Textbook of Pathology, 6th Edition

4. Hyperparathyroidism—Leading to osteitis fibrosa 6. Hyperparathyroidism. 835
cystica (page 816). 7. Deficiency of vitamin D.
5. Pituitary dysfunctions—Hyperpituitarism causing 8. Local factors—which may stimulate osteoclastic resorption
gigantism and acromegaly and hypopituitarism resulting in or slow osteoblastic bone formation.
dwarfism (page 793). Secondary osteoporosis is attributed to a number of
6. Thyroid dysfunctions—Hyperthyroidism causing factors and conditions (e.g. immobilisation, chronic anaemia,
osteoporosis and hypothyroidism leading to cretinism (page acromegaly, hepatic disease, hyperparathyroidism,
802). hypogonadism, thyrotoxicosis and starvation), or as an effect
7. Renal osteodystrophy—Occurring in chronic renal of medication (e.g. hypercortisonism, administration of
failure and resulting in features of osteitis fibrosa cystica, anticonvulsant drugs and large dose of heparin).
osteomalacia and areas of osteosclerosis. MORPHOLOGIC FEATURES. Except disuse or immobi-
8. Skeletal fluorosis—Occurring due to excess of sodium lisation osteoporosis which is localised to the affected limb,
fluoride content in the soil and water in an area. other forms of osteoporosis have systemic skeletal
Many of the conditions listed above have been discussed distribution. Most commonly encountered osteoporotic
in respective chapters already; others are considered below. fractures are: vertebral crush fracture, femoral neck
fracture and wrist fracture. There is enlargement of the
Osteoporosis medullary cavity and thinning of the cortex.
Histologically, osteoporosis may be active or inactive
Osteoporosis or osteopenia is a common clinical syndrome type.
involving multiple bones in which there is quantitative
reduction of bone tissue mass but the bone tissue mass is Active osteoporosis is characterised by increased bone
otherwise normal. This reduction in bone mass results in resorption and formation i.e. accelerated turnover. There is
fragile skeleton which is associated with increased risk of increase in the number of osteoclasts with increased
fractures and consequent pain and deformity. The condition resorptive surface as well as increased quantity of osteoid
is particularly common in elderly people and more frequent with increased osteoblastic surfaces. The width of osteoid
in postmenopausal women. The condition may remain seams is normal. CHAPTER 28
asymptomatic or may cause only backache. However, more Inactive osteoporosis has the features of minimal bone
extensive involvement is associated with fractures, formation and reduced resorptive activity i.e. reduced
particularly of distal radius, femoral neck and vertebral turnover. Histological changes of inactive osteoporosis
bodies. Osteoporosis may be difficult to distinguish radio- include decreased number of osteoclasts with decreased
logically from other osteopenias such as osteomalacia, resorptive surfaces, and normal or reduced amount of
osteogenesis imperfecta, osteitis fibrosa of hyperpara- osteoid with decreased osteoblastic surface. The width of
thyroidism, renal osteodystrophy and multiple myeloma. osteoid seams is usually reduced or may be normal.
Radiologic evidence becomes apparent only after more than
30% of bone mass has been lost. Levels of serum calcium, Osteitis Fibrosa Cystica
inorganic phosphorus and alkaline phosphatase are usually
within normal limits. Hyperparathyroidism of primary or secondary type results The Musculoskeletal System
in oversecretion of parathyroid hormone which causes
PATHOGENESIS. Osteoporosis is conventionally classified increased osteoclastic resorption of the bone. General aspects
into 2 major groups: primary and secondary. of hyperparathyroidism are discussed on page 816. Here,
Primary osteoporosis results primarily from osteopenia skeletal manifestations of hyperparathyroidism are
without an underlying disease or medication. Primary considered. Severe and prolonged hyperparathyroidism
osteoporosis is further subdivided into 2 types: idiopathic type results in osteitis fibrosa cystica. The lesion is generally
found in the young and juveniles and is less frequent, and induced as a manifestation of primary hyperparathyroidism,
involutional type seen in postmenopausal women and aging and less frequently, as a result of secondary hyperpara-
individuals and is more common. The exact mechanism of thyroidism such as in chronic renal failure (renal
primary osteoporosis is not known but there is a suggestion osteodystrophy).
that it is the result of an excessive osteoclastic resorption and The clinical manifestations of bone disease in hyper-
slow bone formation. A number of risk factors have been parathyroidism are its susceptibility to fracture, skeletal
attributed to cause this imbalance between bone resorption deformities, joint pains and dysfunctions as a result of deran-
and bone formation. These include the following: ged weight bearing. The bony changes may disappear after
1. Genetic factors—more marked in whites and Asians than cure of primary hyperparathyroidism such as removal of
blacks. functioning adenoma. The chief biochemical abnormality of
2. Sex—more frequent in females than in males. excessive parathyroid hormone is hypercalcaemia,
3. Reduced physical activity—as in old age. hypophosphataemia and hypercalciuria.
4. Deficiency of sex hormones—oestrogen deficiency in women MORPHOLOGIC FEATURES. The bone lesions of
as in postmenopausal osteoporosis and androgen deficiency primary hyperparathyroidism affect the long bones more
in men.
severely and may range from minor degree of generalised
5. Combined deficiency of calcitonin and oestrogen.

836 bone rarefaction to prominent areas of bone destruction PATHOGENESIS. Renal osteodystrophy involves two
with cyst formation or brown tumours. main events: hyperphosphataemia and hypocalcaemia which,
Grossly, there are focal areas of erosion of cortical bone in turn, leads to parathormone elaboration and resultant
and loss of lamina dura at the roots of teeth. osteoclastic activity and major lesions of renal osteo-
Histologically, the following sequential changes appear dystrophy—osteomalacia (rickets in children), secondary
over a period of time: hyperparathyroidism, osteitis fibrosa cystica, osteosclerosis
Earliest change is demineralisation and increased bone and metastatic calcification.
resorption beginning at the subperiosteal and endosteal The mechanisms underlying renal osteodystrophy are
surface of the cortex and then spreading to the trabecular schematically illustrated in Fig. 28.6 and briefly outlined
bone. below:
There is replacement of bone and bone marrow by 1. Hyperphosphataemia: In CRF, there is impaired renal
fibrosis coupled with increased number of bizarre excretion of phosphate, causing phosphate retention and
osteoclasts at the surfaces of moth-eaten trabeculae and hyperphosphataemia. Hyperphosphataemia, in turn, causes
cortex (osteitis fibrosa). hypocalcaemia which is responsible for secondary
As a result of increased resorption, microfractures and hyperparathyroidism.
microhaemorrhages occur in the marrow cavity leading 2. Hypocalcaemia: Hypocalcaemia may also result from the
to development of cysts (osteitis fibrosa cystica). following:
Haemosiderin-laden macrophages and multinucleate Due to renal dysfunction, there is decreased conversion
giant cells appear at the areas of haemorrhages producing of vitamin D metabolite 25(OH) cholecalciferol to its active
an appearance termed as ‘brown tumour’ or ‘reparative giant form 1,25 (OH) cholecalciferol.
2
cell granuloma of hyperparathyroidism’ requiring Reduced intestinal absorption of calcium.
differentiation from giant cell tumour or osteoclastoma
(page 846). However, the so-called brown tumours, unlike 3. Parathormone secretion: Hypocalcaemia stimulates
osteoclastoma, are not true tumours but instead regress secretion of parathormone, eventually leading to secondary
or disappear on surgical removal of hyperplastic or hyperparathyroidism which, in turn, causes increased
adenomatous parathyroid tissue. osteoclastic activity.
4. Metabolic acidosis: As a result of decreased renal
Renal Osteodystrophy (Metabolic Bone Disease) function, acidosis sets in which may cause osteoporosis and
Renal osteodystrophy is a loosely used term that encom- bone decalcification.
SECTION III
passes a number of skeletal abnormalities appearing in cases 5. Calcium phosphorus product > 70: When the product of
of chronic renal failure and in patients treated by dialysis for biochemical value of calcium and phosphate is higher than
several years (page 656). Renal osteodystrophy is more 70, metastatic calcification may occur at extraosseous sites.
common in children than in adults. Clinical symptoms of 6. Dialysis-related metabolic bone disease: Long-term dia-
bone disease in advanced renal failure appear in less than lysis employing use of aluminium-containing dialysate is
10% of patients but radiologic and histologic changes are currently considered to be a major cause of metabolic bone
observed in fairly large proportion of cases. lesions. Aluminium interferes with deposition of calcium




Systemic Pathology


























Figure 28.6 Pathogenesis of renal osteodystrophy in chronic renal failure. Circled serial numbers in the graphic representation correspond to
the sequence described in the text under pathogenesis.

hydroxyapatite in bone and results in osteomalacia, etiology involving one (monostotic) or more bones 837
secondary hyperparathyroidism and osteitis fibrosa cystica. (polyostotic). The condition affects predominantly males over
In addition, accumulation of β -microglobulin amyloid in the age of 50 years. Though the etiology remains obscure,
2
such cases causes dialysis-related amyloidosis (page 86). following factors have been implicated:
1. There has been some evidence that osteitis deformans is a
MORPHOLOGIC FEATURES. The following skeletal form of slow-virus infection by paramyxovirus (e.g. respiratory
lesions can be identified in renal osteodystrophy: syncytial virus, measles) in osteoclasts. However, the virus
1. Mixed osteomalacia-osteitis fibrosa is the most common has not been cultured from the osteoclasts of Paget’s disease.
manifestation of renal osteodystrophy resulting from
disordered vitamin D metabolism and secondary 2. Autosomal dominant inheritance and genetic susceptibility
have been proposed on the basis of observation of 7-10 fold
hyperparathyroidism. higher prevalence of disease in first-degree relatives. The
2. Pure osteitis fibrosa results from metabolic compli- susceptibility gene located on chromosome 18q encodes for
cations of secondary hyperparathyroidism. a member of tumour necrosis factor called RANK (receptor
3. Pure osteomalacia of renal osteodystrophy is attributed activator of nuclear factor: κB).
to aluminium toxicity. Clinically, the monostotic form of the disease may remain
4. Renal rickets resembling the changes seen in children asymptomatic and the lesion is discovered incidentally or
with nutritional rickets with widened osteoid seams may on radiologic examination. Polyostotic form, however, is more
occur (page 249). widespread and may produce pain, fractures, skeletal
5. Osteosclerosis is characterised by enhanced bone deformities, and occasionally, sarcomatous transformation.
density in the upper and lower margins of vertebrae. Typically, there is marked elevation of serum alkaline
6. Metastatic calcification is seen at extraosseous sites such phosphatase and normal to high serum calcium level.
as in medium-sized blood vessels, periarticular tissues,
myocardium, eyes, lungs and gastric mucosa (page 53). MORPHOLOGIC FEATURES. Monostotic Paget’s
disease involves most frequently: tibia, pelvis, femur, skull
Skeletal Fluorosis and vertebra, while the order of involvement in polyostotic
Paget’s disease is: vertebrae, pelvis, femur, skull, sacrum
Fluorosis of bones occurs due to high sodium fluoride and tibia. Three sequential stages are identified in Paget’s CHAPTER 28
content in soil and water consumed by people in some disease:
geographic areas and is termed endemic fluorosis. Such 1. Initial osteolytic stage: This stage is characterised by
endemic regions exist in some tropical and subtropical areas of osteoclastic resorption produced by increased
areas; in India it exists in parts of Punjab and Andhra number of large osteoclasts.
Pradesh. The condition affects farmers who consume 2. Mixed osteolytic-osteoblastic stage: In this stage,
drinking water from wells. Non-endemic fluorosis results there is imbalance between osteoblastic laying down of
from occupational exposure in manufacturing industries of new bone and osteoclastic resorption so that
aluminium, magnesium, and superphosphate.
mineralisation of the newly-laid matrix lags behind,
PATHOGENESIS. In fluorosis, fluoride replaces calcium as resulting in development of characteristic mosaic pattern
the mineral in the bone and gets deposited without any or jigsaw puzzle appearance of osteoid seams or cement lines.
regulatory control. This results in heavily mineralised bones The narrow space between the trabeculae and cortex is The Musculoskeletal System
which are thicker and denser but are otherwise weak and filled with collagen which gradually becomes less
deformed (just as in osteopetrosis). In addition, there are also vascular.
deposits of fluoride in soft tissues, particularly as nodules in 3. Quiscent osteosclerotic stage: After many years,
the interosseous membrane. The patient develops skeletal excessive bone formation results so that the bone becomes
deformities and mottling of teeth. more compact and dense producing osteosclerosis.
However, newly-formed bone is poorly mineralised, soft
MORPHOLOGIC FEATURES. Grossly, the long bones and susceptible to fractures. Radiologically, this stage
and vertebrae develop nodular swellings which are produces characteristic cotton-wool appearance of the
present both inside the bones and on the surface.
affected bone.
Microscopically, these nodules are composed of heavily
mineralised irregular osteoid admixed with fluoride which TUMOUR-LIKE LESIONS OF BONE
requires confirmation chemically.
In the context of bones, several non-neoplastic conditions
PAGET’S DISEASE OF BONE (OSTEITIS DEFORMANS) resemble true neoplasms and have to be distinguished from
them clinically, radiologically and morphologically.
Paget’s disease of bone* or osteitis deformans was first Table 28.1 gives a list of such tumour-like lesions. A few
described by Sir James Paget in 1877. Paget’s disease of bone common conditions are described below.
is an osteolytic and osteosclerotic bone disease of uncertain
Fibrous Dysplasia
*It is pertinent to recall here that James Paget described Paget’s disease Fibrous dysplasia is not an uncommon tumour-like lesion
at three different anatomic sites which are not mutually interlinked in
any way: Paget’s disease of nipple (page 764), Paget’s disease of vulva of the bone. It is a benign condition, possibly of develop-
(page 722) and Paget’s disease of bone. mental origin, characterised by the presence of localised area

838 of replacement of bone by fibrous connective tissue with a
characteristic whorled pattern and containing trabeculae of
woven bone. Radiologically, the typical focus of fibrous
dysplasia has well-demarcated ground-glass appearance.
Three types of fibrous dysplasia are distinguished—
monostotic, polyostotic, and Albright syndrome. The
spectrum of phenotype of the disease is due to activating
mutation in GNAS1 gene, which encodes for α-subunits of
the stimulatory G-protein, G .
Sα
Monostotic fibrous dysplasia. Monostotic fibrous
dysplasia affects a solitary bone and is the most common
type, comprising about 70% of all cases. The condition affects
either sex and most patients are between 20 and 30 years of
age. The bones most often affected, in descending order of
frequency, are: ribs, craniofacial bones (especially maxilla),
femur, tibia and humerus. The condition generally remains
asymptomatic and is discovered incidentally, but
infrequently may produce tumour-like enlargement of the Figure 28.7 Fibrous dysplasia of the bone. The bony trabeculae
affected bone. have fish-hook appearance (or Chinese-letter appearance) surrounded
by fibrous tissue. The osteoblastic rimming of the bony trabeculae are
Polyostotic fibrous dysplasia. Polyostotic form of fibrous characteristically absent.
dysplasia affecting several bones constitutes about 25% of
all cases. Both sexes are affected equally but the lesions replacement of normal cancellous bone of the marrow
appear at a relatively earlier age than the monostotic form. cavity by gritty, grey-pink, rubbery soft tissue which may
Most frequently affected bones are: craniofacial, ribs, have areas of haemorrhages, myxoid change and cyst
vertebrae and long bones of the limbs. Approximately a formation.
quarter of cases with polyostotic form have more than half Histologically, the lesions of fibrous dysplasia have
of the skeleton involved by disease. The lesions may affect characteristic benign-looking fibroblastic tissue arranged
one side of the body or may be distributed segmentally in a in a loose, whorled pattern in which there are irregular
limb. Spontaneous fractures and skeletal deformities occur and curved trabeculae of woven (non-lamellar) bone in
SECTION III
in childhood polyostotic form of the disease. the form fish-hook appearance or Chinese letter shapes.
Albright syndrome. Also called McCune-Albright Characteristically, there are no osteoblasts rimming then
syndrome, this is a form of polyostotic fibrous dysplasia trabeculae of the bone, suggesting a maturation defect in
associated with endocrine dysfunctions and accounts for less the bone (Fig. 28.7). Rarely, malignant change may occur
than 5% of all cases. Unlike monostotic and polyostotic in fibrous dysplasia, most often an osteogenic sarcoma.
varieties, Albright syndrome is more common in females.
The syndrome is characterised by polyostotic bone lesions, Fibrous Cortical Defect (Metaphyseal
skin pigmentation (cafe-au-lait macular spots) and sexual Fibrous Defect, Non-ossifying Fibroma)
precocity, and infrequently other endocrinopathies. Fibrous cortical defect or metaphyseal fibrous defect is a
rather common benign tumour-like lesion occurring in the
MORPHOLOGIC FEATURES. All forms of fibrous dys- metaphyseal cortex of long bones in children. Most
Systemic Pathology
plasia have an identical pathologic appearance. commonly involved bones are upper or lower end of tibia or
Grossly, the lesions appear as sharply-demarcated, lower end of femur. The lesion is generally solitary but rarely
localised defects measuring 2-5 cm in diameter, present there may be multiple and bilaterally symmetrical defects.
within the cancellous bone, having thin and smooth Radiologically, the lesion is eccentrically located in the
overlying cortex. The epiphyseal cartilages are generally metaphysis and has a sharply-delimited border. The
spared in the monostotic form but involved in the pathogenesis of fibrous cortical defect is unknown. Possibly,
polyostotic form of disease. Cut section of the lesion shows
it arises as a result of some developmental defect at the
epiphyseal plate, or could be a tumour of histiocytic origin
  TABLE 28.1: Classification of Tumour-like Lesions of Bone. because of close resemblance to fibrohistiocytic tumours
(page 864).
1. Fibrous dysplasia Clinically, fibrous cortical defect causes no symptoms and
2. Fibrous cortical defect (metaphyseal fibrous defect, non-ossifying is usually discovered accidentally when X-ray of the region
fibroma)
3. Solitary bone cyst (simple or unicameral bone cyst) is done for some other reason.
4. Aneurysmal bone cyst
5. Ganglion cyst of bone (intraosseous ganglion) MORPHOLOGIC FEATURES. Grossly, the lesion is
6. Brown tumour of hyperparathyroidism (reparative granuloma) (page generally small, less than 4 cm in diameter, granular and
816) brown. Larger lesion (5-10 cm) occurring usually in
7. Langerhans’ cell histiocytosis (Histiocytosis-X) (page 385) response to trauma is referred to as non-ossifying fibroma.

