism are adults with mild renal failure and diabetes pheochromocytoma and myelolipoma.
mellitus. The predominant features are hyperkalaemia and Tumours arising from embryonic nerve cells: These are more
metabolic acidosis. common and include neuroblastoma and ganglioneuroma.
These tumours together with extra-adrenal paragang-
TUMOURS OF ADRENAL GLANDS lioma are described below.
Primary tumours of the adrenal glands are uncommon and
include distinct adrenocortical tumours and medullary Pheochromocytoma (Chromaffin Tumour)
tumours. However, adrenal gland is a more common site for Pheochromocytoma (meaning dusky brown tumour) is
metastatic carcinoma. generally a benign tumour arising from the pheochromocytes
(i.e. chromaffin cells) of the adrenal medulla. The extra-
ADRENOCORTICAL TUMOURS adrenal pheochromocytomas arising from other paraganglia
are preferably called paragangliomas, named along with the
Cortical Adenoma
anatomic site of origin, as described later.
The commonest cortical tumour is adenoma. They are Pheochromocytoma may occur at any age but most
indistinguishable from hyperplastic nodules except that patients are 20-60 years old. Most pheochromocytomas are
lesions smaller than 2 cm diameter are labelled hyperplastic slow-growing and benign but about 5% of the tumours are
nodules. A cortical adenoma is a benign and slow-growing malignant, invasive and metastasising. These tumours are
tumour. It is usually small and nonfunctional. A few large commonly sporadic but 10-20% are associated with familial
adenomas may, however, produce excess of cortisol, syndromes of multiple endocrine neoplasia (MEN) having
aldosterone or androgen. Association of cortical adenomas bilaterality and association with medullary carcinoma of the
with systemic hypertension has been suggested by some thyroid, hyperparathyroidism, pituitary adenoma, mucosal

800 neuromas and von Recklinghausen’s neurofibromatosis in About 10% of pheochromcytomas may be malignant
varying combinations. having tendency for osseous metastases.
The clinical features of pheochromocytoma are
predominantly due to secretion of catecholamines, both Myelolipoma
epinephrine and norepinephrine. The most common feature
is hypertension. Other manifestations due to sudden release Myelolipoma is an uncommon benign adrenal medullary
of catecholamines are congestive heart failure, myocardial tumour found incidentally at autopsy. Less often, it may
infarction, pulmonary oedema, cerebral haemorrhage, and produce symptoms due to excessive hormone elaboration.
even death. The diagnosis is established by measuring 24- MORPHOLOGIC FEATURES. Grossly, a myelolipoma
hour urinary catecholamines or their metabolites such as is usually a small tumour, measuring 0.2-2 cm in diameter.
metanephrine and VMA. Microscopically, it consists of well-differentiated adipose
tissue in which is scattered clumps of haematopoietic cells
MORPHOLOGIC FEATURES. Grossly, the tumour is are seen.
soft, spherical, may be quite variable in size and weight,
and well-demarcated from the adjacent adrenal gland. On Neuroblastoma
cut section, the tumour is grey to dusky brown with areas
of haemorrhages, necrosis, calcification and cystic change Neuroblastoma, also called as sympathicoblastoma, is a
(Fig. 27.3). On immersing the tumour in dichromate common malignant tumour of embryonic nerve cells,
fixative, it turns brown-black due to oxidation of occurring most commonly in children under 5 years of age.
catecholamines in the tumour and hence the name Vast majority of cases occur within the abdomen (in the
chromaffin tumour. adrenal medulla and paravertebral autonomic ganglia) and
Microscopically, the tumour has the following rarely in the cerebral hemisphere. Most cases are sporadic
characteristics (Fig. 27.4): but familial occurrence with autosomal dominant trans-
1. The tumour cells are arranged characteristically as mission is also seen.
well-defined nests (also termed as zellballen pattern) The clinical manifestations of neuroblastoma are related
separated by abundant fibrovascular stroma. to its rapid local growth, metastatic spread or development
2. Other arrangements are as solid columns, sheets, of hormonal syndrome. Local symptoms include abdominal
trabeculae or clumps. distension, fever, weight loss and malaise. Foci of calcification
3. The tumour cells are large, polyhedral and may be observed on radiologic examination of the abdomen.
SECTION III
pleomorphic with abundant granular amphophilic or Metastatic spread occurs early and widely through
basophilic cytoplasm and vesicular nuclei. haematogenous as well as lymphatic routes and involves
4. The tumour cells of pheochromocytoma stain bones (especially skull), liver, lungs and regional lymph
positively with neuroendocrine substances such as nodes. Neuroblastoma produces variable amounts of
neuron-specific enolase (NSE) and chromogranin. catecholamines and its metabolites such as vanillyl mandelic
acid (VMA) and homovanillic acid (HVA), which can be
detected in the 24-hour urine. Less often, the patient develops
carcinoid-like syndrome, probably due to production of
kinins or prostaglandins by the tumour. The features in such
a case include watery diarrhoea, flushing of the skin and

Systemic Pathology






















Figure 27.3 Pheochromocytoma of the adrenal medulla. The
specimen shows compressed kidney at the lower end (arrow) while the
upper end shows a large spherical tumour separate from the kidney. Cut Figure 27.4 Adrenal pheochromocytoma. The tumour has typical
surface of tumour shows cystic change while solid areas show dark brown, zellballen or nested pattern. The tumour cells are large, polyhedral and
necrotic and haemorrhagic tumour. pleomorphic having abundant granular cytoplasm.

801
























Figure 27.5 Neuroblastoma, It shows small, round to oval cells forming irregular sheets separated by fibrovascular stroma. A few Homer-
Wright’s pseudorosettes are also present. Inset shows a close-up view of pseudorosette.


hypokalaemia. Rarely, the tumour may produce sufficient Ganglioneuroma
catecholamines to cause hypertension.
A ganglioneuroma is a mature, benign and uncommon
MORPHOLOGIC FEATURES. Grossly, the tumour is tumour occurring in adults. It is derived from ganglion cells,
generally large, soft and lobulated mass with extensive most often in the posterior mediastinum, and uncommonly
areas of necrosis and haemorrhages. The tumour is usually in other peripheral ganglia and brain. The tumour produces CHAPTER 27
diffusely infiltrating into the adjacent tissues. Cut surface symptoms because of its size and location. Catecholamines
of the tumour is grey white and may reveal minute foci of and their metabolites can be detected in large amounts in
calcification. the 24-hour urine specimen of patients with ganglioneuroma.
Microscopically, neuroblastoma has the following
characteristics (Fig. 27.5): MORPHOLOGIC FEATURES. Grossly, the tumour is
1. The tumour cells are small, round and oval, slightly spherical, firm and encapsulated.
larger than lymphocytes, and have scanty and poorly- Microscopically, it contains large number of well-formed
defined cytoplasm and hyperchromatic nuclei. ganglionic nerve cells scattered in fibrillar stroma and
2. They are generally arranged in irregular sheets myelinated and non-myelinated nerve fibres.
separated by fibrovascular stroma. The Endocrine System
3. Classical neuroblastomas show Homer-Wright’s Extra-adrenal Paraganglioma (Chemodectoma)
rosettes (pseudorosettes) which have a central fibrillar Parasympathetic paraganglia located in extra-adrenal sites
eosinophilic material surrounded by radially arranged such as the carotid bodies, vagus, jugulotympanic and
tumour cells. The central fibrillar material stains positively aorticosympathetic (pre-aortic) paraganglia may produce
by silver impregnation methods indicating their nature neoplasms, collectively termed paragangliomas with the
as young nerve fibrils. anatomic site of origin e.g. carotid body paraganglioma,
4. The tumour cells stain positively with immuno- intravagal paraganglioma, jugulotympanic paraganglioma
histochemical markers such as neuron-specific enolase etc. These tumours are also called chemodectomas because
(NSE), neurofilaments (NF) and chromogranin. of their responsiveness to chemoreceptors. They are
uncommon tumours found in adults and rarely secrete excess
Prognosis of neuroblastoma depends upon a few of catecholamines, except aorticosympathetic paraganglioma
variables: (also termed extra-adrenal pheochromocytoma). Para-
i) Age of the child below 2 years is associated with better gangliomas are generally benign but recurrent tumours. A
prognosis. small proportion of them may metastasise widely.
ii) Extra-abdominal location of the tumour have better outlook
than abdominal masses. THYROID GLAND
iii) Patients in clinical stage I (confined to the organ of origin)
or stage II (tumour extending in continuity beyond the organ NORMAL STRUCTURE
of origin but not crossing the midline) have better prognosis ANATOMY. Embryologically, the thyroid gland arises
than higher stages with distant metastases. from a midline invagination at the root of the tongue and
iv) Tumours with amplification of MYC oncogene and p53 grows downwards in front of trachea and thyroid cartilage
are associated with poor prognosis. to reach its normal position. Failure to descent may produce

802 anomalous lingual thyroid. The thyroglossal duct that 4. Coupling of MIT and DIT in the presence of thyroid
connects the gland to the pharyngeal floor normally peroxidase forms tri-iodothyronine (T ) and thyroxine (T ).
3
4
disappears by 6th week of embryonic life. In adults, its The thyroid hormones so formed are released by
proximal end is represented by foramen caecum at the base endocytosis of colloid and proteolysis of thyroglobulin within
of the tongue and distal end by the pyramidal lobe of the the follicular cells resulting in discharge of T and T into
4
3
thyroid. Persistence of the remnants of thyroglossal duct in circulation where they are bound to thyroxine-binding
the adults may develop into thyroglossal cyst (page 520). The globulin.
C-cells of the thyroid originate from the neuroectoderm. A number of thyroid function tests are currently available.
The thyroid gland in an adult weighs 15-40 gm and is These include the following:
composed of two lateral lobes connected in the midline by Determination of serum levels of T , T by radio-
a broad isthmus which may have a pyramidal lobe immunoassay (RIA). 3 4
extending upwards. Cut section of normal thyroid is
yellowish and translucent. TSH and TRH determination.
Determination of calcitonin secreted by parafollicular C
HISTOLOGY. The thyroid is composed of lobules of colloid- cells.
filled spherical follicles or acini. The lobules are enclosed by
fibrovascular septa. The follicles are the main functional units Estimation of thyroglobulin secreted by thyroid follicular
of the thyroid. They are lined by cuboidal epithelium with cells.
numerous fine microvilli extending into the follicular colloid Assessment of thyroid activity by its ability to uptake
that contains the glycoprotein, thyroglobulin. The follicles are radioactive iodine (RAIU).
separated from each other by delicate fibrous tissue that Assessment whether thyroid lesion is a nonfunctioning
contains blood vessels, lymphatics and nerves. Calcitonin- (‘cold nodule’) or hyperactive mass (‘hot nodule’).
secreting C-cells or parafollicular cells are dispersed within Diseases of the thyroid include: functional disorders
the follicles and can only be identified by silver stains and (hyperthyroidism and hypothyroidism), thyroiditis, Graves’
immunohistochemical methods. disease, goitre and tumours. The relative frequency of some
of these diseases varies in different geographic regions
FUNCTIONS. The major function of the thyroid gland is to according to the iodine content of the diet consumed. One of
maintain a high rate of metabolism which is done by means the important investigation tools available in current times
of iodine-containing thyroid hormones, thyroxine (T ) and is the widespread use of FNAC for thyroid lesions which
4
tri-iodothyronine (T ). helps in avoiding a large number of unwanted diagnostic
3
The thyroid is one of the most labile organs in the body
SECTION III
and responds to numerous stimuli such as puberty, biopsies.
pregnancy, physiologic stress and various pathologic states. FUNCTIONAL DISORDERS
This functional lability of the thyroid is responsible for
transient hyperplasia of the thyroidal epithelium. Under Two significant functional disorders characterised by distinct
normal conditions, the epithelial lining of the follicles may clinical syndromes are described. These are: hyperthyroidism
show changes in various phases of function as under: (thyrotoxicosis) and hypothyroidism.
1. Resting phase is characterised by large follicles lined by
flattened cells and filled with deeply staining homogeneous HYPERTHYROIDISM (THYROTOXICOSIS)
colloid e.g. in colloid goitre and iodine-treated hyper- Hyperthyroidism, also called thyrotoxicosis, is a hyper-
thyroidism. metabolic clinical and biochemical state caused by excess
Systemic Pathology
2. Secretory phase in which the follicles are lined by production of thyroid hormones. The condition is more
cuboidal epithelium and the colloid is moderately dark pink frequent in females and is associated with rise in both T
e.g. in normal thyroid. and T levels in blood, though the increase in T is generally 3
4
3. Resorptive phase is characterised by follicles lined by greater than that of T . 3
columnar epithelium and containing lightly stained 4
vacuolated and scalloped colloid e.g. in hyperthyroidism. ETIOPATHOGENESIS. Hyperthyroidism may be caused
The synthesis and release of the two main circulating by many diseases but three most common causes are: Graves’
thyroid hormones, T and T are regulated by hypophyseal disease (diffuse toxic goitre), toxic multinodular goitre and
4
3
thyroid-stimulating hormone (TSH) and involves the a toxic adenoma. Less frequent causes are hypersecretion of
following steps: pituitary TSH by a pituitary tumour, hypersecretion of TRH,
1. Iodine trapping by thyroidal cells involves absorbing of thyroiditis, metastatic tumours of the thyroid, struma ovarii,
iodine from the blood and concentrating it more than twenty- congenital hyperthyroidism in the newborn of mother with
fold. Graves’ disease, hCG-secreting tumours due to mild
2. Oxidation of the iodide takes place within the cells by a thyrotropic effects of hCG (e.g. hydatidiform mole, chorio-
thyroid peroxidase. carcinoma and testicular tumours), and lastly, by excessive
doses of thyroid hormones or iodine called jodbasedow disease.
3. Iodination occurs next, at the microvilli level between
the oxidised iodine and the tyrosine residues of thyroglobulin CLINICAL FEATURES. Patients with hyperthyroidism have
so as to form mono-iodotyrosine (MIT) and di-iodotyrosine a slow and insidious onset, varying in severity from case to
(DIT). case. The usual symptoms are emotional instability,

nervousness, palpitation, fatigue, weight loss in spite of good 1. Developmental anomalies e.g. thyroid agenesis and ectopic 803
appetite, heat intolerance, perspiration, menstrual thyroid.
disturbances and fine tremors of the outstretched hands. 2. Genetic defect in thyroid hormone synthesis e.g. defect in
Cardiac manifestations in the form of tachycardia, iodine trapping, oxidation, iodination, coupling and
palpitations and cardiomegaly are invariably present in thyroglobulin synthesis.
hyperthyroidism. The skin of these patients is warm, moist 3. Foetal exposure to iodides and antithyroid drugs.
and flushed. Weakness of skeletal muscles and osteoporosis 4. Endemic cretinism in regions with endemic goitre due to
are common. Typical eye changes in the form of exoph- dietary lack of iodine (sporadic cretinism, on the other hand,
thalmos are a common feature in Graves’ disease. Serum is due to developmental anomalies and genetic defects in
levels of T and T are elevated but TSH secretion is usually thyroid hormone synthesis described above).
3
4
inhibited. CLINICAL FEATURES. The clinical manifestations usually
A sudden spurt in the severity of hyperthyroidism termed become evident within a few weeks to months of birth. The
‘thyroid storm’ or ‘thyroid crisis’ may occur in patients who presenting features of a cretin are: slow to thrive, poor
have undergone subtotal thyroidectomy before adequate feeding, constipation, dry scaly skin, hoarse cry and
control of hyperthyroid state, or in a hyperthyroid patient bradycardia. As the child ages, clinical picture of fully-
under acute stress, trauma, and with severe infection. These developed cretinism emerges characterised by impaired
patients develop high grade fever, tachycardia, cardiac skeletal growth and consequent dwarfism, round face,
arrhythmias and coma and may die of congestive heart narrow forehead, widely-set eyes, flat and broad nose, big
failure or hyperpyrexia. protuberant tongue and protuberant abdomen. Neurological
features such as deaf-mutism, spasticity and mental
HYPOTHYROIDISM deficiency are more evident in sporadic cretinism due to
developmental anomalies and dyshormonogenetic defects.
Hypothyroidism is a hypometabolic clinical state resulting
from inadequate production of thyroid hormones for Characteristic laboratory findings include a rise in TSH
prolonged periods, or rarely, from resistance of the peripheral level and fall in T and T levels.
4
3
tissues to the effects of thyroid hormones. The clinical
manifestations of hypothyroidism, depending upon the age Myxoedema CHAPTER 27
at onset of disorder, are divided into 2 forms: The adult-onset severe hypothyroidism causes myxoedema.
1. Cretinism or congenital hypothyroidism is the development The term myxoedema connotes non-pitting oedema due to
of severe hypothyroidism during infancy and childhood. accumulation of hydrophilic mucopolysaccharides in the
2. Myxoedema is the adulthood hypothyroidism. ground substance of dermis and other tissues.
Cretinism ETIOPATHOGENESIS. There are several causes of
myxoedema listed below but the first two are the most
A cretin is a child with severe hypothyroidism present at common causes:
birth or developing within first two years of postnatal life. 1. Ablation of the thyroid by surgery or radiation.
This is the period when brain development is taking place; 2. Autoimmune (lymphocytic) thyroiditis (termed primary The Endocrine System
in the absence of treatment the child is both physically and idiopathic myxoedema).
mentally retarded. The word ‘Cretin’ is derived from the 3. Endemic or sporadic goitre.
French, meaning Christ-like because these children are so 4. Hypothalamic-pituitary lesions.
mentally retarded that they are incapable of committing sins. 5. Thyroid cancer.
ETIOPATHOGENESIS. The causes of congenital 6. Prolonged administration of antithyroid drugs.
hypothyroidism are as follows: 7. Mild developmental anomalies and dyshormonogenesis.
























Figure 27.6 Appearance in functional disorders of the thyroid gland.

804 CLINICAL FEATURES. The onset of myxoedema is slow immune disease of any organ. Autoimmune pathogenesis
and a fully-developed clinical syndrome may appear after of Hashimoto’s thyroiditis is explained by the following
several years of hypothyroidism. The striking features are observations:
cold intolerance, mental and physical lethargy, constipation, 1. Other autoimmune disease association: Like in other
slowing of speech and intellectual function, puffiness of face, autoimmune diseases, Hashimoto’s disease has been found
loss of hair and altered texture of the skin. in association with other autoimmune diseases such as
The laboratory diagnosis in myxoedema is made by low Graves’ disease, SLE, Sjögren’s syndrome, rheumatoid
serum T and T levels and markedly elevated TSH levels as arthritis, pernicious anaemia and Type 1 diabetes mellitus.
4
3
in the case of cretinism but cases with suprathyroid lesions 2. Immune destruction of thyroid cells: The sequence of
(hypothalamic-pituitary disease) have low TSH levels. immune phenomena is initial activation of CD4+ T helper
The clinical appearance of these three major forms of
functional disorders of the thyroid gland is shown in cells. These cells then induce infiltration of CD8+ T cytotoxic
cells in the thyroid parenchyma as well as activate B cells to
Fig. 27.6.
form autoantibodies, which bring about immune destruction
of thyroid parenchyma.
THYROIDITIS
3. Detection of autoantibodies: The following autoanti-
Inflammation of the thyroid, thyroiditis, is more often due bodies against different thyroid cell antigens are detectable
to non-infectious causes and is classified on the basis of onset in the sera of most patients with Hashimoto’s thyroiditis:
and duration of disease into acute, subacute and chronic as i) Thyroid microsomal autoantibodies (against the
under: microsomes of the follicular cells).
I. Acute thyroiditis: ii) Thyroglobulin autoantibodies.
1. Bacterial infection e.g. Staphylococcus, Streptococcus. iii) TSH receptor autoantibodies.
2. Fungal infection e.g. Aspergillus, Histoplasma, Pneumocystis. iv) Less constantly found are thyroid autoantibodies against
3. Radiation injury follicular cell membranes, thyroid hormones themselves, and
colloid component other than thyroglobulin.
II. Subacute thyroiditis:
1. Subacute granulomatous thyroiditis (de Quervain’s 4. Inhibitory TSH-receptor antibodies: TSH-receptor
thyroiditis, giant cell thyroiditis, viral thyroiditis) antibody seen on the surface of thyroid cells in Hashimoto’s
2. Subacute lymphocytic (postpartum, silent) thyroiditis thyroiditis is inhibitory to TSH, producing hypothyroidism.
3. Tuberculous thyroiditis Similar antibody is observed in Graves’ disease where it
SECTION III
causes hyperthyroidism. It appears that TSH-receptor
III. Chronic thyroiditis: antibody may act both to depress or stimulate the thyroid
1. Autoimmune thyroiditis (Hashimoto’s thyroiditis or cells to produce hypo- or hyperthyroidism respectively. Thus,
chronic lymphocytic thyroiditis)
these patients may have alternate episodes of hypo- or
2. Riedel’s thyroiditis (or invasive fibrous thyroiditis). hyperthyroidism.
While acute infectious thyroiditis is uncommon, some of 5. Genetic basis: The disease has higher incidence in first-
the morphologically important forms of thyroiditis from the degree relatives of affected patients. Hashimoto’s thyroiditis
above list are discussed below.
is seen more often with HLA-DR3 and HLA-DR5 subtypes.
HASHIMOTO’S (AUTOIMMUNE, MORPHOLOGIC FEATURES. Pathologically, two
CHRONIC LYMPHOCYTIC) THYROIDITIS varieties of Hashimoto’s thyroiditis are seen: classic form,
Systemic Pathology
the usual and more common, and fibrosing variant found
Hashimoto’s thyroiditis, also called diffuse lymphocytic in only 10% cases of Hashimoto’s thyroiditis.
thyroiditis, struma lymphomatosa or goitrous autoimmune Grossly, the classic form is characterised by diffuse,
thyroiditis, is characterised by 3 principal features: symmetric, firm and rubbery enlargement of the thyroid
1. Diffuse goitrous enlargement of the thyroid. which may weigh 100-300 gm. Sectioned surface of the
2. Lymphocytic infiltration of the thyroid gland. thyroid is fleshly with accentuation of normal lobulations
3. Occurrence of thyroid autoantibodies.
Hashimoto’s thyroiditis occurs more frequently between but with retained normal shape of the gland. The fibrosing
the age of 30 and 50 years and shows an approximately ten- variant has a firm, enlarged thyroid with compression of
the surrounding tissues.
fold preponderance among females. Though rare in children, Histologically, the classic form shows the following
about half the cases of adolescent goitre are owing to features (Fig. 27.7):
autoimmune thyroiditis. Hashimoto’s thyroiditis is the most 1. There is extensive infiltration of the gland by
common cause of goitrous hypothyroidism in regions where lymphocytes, plasma cells, immunoblasts and macro-
iodine supplies are adequate. Regions where iodine intake is phages, with formation of lymphoid follicles having
highest have higher incidence of Hashimoto’s thyroiditis e.g. germinal centres.
in Japan and the United States.
2. There is decreased number of thyroid follicles which
ETIOPATHOGENESIS. Hashimoto’s thyroiditis is an are generally atrophic and are often devoid of colloid.
autoimmune disease is well established. Hashimoto, a 3. The follicular epithelial cells are transformed into their
Japanese surgeon, described it in 1912 as the first auto- degenerated state termed Hurthle cells (also called

805
























Figure 27.7 Hashimoto’s thyroiditis. Histologic features include: lymphoid cell infiltration with formation of lymphoid follicles having germinal
centres; small, atrophic and colloid-deficient follicles; presence of Hurthle cells which have granular oxyphil cytoplasm and large irregular nuclei;
and slight fibrous thickening of lobular septa.



Askanazy cells, or oxyphil cells, or oncocytes). These cells SUBACUTE GRANULOMATOUS (DE QUERVAIN’S)
have abundant oxyphilic or eosinophilic and granular THYROIDITIS
cytoplasm due to large number of mitochondria and Granulomatous thyroiditis, also called de Quervain’s or
contain large bizarre nuclei. subacute, or giant cell thyroiditis, is a distinctive form of self- CHAPTER 27
4. There is slight fibrous thickening of the septa separating limited inflammation of the thyroid gland. Etiology of the
the thyroid lobules. condition is not known but clinical features of a prodromal
The less common fibrosing variant of Hashimoto’s phase and preceding respiratory infection suggest a possible
thyroiditis shows considerable fibrous replacement of viral etiology. The disease is more common in young and
thyroid parenchyma and a less prominent lymphoid middle-aged women and may present clinically with painful
infiltrate. moderate thyroid enlargement with fever, features of hyper-
thyroidism in the early phase of the disease, and
CLINICAL FEATURES. The presenting feature of hypothyroidism if the damage to the thyroid gland is exten-
Hashimoto’s thyroiditis is a painless, firm and moderate sive. The condition is self-limiting and shows complete
goitrous enlargement of the thyroid gland, usually associated recovery of thyroid function in about 6 months.
with hypothyroidism, in an elderly woman. At this stage, The Endocrine System
serum T and T levels are decreased and RAIU is also MORPHOLOGIC FEATURES. Grossly, there is moderate
3
4
reduced. A few cases, however, develop hyperthyroidism, enlargement of the gland which is often asymmetric or
termed hashitoxicosis, further substantiating the similarities focal. The cut surface of the involved area is firm and
in the autoimmune phenomena between Hashimoto’s yellowish-white.
thyroiditis and Graves’ thyrotoxicosis. There is no increased Microscopically, the features vary according to the stage
risk of developing thyroid carcinoma in Hashimoto’s thyroi- of the disease:
ditis but there is increased frequency of malignant lymphoma Initially, there is acute inflammatory destruction of the
in these cases.
thyroid parenchyma and formation of microabscesses.
Later, the more characteristic feature of granulomatous
SUBACUTE LYMPHOCYTIC THYROIDITIS
appearance is produced. These granulomas consist of
Subacute lymphocytic (or painless or silent or postpartum) central colloid material surrounded by histiocytes and
thyroiditis is another variety of autoimmune thyrioditis. scattered multinucleate giant cells.
Clinically, it differs from subacute granulomatous thyroiditis More advanced cases may show fibroblastic proli-
in being non-tender thyroid enlargement. It is seen more often feration.
3-6 months after delivery.
Morphologically similar appearance may be produced
Microscopically, the features are as under: in cases where vigorous thyroid palpation may initiate
1. Dense multifocal infiltrate of lymphocytes and plasma mechanical trauma to follicles, so-called palpation thyroiditis.
cells in the parenchyma.
2. Collapse of thyroid follicles. RIEDEL’S THYROIDITIS
3. Rarely, presence of lymphoid follicles with germinal Riedel’s thyroiditis, also called Riedel’s struma or invasive
centres, simulating Hashimoto’s thyroiditis. fibrous thyroiditis, is a rare chronic disease characterised by

806 stony-hard thyroid that is densely adherent to the adjacent i) Thyroid-stimulating immunoglobulin (TSI): It binds to TSH
structures in the neck. The condition is clinically significant receptor and stimulates increased release of thyroid hormone.
due to compressive clinical features (e.g. dysphagia, ii) Thyroid growth-stimulating immunoglobulins (TGI): It
dyspnoea, recurrent laryngeal nerve paralysis and stridor) stimulates proliferation of follicular epithelium.
and resemblance with thyroid cancer. Riedel’s struma is seen iii) TSH-binding inhibitor immunoglobulins (TBII): It is
more commonly in females in 4th to 7th decades of life. The inhibitory to binding of TSH to its own receptor. Depending
etiology is unknown but possibly Riedel’s thyroiditis is a part upon its action as inhibitory or stimulatory to follicular
of multifocal idiopathic fibrosclerosis (page 591). This group of epithelium, it may result in alternate episodes of hypo- and
disorders includes: idiopathic retroperitoneal, mediastinal hyperthyroidism.
and retro-orbital fibrosis, and sclerosing cholangitis, all of However, it is not quite clear what stimulates B cells to
which may occur simultaneously with Riedel’s thyroiditis. form these autoantibodies in Graves’ disease. Possibly,
intrathyroidal CD4+ helper T cells are responsible for
MORPHOLOGIC FEATURES. Grossly, the thyroid gland stimulating B cells to secrete autoantibodies.
is usually contracted, stony-hard, asymmetric and firmly
adherent to the adjacent structures. Cut section is hard The pathogenesis of Graves’ infiltrative ophthalmopathy
and devoid of lobulations. is also of autoimmune origin. The evidence in support is the
Microscopically, there is extensive fibrocollagenous intense lymphocytic infiltrate around the ocular muscles and
replacement, marked atrophy of the thyroid parenchyma, detection of circulating autoantibodies against muscle
focally scattered lymphocytic infiltration and invasion of antigen that cross-react with thyroid microsomes.
the adjacent muscle tissue by the process. MORPHOLOGIC FEATURES. Grossly, the thyroid is
moderately, diffusely and symmetrically enlarged and
GRAVES’ DISEASE (DIFFUSE TOXIC GOITRE) may weigh up to 70-90 gm. On cut section, the thyroid
Graves’ disease, also known as Basedow’s disease, primary parenchyma is typically homogeneous, red-brown and
hyperplasia, exophthalmic goitre, and diffuse toxic goitre, is meaty and lacks the normal translucency.
characterised by a triad of features: Histologically, the following features are found (Fig. 27.8):
Hyperthyroidism (thyrotoxicosis) 1. There is considerable epithelial hyperplasia and
Diffuse thyroid enlargement hypertrophy as seen by increased height of the follicular
lining cells and formation of papillary infoldings of piled
Ophthalmopathy.
up epithelium into the lumina of follicles which are small.
SECTION III
The disease is more frequent between the age of 30 and 2. The colloid is markedly diminished and is lightly
40 years and has five-fold increased prevalence among staining, watery and finely vacuolated.
females. 3. The stroma shows increased vascularity and
ETIOPATHOGENESIS. Graves’ disease is an autoimmune accumulation of lymphoid cells.
disease and, as already stated, there are many immunologic However, the pathologic changes in gross specimen as
similarities between this condition and Hashimoto’s well as on histologic examination are considerably altered if
thyroiditis. These are as follows: preoperative medication has been administered. Iodine
1. Genetic factor association. Like in Hashimoto’s
thyroiditis. Graves’disease too has genetic predisposition. A
familial occurrence has been observed. Susceptibility to
develop Graves’ disease has been found associated with
Systemic Pathology
HLA-DR3 (Hashimoto’s thyroiditis has both HLA-DR3 and
HLA-DR5 association, page 804), CTLA-4 and PTPN22
(a T-cell regulatory gene).
2. Autoimmune disease association. Graves’ disease may
be found in association with other organ-specific auto-
immune diseases. Hashimoto’s thyroiditis and Graves’
disease are frequently present in the same families and the
two diseases may coexist in the same patient.
3. Other factors. Besides these two factors, Graves’ disease
has higher prevalence in women (7 to 10 times), and
association with emotional stress and smoking.
4. Autoantibodies. Autoantibodies against thyroid antigens
are detectable in the serum of these patients too but their
sites of action are different from that of Hashimoto’s
thyroiditis. In Graves’ disease, TSH-receptor autoantigen is Figure 27.8 Graves’ disease. The follicles are small and are lined
by tall columnar epithelium, which is piled up at places forming papillary
the main antigen against which autoantibodies are directed. infoldings. Colloid is nearly absent and appears lightly staining, watery
These are as under: and finely vacuolated.

administration results in accumulation of colloid in the 807
follicles and decrease in vascularity and height of follicular
cells, while antithyroid drugs such as thiouracil cause marked
hyperplasia.
CLINICAL FEATURES. Graves’ disease generally develops
slowly and insidiously.
Patients are usually young women who present with
symmetric, moderate enlargement of the thyroid gland with
features of thyrotoxicosis (page 802), ophthalmopathy and
dermatopathy.
Ocular abnormalities are lid lag, upper lid retraction, stare,
weakness of eye muscles and proptosis. In extreme cases,
the lids can no longer close and may produce corneal injuries
and ulcerations.
Dermatopathy in Graves’ disease most often consists of
pretibial (localised) myxoedema in the form of firm plaques.
Like in Hashimoto’s thyroiditis, there is no increased risk
of development of thyroid cancer in Graves’ disease.