839





























Figure 28.8 Aneurysmal bone cyst, ulna. The end of the long bone
is expanded due to a cyst. The inner wall of the cyst is tan and
haemorrhagic.



Microscopically, fibrous cortical defect consists of cellular column. The radiographic appearance shows characteristic CHAPTER 28
masses of fibrous tissue showing storiform pattern. There ballooned-out expansile lesion underneath the periosteum.
are numerous multinucleate osteoclast-like giant cells, The pathogenesis is not clear but it has been suggested by
haemosiderin-laden macrophages and foamy cells; hence some authors that the condition probably arises from
the lesion is also termed histiocytic xanthogranuloma or persistent local alteration in haemodynamics. Clinically, the
fibrous xanthoma of bone. aneurysmal bone cyst may enlarge over a period of years
and produce pain, tenderness and pathologic fracture.
Solitary (Simple, Unicameral) Bone Cyst
Solitary, simple or unicameral bone cyst is a benign condition MORPHOLOGIC FEATURES. Grossly, the lesion
occurring in children and adolescents, most frequently consists of a large haemorrhagic mass covered over by
located in the metaphyses at the upper end of humerus and thinned out reactive bone (Fig. 28.8).
femur. The cyst expands the bone causing thinning of the Histologically, the cyst consists of blood-filled aneurys- The Musculoskeletal System
overlying cortex. Possibly, the lesion arises due to local mal spaces of variable size, some of which are endo-
disorder of bone growth and development. Clinically, solitary thelium-lined. The spaces are separated by connective
bone cyst may remain asymptomatic or may cause pain and tissue septa containing osteoid tissue, numerous
fracture. osteoclast-like multinucleate giant cells and trabeculae of
bone (Fig. 28.9). The condition has to be distinguished
MORPHOLOGIC FEATURES. Grossly, simple cyst of the histologically from giant cell tumour or osteoclastoma
bone is generally unilocular with smooth inner surface. (page 846) and telangiectatic osteosarcoma (page 842).
The cavity is filled with clear fluid.
Histologically, the cyst wall consists of thin collagenous
tissue having scattered osteoclast giant cells and newly BONE TUMOURS
formed reactive bony trabeculae. Fracture alters the Bone tumours are comparatively infrequent but they are
appearance and produces sanguineous fluid in the cavity, clinically quite significant since some of them are highly
and haemorrhages, haemosiderin deposits and malignant. Bone tumours may be primary or metastatic. Since
macrophages in the cyst wall.
histogenesis of some bone tumours is obscure, the WHO has
recommended a widely accepted classification of primary
Aneurysmal Bone Cyst
bone tumours based on both histogenesis and histologic
Aneurysmal bone cyst, true to its name, is an expanding criteria. Table 28.2 lists the various types of bone tumours
osteolytic lesion filled with blood (aneurysm = dilatation, arising from different tissue components—osseous and non-
distension). The condition is seen more commonly in young osseous, indigenous to the bone. However, in the discussion
patients under 30 years of age. Most frequently involved below, only osseous bone tumours are considered, while non-
bones are shafts of metaphyses of long bones or the vertebral osseous bone tumours are described elsewhere in the book.

840























Figure 28.9 Aneurysmal bone cyst. Histologic hallmark of lesion is presence of aneurysmal spaces filled with blood, partly lined by endothelium
and separated by connective tissue septa containing osteoclast-like giant cells along the wall of vascular spaces.


The anatomic origin of common primary bone tumours is Osteoid Osteoma and Osteoblastoma
illustrated in Fig. 28.10. Osteoid osteoma and osteoblastoma (or giant osteoid
It may be mentioned here that the diagnosis of any bone osteoma) are closely related benign tumours occurring in
lesion is established by a combination of clinical, radiological children and young adults. Osteoid osteoma is more common
and pathological examination, supplemented by biochemical than osteoblastoma. There are no clear-cut histologic criteria
and haematological investigations wherever necessary. These to distinguish the two. The distinction between them is based
include: serum levels of calcium, phosphorus, alkaline on clinical features, size and radiographic appearance.
phosphatase and acid phosphatase. Specific investigations Osteoid osteoma is small (usually less than 1 cm) and
like plasma and urinary proteins and the bone marrow painful tumour, located in the cortex of a long bone. The
SECTION III
examination in case of myeloma, urinary catecholamines in tumour is clearly demarcated having surrounding zone of
metastatic neuroblastoma and haematologic profile in reactive bone formation which radiographically appears as
lymphoma and leukaemic involvement of the bone, are of
considerable help.

BONE-FORMING (OSTEOBLASTIC) TUMOURS

Bone-forming or osteoblastic group of bone tumours are
characterised by the common property of synthesis of osteoid
or bone, or both, directly by the tumour cells (osteogenesis).
Formation of reactive bone and endochondral ossification
Systemic Pathology
should not be construed as osteogenesis. Benign bone-
forming tumours include: osteoma, osteoid osteoma and
osteoblastoma, while the malignant counterpart is osteo-
sarcoma (osteogenic sarcoma).

Osteoma
An osteoma is a rare benign, slow-growing lesion, regarded
by some as a hamartoma rather than a true neoplasm. Similar
lesions may occur following trauma, subperiosteal
haematoma or local inflammation. Osteoma is almost
exclusively restricted to flat bones of the skull and face. It
may grow into paranasal sinuses or protrude into the orbit.
An osteoma may form a component of Gardner’s syndrome
(page 585). Radiologic appearance is of a dense ivory-like
bony mass.

Microscopically, the lesion is composed of well-differen-
tiated mature lamellar bony trabeculae separated by
fibrovascular tissue. Figure 28.10 Anatomic locations of common primary bone tumours.

a small radiolucent central focus or nidus surrounded by tumour arises in the metaphysis of long bones. Most 841
dense sclerotic bone. common sites, in descending order of frequency, are: the
Osteoblastoma, on the other hand, is larger in size lower end of femur and upper end of tibia (i.e. around knee
(usually more than 1 cm), painless, located in the medulla, joint about 60%); the upper end of humerus (10%); pelvis
commonly in the vertebrae, ribs, ilium and long bones, and and the upper end of femur (i.e. around hip joint about 15%);
there is absence of reactive bone formation. and less often in jaw bones, vertebrae and skull. Rarely, an
osteosarcoma may occur in extraskeletal soft tissues.
Histologically, the distinction between osteoid osteoma Based upon the pathogenesis, osteosarcoma is divided
and osteoblastoma is not obvious. In either case, the lesion into 2 types: primary and secondary.
consists of trabeculae of osteoid, rimmed by osteoblasts
and separated by highly vascularised connective tissue Primary osteosarcoma is more common and occurs in the
stroma. Later, some of the trabeculae are mineralised and absence of any known underlying disease. Its etiology is
calcified. unknown but there is evidence linking this form of
osteosarcoma with genetic factors (e.g. hereditary mutation
Osteosarcoma of chromosome 13 in common with retinoblastoma locus),
period of active bone growth (occurrence of the tumour in
Osteosarcoma or osteogenic sarcoma is the most common younger age), and with certain environmental influences
primary malignant tumour of the bone. The tumour is (e.g. radiation, oncogenic virus). Cases of hereditary retino-
characterised by formation of osteoid or bone, or both, directly by blastoma have a very high prevalence risk of development
sarcoma cells. The tumour is thought to arise from primitive of osteosarcoma implicating RB gene in their pathogenesis.
osteoblast-forming mesenchyme. Depending upon their
locations within the bone, osteosarcomas are classified into About 20% sporadic osteosarcomas show mutation in p53
tumour suppressor gene; some have overexpression of
2 main categories: central (medullary) and surface ( parosteal MDM2 gene and mutation in cyclin D1, p16 and CDK4.
and perosteal).
Secondary osteosarcoma, on the other hand, develops
CENTRAL (MEDULLARY) OSTEOSARCOMA following pre-existing bone disease e.g. Paget’s disease of
This is the more common and classic type and is generally bone, fibrous dysplasia, multiple osteochondromas, chronic
referred to as ‘osteosarcoma’ if not specified. The tumour osteomyelitis, infarcts and fractures of bone. The tumour CHAPTER 28
occurs in young patients between the age of 10 and 20 years. has a more aggressive behaviour than the primary
Males are affected more frequently than females. The osteosarcoma.



  TABLE 28.2: Classification of Primary Bone Tumours.
Histologic Derivation Benign Malignant
A. OSSEOUS TUMOURS
I. Bone-forming Osteoma (40-50 yrs) Osteosarcoma (10-20 yrs)
(osteogenic, osteoblastic) tumours Osteoid osteoma (20-30 yrs) Parosteal (juxtacortical)
Osteoblastoma (20-30 yrs) osteosarcoma (50-60 yrs) The Musculoskeletal System
II. Cartilage-forming Enchondroma (20-50 yrs) Chondrosarcoma (40-60 yrs)
(chondrogenic) Osteochondroma (20-50 yrs)
tumours (Osteocartilaginous exostosis)
Chondroblastoma (10-20 yrs)
Chondromyxoid fibroma (20-30 yrs)
III. Haematopoietic — Myeloma (50-60 yrs)
(marrow) tumours Lymphoplasmacytic lymphoma (50-60 yrs)
IV. Unknown Giant cell tumour (20-40 yrs) Malignant giant cell tumour (30-50 yrs)
(osteoclastoma) Ewing’s sarcoma (5-20 yrs)
Adamantinoma of long bones
V. Notochordal tumour — Chordoma (40-50 yrs)
B. NON-OSSEOUS TUMOURS
I. Vascular tumours Haemangioma Haemangioendothelioma
Haemangiopericytoma
Angiosarcoma
II. Fibrogenic tumours Non-ossifying fibroma Fibrosarcoma
(metaphyseal fibrous defect)
III. Neurogenic tumours Neurilemmoma and neurofibroma Neurofibrosarcoma
IV. Lipogenic tumours Lipoma Liposarcoma
V. Histiocytic tumours Fibrous histiocytoma Malignant fibrous histiocytoma
Figures in brackets indicate common age of occurrence.

842



























Figure 28.11 Osteosarcoma. The lower end of the femur shows a
bulky expanded tumour in the region of metaphysis sparing the epiphyseal
cartilage. Sectioned surface of the tumour shows lifting of the periosteum
by the tumour and eroded cortical bone. The tumour is grey-white with
areas of haemorrhage and necrosis.



Medullary osteosarcoma is a highly malignant tumour. tumour from one area to the other. However, the following
The tumour arises centrally in the metaphysis, extends two features characterise all classic forms of osteosarcomas
longitudinally for variable distance into the medullary cavity, (Fig. 28.12):
SECTION III
expands laterally on either side breaking through the cortex 1. Sarcoma cells. The tumour cells of osteosarcomas are
and lifting the periosteum. If the periosteum is breached, the undifferentiated mesenchymal stromal cells which show
tumour grows relentlessly into the surrounding soft tissues. marked pleomorphism and polymorphism i.e. variation
The only tissue which is able to stop its spread, albeit in size as well as shape. The tumour cells may have various
temporarily, is the cartilage of epiphyseal plate. The shapes such as spindled, round, oval and polygonal and
radiographic appearance is quite distinctive: characteristic bizarre tumour giant cells. The tumour cells have variable
‘sunburst pattern’ due to osteogenesis within the tumour and size and show hyperchromatism and atypical mitoses.
presence of Codman’s triangle formed at the angle between Histochemically, these tumour cells are positive for
the elevated periosteum and underlying surface of the cortex. alkaline phosphatase. Immunohistochemically, sarcoma
Clinically, the usual osteosarcoma presents with pain, cells of osteosarcoma express vimentin, osteocalcin,
tenderness and an obvious swelling of affected extremity. osteonectin and type I collagen.
Systemic Pathology
Serum alkaline phosphatase level is generally raised but 2. Osteogenesis. The anaplastic sarcoma cells form
calcium and phosphorus levels are normal. The tumour osteoid matrix and bone directly; this is found interspersed
metastasises rapidly and widely to distant sites by in the areas of tumour cells. In addition to osteoid and
haematogenous route and disseminates commonly to the bone, the tumour cells may produce cartilage, fibrous
lungs, other bones, brain and various other sites. tissue or myxoid tissue.

MORPHOLOGIC FEATURES. Grossly, the tumour A few histologic variants of the usual osteosarcoma have
appears as a grey-white, bulky mass at the metaphyseal been described as under:
end of a long bone of the extremity. The articular end of Telangiectatic osteosarcoma. The tumour in this variant
the bone is generally uninvolved in initial stage. Codman’s presents with pathological fractures. The tumour has large,
triangle, though identified radiologically, may be obvious cavernous, dilated vascular channels. This variant has a more
on macroscopic examination (Fig. 28.11). Cut surface of aggrieve course.
the tumour is grey-white with areas of haemorrhages and Small cell osteosarcoma. This variant has small, uniform
necrotic bone. Tumours which form abundance of osteoid, tumour cells just like the tumour cells of Ewing’s sarcoma or
bone and cartilage may have hard, gritty and mucoid lymphoma but osteogensis by these tumour cells is the
areas. distinguishing feature.
Fibrohistiocytic osteosarcoma. This variant resembles
Histologically, osteosarcoma shows considerable malignant fibrous histiocytoma but having osteogenesis by
variation in pattern from case-to-case and even within a
the tumour cells.

843

























Figure 28.12 Osteosarcoma. Hallmarks of microscopic picture of the usual osteosarcoma are the sarcoma cells characterised by variation in
size and shape of tumour cells, bizarre mitosis and multinucleate tumour giant cells, and osteogenesis i.e. production of osteoid matrix and bone
directly by the tumour cells.


Anaplastic osteosarcoma. In this variant, the tumour has so Microscopically, periosteal osteosarcoma has cartilaginous
marked anaplasia that it may resemble any other type of differentiation and higher degree of anaplasia than that
pleomorphic sarcoma and is identified by the presence of seen in parosteal osteosarcoma.
osteoid formed directly by the tumour cells.
Well-differentiated osteosarcoma. Although generally classic Table 28.3 sums up the contrasting features of central CHAPTER 28
form of osteosarcoma is a highly malignant tumour, rarely a (medullary) and surface (parosteal and periosteal)
well-differentiated variant having minimal cytologic atypia osteosarcomas.
resembling parosteal osteosarcoma may be seen.
SURFACE OSTEOSARCOMA CARTILAGE-FORMING (CHONDROBLASTIC) TUMOURS
About 5% of osteosarcomas occur on the surface of bone and The tumours which are composed of frank cartilage or
are slow-growing tumours compared to medullary derived from cartilage-forming cells are included in this
osteosarcomas. Surface osteosarcoma includes 2 variants: group. This group comprises benign lesions like osteocartila-
parosteal and periosteal. ginous exostoses (osteochondromas), enchondroma,
Parosteal or juxtacortical osteosarcoma is an uncommon chondroblastoma and chondromyxoid fibroma, and a
form of osteosarcoma having its origin from the metaphysis malignant counterpart, chondrosarcoma. The Musculoskeletal System
on the external surface of the bone (parosteal or juxtacortical
means outer to cortex). The tumour should be distinguished Osteocartilaginous Exostoses (Osteochondromas)
from the more common medullary osteosarcoma because of
its better prognosis and different presentation. The tumour Osteocartilaginous exostoses or osteochondromas are the
occurs in older age group, has no sex predilection and is slow commonest of benign cartilage-forming lesions. Though
growing. Its common locations are metaphysis of long bones, designated and discussed with neoplasms, exostosis or
most frequently lower end of the femur and upper end of osteochondroma is not a true tumour but is regarded as a
the humerus. X-ray examination usually reveals a dense bony disorder of growth and development (page 834). It may occur
mass attached to the outer cortex of the affected long bone. as a ‘solitary sporadic exostosis’ or there may be ‘multiple
Grossly, the tumour is lobulated and circumscribed, hereditary exostoses’.
calcified mass in the subperiosteal location. Exostoses arise from metaphyses of long bones as
Microscopically, the features which characterise the usual exophytic lesions, most commonly lower femur and upper
osteosarcoma (sarcomatous stroma and production of tibia (i.e. around knee) and upper humerus but may also be
neoplastic osteoid and bone) are present, but the tumour found in other bones such as the scapula or ilium. They are
shows a high degree of structural differentiation, and there discovered most commonly in late childhood or adolescence
are generally well-formed bony trabeculae. These features and are more frequent in males. They may remain
account for distinctly better prognosis in these cases. asymptomatic and discovered as an incidental radiographic
finding or may produce obvious deformity. Both solitary and
Periosteal osteosarcoma is a rare form of osteosarcoma that multiple exostoses may undergo transformation into
arises between the cortex and the overlying periosteum. Its chondrosarcoma but the risk is much greater with multiple
common location is the diaphysis of the tibia or the femur. hereditary exostoses.

844
  TABLE 28.3. Contrasting Features of Central (Medullary) and Surface (Parosteal and Periosteal) Osteosarcoma.
Feature Central (Medullary) Surface (Parosteal and Periosteal)
1. Age 10-20 years Older patients
2. Sex More common in males No sex predilection
3. Anatomic site Metaphysis Metaphysis/diaphysis
4. Location Femur (lower end), tibia (upper end), Femur (lower-end), humerus (upper end)
humerus (upper end), around hip
5. Pathogenesis Primary: genetic factors Parosteal: Arises outer to cortex
(mutations in Rb gene, p53, MDM2) Periosteal: Arises between cortex and
Secondary: Paget’s disease, fibrous dysplasia periosteum
6. Behaviour Highly malignant Slow growing
7. G/A Bulky, necrotic, forms Codman’s triangle Smaller, well-formed bone present
8. M/E i. Sarcomas cells: Polymorphic and pleomorphic i. Parosteal: Fibrous stromal cells with
ii. Osteoid formation subtle atypia
ii. Periosteal: High grade
iii. Both form bony trabeculae
9. Histologic types Telangiectatic, small cell, fibrohistiocystic, Parosteal (juxta cortical), periosteal
well differentiated, anaplastic
10. Spread and prognosis Haematogenous spread, Recurrences common, may metastasise,
prognosis poor prognosis generally good, better for
parosteal than periosteal



Enchondroma
MORPHOLOGIC FEATURES. Grossly, osteochondro-
mas have a broad or narrow base (i.e. may be either sessile Enchondroma is the term used for the benign cartilage-
or pedunculated) which is continuous with the cortical forming tumour that develops centrally within the interior
bone. They protrude exophytically as mushroom-shaped, of the affected bone, while chondroma refers to the peripheral
cartilage-capped lesions enclosing well-formed cortical development of lesion similar to osteochondromas.
SECTION III
bone and marrow (Fig. 28.13). Enchondromas may occur singly or they may be multiple,
forming a non-hereditary disorder called enchondromatosis or
Microscopically, they are composed of outer cap Ollier’s disease. The coexistence of multiple enchondromas
composed of mature cartilage resembling epiphyseal with multiple soft tissue haemangiomas constitutes a familial
cartilage and the inner mature lamellar bone and bone syndrome called Maffucci’s syndrome.
marrow (Fig. 28.14). Most common locations for enchondromas are short
tubular bones of the hands and feet, and less commonly, they





Systemic Pathology























Figure 28.13 Osteochondroma (osteocartilaginous exostosis),
upper end humerus. The amputated head of the long bone shows
mushroom-shaped elevated nodular areas. These nodules have
cartilaginous caps and inner osseous tissue.

chondroid tumour with foci of haemorrhages, necrosis and 845
calcification.
Histologically, the tumour is highly cellular and is
composed of small, round to polygonal mononuclear cells
resembling chondroblasts and has multinucleate
osteoclast-like giant cells. There are small areas of
cartilaginous intercellular matrix and focal calcification.

Chondromyxoid Fibroma
Chondromyxoid fibroma is an uncommon benign tumour
of cartilaginous origin arising in the metaphysis of long
bones. Most common locations are upper end of tibia and
lower end of femur i.e. around the knee joint. Majority of
tumours appear in 2nd to 3rd decades of life with male
preponderance. Radiologically, the tumour appears as a
sharply-outlined radiolucent area with foci of calcification
and expansion of affected end of the bone. The lesion may
be asymptomatic, or may cause pain, swelling and discomfort
Figure 28.14 Osteochondroma. The overlying cap shows mature in the affected joint. The lesions may recur after curettage.
cartilage cells covering the underlying mature lamellar bone containing Thus, there are many similarities with chondroblastoma.
marrow spaces.
MORPHOLOGIC FEATURES. Grossly, chondromyxoid
involve the ribs or the long bones. They may appear at any fibroma is sharply-demarcated, grey-white lobulated
age and in either sex. Enchondromas, like osteochondromas, mass, not exceeding 5 cm in diameter, lying in the
may remain asymptomatic or may cause pain and pathologic metaphysis. The tumour is often surrounded by a layer
fractures. X-ray reveals a radiolucent, lobulated tumour mass of dense sclerotic bone. Cut surface of the tumour is soft CHAPTER 28
with spotty calcification. Malignant transformation of solitary to firm and lobulated but calcification within the tumour
enchondroma is rare but multiple enchondromas may is not as common as with other cartilage-forming tumours.
develop into chondrosarcoma. Histologically, the tumour has essentially lobulated
pattern. The lobules are separated by fibrous tissue and
MORPHOLOGIC FEATURES. Grossly, the enchondroma variable number of osteoclast-like giant cells. The lobules
is lobulated, bluish-grey, translucent, cartilaginous mass themselves are composed of immature cartilage consisting
lying within the medullary cavity. of spindle-shaped or stellate cells with abundant myxoid
Histologically, the tumour has characteristic lobulated or chondroid intercellular matrix.
appearance. The lobules are composed of normal adult
hyaline cartilage separated by vascularised fibrous stroma. In view of close histogenetic relationship between
Foci of calcification may be evident within the tumour. chondromyxoid fibroma and chondroblastoma, occasional
Enchondroma is distinguished from chondrosarcoma by tumours show a combination of histological features of both. The Musculoskeletal System
the absence of invasion into surrounding tissues and lack Chondrosarcoma
of cytologic features of malignancy.
Chondrosarcoma is a malignant tumour of chondroblasts.
In frequency, it is next in frequency to osteosarcoma but is
Chondroblastoma
relatively slow-growing and thus has a much better
Chondroblastoma is a relatively rare benign tumour arising prognosis than that of osteosarcoma. Two types of
from the epiphysis of long bones adjacent to the epiphyseal chondrosarcoma are distinguished: central and peripheral.
cartilage plate. Most commonly affected bones are upper tibia Central chondrosarcoma is more common and arises
and lower femur (i.e. about knee) and upper humerus. The within the medullary cavity of diaphysis or metaphysis. This
tumour usually occurs in patients under 20 years of age with type of chondrosarcoma is generally primary i.e. occurs de
male preponderance (male-female ratio 2:1). The novo.
radiographic appearance is of a sharply-circumscribed, lytic Peripheral chondrosarcoma arises in the cortex or peri-
lesion with multiple small foci of calcification. Chondro- osteum of metaphysis. It may be primary or secondary
blastoma may be asymptomatic, or may produce local pain, occurring on a pre-existing benign cartilaginous tumour such
tenderness and discomfort. The behaviour of the tumour is as osteocartilaginous exostoses (osteochondromas), multiple
benign though it may recur locally after curettage. enchondromatosis, and rarely, chondroblastoma.
Both forms of chondrosarcoma usually occur in patients
MORPHOLOGIC FEATURES. Grossly, chondroblastoma
is a well-defined mass, up to 5 cm in diameter, lying in between 3rd and 6th decades of life with slight male
the epiphysis. The tumour is surrounded by thin capsule preponderance. In contrast to benign cartilaginous tumours,
of dense sclerotic bone. Cut surface reveals a soft majority of chondrosarcomas are found more often in the
central skeleton (i.e. in the pelvis, ribs and shoulders); other

846 (Fig. 28.16). However, sometimes distinction between a
well-differentiated chondrosarcoma and a benign
chondroma may be difficult and in such cases location,
clinical features and radiological appearance are often
helpful.
Rare variants of chondrosarcoma are mesenchymal
chondrosarcoma, dedifferentiated chondrosarcoma and clear
cell chondrosarcoma.

GIANT CELL TUMOUR (OSTEOCLASTOMA)

Giant cell tumour or osteoclastoma is a distinctive neoplasm
with uncertain histogenesis and hence classified separately.
The tumour arises in the epiphysis of long bones close to the
articular cartilage. Most common sites of involvement are
lower end of femur and upper end of tibia (i.e. about the
Figure 28.15 Chondrosarcoma, scapula. The bone is expanded knee), lower end of radius and upper end of fibula. Giant
externally due to a gelatinous tumour. Sectioned surface shows lobulated cell tumour occurs in patients between 20 and 40 years of
mass with bluish cartilaginous hue infiltrating the soft tissues.
age with no sex predilection. Clinical features at presentation
include pain, especially on weight-bearing and movement,
site being around the knee joint. Radiologic appearance is of noticeable swelling and pathological fracture. Radiologically,
hugely expansile and osteolytic growth with foci of giant cell tumour appears as a large, lobulated and osteolytic
calcification. Clinically, the tumour is slow-growing and lesion at the end of an expanded long bone with characteristic
comes to attention because of pain and gradual enlargement ‘soap bubble’ appearance.
over the years. Lower grades of the tumour recur following
surgical removal but higher grades cause metastatic MORPHOLOGIC FEATURES. Grossly, giant cell tumour
dissemination, commonly to the lungs, liver, kidney and is eccentrically located in the epiphyseal end of a long bone
brain. which is expanded. The tumour is well-circumscribed,
dark-tan and covered by a thin shell of subperiosteal bone.
SECTION III
MORPHOLOGIC FEATURES. Grossly, chondrosarcoma Cut surface of the tumour is characteristically haemor-
may vary in size from a few centimeters to extremely large rhagic, necrotic, and honey-combed due to focal areas of
and lobulated masses of firm consistency. Cut section of cystic degeneration (Fig. 28.17).
the tumour shows translucent, bluish-white, gelatinous Histologically, the hallmark features of giant cell tumour
or myxoid appearance with foci of ossification (Fig. 28.15). are the presence of large number of multinucleate
Histologically, the two hallmarks of chondrosarcoma are: osteoclast-like giant cells regularly scattered throughout
invasive character and formation of lobules of anaplastic the stromal mononuclear cells (Fig. 28.18):
cartilage cells. These tumour cells show cytologic features Giant cells often contain as many as 100 benign nuclei
of malignancy such as hyperchromatism, pleomorphism, and have many similarities to normal osteoclasts. These
two or more cells in the lacunae and tumour giant cells cells have very high acid phosphatase activity.
Systemic Pathology


























Figure 28.16 Chondrosarcoma. Histologic features include invasion of the tumour into adjacent soft tissues and cytologic characteristics of
malignancy in the tumour cells.

847




























Figure 28.17 Giant cell tumour (osteoclastoma). The end of the
long bone is expanded in the region of epiphysis. Sectioned surface
shows circumscribed, dark tan, haemorrhagic and necrotic tumour.



Stromal cells are mononuclear cells and are the real CELL OF ORIGIN. Though designated as giant cell tumour CHAPTER 28
tumour cells and their histologic appearance determines or osteoclastoma, the true tumour cells are round to spindled
the biologic behaviour of the tumour. Typically, they are mononuclear cells and not osteoclast-like giant cells.
uniform, plump, spindle-shaped or round to oval cells Histogenesis of tumour cells is uncertain but possibly they
with numerous mitotic figures. are of mesenchymal origin. Available evidence suggests that
Other features of the stroma include its scanty collagen osteoclasts are derived from fusion of circulating monocytes,
content, rich vascularity, areas of haemorrhages and the process being facilitated by transforming growth factor-
presence of macrophages. beta (TGF-β).
OTHER GIANT CELL LESIONS. This peculiar tumour with
Giant cell tumour of bone has certain peculiarities which above description is named ‘giant cell tumour’ but giant cells
deserve further elaboration. These are: its cell of origin, its are present in several other benign tumours and tumour-
differentiation from other giant cell lesions and its biologic like lesions from which the giant cell tumour is to be
behaviour. The Musculoskeletal System
distinguished. These benign giant cell lesions are:



























Figure 28.18 Osteoclastoma. Microscopy reveals osteoclast-like multinucleate giant cells which are regularly distributed among the mononuclear
stromal cells.

848



























Figure 28.19 Ewing’s sarcoma. The tumour is largely extending
into soft tissues including the skeletal muscle. Cut surface of the tumour
is grey-white, cystic, soft and friable.



chondroblastoma, brown tumour of hyperparathyroidism, The three are linked together by a common neuroecto-
reparative giant cell granuloma, aneurysmal bone cyst, dermal origin and by a common cytogenetic translocation
simple bone cyst and metaphyseal fibrous defect (non- abnormality t(11; 22) (q24; q12). This suggests a phenotypic
ossifying fibroma). spectrum in these conditions varying from undifferentiated
Ewing’s sarcoma to PNET positive for rosettes and neural
SECTION III
BIOLOGIC BEHAVIOUR. Giant cell tumours are best markers (neuron-specific enolase, S-100). However, PNET
described as aggressive lesions or low grade malignant ultimately has a worse prognosis.
tumour. About 40 to 60% of them recur after curettage, The skeletal Ewing’s sarcoma arises in the medullary
sometimes after a few decades of initial resection. canal of diaphysis or metaphysis. The common sites are
Approximately 4% cases result in distant metastases, mainly shafts and metaphysis of long bones, particularly femur, tibia,
to lungs. Metastases are histologically benign and there is humerus and fibula, although some flat bones such as pelvis
usually history of repeated curettages and recurrences. Thus and scapula may also be involved.
attempts at histologic grading of giant cell tumour do not Clinical features include pain, tenderness and swelling
always yield satisfactory results. One of the factors of the affected area accompanied by fever, leucocytosis and
considered significant in malignant transformation of this elevated ESR. These signs and symptoms may lead to an
tumour is the role of radiotherapy resulting in development erroneous clinical diagnosis of osteomyelitis. However, X-
Systemic Pathology
of post-radiation bone sarcoma though primary (de novo) ray examination reveals a predominantly osteolytic lesion
malignant or dedifferentiated giant cell tumour may also with patchy subperiosteal reactive bone formation producing
occur.
characteristic ‘onion-skin’ radiographic appearance.
EWING’S SARCOMA AND PRIMITIVE MORPHOLOGIC FEATURES. Grossly, Ewing’s sarcoma
NEUROECTODERMAL TUMOUR (ES/PNET)
is typically located in the medullary cavity and produces
Ewing’s sarcoma (ES) is a highly malignant small round cell expansion of the affected diaphysis (shaft) or metaphysis,
tumour occurring in patients between the age of 5 and 20 often extending into the adjacent soft tissues. The tumour
years with predilection for occurrence in females. Since its tissue is characteristically grey-white, soft and friable
first description by James Ewing in 1921, histogenesis of this (Fig. 28.19).
tumour has been a debatable issue. At different times, the Histologically, Ewing’s tumour is a member of small round
possibilities suggested for the cell of origin have been cell tumours which includes other tumours such as: PNET,
endothelial, pericytic, bone marrow, osteoblastic, and mesen- neuroblastoma, embryonal rhabdomyosarcoma,
chymal; currently it is settled for origin from primitive lymphoma-leukaemias, and metastatic small cell
neuroectodermal cells. Now, Ewing’s sarcoma includes 3 carcinoma. Ewing’s tumour shows the following
variants: histologic characteristics (Fig. 28.20):
i) classic (skeletal) Ewing’s sarcoma; 1. Pattern. The tumour is divided by fibrous septa into
ii) soft tissue Ewing’s sarcoma; and irregular lobules of closely-packed tumour cells. These
iii) primitive neuroectodermal tumour (PNET).