GOITRE
The term goitre is defined as thyroid enlargement caused by
compensatory hyperplasia and hypertrophy of the follicular
epithelium in response to thyroid hormone deficiency. The
end-result of this hyperplasia is generally a euthyroid state
(in contrast to thyrotoxicosis occurring in diffuse toxic goitre CHAPTER 27
or Graves’ disease) though at some stages there may be hypo-
or hyperthyroidism. Two morphologic forms of goitre are
distinguished: Figure 27.9 Pathogenesis of simple and nodular goitre.
A. Diffuse goitre (simple nontoxic goitre or colloid goitre).
B. Nodular goitre (multinodular goitre or adenomatous common in females. Simple goitre often appears at puberty
goitre). or in adolescence, following which it may either regress or
may progress to nodular goitre.
Pathogenesis of Goitre

The pathogenetic mechanisms of both forms of goitre can be ETIOLOGY. Epidemiologically, goitre occurs in 2 forms: The Endocrine System
considered together since nodular goitre is generally endemic, and non-endemic or sporadic.
regarded as the end-stage of long-standing simple goitre Endemic goitre. Prevalence of goitre in a geographic area in
(Fig. 27.9). The fundamental defect is deficient production more than 10% of the population is termed endemic goitre.
of thyroid hormones due to various etiologic factors Such endemic areas are several high mountainous regions
described below, but most common is dietary lack of iodine. far from the sea where iodine content of drinking water and
Deficient thyroid hormone production causes excessive TSH food is low such as in the regions of the Himalayas, the Alps
stimulation which leads to hyperplasia of follicular and the Ande. Of late, however, the prevalence in these areas
epithelium as well as formation of new thyroid follicles. has declined due to prophylactic use of iodised salt.
Cyclical hyperplastic stage followed by involution stage Though most endemic goitres are caused by dietary lack
completes the picture of simple goitre. Repeated and of iodine, some cases occur due to goitrogens and genetic
prolonged changes of hyperplasia result in continued growth factors. Goitrogens are substances which interfere with the
of thyroid tissue while involuted areas undergo fibrosis, thus synthesis of thyroid hormones. These substances are drugs
completing the picture of nodular goitre. used in the treatment of hyperthyroidism and certain items
of food such as cabbage, cauliflower, turnips and cassava
Diffuse Goitre roots.
(Simple Non-toxic Goitre, Colloid Goitre) Sporadic (non-endemic) goitre. Non-endemic or sporadic
Diffuse, nontoxic simple or colloid goitre is the name given simple goitre is less common than the endemic variety. In
to diffuse enlargement of the thyroid gland, unaccompanied most cases, the etiology of sporadic goitre is unknown. A
by hyperthyroidism. Most cases are in a state of euthyroid number of causal influences have been attributed. These
though they may have passed through preceding stage of include the following:
hypothyroidism due to inadequate supply of iodine. TSH Suboptimal iodine intake in conditions of increased
levels are invariably elevated. In general, goitre is more demand as in puberty and pregnancy.

808




















Figure 27.10 Simple (diffuse nontoxic or colloid) goitre. The thyroid
gland is enlarged diffusely. Cut section shows lobules of translucent
gelatinous light brown parenchyma and areas of haemorrhage.




Genetic factors. Nodular Goitre
Dietary goitrogenes. (Multinodular Goitre, Adenomatous Goitre)
Hereditary defect in thyroid hormone synthesis and As already stated, nodular goitre is regarded as the end-stage
transport (dyshormonogenesis). of long-standing simple goitre. It is characterised by most
Inborn errors of iodine metabolism. extreme degree of tumour-like enlargement of the thyroid
gland and characteristic nodularity. The enlargement of the
MORPHOLOGIC FEATURES. Grossly, the enlargement gland may be sufficient to not only cause cosmetic
of the thyroid gland in simple goitre is moderate (weighing disfigurement, but in many cases may cause dsyphagia and
up to 100-150 gm), symmetric and diffuse. Cut surface is choking due to compression of oesophagus and trachea. Most
SECTION III
gelatinous and translucent brown (Fig. 27.10). cases are in a euthyroid state but about 10% cases may
Histologically, two stages are distinguished: develop thyrotoxicosis resulting in toxic nodular goitre or
1. Hyperplastic stage is the early stage and is characterised
by tall columnar follicular epithelium showing papillary Plummer’s disease. However, thyrotoxicosis of Plummer’s
disease (toxic nodular goitre) differs from that of Graves’
infoldings and formation of small new follicles. disease (diffuse toxic goitre) in lacking features of ophthalmo-
2. Involution stage generally follows hyperplastic stage pathy and dermatopathy. Such ‘hot nodules’ may be picked
after variable period of time. This stage is characterised up by CT scan or by RAIU studies. Since nodular goitre is
by large follicles distended by colloid and lined by derived from simple goitre, it has the same female
flattened follicular epithelium (Fig. 27.11).


Systemic Pathology
























Figure 27.11 Simple goitre. Microscopy shows large follicles distended by colloid and lined by flattened follicular epithelium.

809




















Figure 27.12 Nodular goitre. The thyroid gland is enlarged and
nodular. Cut surface shows multiple nodules separated from each other
by incomplete fibrous septa. Areas of haemorrhage and cystic change
are also seen.



preponderance but affects older individuals because it is a 2. Fibrous scarring
late complication of simple goitre. 3. Haemorrhages
ETIOLOGY. Etiologic factors implicated in endemic and non- 4. Focal calcification
endemic or sporadic variety of simple goitre are involved in 5. Cystic degeneration.
the etiology of nodular goitre too. However, how nodular Cut surface generally shows multinodularity but CHAPTER 27
pattern is produced is not clearly understood. Possibly, occasionally there may be only one or two nodules which
epithelial hyperplasia, generation of new follicles, and are poorly-circumscribed (unlike complete encapsulation
irregular accumulation of colloid in the follicles—all of thyroid adenoma, described below).
contribute to produce increased tension and stress in the Histologically, the same heterogenicity as seen on gross
thyroid gland causing rupture of follicles and vessels. This appearance is seen. Corresponding microscopic features
is followed by haemorrhages, scarring and sometimes are as follows (Fig. 27.13):
1. Partial or incomplete encapsulation of nodules.
calcification, resulting in development of nodular pattern.
2. The follicles varying from small to large and lined by
MORPHOLOGIC FEATURES. Grossly, the thyroid in flat to high epithelium. A few may show macropapillary
nodular goitre shows asymmetric and extreme formation.
enlargement, weighing 100-500 gm or even more. The five 3. Areas of haemorrhages, haemosiderin-laden macro- The Endocrine System
cardinal macroscopic features are as under (Fig. 27.12): phages and cholesterol crystals.
1. Nodularity with poor encapsulation 4. Fibrous scarring with foci of calcification.
5. Micro-macrocystic change.



























Figure 27.13 Nodular goitre. The predominant histologic features are: nodularity, extensive scarring with foci of calcification, areas of
haemorrhages and variable-sized follicles lined by flat to high epithelium and containing abundant colloid.

810
  TABLE 27.2: Contrasting Features of Simple and Nodular Goitre.
Feature Diffuse Goitre Nodular Goitre
1. Nomenclature Simple goitre, hyperplastic goitre, nontoxic goitre Multinodular, adenomatous goitre
2. Etiology Graves' disease, thyroiditis, puberty Endemic thyroiditis, cancer
3. Pathogenesis Hyperplasia-involution Repeated cycles of hyperplasia with growth and
involution with fibrosis
4. Composition Cellular-rich Colloid-rich
5. Gross Moderate, symmetric, diffuse enlargement, Nodular asymmetric, haemorrhages, scarring, cystic
colloid-filled follicles, gelatinous change, calcification
6. Microscopy Hyperplastic phase: papillary infoldings, Incomplete encapsulation, nodularity, variable-sized
Involution stage: large colloid filled follicles, fibrous scarring, haemorrhages, calcification,
follicles with flat epithelium cyst formation
7. Functional status Hyperthyroidism, euthyroid Hypothyroidism, euthyroid



The contrasting features of diffuse and nodular goitre epithelial cells forming follicles of various sizes or may
are summarised in Table 27.2. show trabecular, solid and cord patterns with little follicle
formation. Accordingly, the following 6 types of growth
THYROID TUMOURS patterns are distinguished, though more than one pattern
Most primary tumours of the thyroid are of follicular may be present in a single tumour:
epithelial origin; a few arise from parafollicular C-cells. The 1. Microfollicular (foetal) adenoma consists of small follicles
most common benign thyroid neoplasm is a follicular containing little or no colloid and separated by abundant
adenoma. Malignant tumours of the thyroid are less common loose stroma (Fig. 27.15).
but thyroid carcinoma is the most common type, though 2. Normofollicular (simple) adenoma has closely packed
rarely lymphomas and sarcomas also occur. follicles like that of normal thyroid gland.
3. Macrofollicular (colloid) adenoma contains large follicles
FOLLICULAR ADENOMA of varying size and distended with colloid.
SECTION III
4. Trabecular (embryonal) adenoma resembles embryonal
Follicular adenoma is the most common benign thyroid
tumour occurring more frequently in adult women. thyroid and consists of closely packed solid or trabecular
Clinically, it appears as a solitary nodule which can be found pattern of epithelial cells with an occasional small abortive
in approximately 1% of the population. Besides the follicular follicle.
adenoma, other conditions which may produce clinically 5. Hurthle cell (oxyphilic) adenoma is an uncommon variant
apparent solitary nodule in the thyroid are a dominant composed of solid trabeculae of large cells having
nodule of nodular goitre and thyroid carcinoma. It is thus abundant granular oxyphilic cytoplasm and vesicular
important to distinguish adenomas from these two
conditions. Though most adenomas cause no clinical problem
and behave as a ‘cold nodule’, rarely they may produce mild
hyperthyroidism and appear as ‘hot nodule’ on RAIU
Systemic Pathology
studies. Adenoma, however, rarely ever becomes malignant.
MORPHOLOGIC FEATURES. Grossly, the follicular
adenoma is characterised by four features so as to
distinguish it from a nodule of nodular goitre (Fig. 27.14):
1. solitary nodule;
2. complete encapsulation;
3. clearly distinct architecture inside and outside the
capsule; and
4. compression of the thyroid parenchyma outside the
capsule
Usually, an adenoma is small (up to 3 cm in diameter)
and spherical. On cut section, the adenoma is grey-white
to red-brown, less colloidal than the surrounding thyroid
parenchyma and may have degenerative changes such as
fibrous scarring, focal calcification, haemorrhages and cyst
formation.
Histologically, the tumour shows complete fibrous Figure 27.14 Follicular adenoma thyroid. Sectioned surface of the
encapsulation. The tumour cells are benign follicular thyroid shows a solitary nodule having capsule. The nodule is grey-white
and is distinct from the adjoining thyroid parenchyma.

811
























Figure 27.15 Follicular adenoma, foetal (microfollicular) type. The tumour is well-encapsulated with compression of surrounding thyroid
parenchyma. The tumour consists of small follicles lined by cuboidal epithelium and contain little or no colloid and separated by abundant loose
stroma.

nuclei. The tumour cells do not form follicles and contain evolve from autoimmune (lymphocytic) thyroiditis (page
little stroma. 804). Sarcomas of the thyroid are extremely rare. About 20%
6. Atypical adenoma is the term used for a follicular of patients dying of metastasising malignancy have
adenoma which has more pronounced cellular prolife- metastatic deposits in the thyroid gland, most commonly
ration so that features may be considered indicative of from malignant melanoma, renal cell carcinoma and CHAPTER 27
malignancy such as pleomorphism, increased mitoses and bronchogenic carcinoma.
nuclear atypia. These tumours, however, do not show In line with most other thyroid lesions, most carcinomas
capsular and vascular invasion—features which of the thyroid too have female preponderance and are twice
distinguish it from follicular carcinoma. more common in women.
Carcinoma of the thyroid gland has 4 major morphologic
THYROID CANCER types with distinctly different clinical behaviour and variable
Approximately 95% of all primary thyroid cancers are prevalence. These are: papillary, follicular, medullary and
carcinomas. Primary lymphomas of the thyroid comprise less undifferentiated (anaplastic) carcinoma; their contrasting
than 5% of thyroid cancers and majority of them possibly features are summed up in Table 27.3. The Endocrine System


 TABLE 27.3: Contrasting Features of Main Histologic Types of Thyroid Carcinoma.
Feature Papillary Follicular Medullary Anaplastic
Carcinoma Carcinoma Carcinoma Carcinoma
1. Frequency 75-80% 10-20% 5% 5%
2. Age All ages Middle to old age Middle to old age; Old age
familial too
3. Female/male ratio 3:1 2.5:1 1:1 1.5:1
4. Relation to radiation Maximum Present None Present
5. Genetic alterations RET gene over- RAS mutation, RET point mutation p53 loss,
expression, NTRK PAX-PPAR γ1 fusion β-catenin mutation
gene rearrangement
6. Cell of origin Follicular Follicular Parafollicular Follicular
7. Gross Small, multifocal Moderate size, nodular Moderate size Invasive growth

8. Pathognomonic Nuclear features, Vascular and capsular Solid nests, Undifferentiated,
microscopy papillary pattern invasion amyloid stroma spindle-shaped, giant cells
9. Regional metastases Common Rare Common Common
10. Distant metastases Rare Common Rare Common
11. 10-year survival 80-95% 50-70% 60-70% 5-10% (median survival about
2 months)

812 ETIOPATHOGENESIS. Most important risk factor translocation between 2 genes—PAX-8 (paired domain
implicated in the etiology of thyroid cancer is external transcription factor) and PPARγ-1 (gene coding for
radiation, and to a some extent there is role of TSH receptors peroxisome proliferator-activator receptor γ-1), has also been
and iodine excess, while pathogenesis of thyroid cancer is described in a proportion of cases of follicular thyroid
explained on genetic alterations. neoplasms, both adenoma and carcinoma.
1. External radiation. The single most important iii) Medullary thyroid carcinoma: Medullary thyroid carcinoma
environmental factor associated with increased risk of arises from parafollicular C-cells in the thyroid. Point
developing thyroid carcinoma after many years of exposure mutation in RET-protooncogene is seen in both familial as a
to external radiation of high dose. Evidences in support well as sporadiac cases of medullary thyroid carcinoma.
include: high incidence of thyroid cancer in individuals iv) Anaplastic thyroid carcinoma: This tumour either arises from
irradiated in early age for enlarged thymus and for skin further dedifferentiation of differentiated papillary or
disorders, in Japanese atomic bomb survivors, and in follicular thyroid carcinoma, or by inactivating point
individuals living in the vicinity of nuclear accident sites. In mutation in p53 tumour suppressor gene or by mutation in
particular, exposure to radiation to children and young adults gene coding for β-catenin pathway.
has been found to be associated with higher incidence of Papillary Thyroid Carcinoma
development of papillary carcinoma later.
2. Iodine excess and TSH. In regions where endemic goitre Papillary carcinoma is the most common type of thyroid
carcinoma, comprising 75-85% of cases. It can occur at all
is widespread, addition of iodine to diet has resulted in ages including children and young adults but the incidence
increase in incidence of papillary cancer. Many well- is higher with advancing age. The tumour is found about
differentiated thyroid cancers express TSH receptors and thus three times more frequently in females than in males.
respond to T suppression of TSH. Papillary carcinoma is typically a slow-growing
4
3. Genetic basis. Familial clustering of thyroid cancer has malignant tumour, most often presenting as an asymptomatic
been observed, especially in medullary carcinoma. Molecular solitary nodule. Involvement of the regional lymph nodes is
studies reveal that thyroid carcinoma is a multistep process common but distant metastases to organs are rare. Some cases
involving genetic alterations but distinct mutations are seen first come to attention by spread to regional lymph nodes
in different histologic types: and cause cervical lymphadenopathy. ‘Lateral aberrant thyroid’
i) Papillary thyroid carcinoma: Mutation in RET gene (gene is the term used for occurrence of thyroid tissue in the lateral
overexpression) located on chromosome 10q is seen in about cervical lymph node, which in most patients represents a
20% cases of papillary thyroid carcinoma. This mutation well-differentiated metastasis of an occult papillary
SECTION III
renders the tyrosine kinase receptor under the target of other carcinoma of the thyroid.
tumour-promoting factors such as radiation exposure in MORPHOLOGIC FEATURES. Grossly, papillary carci-
papillary carcinoma. Another genetic abnormality seen in noma may range from microscopic foci to nodules upto
5-10% cases of papillary thyroid carcinoma is gene 10 cm in diameter and is generally poorly delineated. Cut
rearrangement in NTRK1 (neurotrophic tyrosine kinase surface of the tumour is greyish-white, hard and scar-like
receptor 1 located on chromosome 1q) gene. (Fig. 27.16). Sometimes the tumour is transformed into a
ii) Follicular thyroid carcinoma: About 50% cases of follicular cyst, into which numerous papillae project and is termed
thyroid carcinoma have mutation in RAS family of oncogenes
that includes HRAS, NRAS and KRAS. Besides, fusion- papillary cystadenocarcinoma.

Systemic Pathology























Figure 27.16 Papillary carcinoma of the thyroid. Cut surface of the
enlarged thyroid gland shows a single nodule separated from the rest of
thyroid parenchyma by incomplete fibrous septa (arrow). The nodule is
grey-white soft and shows grossly visible papillary pattern.

813
























Figure 27.17 Papillary carcinoma thyroid. Microscopy shows branching papillae having flbrovascular stalk covered by a single layer of cuboidal
cells having ground-glass nuclei. Colloid-filled follicles and solid sheets of tumour cells are also present.