849
























Figure 28.20 Ewing’s sarcoma. Characteristic microscopic features are irregular lobules of uniform small tumour cells with indistinct cytoplasmic
outlines which are separated by fibrous tissue septa having rich vascularity. Areas of necrosis and inflammatory infiltrate are also included. Inbox in
the right photomicrograph shows PAS positive tumour cells in perivascular location.


tumour cells are characteristically arranged around region, and infrequently in the vertebrae. Chordoma is
capillaries forming pseudorosettes. usually found in patients over the age of 40 years with no
2. Tumour cells. The individual tumour cells comprising sex predilection. Radiographically, the tumour usually
the lobules are small and uniform resembling lymphocytes appears as an osteolytic lesion. Symptoms of spinal cord
and have ill-defined cytoplasmic outlines, scanty compression may be present. The tumour grows slowly and CHAPTER 28
cytoplasm and round nuclei having ‘salt and pepper’ infiltrates adjacent structures but metastases develop rarely.
chromatin and frequent mitoses. Based on these Recurrences after local excision are frequent and the tumour
cytological features the tumour is also called round cell almost invariably proves fatal.
tumour or small blue cell tumour. The cytoplasm contains MORPHOLOGIC FEATURES. Grossly, the tumour is
glycogen that stains with periodic acid-Schiff (PAS) soft, lobulated, translucent and gelatinous with areas of
reaction. The consistently expressed cell surface marker haemorrhages.
by tumour cells of ES/PNET group is CD99 which is a Microscopically, chordoma is composed of highly vacuo-
product of MIC-2 gene located on X and Y chromosome. lated physaliphorous cells surrounded by a sea of
3. Other features. The tumour is richly vascularised and intercellular mucoid material (Fig. 28.21). Histologic
lacks the intercellular network of reticulin fibres. There differentiation between chordoma and chondrosarcoma
may be areas of necrosis and acute inflammatory cell or mucin-secreting carcinoma may sometimes be difficult. The Musculoskeletal System
infiltration. Focal areas of reactive bone formation may
be present.

Ewing’s sarcoma metastasises early by haematogenous
route to the lungs, liver, other bones and brain. Involvement
of other bones has prompted a suggestion of multicentric
origin of Ewing’s sarcoma. The prognosis of Ewing’s sarcoma
used to be dismal (5-year survival rate less than 10%). But
currently, use of combined regimen consisting of
radiotherapy and systemic chemotherapy has improved the
outcome greatly (5-year survival rate 40-80%).

CHORDOMA
Chordoma is a slow-growing malignant tumour arising from
remnants of notochord. Notochord is the primitive axial
skeleton which subsequently develops into the spine.
Normally, remnants of notochord are represented by
notochordal or physaliphorous (physalis = bubble, phorous =
bearing) cells present in the nucleus pulposus and a few
clumps within the vertebral bodies. Chordomas thus occur Figure 28.21 Chordoma. The tumour cells are quite variable in size
having characteristic bubbly cytoplasm (physaliphorous cells) and
in the axial skeleton, particularly sacral and spheno-occipital anisonucleocytosis. The background is myxoid.

850 composed of inner layer of 1-4 cell thick synoviocytes and
outer layer of loose vascular connective tissue. On electron
microscopy, two types of synoviocytes are distinguished:
type A and type B. Type A synoviocytes are more numerous
and are related to macrophages and produce degradative
enzymes, while type B synthesise hyaluronic acid.
Diseases of joints are numerous and joints are also invol-
ved in several systemic disorders. In the following discussion,
only those joint diseases which are morphologically
significant are described. Synovial tumours are discussed in
the next chapter together with other soft tissue tumours.

OSTEOARTHRITIS
Osteoarthritis (OA), also called osteoarthrosis or degenerative
joint disease (DJD), is the most common form of chronic
disorder of synovial joints. It is characterised by progressive
degenerative changes in the articular cartilages over the
Figure 28.22 Osseous deposits from carcinoma breast. years, particularly in weight-bearing joints.

METASTATIC BONE TUMOURS TYPES AND PATHOGENESIS. OA occurs in 2 clinical
forms—primary and secondary.
Metastases to the skeleton are more frequent than the primary Primary OA occurs in the elderly, more commonly in
bone tumours. Metastatic bone tumours are exceeded in women than in men. The process begins by the end of 4th
frequency by only 2 other organs—lungs and liver. Most decade and then progressively and steadily increases
skeletal metastases are derived from haematogenous spread. producing clinical symptoms. Little is known about the
Bony metastases of carcinomas predominate over the etiology and pathogenesis of primary OA. The condition may
sarcomas. Some of the common carcinomas metastasising to be regarded as a reward of longevity. Probably, wear and
the bones are from: breast, prostate, lung, kidney, stomach, tear with repeated minor trauma, heredity, obesity, aging
thyroid, cervix, body of uterus, urinary bladder, testis, per se, all contribute to focal degenerative changes in the
SECTION III
melanoma and neuroblastoma of adrenal gland. Examples articular cartilage of the joints. Genetic factors favouring
of sarcomas which may metastasise to the bone are: embryonal susceptibility to develop OA have been observed; genetic
and alveolar rhabdomyosarcoma, Ewing’s sarcoma and mutations in proteins which regulate the cartilage growth
osteosarcoma. have been identified e.g. FRZB gene.
Skeletal metastases may be single or multiple. Most
Secondary OA may appear at any age and is the result
commonly involved bones are: the spine, pelvis, femur, skull, of any previous wear and tear phenomena involving the joint
ribs and humerus. Usual radiographic appearance is of an
osteolytic lesion. Osteoblastic bone metastases occur in cancer such as previous injury, fracture, inflammation, loose bodies
of the prostate, carcinoid tumour and small cell carcinoma and congenital dislocation of the hip.
of lung. The molecular mechanism of damage to cartilage in OA
Metastatic bone tumours generally reproduce the micros- appears to be the breakdown of collagen type II, probably
Systemic Pathology
copic picture of primary tumour (Fig. 28.22). Many a times, by IL-1, TNF and nitric oxide.
evidence of skeletal metastases is the first clinical manifes- MORPHOLOGIC FEATURES. As mentioned above, the
tation of an occult primary cancer in the body. weight-bearing joints such as hips, knee and vertebrae are
most commonly involved but interphalangeal joints of
JOINTS fingers may also be affected. The pathologic changes occur
in the articular cartilages, adjacent bones and synovium
NORMAL STRUCTURE (Fig. 28.23):
The joints are of 2 types—diarthrodial or synovial joints with a 1. Articular cartilages. The regressive changes are most
joint cavity, and synarthrodial or nonsynovial joints without a marked in the weight-bearing regions of articular
joint cavity. Most of the diseases of joints affect diarthrodial cartilages. Initially, there is loss of cartilaginous matrix
or synovial joints. In diarthrodial joints, the ends of two bones (proteoglycans) resulting in progressive loss of normal
are held together by joint capsule with ligaments and tendons metachromasia. This is followed by focal loss of
inserted at the outer surface of the capsule. The articular chondrocytes, and at other places, proliferation of
surfaces of bones are covered by hyaline cartilage which is chondrocytes forming clusters. Further progression of the
thicker in weight-bearing areas than in nonweight-bearing process causes loosening, flaking and fissuring of the
areas. The joint space is lined by synovial membrane or articular cartilage resulting in breaking off of pieces of
synovium which forms synovial fluid that lubricates the joint cartilage exposing subchondral bone. Radiologically, this
during movements. The synovium may be smooth or thrown progressive loss of cartilage is apparent as narrowed joint
into numerous folds and villi. The synovial membrane is space.

RA is a common disease having peak incidence in 3rd to 851
4th decades of life, with 3-5 times higher preponderance in
females. The condition has high association with HLA-DR4
and HLA-DR1 and familial aggregation. The onset of disease
is insidious, beginning with prodrome of fatigue, weakness,
joint stiffness, vague arthralgias and myalgias. This is
followed by pain and swelling of joints usually in
symmetrical fashion, especially involving joints of hands,
wrists and feet. Unlike migratory polyarthritis of rheumatic
fever, RA usually persists in the involved joint.
Approximately 20% of patients develop rheumatoid nodules
located over the extensor surfaces of the elbows and fingers.
About 80% of cases are seropositive for rheumatoid factor
(RF). However, RF titres are elevated in certain unrelated
Figure 28.23 Fully-developed lesions in osteoarthritis (B), contrasted diseases too such as in: viral hepatitis, cirrhosis, sarcoidosis
with appearance of a normal joint (A). and leprosy. Advanced cases show characteristic radiologic
abnormalities such as narrowing of joint space and ulnar
2. Bone. The denuded subchondral bone appears like deviation of the fingers and radial deviation of the wrist.
polished ivory. There is death of superficial osteocytes and Other laboratory findings include mild normocytic and
increased osteoclastic activity causing rarefaction, normochromic anaemia, elevated ESR, mild leucocytosis and
microcyst formation and occasionally microfractures of hypergammaglobulinaemia. Extra-articular manifestations
the subjacent bone. These changes result in remodelling infrequently produce symptoms, but when present
of bone and changes in the shape of joint surface leading complicate the diagnosis.
to flattening and mushroom-like appearance of the ETIOPATHOGENESIS. Present concept on etiology and
articular end of the bone. The margins of the joints respond
to cartilage damage by osteophyte or spur formation. These pathogenesis proposes that RA occurs in an immunogenetically CHAPTER 28
are cartilaginous outgrowths at the joint margins which predisposed individual to the effect of microbial agents acting as
trigger antigen. The role of superantigens which are produced
later get ossified. Osteophytes give the appearance of by several microorganisms with capacity to bind to HLA-
lipping of the affected joint. Loosened and fragmented DR molecules (MHC-II region) has also emerged.
osteophytes may form free ‘joint mice’ or loose bodies.
3. Synovium. Initially, there are no pathologic changes I. Immunologic derangements. A number of observations
in the synovium but in advanced cases there is low-grade in patients and experimental animals indicate the role of
chronic synovitis and villous hypertrophy. There may be immune processes, particularly autoimmune phenomenon,
some amount of synovial effusion associated with chronic in the development of RA. These include the following:
synovitis. 1. Detection of circulating autoantibody called rheumatoid
factor (RF) against Fc portion of autologous IgG in about 80%
The manifestations of OA are most conspicuous in large cases of RA. RF antibodies are heterogeneous and consist of
joints such as hips, knee and back. However, the pattern of IgM and IgG class. The Musculoskeletal System
joint involvement may be related to the type of physical 2. The presence of antigen-antibody complexes (IgG-RF
activity such as ballet-dancers’ toes, karate fingers etc. Minor complexes) in the circulation as well as in the synovial fluid.
degree of OA may remain asymptomatic. In symptomatic 3. The presence of other autoantibodies such as antinuclear
cases, clinical manifestations are joint stiffness, diminished factor (ANF), antibodies to collagen type II, and antibodies
mobility, discomfort and pain. The symptoms are more to cytoskeleton.
prominent on waking up from bed in the morning. 4. Antigenicity of proteoglycans of human articular
Degenerative changes in the interphalangeal joints lead to cartilage.
hard bony and painless enlargements in the form of nodules 5. The presence of γ-globulin, particularly IgG and IgM, in
at the base of terminal phalanx called Heberden’s nodes. These the synovial fluid.
nodes are more common in females and heredity seems to 6. Association of RA with amyloidosis.
play a role. In the spine, osteophytes of OA may cause com- 7. Activation of cell-mediated immunity as observed by
pression of cervical and lumbar nerve root with pain, muscle presence of numerous inflammatory cells in the synovium,
spasms and neurologic abnormalities. chiefly CD4+ T lymphocytes and some macrophages.
II. Trigger events. Though the above hypothesis of a
RHEUMATOID ARTHRITIS
possible role of autoimmunity in the etiology and patho-
Rheumatoid arthritis (RA) is a chronic multisystem disease genesis of RA is generally widely accepted, controversy
of unknown cause. Though the most prominent mani- continues as regards the trigger events which initiate the
festation of RA is inflammatory arthritis of the peripheral destruction of articular cartilage. Various possibilities which
joints, usually with a symmetrical distribution, its systemic have been suggested are as follows:
manifestations include haematologic, pulmonary, 1. The existence of an infectious agent such as mycoplasma,
neurological and cardiovascular abnormalities. Epstein-Barr virus (EBV), cytomegalovirus (CMV) or rubella

852 Activation of macrophages releases more cytokines which
cause damage to joint tissues and vascularisation of cartilage
termed pannus formation.
Eventually damage and destruction of bone and cartilage
are followed by fibrosis and ankylosis producing joint
deformities.
MORPHOLOGIC FEATURES. The predominant patho-
logic lesions are found in the joints and tendons, and less
often, extra-articular lesions are encountered.
ARTICULAR LESIONS. RA involves first the small joints
of hands and feet and then symmetrically affects the joints
of wrists, elbows, ankles and knees. The proximal
interphalangeal and metacarpophalangeal joints are
affected most severely. Frequently cervical spine is
involved but lumbar spine is spared.
Histologically, the characteristic feature is diffuse
proliferative synovitis with formation of pannus. The
microscopic changes are as under (Fig. 28.25):
1. Numerous folds of large villi of synovium.
2. Marked thickening of the synovial membrane due to
oedema, congestion and multilayering of synoviocytes.
3. Intense inflammatory cell infiltrate in the synovial
membrane with predominence of lymphocytes, plasma
cells and some macrophages, at places forming lymphoid
follicles.
4. Foci of fibrinoid necrosis and fibrin deposition.
The pannus progressively destroys the underlying
SECTION III
cartilage and subchondral bone. This invasion of pannus
results in demineralisation and cystic resorption of under-
lying bone. Later, fibrous adhesions or even bony
ankylosis may unite the two opposing joint surfaces. In
addition, persistent inflammation causes weakening and
even rupture of the tendons.
EXTRA-ARTICULAR LESIONS. Nonspecific inflam-
Figure 28.24 Pathogenesis of rheumatoid arthritis.
matory changes are seen in the blood vessels (acute
vasculitis), lungs, pleura, pericardium, myocardium,
virus, either locally in the synovial fluid or systemic infection lymph nodes, peripheral nerves and eyes. But one of the
some time prior to the attack of RA. characteristic extra-articular manifestation of RA is
Systemic Pathology
2. The possible role of HLA-DR4 and HLA-DR1 in initia- occurrence of rheumatoid nodules in the skin. Rheumatoid
tion of immunologic damage. nodules are particularly found in the subcutaneous tissue
The proposed events in immunopathogenesis of RA are over pressure points such as the elbows, occiput and
as under (Fig. 28.24): sacrum. The centre of these nodules consists of an area of
In response to antigenic exposure (e.g. infectious agent) fibrinoid necrosis and cellular debris, surrounded by
in a genetically predisposed individual (HLA-DR), CD4+ T- several layers of palisading large epithelioid cells, and
cells are activated. peripherally there are numerous lymphocytes, plasma
These cells elaborate cytokines, the important ones being cells and macrophages. Similar nodules may be found in
tumour necrosis factor (TNF)-α, interferon (IF)-γ , interleukin the lung parenchyma, pleura, heart valves, myocardium
(IL)-1 and IL-6. and other internal organs.
These cytokines activate endothelial cells, B lymphocytes There are a few variant forms of RA:
and macrophages. 1. Juvenile RA found in adolescent patients under 16 years
Activation of B-cells releases IgM antibody against IgG of age is characterised by acute onset of fever and
(i.e. anti-IgG); this molecule is termed rheumatoid factor (RF). predominant involvement of knees and ankles. Pathologic
IgG and IgM immune complexes trigger inflammatory changes are similar but RF is rarely present.
damage to the synovium, small blood vessels and collagen. 2. Felty’s syndrome consists of polyarticular RA associated
Activated endothelial cells express adhesion molecules with splenomegaly and hypersplenism and consequent
which stimulate collection of inflammatory cells. haematologic derangements.

853



























Figure 28.25 Rheumatoid arthritis. The characteristic histologic features are villous hypertrophy of the synovium and marked mononuclear
inflammatory cell infiltrate in synovial membrane with formation of lymphoid follicles at places.