Histologically, the following features are present MORPHOLOGIC FEATURES. Grossly, follicular carci-
(Fig. 27.17): noma may be either in the form of a solitary adenoma-
1. Papillary pattern. Papillae composed of fibrovascular like circumscribed nodule or as an obvious cancerous
stalk and covered by single layer of tumour cells is the irregular thyroid enlargement. The cut surface of the
predominant feature. Papillae are often accompanied by tumour is grey-white with areas of haemorrhages, necrosis CHAPTER 27
follicles. and cyst formation and may extend to involve adjacent
2. Tumour cells. The tumour cells have characteristic structures.
nuclear features due to dispersed nuclear chromatin Microscopically, the features are as under (Fig. 27.18):
imparting it ground glass or optically clear appearance and 1. Follicular pattern: Follicular carcinoma, like follicular
clear or oxyphilic cytoplasm. These tumour cells, besides adenoma, is composed of follicles of various sizes and may
covering the papillae, may form follicles and solid sheets. show trabecular or solid pattern. The tumour cells have
3. Invasion. The tumour cells invade the capsule and hyperchromatic nuclei and the cytoplasm resembles that
intrathyroid lymphatics but invasion of blood vessels is of normal follicular cells. However, variants like clear cell
rare. type and Hurthle cell (oxyphilic) type of follicular carcinoma
4. Psammoma bodies. Half of papillary carcinomas show may occur. The tumour differs from papillary carcinoma The Endocrine System
typical small, concentric, calcified spherules called in lacking: papillae, ground-glass nuclei of tumour cells
psammoma bodies in the stroma. and psammoma bodies.
2. Vascular invasion and direct extension: Vascular
The prognosis of papillary carcinoma is good: 10-year invasion and direct extension to involve the adjacent
survival rate is 80-95%, irrespective of whether the tumour structures (e.g. into the capsule) are significant features
is pure papillary or mixed papillary-follicular carcinoma. but lymphatic invasion is rare.

Follicular Thyroid Carcinoma The prognosis of follicular carcinoma is between that of
papillary and undifferentiated carcinoma: 10-year survival
Follicular carcinoma is the other common type of thyroid rate is 50-70%.
cancer, next only to papillary carcinoma and comprises about
10-20% of all thyroid carcinomas. It is more common in Medullary Thyroid Carcinoma
middle and old age and has preponderance in females Medullary carcinoma is a less frequent type derived from
(female-male ratio 2.5:1). In contrast to papillary carcinoma, parafollicular or C-cells present in the thyroid and comprises
follicular carcinoma has a positive correlation with endemic about 5% of thyroid carcinomas. It is equally common in men
goitre but the role of external radiation in its etiology is and women. There are 3 distinctive features which
unclear. distinguish medullary carcinoma from the other thyroid
Follicular carcinoma presents clinically either as a solitary
nodule or as an irregular, firm and nodular thyroid carcinomas. These are: its familial occurrence, secretion of
calcitonin and other peptides, and amyloid stroma.
enlargement. The tumour is slow-growing but more rapid
than the papillary carcinoma. In contrast to papillary 1. Familial occurrence. Most cases of medullary carcinoma
carcinoma, regional lymph node metastases are rare but occur sporadically, but about 10% have a genetic background
distant metastases by haematogenous route are common, with point mutation in RET-protooncogene located on
especially to the lungs and bones. chromosome 10q. The familial form of medullary carcinoma

814

























Figure 27.18 Follicular carcinoma, showing encapsulated tumour with invasion of a capsular vessel. The follicles lined by tumour cells are of
various sizes and there is mild pleomorphism.

has association with pheochromocytoma and parathyroid fibrovascular septa. Sometimes, the tumour cells may be
adenoma (multiple endocrine neoplasia, MEN II A), or with arranged in sheets, ribbons pseudopapillae or small
pheochromocytoma and multiple mucosal neuromas (MEN follicles. The tumour cells are uniform and have the
II B). The sporadic cases occur in the middle and old age structural and functional characteristics of C-cells. Less
(5th-6th decades) and are generally unilateral, while the often, the neoplastic cells are spindle-shaped.
familial cases are found at younger age (2nd-3rd decades) 2. Amyloid stroma: The tumour cells are separated by
and are usually bilateral and multicentric. amyloid stroma derived from altered calcitonin which can

2. Secretion of calcitonin and other peptides. Like normal be demonstrated by immunostain for calcitonin. The
SECTION III
C-cells, tumour cells of medullary carcinoma secrete staining properties of amyloid are similar to that seen in
calcitonin, the hypocalcaemic hormone. In addition, the systemic amyloidosis and may have areas of irregular
tumour may also elaborate prostaglandins, histaminase, calcification but without regular laminations seen in
somatostatin, vasoactive intestinal peptide (VIP) and ACTH. psammoma bodies.
These hormone elaborations are responsible for a number of 3. C-cell hyperplasia: Familial cases generally have
clinical syndromes such as carcinoid syndrome, Cushing’s C-cell hyperplasia as a precursor lesion but not in sporadic
syndrome and diarrhoea. cases.
3. Amyloid stroma. Most medullary carcinomas have Most medullary carcinomas are slow-growing. Regional
amyloid deposits in the stroma which stains positively with lymph node metastases may occur but distant organ
usual amyloid stains such as Congo red. The amyloid metastases are infrequent. The prognosis is better in familial
Systemic Pathology
deposits are believed to represent stored calcitonin derived form than in the sporadic form: overall 10-year survival rate
from neoplastic C-cells in the form of prohormone. is 60-70%.
Most cases of medullary carcinoma present as solitary
thyroid nodule but sometimes an enlarged cervical lymph Anaplastic Carcinoma
node may be the first manifestation. Undifferentiated or anaplastic carcinoma of the thyroid
comprises less than 5% of all thyroid cancers and is one of
MORPHOLOGIC FEATURES. Grossly, the tumour may the most malignant tumour in humans. The tumour is
either appear as a unilateral solitary nodule (sporadic form), predominantly found in old age (7th-8th decades) and is
or have bilateral and multicentric involvement (familial slightly more common in females than in males (female-male
form). However, sporadic neoplasms also eventually ratio 1.5:1). The tumour is widely aggressive and rapidly
spread to the contralateral lobe. Cut surface of tumour in growing. The features at presentation are usually those of
both forms shows well-defined tumour areas which are extensive invasion of adjacent soft tissue, trachea and
firm to hard, grey-white to yellow-brown with areas of oesophagus. These features include: dyspnoea, dysphagia
haemorrhages and necrosis. and hoarseness, in association with rapidly-growing tumour
Histologically, the features are as under (Fig. 27.19): in the neck. The tumour metastasises both to regional lymph
1. Tumour cells: Like other neuroendocrine tumours (e.g. nodes and to distant organs such as the lungs.
carcinoid, islet cell tumour, paraganglioma etc), medullary
carcinoma of the thyroid too has a well-defined organoid MORPHOLOGIC FEATURES. Grossly, the tumour is
pattern, forming nests of tumour cells separated by generally large and irregular, often invading the adjacent

815













































Figure 27.19 Medullary carcinoma thyroid. Microscopy shows CHAPTER 27
organoid pattern of oval tumour cells and abundant amyloid stroma.
Amyloid shows congophilia which depicts apple-green birefringence under
polarising microscopy.



strap muscles of the neck and other structures in the bizarre and lobed nuclei and some assuming spindle The Endocrine System
vicinity of the thyroid. Cut surface of the tumour is white shapes.
and firm with areas of necrosis and haemorrhages.
Histologically, the tumour is too poorly-differentiated to The prognosis is poor: 5-year survival rate is less than
be placed in any other histologic type of thyroid cancer, 10% and median survival after the diagnosis is about
but usually shows a component of either papillary or 2 months.
follicular carcinoma in better differentiated areas. The
tumour is generally composed of 3 types of cells occurring PARATHYROID GLANDS
in varying proportions: small cells, spindle cells and giant
cells. When one of these cell types is predominant, the NORMAL STRUCTURE
histologic variant of undifferentiated carcinoma is named
accordingly. Thus, there are 3 histologic variants: ANATOMY. The parathyroid glands are usually 4 in
1. Small cell carcinoma: This type of tumour is number: the superior pair derived from the 3rd branchial
composed of closely packed small cells having hyper- pouch and inferior pair from the 4th branchial pouch of
chromatic nuclei and numerous mitoses. This variant primitive foregut. Both pairs are usually embedded in the
closely resembles malignant lymphoma. posterior aspect of the thyroid substance but separated from
2. Spindle cell carcinoma: These tumours are composed it by a connective tissue capsule. In the adults, each gland is
of spindle cells resembling sarcoma. Some tumours may an oval, yellowish-brown, flattened body, weighing 35-45
contain obvious sarcomatous component such as areas of mg. There may, however, be variation in the number, location
osteosarcoma, chondrosarcoma or rhabdomyosarcoma. and size of parathyroid glands.
3. Giant cell carcinoma: This type is composed of highly HISTOLOGY AND FUNCTIONS. Microscopically,
anaplastic giant cells showing numerous atypical mitoses, parathyroid glands are composed of solid sheets and cords

816 HYPERPARATHYROIDISM
Hyperfunction of the parathyroid glands occurs due to
excessive production of parathyroid hormone. It is classified
into 3 types—primary, secondary and tertiary.
Primary hyperparathyroidism occurs from oversecretion of
parathyroid hormone due to disease of the parathyroid
glands.
Secondary hyperparathyroidism is caused by diseases in
other parts of the body.
Tertiary hyperparathyroidism develops from secondary
hyperplasia after removal of the cause of secondary
hyperplasia.

Primary Hyperparathyroidism
Primary hyperparathyroidism is not uncommon and occurs
more commonly with increasing age. It is especially likely
to occur in women near the time of menopause.

ETIOLOGY. Common causes of primary hyperpara-
thyroidism are as follows:
1. Most commonly, parathyroid adenomas in approxi-
mately 80% cases.
Figure 27.20 Role of parathormone in regulating calcium metabo- 2. Carcinoma of the parathyroid glands in 2-3% patients.
lism in the body.
3. Primary hyperplasia in about 15% cases (usually chief
cell hyperplasia).
of parenchymal cells and variable amount of stromal fat. The Also included above are the familial cases of multiple
parenchymal cells are of 3 types: chief cells, oxyphil cells and endocrine neoplasia (MEN) syndromes where parathyroid
water-clear cells. The chief cells are most numerous and are adenoma or primary hyperplasia is one of the components.
SECTION III
the major source of parathyroid hormone. The latter two CLINICAL FEATURES. The patients with primary hyper-
types of cells appear to be derived from the chief cells and parathyroidism have the following characteristic biochemical
have sparse secretory granules but are potentially capable abnormalities:
of secreting parathyroid hormone. 1. Elevated levels of parathyroid hormone
The major function of the parathyroid hormone, in
conjunction with calcitonin and vitamin D, is to regulate 2. Hypercalcaemia
3. Hypophosphataemia
serum calcium levels and metabolism of bone. Parathyroid 4. Hypercalciuria
hormone tends to elevate serum calcium level and reduce
serum phosphate level. Secretion of parathyroid hormone Clinical presentation of individuals with primary hyper-
takes place in response to serum levels of calcium by a parathyroidism may be in a variety of ways:
feedback mechanism—lowered serum calcium stimulates 1. Most commonly, nephrolithiasis and or/nephrocalcinosis
Systemic Pathology
secretion of parathyroid hormone, while elevated serum (page 690). These dysfunctions result from excessive
calcium causes decreased secretion of the hormone. The role excretion of calcium in the urine due to hypercalcaemia
of parathyroid hormone in regulating calcium metabolism induced by increased parathyroid hormone level.
in the body is at the following 3 levels (Fig. 27.20): 2. Metastatic calcification, especially in the blood vessels,
1. Parathyroid hormone stimulates osteoclastic activity and kidneys, lungs, stomach, eyes and other tissues (page 53).
results in resorption of bone and release of calcium. Calci- 3. Generalised osteitis fibrosa cystica due to osteoclastic
tonin released by C-cells, on the other hand, opposes resorption of bone and its replacement by connective tissue
parathyroid hormone by preventing resorption of bone and (page 835).
lowering serum calcium level. 4. Neuropsychiatric disturbances such as depression, anxiety,
2. Parathyroid hormone acts directly on renal tubular epithe- psychosis and coma.
lial cells and increases renal reabsorption of calcium and 5. Hypertension is found in about half the cases.
inhibits reabsorption of phosphate; calcitonin enhances renal
excretion of phosphate. 6. Other changes such as pancreatitis, cholelithiasis and
3. Parathyroid hormone increases renal production of the peptic ulcers due to hypercalcaemia and high parathyroid
most active metabolite of vitamin D, i.e. 1, 25-dihydrocholecalci- hormone level are less constant features.
ferol, which in turn increases calcium absorption from the
small intestine. Secondary Hyperparathyroidism
The major parathyroid disorders are its functional Secondary hyperparathyroidism occurs due to increased
disorders (hyper- and hypoparathyroidism) and neoplasms. parathyroid hormone elaboration secondary to a disease

Primary Hypoparathyroidism 817
Primary hypoparathyroidism is caused by disease of the
parathyroid glands. Most common causes of primary
hypoparathyroidism are: surgical procedures involving
thyroid, parathyroid, or radical neck dissection for cancer.
Other causes are uncommon and include idiopathic
hypoparathyroidism of autoimmune origin in children and
may occur as sporadic or familial cases. These cases are
generally associated with other autoimmune diseases.
CLINICAL FEATURES. The main biochemical dysfunctions
in primary hypoparathyroidism are hypocalcaemia,
hyperphosphataemia and hypocalciuria. The clinical
manifestations of these abnormalities are as under:
1. Increased neuromuscular irritability and tetany
2. Calcification of the lens and cataract formation
3. Abnormalities in cardiac conduction
4. Disorders of the CNS due to intracranial calcification
5. Abnormalities of the teeth.
Figure 27.21 Major clinical manifestations of hyperparathyroidism.
Pseudo-hypoparathyroidism
elsewhere in the body. Hypocalcaemia stimulates compen-
satory hyperplasia of the parathyroid glands and causes In pseudo-hypoparathyroidism, the tissues fail to respond
secondary hyperparathyroidism. to parathyroid hormone though parathyroid glands are
usually normal. It is a rare inherited condition with an
ETIOLOGY. Though any condition that causes hypo- autosomal dominant character. The patients are generally
calcaemia stimulates excessive secretion of parathyroid females and are characterised by signs and symptoms of
hormone, the important causes of secondary hyper- hypoparathyroidism and other clinical features like short CHAPTER 27
parathyroidism are as under: stature, short metacarpals and metatarsals, flat nose, round
1. Chronic renal insufficiency resulting in retention of face and multiple exostoses. Since renal tubules cannot
phosphate and impaired intestinal absorption of calcium. adequately respond to parathyroid hormone, there is hyper-
2. Vitamin D deficiency and consequent rickets and calciuria, hypocalcaemia and hyperphosphataemia.
osteomalacia may cause parathyroid hyperfunction.
3. Intestinal malabsorption syndromes causing deficiency of Pseudopseudo-hypoparathyroidism
calcium and vitamin D. Pseudopseudo-hypoparathyroidism is another rare familial
CLINICAL FEATURES. The main biochemical abnormality disorder in which all the clinical features of pseudo-
in secondary hyperparathyroidism is mild hypocalcaemia, hypoparathyroidism are present except that these patients The Endocrine System
in striking contrast to hypercalcaemia in primary have no hypocalcaemia or hyperphosphataemia and the
hyperparathyroidism. The patients with secondary tissues respond normally to parathyroid hormone.
hyperparathyroidism have signs and symptoms of the Pseudopseudo-hypoparathyroidism has been considered an
disease which caused it. Usually, secondary hyperparathy- incomplete form of pseudo-hypoparathyroidism.
roidism is a beneficial compensatory mechanism, but more
severe cases may be associated with renal osteodystrophy PARATHYROID TUMOURS
(i.e. features of varying degree of osteitis fibrosa, osteo-
malacia, osteoporosis and osteosclerosis in cases of chronic Parathyroid adenoma and carcinoma are the neoplasms
renal insufficiency) and soft tissue calcification (Fig. 27.21). found in parathyroid glands, the former being much more
common than the latter.
Tertiary Hyperparathyroidism
Tertiary hyperparathyroidism is a complication of secondary Parathyroid Adenoma
hyperparathyroidism in which the hyperfunction persists in The commonest tumour of the parathyroid glands is an
spite of removal of the cause of secondary hyperplasia. adenoma. It may occur at any age and in either sex but is
Possibly, a hyperplastic nodule in the parathyroid gland found more frequently in adult life. Most adenomas are first
develops which becomes partially autonomous and brought to attention because of excessive secretion of
continues to secrete large quantities of parathyroid hormone parathyroid hormone causing features of hyperparathy-
without regard to the needs of the body. roidism as described above.

HYPOPARATHYROIDISM MORPHOLOGIC FEATURES. Grossly, a parathyroid
adenoma is small (less than 5 cm diameter) encapsulated,
Deficiency or absence of parathyroid hormone secretion yellowish-brown, ovoid nodule and weighing up to 5 gm
causes hypoparathyroidism. Hypoparathyroidism is of 3 or more.
types—primary, pseudo- and pseudopseudo-hypoparathyroidism.