3. Ankylosing spondylitis or rheumatoid spondylitis is TUBERCULOUS ARTHRITIS
rheumatoid involvement of the spine, particularly sacroiliac Tuberculous infection of the joints results most commonly
joints, in young male patients. The condition has a strong from haematogenous dissemination of the organisms from CHAPTER 28
HLA-B27 association and may have associated inflammatory pulmonary or other focus of infection. Another route of
diseases such as inflammatory bowel disease, anterior uveitis infection is direct spread from tuberculous osteomyelitis close
and Reiter’s syndrome.
to the joint. Uncommon in the West, the disease is seen not
infrequently in developing countries more commonly in
SUPPURATIVE ARTHRITIS
children and also in adults.
Infectious or suppurative arthritis is invariably an acute
inflammatory involvement of the joint. Bacteria usually reach MORPHOLOGIC FEATURES. Tuberculous involvement
the joint space from the bloodstream but other routes of of the joints is usually monoarticular type but tends to be
infection by direct contamination of an open wound or more destructive than the suppurative arthritis. Most
lymphatic spread may also occur. Immunocompromised and commonly involved sites are the spine, hip joint and knees,
debilitated patients are increasingly susceptible to and less often other joints are affected. Tuberculosis of The Musculoskeletal System
suppurative arthritis. The common causative organisms are the spine is termed Pott’s disease or tuberculous spondylitis.
gonococci, meningococci, pneumococci, staphylococci, Grossly, the affected articular surface shows deposition
streptococci, H. influenzae and gram-negative bacilli. of grey-yellow exudate and occasionally tubercles are
Clinically, the patients present with manifestations of any present. The joint space may contain tiny grey-white loose
local infection such as redness, swelling, pain and joint bodies and excessive amount of fluid.
effusion. Constitutional symptoms such as fever, neutrophilic Histologically, the synovium is studded with solitary or
leucocytosis and raised ESR are generally associated. confluent caseating tubercles. The underlying articular
cartilage and bone may be involved by extension of
MORPHOLOGIC FEATURES. The haematogenous infec- tuberculous granulation tissue and cause necrosis (caries).
tious joint involvement is more often monoarticular rather
than polyarticular. The large joints of lower extremities
such as the knee, hip and ankle, shoulder and GOUT AND GOUTY ARTHRITIS
sternoclavicular joints are particularly favoured sites. The Gout is a disorder of purine metabolism manifested by the
process begins with hyperaemia, synovial swelling and following features, occurring singly or in combination:
infiltration by polymorphonuclear and mononuclear 1. Increased serum uric acid concentration (hyperuricaemia).
leucocytes alongwith development of effusion in the joint 2. Recurrent attacks of characteristic type of acute arthritis
space. There may be formation of inflammatory in which crystals of monosodium urate monohydrate may be
granulation tissue and onset of fibrous adhesions between demonstrable in the leucocytes present in the synovial fluid.
the opposing articular surfaces resulting in permanent 3. Aggregated deposits of monosodium urate monohydrate
ankylosis. (tophi) in and around the joints of the extremities.

854 4. Renal disease involving interstitial tissue and blood therapy, drug-induced (e.g. aspirin, pyrazinamide, nicotinic
vessels. acid, ethambutol and ethanol), adrenal insufficiency,
5. Uric acid nephrolithiasis. starvation, diabetic ketosis, and disorders of parathyroid and
The disease usually begins in 3rd decade of life and affects thyroid. Renal disease per se rarely causes secondary
men more often than women. A family history of gout is hyperuricaemia such as in polycystic kidney disease and
present in a fairly large proportion of cases indicating role of leads to urate nephropathy.
inheritance in hyperuricaemia. Clinically, the natural history
of gout comprises 4 stages: asymptomatic hyperuricaemia, MORPHOLOGIC FEATURES. The pathologic mani-
acute gouty arthritis, asymptomatic intervals of intercritical festations of gout include: acute gouty arthritis, chronic
periods, and chronic tophaceous stage. In addition, gout tophaceous arthritis, tophi in soft tissues, and renal lesions
nephropathy and urate nephrolithiasis may occur (page 692). as under:
1. Acute gouty arthritis. This stage is characterised by
TYPES AND PATHOGENESIS. The fundamental bio- acute synovitis triggered by precipitation of sufficient
chemical hallmark of gout is hyperuricaemia. A serum uric amount of needle-shaped crystals of monosodium urate
acid level in excess of 7 mg/dl, which represents the upper from serum or synovial fluid. There is joint effusion
limit of solubility of monosodium urate in serum at 37°C at containing numerous polymorphs, macrophages and
blood pH, is associated with increased risk of development microcrystals of urates. The mechanism of acute
of gout. Thus, pathogenesis of gout is pathogenesis of hyper- inflammation appears to include phagocytosis of crystals
uricaemia. by leucocytes, activation of the kallikrein system, activa-
Hyperuricaemia and gout may be classified into 2 types: tion of the complement system and urate-mediated
metabolic and renal, each of which may be primary or secondary. disruption of lysosomes within the leucocytes leading to
Primary refers to cases in which the underlying biochemical release of lysosomal products in the joint effusion. Initially,
defect causing hyperuricaemia is not known, while secondary there is monoarticular involvement accompanied with
denotes cases with known causes of hyperuricaemia.
intense pain, but later it becomes polyarticular along with
1. Hyperuricaemia of metabolic origin. This group constitutional symptoms like fever. Acute gouty arthritis
comprises about 10% cases of gout which are characterised is predominantly a disease of lower extremities, affecting
by overproduction of uric acid. There is either an accelerated most commonly great toe. Other joints affected, in order
rate of purine biosynthesis de novo, or an increased turnover of decreasing frequency, are: the instep, ankles, heels,
of nucleic acids. The causes of primary metabolic gout include knees, wrists, fingers and elbows.
SECTION III
a number of specific enzyme defects in purine metabolism 2. Chronic tophaceous arthritis. Recurrent attacks of
which may be either of unknown cause or are inborn errors acute gouty arthritis lead to progressive evolution into
of metabolism. The secondary metabolic gout is due to either chronic arthritis. The deposits of urate encrust the articular
increased purine biosynthesis or a deficiency of glucose-6- cartilage. There is synovial proliferation, pannus
phosphatase. formation and progressive destruction of articular
2. Hyperuricaemia of renal origin. About 90% cases of gout cartilage and subchondral bone. Deposits of urates in the
are the result of reduced renal excretion of uric acid. Altered form of tophi may be found in the periarticular tissues.
renal excretion could be due to reduced glomerular filtration 3. Tophi in soft tissue. A tophus (meaning ‘a porous
of uric acid, enhanced tubular reabsorption or decreased stone’) is a mass of urates measuring a few millimeters to
secretion. The causes of gout of renal origin include diuretic
Systemic Pathology


























Figure 28.26 A gouty tophus, showing central aggregates of urate crystals surrounded by inflammatory cells, fibroblasts and occasional giant
cells.

a few centimeters in diameter. Tophi may be located in 855
the periarticular tissues as well as subcutaneously such
as on the hands and feet. Tophi are surrounded by
inflammatory reaction consisting of macrophages,
lymphocytes, fibroblasts and foreign body giant cells
(Fig. 28.26).
4. Renal lesions. Chronic gouty arthritis frequently
involves the kidneys. Three types of renal lesions are
described in the kidneys: acute urate nephropathy, chronic
urate nephropathy and uric acid nephrolithiasis.
i) Acute urate nephropathy is attributed to the intratubular
deposition of monosodium urate crystals resulting in acute
obstructive uropathy.
ii) Chronic urate nephropathy refers to the deposition of
urate crystals in the renal interstitial tissue.
iii) Uric acid nephrolithiasis is related to hyperuricaemia
resulting in hyperuricaciduria (page 692).
Figure 28.27 Tenosynovial giant cell tumour. The tumour shows
PSEUDOGOUT (PYROPHOSPHATE ARTHROPATHY) infiltrate of small oval to spindled histiocytes with numerous interspersed
multinucleate giant cells lyning in a background of fibrous tissue.
Pseudogout refers to an inflammatory joint involvement due
to deposition of calcium pyrophosphate in the joint space. MORPHOLOGIC FEATURES. Though the two condi-
The condition is seen in middle-aged and elderly individuals tions have many morphologic similarities, they are best
of either sex. The pain is usually less severe and involvement described separately.
of big toe is rare. The pathogenesis is unclear but several Giant cell tumour of tendon sheath (Nodular
factors have been implicated. These include: associated tenosynovitis). The localised nodular tenosynovitis is seen CHAPTER 28
metabolic disease (e.g. hyperparathyroidism, hypothyroi- most commonly in the tendons of fingers.
dism, gout, ochronosis, Wilson’s disease and haemochroma- Grossly, it takes the form of a solitary, circumscribed,
tosis), heredity, familial occurrence, rheumatoid arthritis and pedunculated, small and lobulated nodule, measuring less
osteoarthritis.
than 2 cm in diameter. It is closely attached to and
sometimes grooved by the underlying tendon. On section,
MORPHOLOGIC FEATURES. The involvement may be the lesion is yellowish-brown.
monoarticular or polyarticular but large joints such as Histologically, it is well encapsulated and is composed
knees, hips and shoulders are more often affected. The of sheets of small oval to spindle-shaped cells, foamy
joint effusion contains crystals of calcium pyrophosphate. xanthoma cells, scattered multinucleate giant cells and
There is acute inflammatory response and deposits of irregular bundles of collagen. Many of the spindle-shaped
rhomboid crystals on the articular cartilage, ligaments, cells are haemosiderin-laden (Fig. 28.27).
tendons and joint capsule, termed chondrocalcinosis. The Musculoskeletal System
Pigmented villonodular tenosynovitis. This is a
diffuse form of synovial overgrowth seen most commonly
PIGMENTED VILLONODULAR SYNOVITIS AND in the knee and hip.
TENOSYNOVIAL GIANT CELL TUMOUR Grossly, the synovium has characteristic sponge-like
(NODULAR TENOSYNOVITIS) reddish-brown or tan appearance with intermingled
elongated villous projections and solid nodules.
The terms ‘pigmented villonodular synovitis’ and ‘nodular
tenosynovitis’ represent diffuse and localised form Histologically, the changes are modified by recurrent
respectively of the same underlying process. The localised injury. The enlarged villi are covered by hyperplastic
synovium and abundant subsynovial infiltrate of
form of lesion is also termed xanthofibroma or benign lymphocytes, plasma cells and macrophages, many of
synovioma. When the giant cells are numerous in localised which are lipid-laden and haemosiderin-laden.
tenosynovitis, the condition is called giant cell tumour of tendon Multinucleate giant cells are scattered in these areas.
sheath.
The origin and histogenesis of these conditions are
unknown. They were initially regarded as inflammatory in CYST OF GANGLION
origin and hence the name synovitis. But currently cyto- A ganglion is a small, round or ovoid, movable, subcuta-
genetic studies have shown clonal proliferation of cells neous cystic swelling. The most common location is dorsum
indicating that these lesions are neoplastic. Clinically, they of wrist but may be found on the dorsal surface of foot near
present with pain, swelling and limitation of movement of the ankle. Histogenesis of the ganglion is disputed. It may
the affected joint and may be easily mistaken for rheumatoid be the result of herniated synovium, embryologically
or infective arthritis. The lesions are adequately treated by displaced synovial tissue, or posttraumatic degeneration of
excision but recurrences are common. connective tissue.

856 Individual muscle fibre is an elongated multinucleated
syncytium-like cell about 100 μm in diameter and several
centimeters in length. The muscle nuclei are spindle-shaped
and lie at the periphery of fibre under the sarcolemma, the
plasma membrane of muscle fibre. The cytoplasm of the
muscle fibre contains myofilaments which are contractile
elements. Myofilaments are of 2 types—myosin comprising
thick filaments and actin constituting thin filaments. These
together produce cross-striations in muscle fibres seen in
longitudinal sections on light microscopy. Sarcomeres are the
partitions of myofilaments into equal zones. Each sarcomere
represents the distance between consecutive Z bands and
contains the central A (anisotropic) band, and the lateral I
(isotropic) bands.
The major functions of striated skeletal muscle are to
convert chemical energy into mechanical energy, to act as a
store of energy and proteins, and to play a role in the
Figure 28.28 Cyst of ganglion. The cyst wall is composed of dense metabolism of the body. The muscle, however, cannot
connective tissue lined internally by flattened lining. The cyst wall shows function as a contractile organ without a nerve supply. For
myxoid degeneration. this purpose, there are motor units, each of which consists
of the following:
MORPHOLOGIC FEATURES. Grossly, a ganglion is a 1. Motor neuron cell body located in the spinal cord anterior
small cyst filled with clear mucinous fluid. It may or may horn, or a cranial nerve nucleus.
not communicate with the joint cavity or tendon where it 2. The axon of the motor neuron in the peripheral or cranial
is located. nerve.
Microscopically, the cyst has a wall composed of dense 3. The neuromuscular junction.
or oedematous connective tissue which is sometimes lined 4. The muscle fibres innervated by the motor neuron.
by synovial cells but more often has indistinct lining The muscle fibre contraction occurs by action potential
(Fig. 28.28). generated by chemical transmission of the impulse across
SECTION III
the synaptic gap by acetylcholine.
BURSITIS Skeletal muscles are affected in a number of systemic
diseases and pathologic processes such as ischaemia and
Inflammation of bursa is termed bursitis. Bursae are synovial- toxic (Zenker’s) necrosis; atrophy and hypertrophy;
lined sacs found over bony prominences. Bursitis occurs degeneration and regeneration; and polymyositis, dermato-
following mechanical trauma or inflammation. It may result myositis, and various forms of infective myositis (e.g. viral
following a single injury such as olecranon bursitis and myositis, pyogenic myositis, gas gangrene and parasitic
prepatellar bursitis, but is more often due to repeated injuries involvements such as cysticercosis). Most of the conditions
from excessive pressure such as in housemaid’s knee or tennis have been considered already in different chapters. Here, two
elbow. important groups of specific diseases—neurogenic and
myopathic diseases, are discussed. A classification of
Systemic Pathology
MORPHOLOGIC FEATURES. Grossly, the bursal sac is neuromuscular disorders based on the part of the motor unit
thick-walled and may contain watery, mucoid or granular involved is presented in Table 28.4.
brown material.
Histologically, the bursal wall is composed of dense
fibrous tissue lined by inflammatory granulation tissue.   TABLE 28.4: Classification of Neuromuscular Diseases.
The wall is infiltrated by lymphocytes, plasma cells and Site of Motor Unit Disease
macrophages and may show focal calcium deposits.
I. ANTERIOR HORN CELL
1. Without upper motor Spinal muscular atrophy
neuron involvement
SKELETAL MUSCLES 2. With upper motor Amyotrophic lateral sclerosis
neuron involvement
NORMAL STRUCTURE II. PERIPHERAL NERVE
Striated skeletal muscles consist of bundles of fibres called 1. Unifocal Carpal-tunnel syndrome
fascicles, each of which is surrounded by connective tissue 2. Multifocal Mononeuritis multiplex
sheath termed perimysium. Perimysium contains blood 3. Diffuse Diabetic neuropathy
vessels and nerve supply of the muscle fascicles. Each muscle III. NEUROMUSCULAR JUNCTION Myasthenia gravis
fibre is enveloped by delicate fibrous stroma called
IV. MUSCLE Duchenne’s muscular dystrophy
endomysium.

857





















Figure 28.29 Neuromuscular junction in normal transmission (A) and in myasthenia gravis (B). The junction in MG shows reduced number of
AChRs, flattened and simplified postsynaptic folds, a widened synaptic space but a normal nerve terminal.


NEUROGENIC DISEASES failure to trigger muscle action potentials and consequent
The group of neurogenic diseases affecting skeletal muscles weakened muscle contraction. The neuromuscular
is characterised by a combination of muscular weakness and abnormalities in MG are mediated by autoimmune response.
fatiguability. The most common of these is myasthenia About 85-90% patients of MG have anti-AChR-antibodies in
gravis; others are congenital myasthenia, an acquired Eaton- their sera. These antibodies reduce the number of available
Lambert syndrome associated with carcinoma of the lung, AChRs either by blocking the active sites of the receptors or
and denervation atrophy. by damaging the post-synaptic muscle membrane in
collaboration with complement. The exact mechanism how CHAPTER 28
MYASTHENIA GRAVIS autoimmune response is initiated is not completely
understood but the thymus appears to play a role in this
Myasthenia gravis (MG) is a neuromuscular disorder of process (page 388). Majority of patients of MG may have
autoimmune origin in which the acetylcholine receptors either thymoma or thymic hyperplasia; thymectomy is
(AChR) in the motor end-plates of the muscles are damaged. helpful in ameliorating the condition. The thymus possibly
The term ‘myasthenia’ means ‘muscular weakness’ and ‘gravis’ sensitises B cells to produce anti-AChR antibodies.
implies ‘serious’; thus both together denote the clinical
characteristics of the disease. MG may be found at any age MORPHOLOGIC FEATURES. Grossly, the muscles
but adult women are affected more often than adult men in appear normal until late in the course of disease when
the ratio of 3:2. The condition presents clinically with they become wasted.
muscular weakness and fatiguability, initially in the ocular
musculature but later spreads to involve the trunk and limbs. By light microscopy, a few clumps of lymphocytes may The Musculoskeletal System
There is about 10% mortality in MG which is due to severe be found around small blood vessels. Degenerating
generalised disease and involvement of respiratory muscles. muscle fibres are present in half the cases.
Several other autoimmune diseases have been found Electron microscopy reveals reduction in synaptic area
associated with MG such as autoimmune thyroiditis, of the motor axons due to flattening or simplification of
rheumatoid arthritis, SLE, pernicious anaemia and collagen- postsynaptic folds. The number of AChRs is greatly
vascular diseases. reduced. By immunocytochemistry combined with
electron microscopy, it is possible to demonstrate the
PATHOGENESIS. The pathogenesis of MG is best complex of IgG and complement at the neuromuscular
understood in the context of normal muscle metabolism junctions.
(Fig. 28.29):
Normally, acetylcholine is synthesised in the motor nerve DENERVATION ATROPHY
terminal and stored in vesicles that are released If the muscle or a part of muscle is deprived of its motor
spontaneously when an action potential reaches the nerve nerve supply, the affected muscle undergoes atrophy. In
terminal. Acetylcholine from released vesicles combines with demyelination, on the other hand, there is conduction block
AChRs, initiating an action potential which is propagated in the nerve impulse but no denervation and hence muscle
along the muscle fibre triggering muscle contraction. atrophy does not occur.
In MG, the basic defect is reduction in the number of Denervating diseases are characterised by axonal
available AChRs at the postsynaptic muscle membrane. In degeneration and consequent muscle atrophy. These include
addition, the postsynaptic folds are flattened. These changes amyotrophic lateral sclerosis as an example of anterior horn
result in decreased neuromuscular transmission leading to cell disease, and peripheral neuropathy causing injury to

858


























Figure 28.30 Normal skeletal muscle (A) contrasted with findings in Duchenne’s muscular dystrophy (B) showing hyaline fibres, fibre degeneration,
loss of fibres and replacement by interstitial fibrosis and adipose tissue.

myelinated axon. The clinical manifestations of denervation MYOPATHIC DISEASES (MYOPATHIES)
atrophy are combination of muscular weakness and reduced Myopathies are primary skeletal muscle diseases resulting
muscle bulk. In amyotrophic lateral sclerosis, there are in chronic muscle weakness. These are divided into 5 broad
characteristic fasciculations of muscles of the shoulder and groups: hereditary (muscular dystrophies), inflammatory,
tongue.
endocrine, metabolic and toxic myopathies. Only the
MORPHOLOGIC FEATURES. Denervation atrophy is hereditary myopathies, also termed muscular dystrophies,
pathologically characterised by groups of small angulated are briefly considered below.
SECTION III
muscle fibres alternating with groups of plump, normal
or even hypertrophic fibres with intact innervation. MUSCULAR DYSTROPHIES
Further progression of the process may produce Muscular dystrophies are a group of genetically-inherited
superimposed changes of muscular dystrophy. primary muscle diseases, having in common, progressive and



  TABLE 28.5: Contrasting Features of Muscular Dystrophies.
Type Inheritance Age at Clinical Features Other Systems Course
Onset Involved
1. Duchenne’s X-linked By age 5 Symmetric weakness; initially Cardiomegaly; Progressive;
type recessive pelvifemoral; later weakness reduced intelligence death by age 20
Systemic Pathology
of girdle muscles; pseudo- due to respiratory
hypertrophy of calf muscles failure
2. Becker’s X-linked By 2nd Slow progressive weakness Cardiomegaly Benign
type recessive decade of girdle muscle (minor variant
of Duchenne’s type)
3. Myotonic Autosomal Any Slow progressive weakness Cardiac conduction Benign
type dominant decade and myotonia of eyelids, defects; mental
face, neck, distal limb impairment; cataracts;
muscles frontal baldness;
gonadal atrophy
4. Facioscapulo- Autosomal 2nd-4th Slowly progressive weakness Hypertension Benign
humeral type dominant decade of facial, scapular and
humeral muscles
5. Limb-girdle Autosomal Early child- Slowly progressive weakness Cardiomyopathy Variable
type recessive hood to of shoulder and hip progression
adult girdle muscles
6. Oculo- Autosomal 5th-6th Slowly progressive weakness — Rarely
pharyngeal dominant decade of extraocular eyelid, face and progressive
type pharyngeal muscles

unremitting muscular weakness. Six major forms of muscular childhood or in early adulthood. Family history of 859
dystrophies are described: Duchenne’s, Becker’s, myotonic, neuromuscular disease is elicited in many cases.
facio-scapulohumeral, limb-girdle and oculopharyngeal type. Each
type of muscular dystrophy is a distinct entity having MORPHOLOGIC FEATURES. Common to all forms of
differences in inheritance pattern, age at onset, clinical muscular dystrophies are muscle fibre necrosis,
features, other organ system involvements and clinical regenerative activity, replacement by interstitial fibrosis
course. These differences are summarised in Table 28.5. and adipose tissue (Fig. 28.30).
However, in general, muscular dystrophies manifest in
q CHAPTER 28



















































The Musculoskeletal System

860


Chapter 29 Soft Tissue Tumours
Chapter 29








GENERAL FEATURES ETIOLOGY AND PATHOGENESIS. Etiology of soft tissue
tumours remains largely unknown; however, a few common
INTRODUCTION. For the purpose of classification of this features in etiology and pathogenesis apply to many soft
group of tumours, the WHO has defined soft tissues as all tissue tumours:
“non-epithelial extra-skeletal tissues of the body except the 1. Frequently there is history of antecedent trauma which may
reticuloendothelial system, the glia and the supporting bring the tumour to attention of the patient.
tissues of specific organs and viscera”. Thus, soft tissues 2. Molecular and cytogenetic studies in many soft tissue
included for the purpose of categorisation of their tumours tumours reveal chromosomal abnormalities and mutations in
are: fibrous tissue, adipose tissue, muscle tissue, synovial genes which can be used as a marker for diagnosis and
tissue, blood vessels and neuroectodermal tissues of the histogenesis e.g. translocations, various fusion genes etc.
peripheral and autonomic nervous system. The lesions of 3. Most of the soft tissue tumours occur sporadically; however
these tissues are embryologically derived from mesoderm, there are a few examples which are components of genetic
except those of peripheral nerve which are derived from ecto- syndromes e.g. neurofibromatosis type 1, Li-Fraumeni
derm. Tumours of smooth muscle tissue, blood vessels and syndrome, Osler-Weber-Rendu syndrome etc.
nerves are described elsewhere in the book, while tumours CLASSIFICATION. Currently, the WHO classification
and tumour-like lesions composed of other soft tissues are divides all soft tissue tumours into following 4 categories:
discussed in this chapter.
Benign soft tissue tumours are about 100 times more Benign: These soft tissue tumours generally do not recur and
common than sarcomas. Sarcomas rarely arise from malig- are cured by complete excision. Common example is lipoma.
SECTION III
nant transformation of a pre-existing benign tumour. Instead, Intermediate, locally aggressive: These tumours are locally
sarcomas originate from the primitive mesenchymal cells destructive, infiltrative and often recur but do not
having the capacity to differentiate along different cell path- metastasise. Such tumours are generally treated by wide
ways. As discussed in Chapter 8, soft tissue sarcomas excision; for example desmoid tumour.
metastasise most frequently by the haematogenous route and Intermediate, rarely metstasising: This category of tumours
disseminate commonly to the lungs, liver, bone and brain. are also locally destructive, infiltrative and recurrent but in
Lymph node metastases are often late and are associated with addition about 2% cases may have clinical metastasis which
widespread dissemination of the tumour. Histologic differen- may not be predicted by morphology. Common example in
tiation and grading of soft tissue sarcomas are important this category is dermtofibrosarcoma protuberans.
because of varying clinical behaviour, prognosis and Malignant: Tumours in this category are clearly malignant—
response to therapy. they are locally destructive, infiltrative and metastasise in a
Systemic Pathology
Majority of soft tissue tumours have following important
general features: high percent of cases. The metastatic rate in low-grade
sarcomas is about 2-10% and in high-grade sarcomas is
Superficially-located tumours tend to be benign while 20-100%.
deep-seated lesions are more likely to be malignant.
Large-sized tumours are generally more malignant than DIAGNOSTIC CRITERIA. Accurate pathological diagnosis
small ones. of soft tissue tumours is based on histogenesis which is
Rapidly-growing tumours often behave as malignant important for determining the prognosis and can be made
tumours than those that develop slowly. by the following plan:
Malignant tumours have frequently increased vascularity 1. Cell patterns: Several morphological patterns in which
while benign tumours are selectively avascular. tumour cells are arranged are peculiar in different tumours
Although soft tissue tumours may arise anywhere in the e.g.
body but in general more common locations are: lower i) Smooth muscle tumours: interlacing fascicles of pink staining
extremity (40%), upper extremity (20%), trunk and tumour cells.
retroperitoneum (30%) and head and neck (10%). ii) Fibrohistiocytic tumours: characteristically have storiform
Generally, males are affected more commonly than pattern in which spindle tumour cells radiate from the centre
females. in a spoke-wheel manner.
Approximately 15% of soft tissue tumours occur in iii) Herringbone pattern: is seen in fibrosarcoma in which
children and include some specific examples of soft tissue the tumour cells are arranged like the vertebral column of
sarcomas e.g. rhabdomyosarcoma, synovial sarcoma. seafish.

iv) Pallisaded arrangement: is characteristically seen in 4. Electron microscopy: EM as such is mainly a research 861
schwannomas in which the nuclei of tumour cells are piled tool and does not have much diagnostic value in soft tissue
upon each other. tumours but can be applied sometimes to look for
v) Biphasic pattern: is the term used for a combination tonofilaments or cell organelles.
arrangement of two types—fascicles and epithelial-like e.g. 5. Cytogenetics: Many soft tissue tumours have specific
in synovial sarcoma. genetic and chromosomal changes which can be done for
2. Cell types: After looking at the pattern of cells described determining histogenesis, or for diagnosis and prognosis.
above, preliminary categorisation of soft tissue tumours is GRADING. The number of pathological grades of soft tissue
done on the basis of cell types comprising the soft tissue tumours may vary according to different grading systems:
tumour:
2 grade system (grade I-II as low and high grade), 3-grade
i) Spindle cells: These are the most common cell types in system (grade I, II, III as low, intermediate and high grade)
most sarcomas. However, there are subtle differences in and 4 grade system (grade I-IV). Pathological grading is
different types of spindle cells e.g. based on following 3 features:
a) Fibrogenic tumours have spindle cells with light pink i) Tumour differentiation or degree of cytologic atypia
cytoplasm and tapering-ended nuclei. ii) Mitotic count
b) Neurogenic (Schwann cell) tumours have tumour cells similar iii) Tumour necrosis
to fibrogenic cells but have curved nuclei.
c) Leiomyomatous tumours have spindle cells with blunt-ended STAGING. Different staging systems for soft tissue sarcomas
(cigar-shaped) nuclei and more intense eosinophilic have been described but two of the most accepted staging
cytoplasm. systems are Enneking’s staging and American Joint Committee
d) Skeletal muscle tumours have spindle cells similar to (AJC) staging system:
leiomyomatous cells but in addition have cytoplasmic Enneking’s staging: This staging system is accepted by most
striations. oncologists and is based on grade and location of tumour as
ii) Small round cells: Some soft tissue sarcomas are under:
characterised by dominant presence of small round cells or According to tumour location: T1 (intracompartmental) and CHAPTER 29
blue cells and are termed by various names such as malignant T2 (extracompartmental) tumours.
small round cell tumours, round cell sarcomas, or blue cell According to tumour grade : G1 (low grade) and G2 (high
tumours (due to presence of lymphocyte-like round nuclear grade) tumours.
size and dense blue chromatin). Examples of this group of Accordingly, the stages of soft tissue tumours vary from
tumours are as under: stage I to stage III as under:
a) Rhabdomyosarcoma (embryonal and alveolar types) Stage I: G1 and T1-T2 tumours, but no metastases.
b) Primitive neuroectodermal tumour (PNET) Stage II: G2 and T1 -T2 tumours, but without metstases.
c) Ewing’s sarcoma Stage III: G1 or G2 , T1 or T2 tumours, but with metastases.
d) Neuroblastoma AJC staging: This AJC system of staging is similar to
e) Malignant lymphomas. staging for other tumours. It is based on TNM system in Soft Tissue Tumours
A few examples of epithelial tumours such as small cell which the primary tumor (T), the status of lymph nodes
carcinoma and malignant carcinoid tumours enter in the (N) and presence or absence of metastases (M) are taken
differential diagnosis of small round cell tumours. into consideration for staging, besides the histologic grade
of the tumour.
iii) Epithelioid cells: Some soft tissue tumours have either After these brief general comments, some important
epithelioid cells as the main cells (e.g. epithelioid sarcoma) examples of tumours of different types of mesenchymal
or have epithelial-like cells as a part of biphasic pattern of tissue origin are described below.
the tumour (e.g. synovial sarcoma).
3. Immunohistochemistry: Soft tissue tumours are TUMOURS AND TUMOUR-LIKE
distinguished by application of immunohistochemical stains.
Antibody stains are available against almost each cell LESIONS OF FIBROUS TISSUE
constituent. Based on differential diagnosis made on routine Fibromas, fibromatosis and fibrosarcoma are benign, tumour-
morphology, the panel of antibody stains is chosen for like, and malignant neoplasms respectively, of fibrous
applying on paraffin sections for staining. Some common connective tissue.
examples are as under:
i) Smooth muscle actin (SMA): for smooth muscle tumours. FIBROMAS
ii) Vimentin: as common marker to distinguish mesenchymal
cells from epithelium. True fibromas are uncommon tumours in soft tissues. Many
iii) Desmin: for skeletal muscle cells. fibromas are actually examples of hyperplastic fibrous tissue
iv) S-100: for nerve fibres. rather than true neoplasms. On the other hand, combinations
v) Factor VIII: antigen for vascular endothelium. of fibrous growth with other mesenchymal tissue elements
vi) LCA (leucocyte common antigen): common marker for are more frequent e.g. neurofibroma, fibromyoma etc.
lymphoid cells. Three types of fibromas are distinguished:

862 KELOID. A keloid is a progressive fibrous overgrowth in
response to cutaneous injury such as burns, incisions, insect
bites, vaccinations and others. Keloids are found more often
in blacks. Their excision is frequently followed by
recurrences.