818 Microscopically, majority of adenomas are predominantly causes secretory diarrhoea by stimulation of gastrointestinal
composed of chief cells arranged in sheets or cords. fluid secretion.
Oxyphil cells and water-clear cells may be found 2. Enterochromaffin cells synthesise serotonin which in
intermingled in varying proportions. Usually, a rim of pancreatic tumours may induce carcinoid syndrome.
normal parathyroid parenchyma and fat are present
external to the capsule which help to distinguish an DIABETES MELLITUS
adenoma from diffuse hyperplasia. Definition and Epidemiology

Parathyroid Carcinoma As per the WHO, diabetes mellitus (DM) is defined as a hetro-
geneous metabolic disorder characterised by common feature
Carcinoma of the parathyroid is rare and produces manifes- of chronic hyperglycaemia with disturbance of carbohydrate,
tations of hyperparathyroidism which is often more fat and protein metabolism.
pronounced. Carcinoma tends to be irregular in shape and DM is a leading cause of morbidity and mortality world
is adherent to the adjacent tissues. Most parathyroid over. It is estimated that approximately 1% of population
carcinomas are well-differentiated. It may be difficult to suffers from DM. The incidence is rising in the developed
distinguish carcinoma of parathyroid gland from an adenoma countries of the world at the rate of about 10% per year,
but local invasion of adjacent tissues and distant metastases especially of type 2 DM, due to rising incidence of obesity
are helpful criteria of malignancy in such cases. and reduced activity levels. DM is expected to continue as a
major health problem owing to its serious complications,
ENDOCRINE PANCREAS especially end-stage renal disease, IHD, gangrene of the
lower extremities, and blindness in the adults. It is anticipated
The human pancreas, though anatomically a single organ, that the number of diabetics will exceed 250 million by the
histologically and functionally, has 2 distinct parts—the year 2010.
exocrine and endocrine. The exocrine part of the gland and
its disorders have already been discussed in Chapter 21. Classification and Etiology
The discussion here is focused on the endocrine pancreas The older classification systems dividing DM into primary
and its two main disorders: diabetes mellitus and islet cell (idiopathic) and secondary types, juvenile-onset and maturity
tumours. onset types, and insulin-dependent (IDDM) and non-insulin
dependent (NIDDM) types, have become obsolete and
NORMAL STRUCTURE
undergone major revision due to extensive understanding
SECTION III
The endocrine pancreas consists of microscopic collections of etiology and pathogenesis of DM in recent times.
of cells called islets of Langerhans found scattered within As outlined in Table 27.4, current classification of DM
the pancreatic lobules, as well as individual endocrine cells based on etiology divides it into two broad categories—type
found in duct epithelium and among the acini. The total
weight of endocrine pancreas in the adult, however, does   TABLE 27.4: Etiologic Classification of Diabetes Mellitus
not exceed 1-1.5 gm (total weight of pancreas 60-100 gm). (as per American Diabetes Association, 2007).
The islet cell tissue is greatly concentrated in the tail than in I. TYPE 1 DIABETES MELLITUS (10%)
the head or body of the pancreas. Islets possess no ductal (earlier called Insulin-dependent, or juvenile-onset diabetes)
system and they drain their secretory products directly into Type IA DM: Immune-mediated
the circulation. Ultrastructurally and immunohistochemi- Type IB DM: Idiopathic
cally, 4 major and 2 minor types of islet cells are distinguished,
Systemic Pathology
each type having its distinct secretory product and function. II. TYPE 2 DIABETES MELLITUS (80%)
These are as follows: (earlier called non-insulin-dependent, or maturity-onset diabetes)
A. Major cell types: III. OTHER SPECIFIC TYPES OF DIABETES (10%)
A. Genetic defect of β-cell function due to mutations in various
1. Beta (β) or B cells comprise about 70% of islet cells and enzymes (earlier called maturity-onset diabetes of the young
secrete insulin, the defective response or deficient synthesis or MODY) (e.g. hepatocyte nuclear transcription factor—HNF,
of which causes diabetes mellitus. glucokinase)
2. Alpha (α) or A cells comprise 20% of islet cells and secrete B. Genetic defect in insulin action (e.g. type A insulin resistance)
C. Diseases of exocrine pancreas (e.g. chronic pancreatitis,
glucagon which induces hyperglycaemia. pancreatic tumours, post-pancreatectomy)
3. Delta (δ) or D cells comprise 5-10% of islet cells and secrete D. Endocrinopathies (e.g. acromegaly, Cushing's syndrome,
somatostatin which suppresses both insulin and glucagon pheochromocytoma)
release. E. Drug- or chemical-induced (e.g. steroids, thyroid hormone,
4. Pancreatic polypeptide (PP) cells or F cells comprise 1-2% of thiazides, β-blockers etc)
islet cells and secrete pancreatic polypeptide having some F. Infections (e.g. congenital rubella, cytomegalovirus)
G. Uncommon forms of immune-mediated DM (stiff man
gastrointestinal effects. syndrome, anti-insulin receptor antibodies)
H. Other genetic syndromes (e.g. Down's syndrome, Klinefelter's
B. Minor cell types: syndrome, Turner's syndrome)
1. D1 cells elaborate vasoactive intestinal peptide (VIP) IV. GESTATIONAL DIABETES MELLITUS
which induces glycogenolysis and hyperglycaemia and

 TABLE 27.5. Major Risk Factors for Type 2 Diabetes Mellitus GESTATIONAL DM. About 4% pregnant women develop 819
(ADA Recommendations, 2007). DM due to metabolic changes during pregnancy. Although
they revert back to normal glycaemia after delivery, these
1. Family history of type 2 DM
2. Obesity women are prone to develop DM later in their life.
3. Habitual physical inactivity
4. Race and ethnicity (Blacks, Asians, Pacific Islanders) Pathogenesis
5. Previous identification of impaired fasting glucose or impaired Depending upon etiology of DM, hyperglycaemia may result
glucose tolerance from the following:
6. History of gestational DM or delivery of baby heavier than 4 kg Reduced insulin secretion
7. Hypertension Decreased glucose use by the body
8. Dyslipidaemia (HDL level < 35 mg/dl or triglycerides > 250 mg/dl) Increased glucose production.
9. Polycystic ovary disease and acanthosis nigricans
10. History of vascular disease Pathogenesis of two main types of DM and its
complications is distinct. In order to understand it properly,
it is essential to first recall physiology of normal insulin
1 and type 2; besides there are a few uncommon specific synthesis and secretion.
etiologic types, and gestational DM. American Diabetes NORMAL INSULIN METABOLISM. The major stimulus for
Association (2007) has identified risk factors for type 2 DM both synthesis and release of insulin is glucose. The steps involved
listed in Table 27.5. in biosynthesis, release and actions of insulin are as follows
Brief comments on etiologic terminologies as contrasted (Fig. 27.22):
with former nomenclatures of DM are as under: Synthesis. Insulin is synthesised in the β-cells of pancreatic
TYPE 1 DM. It constitutes about 10% cases of DM. It was islets of Langerhans:
previously termed as juvenile-onset diabetes (JOD) due to i) It is initially formed as pre-proinsulin which is single-chain
its occurrence in younger age, and was called insulin- 86-amino acid precursor polypeptide.
dependent DM (IDDM) because it was known that these ii) Subsequent proteolysis removes the amino terminal signal
patients have absolute requirement for insulin replacement peptide, forming proinsulin. CHAPTER 27
as treatment. However, in the new classification, neither age iii) Further cleavage of proinsulin gives rise to A (21 amino
nor insulin-dependence are considered as absolute criteria. acids) and B (30 amino acids) chains of insulin, linked together
Instead, based on underlying etiology, type 1 DM is further by connecting segment called C-peptide, all of which are
divided into 2 subtypes: stored in the secretory granules in the β-cells. As compared
Subtype 1A (immune-mediated) DM characterised by to A and B chains of insulin, C-peptide is less susceptible to
autoimmune destruction of β-cells which usually leads to degradation in the liver and is therefore used as a marker to
insulin deficiency. distinguish endogenously synthesised and exogenously
Subtype 1B (idiopathic) DM characterised by insulin administered insulin.
deficiency with tendency to develop ketosis but these patients For therapeutic purposes, human insulin is now produced
are negative for autoimmune markers. by recombinant DNA technology. The Endocrine System
Though type 1 DM occurs commonly in patients under Release. Glucose is the key regulator of insulin secretion from
30 years of age, autoimmune destruction of β-cells can occur β-cells by a series of steps:
at any age. In fact, 5-10% patients who develop DM above i) Hypoglycaemia (glucose level below 70 mg/dl or below
30 years of age are of type 1A DM and hence the term JOD 3.9 mmol/L) stimulates transport into β-cells of a glucose
has become obsolete. transporter, GLUT2. Other stimuli influencing insulin release
include nutrients in the meal, ketones, amino acids etc.
TYPE 2 DM. This type comprises about 80% cases of DM. It ii) An islet transcription factor, glucokinase, causes glucose
was previously called maturity-onset diabetes, or non-insulin phosphorylation, and thus acts as a step for controlled release
dependent diabetes mellitus (NIDDM) of obese and non- of glucose-regulated insulin secretion.
obese type.
iii) Metabolism of glucose to glucose-6-phosphate by
Although type 2 DM predominantly affects older glycolysis generates ATP.
individuals, it is now known that it also occurs in obese iv) Generation of ATP alters the ion channel activity on the
adolescent children; hence the term MOD for it is membrane. It causes inhibition of ATP-sensitive K channel
+
inappropriate. Moreover, many type 2 DM patients also on the cell membrane and opening up of calcium channel
require insulin therapy to control hyperglycaemia or to with resultant influx of calcium, which stimulates insulin
prevent ketosis and thus are not truly non-insulin dependent release.
contrary to its former nomenclature.
Action. Half of insulin secreted from β-cells into portal vein
OTHER SPECIFIC ETIOLOGIC TYPES OF DM. Besides is degraded in the liver while the remaining half enters the
the two main types, about 10% cases of DM have a known systemic circulation for action on the target cells:
specific etiologic defect listed in Table 27.4. One important i) Insulin from circulation binds to its receptor on the target
subtype in this group is maturity-onset diabetes of the young cells. Insulin receptor has intrinsic tyrosine kinase activity.
(MODY) which has autosomal dominant inheritance, early ii) This, in turn, activates post-receptor intracellular signalling
onset of hyperglycaemia and impaired insulin secretion. pathway molecules, insulin receptor substrates (IRS) 1 and 2

820




























Figure 27.22 A, Pathway of normal insulin synthesis and release in β-cells of pancreatic islets. B, Chain of events in action of insulin on target
cell.


proteins, which initiate sequence of phosphorylation and i) Presence of islet cell antibodies against GAD (glutamic
dephosphorylation reactions. acid decarboxylase), insulin etc, though their assay largely
iii) These reactions on the target cells are responsible for the remains a research tool due to tedious method.
main mitogenic and anabolic actions of insulin—glycogen ii) Occurrence of lymphocytic infiltrate in and around the
synthesis, glucose transport, protein synthesis, lipogenesis. pancreatic islets termed insulitis. It chiefly consists of CD8+
iv) Besides the role of glucose in maintaining equilibrium of T lymphocytes with variable number of CD4+ T lymphocytes
SECTION III
insulin release, low insulin level in the fasting state promotes and macrophages.
hepatic gluconeogenesis and glycogenolysis, reduced glucose iii) Selective destruction of β-cells while other islet cell types
uptake by insulin-sensitive tissues and promotes (glucagon-producing alpha cells, somatostatin-producing
mobilisation of stored precursors, so as to prevent delta cells, or polypeptide-forming PP cells) remain
hypoglycaemia. unaffected. This is mediated by T-cell mediated cytotoxicity
or by apoptosis.
PATHOGENESIS OF TYPE 1 DM. The basic phenomenon in iv) Role of T cell-mediated autoimmunity is further supported
type 1 DM is destruction of β-cell mass, usually leading to absolute by transfer of type 1A DM from diseased animal by infusing
insulin deficiency. While type 1B DM remains idiopathic, T lymphocytes to a healthy animal.
pathogenesis of type 1A DM is immune-mediated and has v) Association of type 1A DM with other autoimmune diseases
been extensively studied. Currently, pathogenesis of type 1A in about 10-20% cases such as Graves’ disease, Addison’s
Systemic Pathology
DM is explained on the basis of 3 mutually-interlinked disease, Hashimoto’s thyroiditis, pernicious anaemia.
mechanisms: genetic susceptibility, autoimmune factors, and vi) Remission of type 1A DM in response to immunosuppres-
certain environmental factors (Fig. 27.23,A). sive therapy such as administration of cyclosporin A.
1. Genetic susceptibility. Type 1A DM involves inheritance 3. Environmental factors. Epidemiologic studies in type 1A
of multiple genes to confer susceptibility to the disorder: DM suggest the involvement of certain environmental factors
i) It has been observed in identical twins that if one twin has in its pathogenesis, though role of none of them has been
type 1A DM, there is about 50% chance of the second twin conclusively proved. In fact, the trigger may precede the
developing it, but not all. This means that some additional occurrence of the disease by several years. It appears that
modifying factors are involved in development of DM in certain viral and dietary proteins share antigenic properties
these cases. with human cell surface proteins and trigger the immune
ii) About half the cases with genetic predisposition to type attack on β-cells by a process of molecular mimicry. These
1A DM have the susceptibility gene located in the HLA region factors include the following:
of chromosome 6 (MHC class II region), particularly HLA i) Certain viral infections preceding the onset of disease e.g.
DR3, HLA DR4 and HLA DQ locus. mumps, measles, coxsackie B virus, cytomegalovirus and
infectious mononucleosis.
2. Autoimmune factors. Studies on humans and animal ii) Experimental induction of type 1A DM with certain
models on type 1A DM have shown several immunologic chemicals has been possible e.g. alloxan, streptozotocin and
abnormalities: pentamidine.

821





































Figure 27.23 Schematic mechanisms involved in pathogenesis of two main types of diabetes mellitus. CHAPTER 27


iii) Geographic and seasonal variations in its incidence suggest 1. Genetic factors. Genetic component has a stronger basis
some common environmental factors. for type 2 DM than type 1A DM. Although no definite and
iv) Possible relationship of early exposure to bovine milk consistent genes have been identified, multifactorial
proteins and occurrence of autoimmune process in type 1A inheritance is the most important factor in development of
DM is being studied. type 2 DM:
i) There is approximately 80% chance of developing
KEY POINTS: Pathogenesis of type 1A DM can be summed diabetes in the other identical twin if one twin has the disease.
up by interlinking the above three factors as under: The Endocrine System
1. At birth, individuals with genetic susceptibility to this ii) A person with one parent having type 2 DM is at an
disorder have normal β-cell mass. increased risk of getting diabetes, but if both parents have type
2. β-cells act as autoantigens and activate CD4+ T lympho- 2 DM the risk in the offspring rises to 40%.
cytes, bringing about immune destruction of pancreatic 2. Constitutional factors. Certain environmental factors
β-cells by autoimmune phenomena and takes months to years. such as obesity, hypertension, and level of physical activity
Clinical features of diabetes manifest after more than 80% of play contributory role and modulate the phenotyping of the
β-cell mass has been destroyed. disease.
3. The trigger for autoimmune process appears to be some 3. Insulin resistance. One of the most prominent metabolic
infectious or environmental factor which specifically targets features of type 2 DM is the lack of responsiveness of
β-cells. peripheral tissues to insulin, especially of the skeletal muscle
and liver. Obesity, in particular, is strongly associated with
PATHOGENESIS OF TYPE 2 DM. The basic metabolic insulin resistance and hence type 2 DM. Mechanism of
defect in type 2 DM is either a delayed insulin secretion hyperglycaemia in these cases is explained as under:
relative to glucose load (impaired insulin secretion), or the
i) Resistance to action of insulin impairs glucose utilisation
peripheral tissues are unable to respond to insulin (insulin and hence hyperglycaemia.
resistance).
Type 2 DM is a heterogeneous disorder with a more ii) There is increased hepatic synthesis of glucose.
complex etiology and is far more common than type 1, but iii) Hyperglycaemia in obesity is related to high levels of free
much less is known about its pathogenesis. A number of fatty acids and cytokines (e.g. TNF-α and adiponectin) affect
factors have been implicated though, but HLA association peripheral tissue sensitivity to respond to insulin.
and autoimmune phenomena are not implicated. These The precise underlying molecular defect responsible for
factors are as under (Fig. 27.23,B): insulin resistance in type 2 DM has yet not been fully