Grossly, the keloid is a firm, smooth, pink, raised patch
from which extend claw-like processes (keloid-claw).
Histologically, it is composed of thick, homogeneous,
eosinophilic hyalinised bands of collagen admixed with
thin collagenous fibres and large active fibroblasts. The
adnexal structures are atrophic or destroyed.
There are some differences between a keloid and a
hypertrophic scar. A hypertrophic scar of the skin is more
cellular and has numerous fibroblasts than a keloid and is
composed of thinner collagenous fibres. A keloid is a
progressive lesion and liable to recurrences after surgical
Figure 29.1 Fibroma of the oral cavity. The circumscribed lesion is excision.
composed of mature collagenised fibrous connective tissue.
NODULAR FASCITIS. Nodular fascitis, also called
pseudosarcomatous fibromatosis, is a form of benign and
1. Fibroma durum is a benign, often pedunculated and well- reactive fibroblastic growth extending from superficial fascia
circumscribed tumour occurring on the body surfaces and into the subcutaneous fat, and sometimes into the subjacent
mucous membranes. It is composed of fully matured and muscle. The most common locations are the upper extremity,
richly collagenous fibrous connective tissue (Fig. 29.1). trunk and neck region of young adults. Local excision is
generally curative. Less than 5% cases may have local
2. Fibroma molle or fibrolipoma, also termed soft fibroma, recurrence.
is similar type of benign growth composed of mixture of
mature fibrous connective tissue and adult-type fat. Grossly, the lesion appears as a solitary well-cirumscribed
nodule (true to its name) in the superficial fascia. The size
SECTION III
3. Elastofibroma is a rare benign fibrous tumour located in may vary from a centimeter to several centimeters in
the subscapular region. It is characterised by association of diameter.
collagen bundles and branching elastic fibres.
Microscopically, various morphologic patterns may be
seen but most common is a whorled or S-shaped pattern
FIBROMATOSIS
of fibroblasts present in oedematous background. The
‘Fibromatosis’ is the term used for tumour-like lesions of individual cells are spindle-shaped, plump fibroblasts
fibrous tissue which continue to proliferate actively and may showing mild nuclear atypia. Typical mitoses are frequent
be difficult to differentiate from sarcomas. These lesions may, but atypical mitoses are not present.
therefore, be regarded as non-metastasising fibroblastic
tumours which tend to invade locally and recur after surgical PALMAR AND PLANTAR FIBROMATOSES. These
excision. In addition, electron microscopy has shown that fibromatoses, also called Dupuytren-like contractures are the
Systemic Pathology
the cells comprising these lesions have features not only of most common form of fibromatoses occurring superficially.
fibroblasts but of both fibroblasts and smooth muscle cells, Palmar fibromatosis is more common in the elderly males
so called myofibroblasts. Depending upon the anatomic occurring in the palmar fascia and leading to flexion
locations and the age group affected, fibromatoses are contractures of the fingers (Dupuytren’s contracture). It
broadly grouped as under: appears as a painless, nodular or irregular, infiltrating,
benign fibrous subcutaneous lesion. In almost half the cases,
A. Infantile or juvenile fibromatoses include: fibrous the lesions are bilateral.
hamartoma of infancy, fibromatosis colli, diffuse infantile
fibromatosis, juvenile aponeurotic fibroma, juvenile Plantar fibromatosis is a similar lesion occurring on the
nasopharyngeal angiofibroma and congenital (generalised medial aspect of plantar arch. However, plantar lesions are
and solitary) fibromatosis. less common than palmar type and do not cause contractures
as frequently as palmar lesions. They are seen more often in
B. Adult type of fibromatoses are: palmar and plantar adults and are infrequently multiple and bilateral. Essentially
fibromatosis, nodular fascitis, cicatricial fibromatosis, keloid, similar lesions occur in the shaft of the penis (penile
irradiation fibromatosis, penile fibromatosis (Peyronie’s fibromatosis or Peyronie’s disease) and in the soft tissues of the
disease), abdominal and extra-abdominal desmoid knuckles (knuckle pads).
fibromatosis, and retroperitoneal fibromatosis.
Obviously, it is beyond the scope of the present discus- Histologically, palmar and plantar fibromatoses have
sion to cover all these lesions. Some of the important forms similar appearance. The nodules are composed of
of fibromatoses are briefly discussed here. fibrovascular tissue having plump, tightly-packed fibro-

blasts which have high mitotic rate. Ultrastructurally, 863
some of the fibroblasts have features of myofibroblasts
having contractile nature. The palmar lesions frequently
extend into soft tissues causing contractures. Both palmar
and plantar lesions may remain stationary at nodular
stage, progress, or regress spontaneously. Recurrence rate
after surgical excision in both forms is as high as 50-60%.

DESMOID FIBROMATOSES. Desmoid fibromatoses or
musculo-aponeurotic fibromatoses, commonly referred to as
desmoid tumours, are of 2 types: abdominal and extra-
abdominal. Both types are, however, histologically similar.
Clinically, both types behave in an aggressive manner and
have to be distinguished from sarcomas. Recurrences are
frequent and multiple. The pathogenesis of these lesions is
not known but among the factors implicated are the role of
antecedent trauma, genetic influences and relationship to
oestrogen as obsereved by occurrence of these lesions in Figure 29.2 Fibrosarcoma, common clinical location.
pregnancy.
Abdominal desmoids are locally aggressive infiltrating are composed of uniform-looking fibroblasts arranged in
tumour-like fibroblastic growths, often found in the musculo- bands and fascicles. Pleomorphism and mitoses are
aponeurotic structures of the rectus muscle in the anterior infrequent. The older regions of the tumour have hypo-
abdominal wall in women during or after pregnancy.
cellular hyalinised collagen.
Extra-abdominal desmoids, on the other hand, are more
common in men and are widely distributed such as in the CHAPTER 29
upper and lower extremities, chest wall, back, buttocks, and FIBROSARCOMA
head and neck region. The number of soft tissue tumours diagnosed as fibrosarcoma
Intra-abdominal desmoids present at the root of the small has now dropped, partly because of reclassification of
bowel mesentery are associated with Gardner’s syndrome fibromatoses which have aggressive and recurrent behaviour,
(consisting of fibromatosis, familial intestinal polyposis, and partly due to inclusion of many of such tumours in the
osteomas and epidermal cysts). group of fibrous histiocytomas (described later).
Fibrosarcoma is a slow-growing tumour, affecting adults
Grossly, desmoids are solitary, large, grey-white, firm and between 4th and 7th decades of life. Most common locations
unencapsulated tumours infiltrating the muscle locally. are the lower extremity (especially thigh and around the
Cut surface is whorled and trabeculated. knee), upper extremity, trunk, head and neck, and Soft Tissue Tumours
Microscopically, their appearance is rather misleadingly retroperitoneum (Fig. 29.2). The tumour is capable of
bland in contrast with aggressive local behaviour. They metastasis, chiefly via the blood stream.





























Figure 29.3 Fibrosarcoma. Microscopy shows a well-differentiated tumour composed of spindle-shaped cells forming interlacing fascicles
producing a typical Herring-bone pattern. A few mitotic figures are also seen.

864 Grossly, fibrosarcoma is a grey-white, firm, lobulated and
characteristically circumscribed mass. Cut surface of the
tumour is soft, fishflesh-like, with foci of necrosis and
haemorrhages.
Histologically, the tumour is composed of uniform,
spindle-shaped fibroblasts arranged in intersecting
fascicles. In well-differentiated tumours, such areas
produce ‘herring-bone pattern’ (herring-bone is a sea fish)
(Fig. 29.3). Poorly-differentiated fibrosarcoma, however,
has highly pleomorphic appearance with frequent mitoses
and bizarre cells.

FIBROHISTIOCYTIC TUMOURS

The group of fibrohistiocytic tumours is characterised by
distinctive light microscopic features that include presence
of cells with fibroblastic and histiocytic features in varying
proportion and identification of characteristic cart-wheel or Figure 29.4 Malignant fibrous histiocytoma. The lobulated tumour
storiform pattern in which the spindle cells radiate outward infiltrating the skeletal muscle is somewhat circumscribed. Cut surface
is grey-white fleshy with areas of haemorrhage and necrosis.
from the central focus. The histogenesis of these cells is
uncertain but possibly they arise from primitive
mesenchymal cells or facultative fibroblasts which are
capable of differentiating along different cell lines. The group 5th to 7th decades. Most common locations are the lower
includes full spectrum of lesions varying from benign (benign and upper extremities and retroperitoneum. It begins as a
painless, enlarging mass, generally in relation to skeletal
fibrous histiocytoma) to malignant (malignant fibrous muscle, deep fascia or subcutaneous tissue. The tumour is
histiocytoma), with dermatofibrosarcoma protuberans believed to arise from primitive mesenchymal cells which
occupying the intermediate (low-grade malignancy) position.
are capable of differentiating towards both fibroblastic and
histiocytic cell lines.
SECTION III
BENIGN FIBROUS HISTIOCYTOMA
Grossly, MFH is a multilobulated, well-circumscribed,
Depending upon the location and predominant pattern, firm or fleshy mass, 5-10 cm in diameter. Cut surface is
benign fibrous histiocytomas include a number of diverse grey-white, soft and myxoid (Fig. 29.4).
entities such as dermatofibroma, sclerosing haemangioma, Histologically, there is marked variation in appearance
fibroxanthoma, xanthogranuloma, giant cell tumour of
tendon sheath and pigmented villonodular synovitis. All from area to area within the same tumour. In general,
these tumours have mixed composition of benign fibroblastic there is admixture of spindle-shaped fibroblast-like cells
and histiocytic pattern of cells and have been described in and mononuclear round to oval histiocyte-like cells which
relevant sections already. may show phagocytic function. There is tendency for the
spindle shaped cells to be arranged in characteristic cart-
DERMATOFIBROSARCOMA PROTUBERANS wheel or storiform pattern. The tumour cells show
Systemic Pathology
varying degree of pleomorphism, hyperchromatism,
Dermatofibrosarcoma protuberans is a low-grade malignant mitotic activity and presence of multinucleate bizarre
cutaneous tumour of fibrohistiocytic origin. The tumour tumour giant cells. Usually there are numerous blood
recurs locally, and in rare instances gives rise to distant vessels and some scattered lymphocytes and plasma cells
metastases. Most frequent location is the trunk. (Fig. 29.5). Important immunohistochemical markers for
Grossly, the tumour forms a firm, solitary or multiple, MFH include vimentin, α-chymotrypsin, CD68 and
satellite nodules extending into the subcutaneous fat and factor VIII-a.
having thin and ulcerated skin surface. Besides the storifrom pleomorphic MFH as the
Histologically, the tumour is highly cellular and is prototype, a few morphologic variants of MFH having
composed of fibroblasts arranged in a cart-wheel or bearing on prognosis include the following:
storiform pattern. Myxoid MFH shows areas of loose myxoid stroma
in the cellular areas and has an overall better prognosis.
MALIGNANT FIBROUS HISTIOCYTOMA Inflammatory MFH is an undifferentiated high-grade
MFH having prominent neutrophilic infiltrate besides
Malignant fibrous histiocytomas (MFH) represent approxi- the presence of eosinophils, histiocytes and xanthoma
mately 20-30% of all soft tissue sarcomas. It is the most cells.
common soft tissue sarcoma and is the most frequent sarcoma
associated with radiotherapy. The tumour occurs more Prognosis is determined by 2 parameters: depth of
commonly in males and more frequently in the age group of location and size of the tumour. Deep-seated and large MFH

865

























Figure 29.5 Malignant fibrous histiocytoma. The tumour shows admixture of spindle-shaped pleomorphic cells forming storiform (cart-wheel)
pattern and histiocyte-like round to oval cells. Bizarre pleomorphic multinucleate tumour giant cells and some mononuclear inflammatory cells are
also present.

such as of the retroperitoneum have poorer prognosis than sites are the subcutaneous tissues in the neck, back and
those small in size and located superficially which come to shoulder (Fig. 29.6,A). A lipoma rarely ever transforms into
attention earlier. Metastases are frequent, most often to the liposarcoma.
lungs and regional lymph nodes. Five-year survival rate is
approximately 30-50%. Grossly, a subcutaneous lipoma is usually small, round CHAPTER 29
to oval and encapsulated mass. The cut surface is soft,
TUMOURS OF ADIPOSE TISSUE lobulated, yellowish-orange and greasy (Fig. 29.6, B).
Histologically, the tumour is composed of lobules of
Lipomas and liposarcomas are the common examples of mature adipose cells separated by delicate fibrous septa.
benign and malignant tumours respectively of adipose tissue. A thin fibrous capsule surrounds the tumour (Fig. 29.7).
Uncommon varieties of adipose tissue tumours include
hibernoma, a benign tumour arising from brown fat, and A variety of admixture of lipoma with other tissue
lipoblastoma (foetal lipoma) resembling foetal fat and found components may be seen. These include: fibrolipoma
predominantly in children under 3 years of age. (admixture with fibrous tissue), angiolipoma (combination Soft Tissue Tumours
with proliferating blood vessels) and myelolipoma
LIPOMA (admixture with bone marrow elements as seen in adrenals).
Lipoma is the commonest soft tissue tumour. It appears as a Infrequently, benign lipoma may infiltrate the striated muscle
solitary, soft, movable and painless mass which may remain (infiltrating or intramuscular lipoma). Spindle cell lipoma
stationary or grow slowly. Lipomas occur most often in 4th and pleomorphic (atypical) lipoma are the other unusual
to 5th decades of life and are frequent in females. They may variants of lipoma. The latter type may be particularly
be found at different locations in the body but most common difficult to distinguish from well-differentiated liposarcoma.





















Figure 29.6 Lipoma. A, Common clinical location. B, The cut surface
of the tumour is soft, lobulated, yellowish and greasy.

866
























Figure 29.7 Lipoma. The tumour shows a thin capsule and underlying lobules of mature adipose cells separated by delicate fibrous septa.



LIPOSARCOMA Histologically, the hallmark of diagnosis of liposarcoma
Liposarcoma is one of the most common soft tissue is the identification of variable number of lipoblasts which
sarcomas in adults, perhaps next in frequency only to may be univacuolated or multivacuolated (Fig. 29.4). The
malignant fibrous histiocytoma. Unlike lipoma which vacuoles represent fat in the cytoplasm. Four major
originates from mature adipose cells, liposarcoma arises histologic varieties of liposarcomas are distinguished:
from primitive mesenchymal cells, the lipoblasts. The peak well-differentiated, myxoid, round cell, and pleomorphic
incidence is in 5th to 7th decades of life. In contrast to (Fig. 29.8):
lipomas which are more frequently subcutaneous in 1. Well-differentiated liposarcoma resembles lipoma but
SECTION III
location, liposarcomas often occur in the deep tissues. Most contains uni- or multi-vacuolated lipoblasts.
frequent sites are intermuscular regions in the thigh, 2. Myxoid liposarcoma is the most common histologic type.
buttocks and retroperitoneum. It is composed of monomorphic, fusiform or stellate cells
representing primitive mesenchymal cells, lying dispersed
Grossly, liposarcoma appears as a nodular mass, 5 cm or in mucopolysaccharide-rich ground substance. Occasional
more in diameter. The tumour is generally circumscribed tumour giant cells may be present. Prominent meshwork
but infiltrative. Cut surface is grey-white to yellow, of capillaries forming chicken-wire pattern is a
myxoid and gelatinous. Retroperitoneal masses are conspicuous feature.
generally much larger.


Systemic Pathology


























Figure 29.8 Liposarcoma. The tumour shows characteristic, univacuolated and multivacuolated lipoblasts with bizarre nuclei. Inset in the right
photomicrograph shows close-up view of a typical lipoblast having multivacuolated cytoplasm indenting the atypical nucleus.

3. Round cell liposarcoma is composed of uniform, round Histologically, the tumour cells have resemblance to 867
to oval cells having fine multivacuolated cytoplasm with embryonal stage of development of muscle fibres. There
central hyperchromatic nuclei. Round cell liposarcoma is considerable variation in cell types. Generally, the
may resemble a signet-ring carcinoma but mucin stains tumour consists of a mixture of small, round to oval cells
help in distinguishing the two. and spindle-shaped strap cells having tapering bipolar
4. Pleomorphic liposarcoma is highly undifferentiated and cytoplasmic processes in which cross-striations may be
the most anaplastic type. There are numerous large evident. The tumour cells form broad fascicles or bands.
tumour giant cells and bizarre lipoblasts. Mitoses are frequent.
The prognosis of liposarcoma depends upon the location 2. BOTRYOID RHABDOMYOSARCOMA. Botryoid
and histologic type. In general, well-differentiated and variety is regarded as a variant of embryonal rhabdomyo-
myxoid varieties have excellent prognosis, while sarcoma occurring in children under 10 years of age. It is
pleomorphic liposarcoma has significantly poorer prognosis. seen most frequently in the vagina, urinary bladder and nose
Round cell and pleomorphic variants metastasise frequently (page 724).
to the lungs, other visceral organs and serosal surfaces.
Grossly, the tumour forms a distinctive grape-like
SKELETAL MUSCLE TUMOURS gelatinous mass protruding into the hollow cavity.
Histologically, the tumour grows underneath the muco-
Rhabdomyoma and rhabdomyosarcoma are the benign and sal layer, forming the characteristic cambium layer of
malignant tumours respectively of striated muscle. tumour cells. The tumour is hypocellular and myxoid with
predominance of small, round to oval tumour cells
RHABDOMYOMA (Fig. 29.9).
Rhabdomyoma is a rare benign soft tissue tumour. It should
not be confused with glycogen-containing lesion of the heart 3. ALVEOLAR RHABDOMYOSARCOMA. Alveolar type
designated as cardiac rhabdomyoma which is probably a of rhabdomyosarcoma is more common in older children and
hamartomatous lesion and not a true tumour. Soft tissue young adults under the age of 20 years. The most common CHAPTER 29
rhabdomyomas are predominantly located in the head and locations, unlike the embryonal variety, are the extremities.
neck, most often in the upper neck, tongue, larynx and Grossly, the tumour differs from embryonal type in arising
pharynx.
directly from skeletal muscle and grows rapidly as soft
Histologically, the tumour is composed of large, round and gelatinous mass.
to oval cells, having abundant, granular, eosinophilic Histologically, the tumour shows characteristic alveolar
cytoplasm which is frequently vacuolated and contains pattern resembling pulmonary alveolar spaces. These
glycogen. Cross-striations are generally demonstrable in spaces are formed by fine fibrocollagenous septa. The
some cells with phosphotungstic acid-haematoxylin tumour cells lying in these spaces and lining the fibrous
(PTAH) stain. The tumour is divided into adult and foetal Soft Tissue Tumours
types, depending upon the degree of resemblance of
tumour cells to normal muscle cells.