822 identified. Currently, it is proposed that insulin resistance 3. Two main mechanisms for hyperglycaemia in type 2 DM—
may be possibly due to one of the following defects: insulin resistance and impaired insulin secretion, are interlinked.
Polymorphism in various post-receptor intracellular signal 4. While obesity plays a role in pathogenesis of insulin
pathway molecules. resistance, impaired insulin secretion may be from many
Elevated free fatty acids seen in obesity may contribute e.g. constitutional factors.
by impaired glucose utilisation in the skeletal muscle, by 5. Increased hepatic synthesis of glucose in initial period of
increased hepatic synthesis of glucose, and by impaired disease contributes to hyperglycaemia.
β-cell function.
Insulin resistance syndrome is a complex of clinical features Morphologic Features in Pancreatic Islets
occurring from insulin resistance and its resultant metabolic Morphologic changes in islets have been demonstrated
derangements that includes hyperglycaemia and in both types of diabetes, though the changes are more
compensatory hyperinsulinaemia. The clinical features are distinctive in type 1 DM:
in the form of accelerated cardiovascular disease and may
occur in both obese as well as non-obese type 2 DM patients. 1. Insulitis:
The features include: mild hypertension (related to In type 1 DM, characteristically, in early stage there is
endothelial dysfunction) and dyslipidaemia (characterised lymphocytic infiltrate, mainly by T cells, in the islets which
by reduced HDL level, increased triglycerides and LDL level). may be accompanied by a few macrophages and
4. Impaired insulin secretion. In type 2 DM, insulin polymorphs. Diabetic infants born to diabetic mothers,
resistance and insulin secretion are interlinked: however, have eosinophilic infiltrate in the islets.
i) Early in the course of disease, in response to insulin In type 2 DM, there is no significant leucocytic infiltrate
resistance there is compensatory increased secretion of in the islets but there is variable degree of fibrous tissue
insulin (hyperinsulinaemia) in an attempt to maintain normal in the islets.
blood glucose level. 2. Islet cell mass:
ii)Eventually, however, there is failure of β-cell function to
secrete adequate insulin, although there is some secretion of In type 1 DM, as the disease becomes chronic there is
insulin i.e. cases of type 2 DM have mild to moderate progressive depletion of β−cell mass, eventually resulting
deficiency of insulin (which is much less severe than that in in total loss of pancreatic β−cells and its hyalinisation.
type 1 DM) but not its total absence. In type 2 DM, β-cell mass is either normal or mildly
SECTION III
The exact genetic mechanism why there is a fall in insulin reduced. Infants of diabetic mothers, however, have
secretion in these cases is unclear. However, following hyperplasia and hypertrophy of islets as a compensatory
possibilities are proposed: response to maternal hyperglycaemia.
Islet amyloid polypeptide (amylin) which forms fibrillar 3. Amyloidosis:
protein deposits in pancreatic islets in longstanding cases of In type 1 DM, deposits of amyloid around islets are
type 2 DM may be responsible for impaired function of absent.
β-cells of islet cells. In type 2 DM, characteristically chronic long-standing
Metabolic environment of chronic hyperglycaemia cases show deposition of amyloid material, amylin,
surrounding the islets (glucose toxicity) may paradoxically around the capillaries of the islets causing compression
impair islet cell function. and atrophy of islet tissue (Fig. 27.24).
Systemic Pathology
Elevated free fatty acid levels (lipotoxicity) in these cases
may worsen islet cell function.
5. Increased hepatic glucose synthesis. One of the normal
roles played by insulin is to promote hepatic storage of
glucose as glycogen and suppress gluconeogenesis. In type
2 DM, as a part of insulin resistance by peripheral tissues,
the liver also shows insulin resistance i.e. in spite of hyper-
insulinaemia in the early stage of disease, gluconeogenesis
in the liver is not suppressed. This results in increased hepatic
synthesis of glucose which contributes to hyperglycaemia
in these cases.
KEY POINTS: In essence, hyperglycaemia in type 2 DM is
not due to destruction of β-cells but is instead a failure of β-
cells to meet the requirement of insulin in the body. Its
pathogenesis can be summed up by interlinking the above
factors as under:
1. Type 2 DM is a more complex multifactorial disease. Figure 27.24 Amyloidosis of the pancreatic islet tissue. The islets
are mostly replaced by structureless eosinophilic material which stains
2. There is greater role of genetic defect and heredity. positively with Congo red.

823







































Figure 27.25 Pathophysiological basis of common signs and symptoms due to uncontrolled hyperglycaemia in diabetes mellitus. CHAPTER 27


4. ββ ββ β-cell degranulation: In type 1 DM, EM shows diseases and symptoms, especially due to complications.
degranulation of remaining β-cells of islets. Two main types of DM can be distinguished clinically to
In type 2 DM, no such change is observed. the extent shown in Table 27.6. However, overlapping of
clinical features occurs as regards the age of onset, duration
Clinical Features of symptoms and family history. Pathophysiology in
It can be appreciated that hyperglycaemia in DM does not evolution of clinical features is schematically shown in The Endocrine System
cause a single disease but is associated with numerous Fig. 27.25.

 TABLE 27.6: Contrasting Features of Type 1 and Type 2 Diabetes Mellitus.
Feature Type 1 DM Type 2 DM
1. Frequency 10-20% 80-90%
2. Age at onset Early (below 35 years) Late (after 40 years)
3. Type of onset Abrupt and severe Gradual and insidious
4. Weight Normal Obese/non-obese
5. HLA Linked to HLA DR3, HLA DR4, HLA DQ No HLA association
6. Family history < 20% About 60%
7. Genetic locus Unknown Chromosome 6
8. Diabetes in identical twins 50% concordance 80% concordance
9. Pathogenesis Autoimmune destruction of β-cells Insulin resistance, impaired insulin
secretion
10. Islet cell antibodies Yes No
11. Blood insulin level Decreased insulin Normal or increased insulin
12. Islet cell changes Insulitis, β-cell depletion No insulitis, later fibrosis of islets
13. Amyloidosis Infrequent Common in chronic cases
14. Clinical management Insulin and diet Diet, exercise, oral drugs, insulin
15. Acute complications Ketoacidosis Hyperosmolar coma

824 Type 1 DM: Pathogenesis of Complications
i) Patients of type 1 DM usually manifest at early age, It is now known that in both type 1 and 2 DM, severity and
generally below the age of 35. chronicity of hyperglycaemia forms the main pathogenetic
ii) The onset of symptoms is often abrupt. mechanism for ‘microvascular complications’ (e.g.
iii) At presentation, these patients have polyuria, polydipsia retinopathy, nephropathy, neuropathy); therefore control of
and polyphagia. blood glucose level constitutes the mainstay of treatment for
iv) The patients are not obese but have generally progressive minimising development of these complications.
loss of weight. Longstanding cases of type 2 DM, however, in addition,
v) These patients are prone to develop metabolic frequently develop ‘macrovascular complications’
complications such as ketoacidosis and hypoglycaemic (e.g. atherosclerosis, coronary artery disease, peripheral
episodes. vascular disease, cerebrovascular disease) which are more
difficult to explain on the basis of hyperglycaemia alone.
Type 2 DM: The following biochemical mechanisms have been
i) This form of diabetes generally manifests in middle life proposed to explain the development of complications of
or beyond, usually above the age of 40. diabetes mellitus (Fig. 27.26, A):
ii) The onset of symptoms in type 2 DM is slow and 1. Non-enzymatic protein glycosylation: The free amino
insidious. group of various body proteins binds by non-enzymatic
iii) Generally, the patient is asymptomatic when the mechanism to glucose; this process is called glycosylation and
diagnosis is made on the basis of glucosuria or hyper- is directly proportionate to the severity of hyperglycaemia.
glycaemia during physical examination, or may present with Various body proteins undergoing chemical alterations in
polyuria and polydipsia. this way include haemoglobin, lens crystalline protein, and
iv) The patients are frequently obese and have unexplained basement membrane of body cells. An example is the
weakness and loss of weight. measurement of a fraction of haemoglobin called
v) Metabolic complications such as ketoacidosis are glycosylated haemoglobin (HbA ) as a test for monitoring
1C
infrequent. glycaemic control in a diabetic patient during the preceding



SECTION III














Systemic Pathology

























Figure 27.26 Long-term complications of diabetes mellitus. A, Pathogenesis. B, Secondary systemic complications.

90 to 120 days which is lifespan of red cells (page 288) . are the usual precipitating causes. Severe lack of insulin 825
Similarly, there is accumulation of labile and reversible glyco- causes lipolysis in the adipose tissues, resulting in release of
sylation products on collagen and other tissues of the blood free fatty acids into the plasma. These free fatty acids are
vessel wall which subsequently become stable and taken up by the liver where they are oxidised through acetyl
irreversible by chemical changes and form advanced glyco- coenzyme-A to ketone bodies, principally acetoacetic acid
sylation end-products (AGE). The AGEs bind to receptors and β-hydroxybutyric acid. Such free fatty acid oxidation to
on different cells and produce a variety of biologic and ketone bodies is accelerated in the presence of elevated level
chemical changes e.g. thickening of vascular basement of glucagon. Once the rate of ketogenesis exceeds the rate at
membrane in diabetes. which the ketone bodies can be utilised by the muscles and
other tissues, ketonaemia and ketonuria occur. If urinary
2. Polyol pathway mechanism. This mechanism is excretion of ketone bodies is prevented due to dehydration,
responsible for producing lesions in the aorta, lens of the systemic metabolic ketoacidosis occurs. Clinically, the
eye, kidney and peripheral nerves. These tissues have an condition is characterised by anorexia, nausea, vomitings,
enzyme, aldose reductase, that reacts with glucose to form deep and fast breathing, mental confusion and coma. Most
sorbitol and fructose in the cells of the hyperglycaemic patient patients of ketoacidosis recover.
as under:
2. Hyperosmolar hyperglycaemic nonketotic coma (HHS).
aldose reductase
Glucose + NADH + H + > Sorbitol + NAD + Hyperosmolar hyperglycaemic nonketotic coma is usually a
complication of type 2 DM. It is caused by severe dehydration
sorbitol resulting from sustained hyperglycaemic diuresis. The loss
dehydrogenase of glucose in urine is so intense that the patient is unable to
Sorbitol + NAD > Fructose + NADH + H +
drink sufficient water to maintain urinary fluid loss. The
usual clinical features of ketoacidosis are absent but
Intracellular accumulation of sorbitol and fructose so
produced results in entry of water inside the cell and prominent central nervous signs are present. Blood sugar is
consequent cellular swelling and cell damage. Also, intra- extremely high and plasma osmolality is high. Thrombotic
cellular accumulation of sorbitol causes intracellular and bleeding complications are frequent due to high viscosity CHAPTER 27
deficiency of myoinositol which promotes injury to Schwann of blood. The mortality rate in hyperosmolar nonketotic coma
cells and retinal pericytes. These polyols result in disturbed is high.
processing of normal intermediary metabolites leading to The contrasting features of diabetic ketoacidosis and
complications of diabetes. hyperosmolar non-ketotic coma are summarised in
Table 27.7.
3. Excessive oxygen free radicals. In hyperglycaemia, there 3. Hypoglycaemia. Hypoglycaemic episode may develop
is increased production of reactive oxygen free radicals from in patients of type 1 DM. It may result from excessive
mitochondrial oxidative phosphorylation which may damage administration of insulin, missing a meal, or due to stress.
various target cells in diabetes.
Hypoglycaemic episodes are harmful as they produce
permanent brain damage, or may result in worsening of
Complications of Diabetes The Endocrine System
diabetic control and rebound hyperglycaemia, so called
As a consequence of hyperglycaemia of diabetes, every tissue Somogyi’s effect.
and organ of the body undergoes biochemical and structural II. LATE SYSTEMIC COMPLICATIONS. A number of
alterations which account for the major complications in systemic complications may develop after a period of
diabetics which may be acute metabolic or chronic systemic.
Both types of diabetes mellitus may develop compli-
cations which are broadly divided into 2 major groups:  TABLE 27.7: Contrasting Features of Diabetic Ketoacidosis
I. Acute metabolic complications: These include diabetic (DKA) and Hyperosmolar Hyperglycaemic Non-ketotic Coma
ketoacidosis, hyperosmolar nonketotic coma, and (HHS).
hypoglycaemia. Lab Findings DKA HHS
II. Late systemic complications: These are atherosclerosis, i. Plasma glucose (mg/dL) 250-600 > 600
diabetic microangiopathy, diabetic nephropathy, diabetic ii. Plasma acetone + Less +
neuropathy, diabetic retinopathy and infections. iii. S. Na (mEq/L) Usually low N, ↑↑ ↑↑ ↑ or low
+
iv. S. K (mEq/L) N, ↑↑ ↑↑ ↑ or low N or ↑↑ ↑↑ ↑
+
I. ACUTE METABOLIC COMPLICATIONS. Metabolic v. S. phosphorus (mEq/L) N or ↑↑ ↑↑ ↑ N or ↑↑ ↑↑ ↑
complications develop acutely. While ketoacidosis and ++ N or ↑↑ ↑↑ ↑ N or ↑↑ ↑↑ ↑
hypoglycaemic episodes are primarily complications of type vi. S. Mg
1 DM, hyperosmolar nonketotic coma is chiefly a vii. S. bicarbonate (mEq/L) Usually <15 Usually >20
complication of type 2 DM (also see Fig. 27.25). viii. Blood pH <7.30 > 7.30
ix. S. osmolarity (mOsm/L) <320 > 330
1. Diabetic ketoacidosis (DKA). Ketoacidosis is almost x. S. lactate (mmol/L) 2-3 1-2
exclusively a complication of type 1 DM. It can develop in Less ↑↑ ↑↑ ↑ Greater ↑↑ ↑↑ ↑
patients with severe insulin deficiency combined with xi. S. BUN (mg/dL)
glucagon excess. Failure to take insulin and exposure to stress xii. Plasma insulin Low to 0 Some

826 15-20 years in either type of diabetes. Late complications are 6. Infections. Diabetics have enhanced susceptibility to
largely responsible for morbidity and premature mortality various infections such as tuberculosis, pneumonias,
in diabetes mellitus. These complications are briefly outlined pyelonephritis, otitis, carbuncles and diabetic ulcers. This
below as they are discussed in detail in relevant chapters could be due to various factors such as impaired leucocyte
(Fig. 27.26,B). functions, reduced cellular immunity, poor blood supply due
1. Atherosclerosis. Diabetes mellitus of both type 1 and to vascular involvement and hyperglycaemia per se.
type 2 accelerates the development of atherosclerosis.
Consequently, atherosclerotic lesions appear earlier than in Diagnosis of Diabetes
the general population, are more extensive, and are more
often associated with complicated plaques such as ulceration, Hyperglycaemia remains the fundamental basis for the
calcification and thrombosis (page 398). The cause for this diagnosis of diabetes mellitus. In symptomatic cases, the
accelerated atherosclerotic process is not known but possible diagnosis is not a problem and can be confirmed by finding
contributory factors are hyperlipidaemia, reduced HDL glucosuria and a random plasma glucose concentration
levels, nonenzymatic glycosylation, increased platelet above 200 mg/dl.
adhesiveness, obesity and associated hypertension in The severity of clinical symptoms of polyuria and
diabetes. polydipsia is directly related to the degree of hyperglycaemia.
The possible ill-effects of accelerated atherosclerosis in In asymptomatic cases, when there is persistently elevated
diabetes are early onset of coronary artery disease, silent fasting plasma glucose level, diagnosis again poses no
myocardial infarction, cerebral stroke and gangrene of the difficulty.
toes and feet. Gangrene of the lower extremities is 100 times The problem arises in asymptomatic patients who have
more common in diabetics than in non-diabetics. normal fasting glucose level in the plasma but are suspected
2. Diabetic microangiopathy. Microangiopathy of diabetes to have diabetes on other grounds and are thus subjected to
is characterised by basement membrane thickening of small oral glucose tolerance test (GTT). If abnormal GTT values
blood vessels and capillaries of different organs and tissues are found, these subjects are said to have ‘chemical diabetes’
such as the skin, skeletal muscle, eye and kidney. Similar (Fig. 27.27). The American Diabetes Association (2007) has
type of basement membrane-like material is also deposited recommended definite diagnostic criteria for early diagnosis
in nonvascular tissues such as peripheral nerves, renal of diabetes mellitus (Table 27.8).
tubules and Bowman’s capsule. The pathogenesis of diabetic The following investigations are helpful in establishing
microangiopathy as well as of peripheral neuropathy in dia- the diagnosis of diabetes mellitus:
SECTION III
betics is believed to be due to recurrent hyperglycaemia that I. URINE TESTING. Urine tests are cheap and convenient
causes increased glycosylation of haemoglobin and other but the diagnosis of diabetes cannot be based on urine testing
proteins (e.g. collagen and basement membrane material) alone since there may be false-positives and false-negatives.
resulting in thickening of basement membrane.
They can be used in population screening surveys. Urine is
3. Diabetic nephropathy. Renal involvement is a common tested for the presence of glucose and ketones.
complication and a leading cause of death in diabetes. Four
types of lesions are described in diabetic nephropathy (page 1. Glucosuria. Benedict’s qualitative test detects any reducing
677): substance in the urine and is not specific for glucose. More
i) Diabetic glomerulosclerosis which includes diffuse and
nodular lesions of glomerulosclerosis.  TABLE 27.8: Revised Criteria for Diagnosis of Diabetes by
Systemic Pathology
ii) Vascular lesions that include hyaline arteriolosclerosis of Oral GTT (as per American Diabetes Association, 2007).
afferent and efferent arterioles and atheromas of renal Plasma Glucose Value* Diagnosis
arteries. FASTING (FOR > 8 HOURS) VALUE
iii) Diabetic pyelonephritis and necrotising renal papillitis. Below 100 mg/dl (< 5.6 mmol/L) Normal fasting value
iv) Tubular lesions or Armanni-Ebstein lesion. 100-125 mg/dl (5.6-6.9 mmol/L) Impaired fasting glucose (IFG)**
4. Diabetic neuropathy. Diabetic neuropathy may affect all 126 mg/dl (7.0 mmol/L) or more Diabetes mellitus
parts of the nervous system but symmetric peripheral
neuropathy is most characteristic. The basic pathologic TWO-HOUR AFTER 75 GM ORAL GLUCOSE LOAD
changes are segmental demyelination, Schwann cell injury < 140 mg/dl (< 7.8 mmol/L) Normal post-prandial GTT
and axonal damage (page 892). The pathogenesis of 140-199 mg/dl (7.8-11.1 mmol/L) Impaired post-prandial glucose
neuropathy is not clear but it may be related to diffuse tolerance (IGT)**
microangiopathy as already explained, or may be due to 200 mg/dl (11.1 mmol/L) or more Diabetes mellitus
accumulation of sorbitol and fructose as a result of
hyperglycaemia, leading to deficiency of myoinositol. RANDOM VALUE
200 mg/dl (11.1 mmol/L) or more Diabetes mellitus
5. Diabetic retinopathy. Diabetic retinopathy is a leading in a symptomatic patient
cause of blindness. There are 2 types of lesions involving
retinal vessels: background and proliferative (page 508). Besides Note: * Plasma glucose values are 15% higher than whole blood glucose
retinopathy, diabetes also predisposes the patients to early value.
** Individuals with IFG and IGT are at increased risk for development of
development of cataract and glaucoma. type 2 DM later.

827

























Figure 27.27 The glucose tolerance test, showing blood glucose curves (venous blood glucose) and glucosuria after 75 gm of oral glucose.


sensitive and glucose specific test is dipstick method based Besides uncontrolled diabetes, ketonuria may appear in
on enzyme-coated paper strip which turns purple when individuals with prolonged vomitings, fasting state or
dipped in urine containing glucose. exercising for long periods.
The main disadvantage of relying on urinary glucose test
alone is the individual variation in renal threshold. Thus, a II. SINGLE BLOOD SUGAR ESTIMATION. For diag-
nosis of diabetes, blood sugar determinations are absolutely
diabetic patient may have a negative urinary glucose test necessary. Folin-Wu method of measurement of all reducing CHAPTER 27
and a nondiabetic individual with low renal threshold may substances in the blood including glucose is now obsolete.
have a positive urine test.
Besides diabetes mellitus, glucosuria may also occur in Currently used are O-toluidine, Somogyi-Nelson and glucose
certain other conditions such as: renal glycosuria, alimentary oxidase methods. Whole blood or plasma may be used but
(lag storage) glucosuria, many metabolic disorders, whole blood values are 15% lower than plasma values.
A grossly elevated single determination of plasma
starvation and intracranial lesions (e.g. cerebral tumour, glucose may be sufficient to make the diagnosis of diabetes.
haemorrhage and head injury). However, two of these
conditions—renal glucosuria and alimentary glucosuria, A fasting plasma glucose value above 126 mg/dl (>7 mmol/L) is
certainly indicative of diabetes. In other cases, oral GTT is
require further elaboration here. performed.
Renal glucosuria (Fig. 27.27,B): After diabetes, the next The Endocrine System
most common cause of glucosuria is the reduced renal III. SCREENING BY FASTING GLUCOSE TEST. Fasting
threshold for glucose. In such cases although the blood plasma glucose determnitation is a screening test for DM
glucose level is below 180 mg/dl (i.e. below normal renal type 2. It is recommended that all individuals above 45 years
threshold for glucose) but glucose still appears regularly and of age must undergo screening fasting glucose test every
consistently in the urine due to lowered renal threshold. 3-years, and relatively earlier if the person is overweight or
Renal glucosuria is a benign condition unrelated to at risk because of the following reasons:
diabetes and runs in families and may occur temporarily in i) Many of the cases meeting the current criteria of DM are
pregnancy without symptoms of diabetes. asymptomatic and donot know that they have the disorder.
Alimentary (lag storage) glucosuria (Fig. 27.27,C): A rapid ii) Studies have shown that type 2 DM may be present for
and transitory rise in blood glucose level above the normal about 10 years before symptomatic disease appears.
renal threshold may occur in some individuals after a meal. iii) About half the cases of type 2 DM have some diabetes-
During this period, glucosuria is present. This type of related comlication at the time of diagnosis.
response to meal is called ‘lag storage curve’ or more iv) The course of disease is favourably altered with treat-
appropriately ‘alimentary glucosuria’. A characteristic ment.
feature is that unusually high blood glucose level returns to
normal 2 hours after meal. IV. ORAL GLUCOSE TOLERANCE TEST. Oral GTT is
2. Ketonuria. Tests for ketone bodies in the urine are performed principally for patients with borderline fasting
required for assessing the severity of diabetes and not for plasma glucose value (i.e. between 100-140 mg/dl). The
diagnosis of diabetes. However, if both glucosuria and patient who is scheduled for oral GTT is instructed to eat a
ketonuria are present, diagnosis of diabetes is almost certain. high carbohydrate diet for at least 3 days prior to the test
Rothera’s test (nitroprusside reaction) and strip test are and come after an overnight fast on the day of the test (for at
conveniently performed for detection of ketonuria. least 8 hours). A fasting blood sugar sample is first drawn.

828 Then 75 gm of glucose dissolved in 300 ml of water is given. 6. Insulin assay. Plasma insulin can be measured by
Blood and urine specimen are collected at half-hourly radioimmunoasay and ELISA technique. Plasma insulin
intervals for at least 2 hours. Blood or plasma glucose content deficiency is crucial for type 1 DM but is not essential for
is measured and urine is tested for glucosuria to determine making the diagnosis of DM.
the approximate renal threshold for glucose. Venous whole 7. Proinsulin assay. Proinsulin is included in immunoassay
blood concentrations are 15% lower than plasma glucose of insulin; normally it is <20% of total insulin.
values. 8. C-peptide assay. C-peptide is released in circulation
Currently accepted criteria for diagnosis of DM (as per
American Diabetes Association, 2007) are given in Table 27.8: during conversion of proinsulin to insulin in equimolar
quantities to insulin; thus its levels correlate with insulin level
Normal cut off value for fasting blood glucose level is in blood except in islet cell tumours and in obesity. This test
considered as 100 mg/dl. is even more sensitive than insulin assay because its levels
Cases with fasting blood glucose value in range of 100- are not affected by insulin therapy.
125 mg/dl are considered as impaired fasting glucose tolerance 9. Islet autoantibodies. Glutamic acid decarboxylase and
(IGT); these cases are at increased risk of developing diabetes islet cell cytoplasmic antibodies may be used as a marker for
later and therefore kept under observation for repeating the type 1 DM.
test. During pregnancy, however, a case of IGT is treated as
a diabetic. 10. Screening for diabetes-associated complications.
Individuals with fasting value of plasma glucose higher Besides making the diagnosis of DM based on the defined
than 126 mg/dl and 2-hour value after 75 gm oral glucose criteria, screening tests are done for DM-associated
complications e.g. microalbuniuria, dyslipidaemia, thyroid
higher than 200 mg/dl are labelled as diabetics (Fig. 27.27,D). dysfunction etc.
In symptomatic case, the random blood glucose value
above 200 mg/dl is diagnosed as diabetes mellitus. ISLET CELL TUMOURS
V. OTHER TESTS. A few other tests are sometimes Islet cell tumours are rare as compared with tumours of the
performed in specific conditions in diabetics and for research exocrine pancreas. Islet cell tumours are generally small and
purposes: may be hormonally inactive or may produce hyperfunction.
1. Glycosylated haemoglobin (HbA1C). Measurement of They may be benign or malignant, single or multiple. They
blood glucose level in diabetics suffers from variation due are named according to their histogenesis such as: β-cell
to dietary intake of the previous day. Long-term objective tumour (insulinoma), G-cell tumour (gastrinoma), A-cell
SECTION III
assessment of degree of glycaemic control is better tumour (glucagonoma) D-cell tumour (somatostatinoma),
monitored by measurement of glycosylated haemoglobin vipoma (diarrhoeagenic tumour from D cells which elaborate
1
(HbA ), a minor haemoglobin component present in normal VIP), pancreatic polypeptide (PP)-secreting tumour, and
1C
persons. This is because the non-enzymatic glycosylation of carcinoid tumour. However, except insulinoma and
haemoglobin takes place over 90-120 days, lifespan of red gastrinoma, all others are extremely rare and require no
blood cells. HbA assay, therefore, gives an estimate of further comments.
1C
diabetic control and compliance for the preceding 3-4
months. This assay has the advantage over traditional blood Insulinoma (ββ ββ β-Cell Tumour)
glucose test that no dietary preparation or fasting is required. Insulinomas or beta (β)-cell tumours are the most common
Increased HbA value almost certainly means DM but islet cell tumours. The neoplastic β-cells secrete insulin into
1C
normal value does not rule out IGT; thus the test is not used the blood stream which remains unaffected by normal
Systemic Pathology
for making the diagnosis of DM. Moreover, since HbA 1C regulatory mechanisms. This results in characteristic attacks
assay has a direct relation between poor control and of hypolgycaemia with blood glucose level falling to 50 mg/
development of complications, it is also a good measure of dl or below, high plasma insulin level (hyperinsulinism) and
prediction of microvascular complications. Care must be high insulin-glucose ratio. The central nervous mani-
taken in iterpretation of the HbA value because it varies festations are conspicuous which are promptly relieved by
1C
with the assay method used and is affected by presence of intake of glucose. Besides insulinoma, however, there are
haemoglobinopathies, anaemia, reticulocytosis, transfusions other causes of hypoglycaemia such as: in starvation, partial
and uraemia. gastrectomy, diffuse liver disease, hypopituitarism and
hypofunction of adrenal cortex.
2. Glycated albumin. This is used to monitor degree of
hyperglycaemia during previous 1-2 weeks when HbA can MORPHOLOGIC FEATURES. Grossly, insulinoma is
1C
not be used. usually solitary and well-encapsulated tumour which may
3. Extended GTT. The oral GTT is extended to 3-4 hours for vary in size from 0.5 to 10 cm. Rarely, they are multiple.
appearance of symptoms of hyperglycaemia. It is a useful Microscopically, the tumour is composed of cords and
test in cases of reactive hypoglycaemia of early diabetes. sheets of well-differentiated β-cells which do not differ
4. Intravenous GTT. This test is performed in persons who from normal cells. Electron microscopy reveals typical
have intestinal malabsorption or in postgastrectomy cases. crystalline rectangular granules in the neoplastic cells. It
is extremely difficult to assess the degree of anaplasia to
5. Cortisone-primed GTT. This provocative test is a useful
investigative aid in cases of potential diabetics. distinguish benign from malignant β-cell tumour.

Gastrinoma 2. Pancreatic islet cells: Hyperplasia or adenoma seen in 80% 829
(G-Cell Tumour, Zollinger-Ellison Syndrome) cases; frequently with Zollinger-Ellison syndrome.
3. Pituitary: Hyperplasia or adenoma in 65% cases; manifest
Zollinger and Ellison described diagnostic triad consisting
of the following: as acromegaly or hypopituitarism.
Fulminant peptic ulcer disease 4. Adrenal cortex: Uncommonly involved by adenoma or
Gastric acid hypersecretion pheochromocytoma.
5. Thyroid: Less commonly involved by adenoma or
Presence of non-β pancreatic islet cell tumour. hyperplasia.
Such non-β pancreatic islet cell tumour is the source of
gastrin, producing hypergastrinaemia and hence named 2. MEN type 2 syndrome (Sipple’s syndrome) is
gastrinoma. Definite G cells similar to intestinal and gastric characterised by medullary carcinoma thyroid and
G cells which are normally the source of gastrin in the body, pheochromocytoma. Genetic abnormality in these cases is
have not been identified in the normal human pancreas but mutation in RET gene in almost all cases. MEN 2 has two
neoplastic cells of certain islet cell tumours have major syndromes:
ultrastructural similarities. MEN type 2A is the combination of medullary carcinoma
thyroid, pheochromocytoma and hyperparathytroidism.
MORPHOLOGIC FEATURES. Majority of gastrinomas MEN type 2A has further three subvariants:
occur in the wall of the duodenum. They may be benign i) MEN 2A with familial medullary carcinoma thyroid
or malignant. Gastrinomas are associated with peptic ii) MEN 2A with cutaneous lichen amyloidosis
ulcers at usual sites such as the stomach, first and second iii) MEN 2A with Hirschsprung’s disease.
part of the duodenum, or sometimes at unusual sites such MEN type 2B the combination of medullary carcinoma
as in the oesophagus and jejunum. About one-third of thyroid, pheochromocytoma, mucosal neuromas, intestinal
patients have multiple endocrine neoplasia—multiple ganglioneuromatosis, and marfanoid features.
adenomas of the islet cells, pituitary, adrenal and 3. Mixed syndromes include a variety of endocrine
parathyroid glands.
neoplastic combinations which are distinct from those in
MEN type 1 and type 2. A few examples are as under: CHAPTER 27
MISCELLANEOUS ENDOCRINE TUMOURS von Hippel-Lindau syndrome from mutation in VHL
gene is association of CNS tumours, renal cell carcinoma,
MULTIPLE ENDOCRINE NEOPLASIA (MEN) pheochromocytoma and islet cell tumours.
SYNDROMES Type 1 neurofibromatosis from inactivation of neurofibro-
min protein and activation of RAS gene, is associated with
Multiple adenomas and hyperplasias of different endocrine MEN type 1 or type 2 features.
organs are a group of genetic diorders which produce
heterogeneous clinical features called multiple endocrine POLYGLANDULAR AUTOIMMUNE (PGA) SYNDROMES
neoplasia (MEN) syndromes. Presently, 4 distinct types of
MEN syndromes are distinguished. These are briefly outlined Immunologic syndromes affecting two or more endocrine The Endocrine System
below along with major disease associations: glands and some non-endocrine immune disturbances
produce syndromic presentation termed polyglandular
1. MEN type 1 syndrome (Wermer’s syndrome) includes autoimmune (PGA) syndromes. PGA syndromes are of two
adenomas of the parathyroid glands, pancreatic islets and types:
pituitary. The syndrome is inherited as an autosomal
dominant trait. There is 50% chance of transmitting the PGA type I occurring in children is characterised by
predisposing gene, MEN 1 (or menin) gene, to the child of an mucocutaneous candidiasis, hypoparathyroidism, and
affected person. MEN 1 is characterised by the following adrenal insufficiency.
features: PGA type II (Schmidt syndrome) presents in adults and
1. Parathyroid: Hyperplasia or adenoma; hyperparathy- commonly comprises of adrenal insufficiency, autoimmune
roidism is the most common (90%) clinical manifestation. thyroiditis, and type 1 diabetes mellitus.

❑

830


Chapter 28 The Musculoskeletal System
Chapter 28








SKELETAL SYSTEM line phosphatase (other being hepatic alkaline phosphatase) is
a marker for osteoblastic activity. Its levels are raised in
The skeleton consists of cartilage and bone. Cartilage has a puberty during period of active bone growth and in
role in growth and repair of bone, and in the adults forms pathologic conditions associated with high osteoblastic
the articular skeleton responsible for movement of joints. activity such as in fracture repair and Paget’s disease of the
Bone is a specialised form of connective tissue which bone.
performs the function of providing mechanical support and 2. Osteocytes. Osteocytes are those osteoblasts which get
is also a mineral reservoir for calcium homeostasis. There incorporated into the bone matrix during its synthesis. Osteo-
are 206 bones in the human body, and depending upon their cytes are found within small spaces called lacunae lying in
size and shape may be long, flat, tubular etc. the bone matrix. The distribution of the osteocytic lacunae is
a reliable parameter for distinguishing between woven and
NORMAL STRUCTURE OF BONE lamellar bone.
Bone is divided into 2 components (Fig. 28.1): Woven bone is immature and is rapidly deposited. It
Cortical or compact bone comprises 80% of the skeleton contains large number of closely-packed osteocytes and
and is the dense outer shell responsible for structural rigidity. consists of irregular interlacing pattern of collagen fibre
bundles in bone matrix. Woven bone is seen in foetal life
It consists of haversian canals with blood vessels surrounded and in children under 4 years of age.
by concentric layers of mineralised collagen forming osteons
Lamellar bone differs from woven bone in having smaller
which are joined together by cement lines. and less numerous osteocytes and fine and parallel or
SECTION III
Trabecular or cancellous bone composes 20% of the lamellar sheets of collagen fibres. Lamellar bone usually
skeleton and has trabeculae traversing the marrow space. replaces woven bone or pre-existing cartilage.
Its main role is in mineral homeostasis.
3. Osteoclasts. Osteoclasts are large multinucleate cells of
HISTOLOGY. Bone consists of large quantities of extra- mononuclear-macrophage origin and are responsible for
cellular matrix which is loaded with calcium hydroxyapatite bone resorption. The osteoclastic activity is determined by
and relatively small number of bone cells which are of 3 main bone-related serum acid phosphatase levels (other being
types: osteoblasts, osteocytes and osteoclasts, besides the prostatic acid phosphatase). Osteoclasts are found along the
ground substance, the osteoid matrix. endosteal surface of the cortical (compact) bone and the
1. Osteoblasts. Osteoblasts are uninucleate cells found trabeculae of trabecular (cancellous) bone.
abundantly along the new bone-forming surfaces. They syn- 4. Osteoid matrix. The osteoid matrix of bone consists of
Systemic Pathology
thesise bone matrix. The serum levels of bone-related alka- 90-95% of collagen type I and comprises nearly half of total
























Figure 28.1 The normal structure of cortical (compact) bone (A) and trabecular (cancellous) bone (B) in transverse section. The cortical bone
forming the outer shell shows concentric lamellae along with osteocytic lacunae surrounding central blood vessels, while the trabecular bone
forming the marrow space shows trabeculae with osteoclastic activity at the margins.

body’s collagen. Virtually whole of body’s hydroxyproline Hyaline cartilage is the type found in most cartilage-forming 831
and hydroxylysine reside in the bone. The architecture of tumours and in the fracture callus.
bone collagen reflects the rate of its synthesis and may be 2. Fibrocartilage is a hyaline cartilage that contains more
woven or lamellar, as described above. abundant type II collagen fibres. It is found in annulus
BONE FORMATION AND RESORPTION. Bone is not a fibrosus of intervertebral disc, menisci, insertions of joint
static tissue but its formation and resorption are taking place capsules, ligament and tendons. Fibrocartilage may also be
during period of growth as well as in adult life. Bone found in some cartilage-forming tumours and in the fracture
deposition is the result of osteoblasts while bone resorption callus.
is the function of osteoclasts. Bone formation may take place 3. Elastic cartilage is hyaline cartilage that contains abundant
directly from collagen called membranous ossification seen in elastin. Elastic cartilage is found in the pinna of ears,
certain flat bones, or may occur through an intermediate stage epiglottis and arytenoid cartilage of the larynx.
of cartilage termed endochondral ossification found in Diseases of skeletal system include infection (osteo-
metaphysis of long bones. In either case, firstly an uncalcified myelitis), disordered growth and development (skeletal dys-
osteoid matrix is formed by osteoblasts which is then plasias), metabolic and endocrine derangements, and
mineralised in 12-15 days. This delay in mineralisation results tumours and tumour-like conditions.
in formation of about 15 μm thick osteoid seams at
calcification fronts (About > 1 μm of matrix osteoid is formed OSTEOMYELITIS
daily). Uncalcified osteoid appears eosinophilic in H & E
stains and does not stain with von Kossa reaction, while An infection of the bone is termed osteomyelitis (myelo =
mineralised osteoid is basophilic in appearance and stains marrow). A number of systemic infectious diseases may
black with von Kossa reaction (a stain for calcium). Areas of spread to the bone such as enteric fever, actinomycosis,
active bone resorption have scalloped edges of bone surface mycetoma (madura foot), syphilis, tuberculosis and
called Howship’s lacunae and contain multinucleated brucellosis. However, two of the conditions which produce
osteoclasts. In this way, osteoblastic formation and significant pathologic lesions in the bone, namely pyogenic
osteoclastic resorption continue to take place into adult life osteomyelitis and tuberculous osteomyelitis, are described
in a balanced way termed bone modelling. The important role below. CHAPTER 28
of vitamin D , parathyroid hormone and calcitonin in calcium
1
metabolism has already been discussed on page 248. Pyogenic Osteomyelitis

NORMAL STRUCTURE OF CARTILAGE Suppurative osteomyelitis is usually caused by bacterial
infection and rarely by fungi. Pyogenic osteomyelitis by
Unlike bone, the cartilage lacks blood vessels, lymphatics haematogenous route occurs most commonly in the long
and nerves. It may have focal areas of calcification. Carti- bones of infants and young children (5-15 years of age),
lage consists of 2 components: cartilage matrix and particularly in the developing countries of the world. In the
chondrocytes. developed world, however, where institution of antibiotics
Cartilage matrix. Like bone, cartilage too consists of organic is early and prompt, haematogenous spread of infection to
and inorganic material. Inorganic material of cartilage is the bone is uncommon. In such cases, instead, direct The Musculoskeletal System
calcium hydroxyapatite similar to that in bone matrix but extension of infection from the adjacent area, frequently
the organic material of the cartilage is distinct from the bone. involving the jaws and skull, is more common mode of
It consists of very high content of water (80%) and remaining spread. Bacterial osteomyelitis may be a complication at all
20% consists of type II collagen and proteoglycans. High ages in patients with compound fractures, surgical
water content of cartilage matrix is responsible for function procedures involving prosthesis or implants, gangrene of a
of articular cartilage and lubrication. Proteoglycans are limb in diabetics, debilitation and immunosuppression.
macromolecules having proteins complexed with Though any etiologic agent may cause osteomyelitis,
polysaccharides termed glycosaminoglycans. Cartilage Staphylococcus aureus is implicated in a vast majority of cases.
glycosaminoglycans consist of chondroitin sulfate and Less frequently, other organisms such as streptococci,
keratan sulfate, the former being most abundant comprising Escherichia coli, Pseudomonas, Klebsiella and anaerobes are
55-90% of cartilage matrix varying on the age of the cartilage. involved. Mixed infections are common in post-traumatic
cases of osteomyelitis. There may be transient bacteraemia
Chondrocytes. Primitive mesenchymal cells which form bone preceding the development of osteomyelitis so that blood
cells form chondroblasts which give rise to chondrocytes. cultures may be positive.
However, calcified cartilage is removed by the osteoclasts. Clinically, the child with acute haematogenous osteo-
Depending upon location and structural composition, myelitis has painful and tender limb. Fever, malaise and
cartilage is of 3 types: leucocytosis generally accompany the bony lesion. Radio-
1. Hyaline cartilage is the basic cartilaginous tissue logic examination confirms the bony destruction.
comprising articular cartilage of joints, cartilage in the growth Occasionally, osteomyelitis remains undiscovered until
plates of developing bones, costochondral cartilage, cartilage it becomes chronic. Draining sinus tracts may form which
in the trachea, bronchi and larynx and the nasal cartilage. may occasionally be the site for development of squamous
carcinoma. Persistence, neglect and chronicity of osteo-

832



















Figure 28.2 Pathogenesis of pyogenic osteomyelitis. A, The process begins as a focus of microabscess in a vascular loop in the marrow which
expands to stimulate resorption of adjacent bony trabeculae. Simultaneously, there is beginning of reactive woven bone formation by the periosteum.
B, The abscess expands further causing necrosis of the cortex called sequestrum. The formation of viable new reactive bone surrounding the
sequestrum is called involucrum. The extension of infection into the joint space, epiphysis and the skin produces a draining sinus.



myelitis over a longer period of time may lead to develop- 4. Combination of suppuration and impaired blood
ment of amyloidosis. supply to the cortical bone results in erosion, thin-
ning and infarction necrosis of the cortex called
MORPHOLOGIC FEATURES. Depending upon the
sequestrum.
duration, osteomyelitis may be acute, subacute or chronic. 5. With passage of time, there is formation of new bone
The basic pathologic changes in any stage of osteomyelitis
are: suppuration, ischaemic necrosis, healing by fibrosis beneath the periosteum present over the infected bone.
and bony repair. The sequence of pathologic changes is as This forms an encasing sheath around the necrosed bone
under (Fig. 28.2): and is known as involucrum. Involucrum has irregular
1. The infection begins in the metaphyseal end of the surface and has perforations through which discharging
marrow cavity which is largely occupied by pus. At this sinus tracts pass.
SECTION III
stage, microscopy reveals congestion, oedema and an 6. Long continued neo-osteogenesis gives rise to dense
exudate of neutrophils. sclerotic pattern of osteomyelitis called chronic sclerosing
2. The tension in the marrow cavity is increased due to nonsuppurative osteomyelitis of Garré.
pus and results in spread of infection along the marrow 7. Occasionally, acute osteomyelitis may be contained to
cavity, into the endosteum, and into the haversian and a localised area and walled off by fibrous tissue and
granulation tissue. This is termed Brodie’s abscess.
Volkmann’s canal, causing periosteitis. 8. In vertebral pyogenic osteomyelitis, infection begins from
3. The infection may reach the subperiosteal space
forming subperiosteal abscesses. It may penetrate through the disc (discitis) and spreads to involve the vertebral
the cortex creating draining skin sinus tracts (Fig. 28.3). bodies (Fig. 28.4,A).
Systemic Pathology


























Figure 28.3 Chronic suppurative osteomyelitis. Histologic appearance shows necrotic bone and extensive purulent inflammatory exudate.

833




















Figure 28.4 Osteomyelitis of the vertebral body.


COMPLICATIONS. Osteomyelitis may result in the from infection elsewhere, usually from the lungs, and
following complications: infrequently by direct extension from the pulmonary or
1. Septicaemia. gastrointestinal tuberculosis (page 156). The disease affects
2. Acute bacterial arthritis. adolescents and young adults more often. Most frequently
3. Pathologic fractures. involved are the spine and bones of extremities.
4. Development of squamous cell carcinoma in long-
standing cases. MORPHOLOGIC FEATURES. The bone lesions in tuber-
5. Secondary amyloidosis in long-standing cases. culosis have the same general histological appearance as
6. Vertebral osteomyelitis may cause vertebral collapse with in tuberculosis elsewhere and consist of central caseation CHAPTER 28
paravertebral abscess, epidural abscess, cord compression necrosis surrounded by tuberculous granulation tissue
and neurologic deficits. and fragments of necrotic bone (Fig. 28.5). The tuberculous
lesions appear as a focus of bone destruction and replace-
Tuberculous Osteomyelitis ment of the affected tissue by caseous material and
formation of multiple discharging sinuses through the soft
Tuberculous osteomyelitis, though rare in developed tissues and skin. Involvement of joint spaces and
countries, continues to be a common condition in under- intervertebral disc are frequent. Tuberculosis of the spine,
developed and developing countries of the world. The Pott’s disease, often commences in the vertebral body and
tubercle bacilli, M. tuberculosis, reach the bone marrow and may be associated with compression fractures and
synovium most commonly by haematogenous dissemination
destruction of intervertebral discs, producing permanent
damage and paraplegia. Extension of caseous material
along with pus from the lumbar vertebrae to the sheaths The Musculoskeletal System
of psoas muscle produces psoas abscess or lumbar cold
abscess (Fig. 28.4,B). The cold abscess may burst through
the skin and form sinus. Long-standing cases may develop
systemic amyloidosis.

AVASCULAR NECROSIS (OSTEONECROSIS)
Avascular necrosis of the bones or osteonecrosis results from
ischaemia. It is a relatively common condition.

ETIOPATHOGENESIS. It may occur from following
causes:
1. Fracture or dislocation
2. Sickle cell disease
3. Corticosteroid administration
4. Radiation therapy
5. Chronic alcoholism
6. Idiopathic
The pathogenetic mechanism of osteonecrosis in many
cases remains obscure, while in others it is by interruption
Figure 28.5 Tuberculous osteomyelitis. There are epithelioid cell in the blood supply to the bones induced by direct trauma,
granulomas with minute areas of caseation necrosis and surrounded by
Langhans’ giant cells. Pieces of necrotic bone are also seen. compression, or thromboembolic obstruction.

834 MORPHOLOGIC FEATURES. There are pathological Osteogenesis Imperfecta
fractures of the involved bone due to infarcts. Most Osteogenesis imperfecta is an autosomal dominant or reces-
common sites are the ones where the disruption in blood sive disorder of synthesis of type I collagen that constitutes
supply is at end-arterial circulation. The infarcts mainly 90-95% of bone matrix. The disorder, thus, involves not only
involve the medulla of the long bone in the diaphysis. This the skeleton but other extra-skeletal tissues as well
is because the nutrient arteries supply blood to sinusoids containing type I collagen such as sclera, eyes, joints,
of the medulla and the inner cortex after penetrating the ligaments, teeth and skin. The skeletal manifestations of
cortex, while the cortex is relatively unaffected due to osteogenesis imperfecta are due to defective osteoblasts
collateral circulation. which normally synthesise type I collagen. This results in
Grossly, the lesional area shows a wedge-shaped area of thin or non-existent cortices and irregular trabeculae (too
infarction in the subchondral bone under the convex little bone) so that the bones are very fragile and liable to
surface of the joint. multiple fractures. The growth plate cartilage is, however,
Microscopically, the infracted medulla shows saponified normal. The condition may be evident at birth (osteogenesis
marrow fat. The overlying cartilage and the cortex of the imperfecta congenita) when it is more severe, or may appear
long bones are relatively unaffected. during adolescence (osteogenesis imperfecta tarda) which
Longterm sequelae of osteonecrosis include occurrence is a less incapacitating form. Extraskeletal lesions of osteo-
of malignant tumours in this location such as osteosarcoma, genesis imperfecta include blue and translucent sclerae,
malignant fibrous histiocytoma and fibrosarcoma etc. hearing loss due to bony abnormalities of the middle and
inner ear, and imperfect teeth.
FRACTURE HEALING
Osteopetrosis
Fracture of the bone initiates a series of tissue changes which
eventually lead to restoration of normal structure and Osteopetrosis, also called marble bone disease, is an autosomal
function of the affected bone. Fracture of a bone is commonly dominant or recessive disorder of increased skeletal mass or
associated with injury to the soft tissues. The various types osteosclerosis caused by a hereditary defect in osteoclast
of fractures and their mechanism of healing are discussed function. The condition may appear in 2 forms: autosomal
along with healing of specialised tissues in Chapter 6 recessive (malignant infantile form) and autosomal dominant
(page 171). (benign adult form). Failure of normal osteoclast function of
bone resorption coupled with continued bone formation and
SECTION III
DISORDERS OF BONE GROWTH AND DEVELOPMENT endochondral ossification results in net overgrowth of
(SKELETAL DYSPLASIAS) calcified dense bone (too much bone) which occupies most of
the available marrow space. Despite increased density of the
A number of abnormalities of the skeleton are due to dis- bone, there is poor structural support so that the skeleton is
ordered bone growth and development and are collectively susceptible to fractures. Besides the skeletal abnormalities,
termed skeletal dysplasias. These include both local and the infantile malignant form is characterised by effects of
systemic disorders. marrow obliteration such as anaemia, neutropenia, thrombo-
Local defects involve a single bone or a group of bones cytopenia, hepatosplenomegaly with extramedullary
such as: absence or presence in diminished form, fused with haematopoiesis, hydrocephalus and neurologic involvement
neighbouring bones (e.g. syndactyly), and formation of extra with consequent deafness, optic atrophy and blindness.
bones (e.g. supernumerary ribs). Metabolically, hypocalcaemia occurs due to defective
Systemic Pathology
However, more importantly, skeletal dysplasias include osteoclast function.
systemic disorders involving particular epiphyseal growth Histologically, the number of osteoclasts is increased
plate. These include: achondroplasia (disorder of which have dysplastic, bizarre and irregular nuclei and
chondroblasts), osteogenesis imperfecta (disorder of are dysfunctional.
osteoblasts), osteopetrosis (disorder of osteoclasts) and foetal
rickets (disorder of mineralisation). Though multiple METABOLIC AND ENDOCRINE BONE DISEASES
exostoses (osteochondromas) is a hereditary lesion, it is
described later along with solitary sporadic exostosis on page A large number of metabolic and endocrine disorders
843. produce generalised skeletal disorders. These include the
following:
Achondroplasia 1. Osteoporosis—Resulting from quantitative reduction in
otherwise normal bone.
Achondroplasia is an autosomal dominant genetic abnor-
mality. There is selective interference with normal endo- 2. Osteomalacia and rickets—Characterised by qualitative
chondral ossification at the level of epiphyseal cartilaginous abnormality in the form of impaired bone mineralisation due
growth plates of long bones. Thus, the long bones are to deficiency of vitamin D in adults and children respectively
abnormally short but the skull grows normally leading to (page 249).
relatively large skull. Achondroplasia is the commonest 3. Scurvy—Caused by deficiency of vitamin C resulting in
cause of dwarfism. subperiosteal haemorrhages (page 251).