RHABDOMYOSARCOMA
Rhabdomyosarcoma is a much more common soft tissue
tumour than rhabdomyoma, and is the commonest soft tissue
sarcoma in children and young adults. It is a highly malignant
tumour arising from rhabdomyoblasts in varying stages of
differentiation with or without demonstrable cross-striations.
Depending upon the growth pattern and histology, 4 types
are distinguished: embryonal, botryoid, alveolar and
pleomorphic.
1. EMBRYONAL RHABDOMYOSARCOMA. The
embryonal form is the most common of the rhabdo-
myosarcomas. It occurs predominantly in children under 12
years of age. The common locations are in the head and neck
region, most frequently in the orbit, urogenital tract and the
retroperitoneum.

Grossly, the tumour forms a gelatinous mass growing
between muscles or in the deep subcutaneous tissues but Figure 29.9 Botryoid rhabdomyosarcoma, nose. The tumour shows
generally has no direct relationship to the skeletal muscle. the characteristic submucosal Cambium layer of tumour cells. The tumour
cells are round to oval and have anaplasia.

868























Figure 29.10 Alveolar rhabdomyosarcoma. The tumour is divided into alveolar spaces composed of fibrocollagenous tissue. The fibrous
trabeculae are lined by small, dark, undifferentiated tumour cells, with some cells floating in the alveolar spaces. A few multinucleate tumour giant
cells are also present.



trabeculae are generally small, lymphocyte-like with 855. Synovial sarcoma or malignant synovioma, on the other
frequent mitoses and some multinucleate tumour giant hand, is a distinctive soft tissue sarcoma arising from
cells (Fig. 29.10). Cross-striation can be demonstrated in synovial tissues close to the large joints, tendon sheaths,
about a quarter of cases. bursae and joint capsule but almost never arising within
joint cavities. Most common locations are the extremities,
4. PLEOMORPHIC RHABDOMYOSARCOMA. This less frequently the lower extremity. However, synovial sarcoma
frequent variety of rhabdomyosarcoma occurs is also found in regions where synovial tissue is not present
predominantly in older adults above the age of 40 years. They such as in the anterior abdominal wall, parapharyngeal
SECTION III
are most common in the extremities, most frequently in the region and the pelvis. The tumour principally occurs in
lower limbs. young adults, usually under 40 years of age. The tumour
grows slowly as a painful mass but may metastasise via
Grossly, the tumour forms a well-circumscribed, soft, blood stream, chiefly to the lungs.
whitish mass with areas of haemorrhages and necrosis. The histogenesis of tumour is, believed to be from
Histologically, the tumour cells show considerable multipotent mesenchymal cells which may differentiate
variation in size and shape. The tumour is generally along different cell lines.
composed of highly anaplastic cells having bizarre
appearance and numerous multinucleate giant cells. Grossly, the tumour is of variable size and is grey-white,
Various shapes include racquet shape, tadpole appear- round to multilobulated and encapsulated. Cut surface
ance, large strap cells, and ribbon shapes containing shows fishflesh-like sarcomatous appearance with foci of
Systemic Pathology
several nuclei in a row. calcification, cystic spaces and areas of haemorrhages and
Conventionally, the cross-striations can be demons- necrosis.
trated with PTAH stain in a few rhabdomyosracomas. Microscopically, classic synovial sarcoma shows a
Immunohistochemical stains include: myogenin, Myo-D1, characteristic biphasic cellular pattern composed of clefts
desmin, actin, myosin, myoglobin, and vimentin. or gland-like structures lined by cuboidal to columnar
epithelial-like cells and plump to oval spindle cells
(Fig. 29.11). Reticulin fibres are present around spindle
TUMOURS OF UNCERTAIN HISTOGENESIS cells but absent within the epithelial foci. The spindle cell
areas form interlacing bands similar to those seen in
Some soft tissue tumours have a distinctive morphology but fibrosarcoma. Myxoid matrix, calcification and
their exact histogenesis is unclear. A few examples are hyalinisation are frequently present in the stroma. Mitoses
described below. and multinucleate giant cells are infrequent. Immuno-
histochemically, both types of tumour cells are positive
SYNOVIAL SARCOMA (MALIGNANT SYNOVIOMA) for cytokeratin.
Whether true benign tumours of synovial tissue exist is An uncommon variant of synovial sarcoma is monophasic
controversial. Pigmented villonodular synovitis and giant pattern in which the epithelial component is exceedingly rare
cell tumours of tendon sheaths, both of which are tumour- and thus the tumour may be difficult to distinguish from
like lesions of synovial tissues are discussed already on page fibrosarcoma.

869

























Figure 29.11 Classic synovial sarcoma, showing characteristic biphasic cellular pattern. The tumour is composed of epithelial-like cells lining
cleft-like spaces and gland-like structures, and spindle cell areas forming fibrosarcoma-like growth pattern.


ALVEOLAR SOFT PART SARCOMA the skin and subcutaneous tissues as a small swelling. The
tumour is slow growing but metastasising.
Alveolar soft part sarcoma is a histologically distinct, slow-
growing malignant tumour of uncertain histogenesis. The Grossly, the tumour is somewhat circumscribed and has
tumour may occur at any age but affects children and young nodular appearance with central necrosis. CHAPTER 29
adults more often. Most alveolar soft part sarcomas occur in Microscopically, the tumour cells comprising the nodules
the deep tissues of the extremities, along the musculofascial have epithelioid appearance by having abundant pink
planes, or within the skeletal muscles. cytoplasm and the centres of nodules show necrosis and
Grossly, the tumour is well-demarcated, yellowish and thus can be mistaken for a granuloma.
firm.
Microscopically, the tumour shows characteristic alveo- CLEAR CELL SARCOMA
lar pattern. Organoid masses of tumour cells are separated Clear cell sarcoma, first described by Enginzer, is seen in
by fibrovascular septa. The tumour cells are large and skin and subcutaneous tissues, especially of hands and feet.
regular and contain abundant, eosinophilic, granular Soft Tissue Tumours
cytoplasm which contains diastase-resistant PAS-positive Microscopically, it closely resembles malignant
material. This feature distinguishes the tumour from melanoma, and is therefore also called melanoma of the
paraganglioma, with which it closely resembles. soft tissues.

GRANULAR CELL MYOBLASTOMA TUMOUR-LIKE LESIONS
Granular cell tumour is a benign tumour of unknown histo- Besides the soft tissue tumours, there are some proliferative
genesis. It may occur at any age but most often affected are conditions of the soft tissues which resemble clinically and
young to middle-aged adults. The most frequent locations morphologically with soft tissue tumours. Important
are the tongue and subcutaneous tissue of the trunk and examples are nodular fascitis (pseudosarcomatous fascitis)
extremities. and myositis ossificans. The former condition has already
been described under fibromatous lesions while the latter is
Grossly, the tumour is generally small, firm, grey-white discussed below.
to yellow-tan nodular mass.

Histologically, the tumour consists of nests or ribbons of MYOSITIS OSSIFICANS
large, round or polygonal, uniform cells having finely
granular, acidophilic cytoplasm and small dense nuclei. Myositis ossificans is a benign, tumour-like lesion
The tumours located in the skin are frequently associated characterised by osteoid and heterotopic bone formation in
with pseudoepitheliomatous hyperplasia of the overlying the soft tissues. It is a misnomer since the lesion neither occurs
skin. exclusively in the skeletal muscle as the name leads one to
believe, nor are the inflammation or ossification always
essential.
EPITHELIOID SARCOMA
Myositis ossificans is generally preceded by history of
This soft tissue sarcoma occurring in young adults is peculiar antecedent trauma to a skeletal muscle or its tendon. The
in that it presents as an ulcer with sinuses, often located on trauma may be minor and repetitive e.g. to the adductor

870 muscles of the thigh of a horseman, or may be single injury Histologically, the central region of the mass shows
followed by haemorrhage into the muscle. The patient loosely-arranged fibroblasts having high mitotic activity.
generally complains of pain, tenderness and swelling. Towards the periphery, there is presence of osteoid matrix
Richly vascularised granulation tissue replaces the affected and formation of woven mineralised bone with trapped
muscle or tendon. Then follows development of osteoid skeletal muscle fibres and regenerating muscle (myogenic)
and bone at the periphery, giving characteristic X-ray giant cells. The appearance is sufficiently atypical to
appearance. suggest osteosarcoma but osteosarcoma lacks maturation
phenomena seen in myositis ossificans. This is why the
Grossly, the lesion appears as unencapsulated, gritty mass condition is also called pseudomalignant osseous tumour of
replacing the muscle.
the soft tissues.


❑























SECTION III














Systemic Pathology

871


Chapter 30 The Nervous System
Chapter 30








CENTRAL NERVOUS SYSTEM dendrites (Fig. 30.1,A). The cell body (or perikaryon) is the
main constituent of the neuron from which an axon and
NORMAL STRUCTURE numerous dendritic processes extend. The cell bodies may
be arranged in layers as in the cerebral cortex, or may be
The skull and the vertebrae form a rigid compartment aggregated as in the basal ganglia. The cell body possesses a
encasing the delicate brain and spinal cord. The average large, round, centrally-placed nucleus having finely granular
weight of the brain is about 1400 gm in men and 1250 gm in nuclear chromatin and a prominent nucleolus. The cytoplasm
women. The two main divisions of the brain— the cerebrum contains polygonal, basophilic structures called Nissl
and the cerebellum, are quite distinct in structure. The brain substance. It consists of aggregates of RNA, sheaves of rough
does not have lymphatic drainage. There are 2 types of tissues endoplasmic reticulum and intervening groups of free
in the nervous system: ribosomes. Besides Nissl substance, other special features of
1. Neuroectodermal tissues which include neurons (nerve the cytoplasm of neuronal cell body are the presence of
cells) and neuroglia, and together form the predominant microtubules, synaptic vesicles and neurofilaments which
constituent of the CNS. are a form of intermediate filaments specific to neurons.
2. Mesodermal tissues are microglia, dura mater, the lepto- Lipofuscin may be present due to ageing. Neuromelanin is
meninges (pia-arachnoid), blood vessels and their found in neurons in the substantia nigra and pigmented CHAPTER 30
accompanying mesenchymal cells. nucleus of the pons.
The predominant tissues comprising the nervous system Neurons respond to injury in a variety of ways depen-
and their general response to injury are briefly considered ding upon the etiologic agent and the pathologic processes.
below:
These include central chromatolysis, atrophy and
1. NEURONS. The neurons are highly specialised cells of degeneration of neurons and axons, and intraneuronal
the body which are incapable of dividing after the first few storage of substances.
weeks of birth. Thus, brain damage involving the neurons is Neuropil is the term used for the fibrillar network formed
irreversible. Neurons vary considerably in size and shape. by processess of all the neuronal cells.
Their size may range from the small granular cells of the
cerebellum to large Betz cells of the motor cortex. Some 2. NEUROGLIA. The neuroglia provides supportive matrix The Nervous System
neurons are round, others oval or fusiform but the prototype and maintenance to the neurons. It includes 3 types of cells:
of cortical neuron is pyramidal in shape. A neuron consists astrocytes, oligodendrocytes and ependymal cells
of 3 main parts: the cell body, an axon and numerous (Fig. 30.1,B). Neuroglia is generally referred to as glia; the





























Figure 30.1 Cells comprising the nervous system.

872 tumours originating from it are termed gliomas, and reactive system, aqueduct, central canal of the spinal cord and cover
proliferation of the astrocytes being called gliosis. the choroid plexus. They are cuboidal to columnar cells and
i) Astrocytes. The astrocytes are stellate cells with have ciliated luminal surface, just beneath which are present
numerous fine branching processes. In routine haematoxylin small bodies termed blepharoplasts.
and eosin stains, an astrocyte has round or oval vesicular The ependymal cells influence the formation and
nucleus, but unlike neuron, lacks a prominent nucleolus. The composition of the cerebrospinal fluid (CSF) by processes of
cytoplasm is generally scanty. The processes radiate from active secretion, diffusion, absorption and exchange. The
the cell body. Depending upon the type of processes, two function of cilia is not very clear but probably they play a
types of astrocytes are distinguished: role in the circulation of CSF. The ependymal cells respond
to injury by cell loss and the space left is filled by proliferation
Protoplasmic astrocytes have branched processes and are of underlying glial fibres.
found mostly in the grey matter.
3. MICROGLIA. Microglia is the nervous system counter-
Fibrous astrocytes have long, thin processes and are present
mainly in the white matter. part of the monocyte-macrophage system. Although the term
Some astrocytic processes are directed towards neurons ‘microglia’ is commonly used but it is inappropriate since
and their processes, which others surround capillaries by these cells, unlike neuroglia, are not of neuroectodermal
terminal expansions called foot processes. The astrocytic origin. Microglial cells (or Hortega cells) are not fixed but
processes may not be visible by routine stains but can be are mobile cells. These cells are found throughout the brain
demonstrated by phosphotungstic acid haematoxylin and are often present close to the blood vessels. Normally,
(PTAH) stain. Ultrastructurally, these processes are microglial cells appear as small inconspicuous cells with
composed of abundant intermediate filaments, mostly bean-shaped vesicular nuclei, scanty cytoplasm and long
vimentin. cytoplasmic processes (Fig. 30.1,C). In response to injury or
The main functions of astrocytes in health are physio- damage, however, these cells have capability to enlarge in
logical and biochemical support to the neurons and size, proliferate and develop elongated nuclei, so called rod
interactions with capillary endothelial cells to establish blood cells. Microglial cells may actually assume the shape and
brain barrier. In case of damage to the brain, astrocytes act phagocytic function of macrophages and form gitter cells. The
like fibroblasts of other tissues. The astrocytes in respond to foci of necrosis and areas of selective hypoxic damage to the
injury undergo hyperplasia and hypertrophy termed ‘gliosis’ neurons are surrounded by microglial cells which perform
which is an equivalent of scar elsewhere in the body. phagocytosis of damaged and necrosed cells; this is known
SECTION III
as neuronophagia.
Gemistocytic astrocytes are early reactive astrocytes having
prominent pink cytoplasm. Long-standing progressive 4. DURA MATER. The dura mater is a tough fibrous
gliosis results in the development of Rosenthal fibres which covering of the brain which is closely attached to the skull
are eosinophilic, elongated or globular bodies present on the on its inner layer of endocranial periosteum. In the region of
astrocytic processes. spinal canal, it encloses a potential space, the epidural space,
Corpora amylacea are basophilic, rounded, sometimes between the bone and the dura. The dura is composed of
laminated bodies, present in elderly people in the white dense collagen, fused with periosteum of the skull.
matter and result from accumulation of starch-like material 5. PIA-ARACHNOID (LEPTOMENINGES). The lepto-
in the degenerating astrocytes. meninges (lepto=thin, slender) consisting of the pia and
ii) Oligodendrocytes. Oligodendrocytes are so named arachnoid mater form the delicate vascular membranous
Systemic Pathology
because of their short and fewer processes when examined covering of the central nervous system. The pia mater is
by light microscopy with special stains (oligo=short). In closely applied to the brain and its convolutions, while the
haematoxylin-eosin stained sections, these cells appear as arachnoid mater lies between the pia mater and the dura
small cells with a darkly-staining nucleus resembling that of mater without dipping into sulci. Thus, a space is left between
small lymphocyte. The cytoplasm appears as a clear halo the two layers of leptomeninges, known as subarachnoid space,
around the nucleus. Oligodendrocytes are present which contains the CSF. The major arteries and veins run in
throughout the brain in grey as well as white matter and are the subarachnoid space and small nutrient arteries pass into
most numerous of all other cells in the CNS. In grey matter, the cortex. Extension of the subarachnoid space between the
they are clustered around the neurons and are called satellite wall of blood vessels entering the brain and their pial sheaths
cells. In white matter, they are present along the myelinated form a circumvascular space called Virchow-Robin space.
nerve fibres and are termed interfascicular oligodendroglia. Another important potential space is enclosed between the
The major function of oligodendrocytes is formation and dura and the arachnoid membrane known as subdural space.
maintenance of myelin. Thus, in this respect they are
counterparts of Schwann cells of the peripheral nervous DEVELOPMENTAL ANOMALIES
system. Diseases of oligodendrocytes are, therefore, disorders These malformations are the result of various inherited and
of myelin and myelinisation such as inherited leucodys- acquired factors. The acquired conditions include viral
trophies and acquired demyelinating diseases. infections of the mother and foetus (e.g. rubella), intake of
iii) Ependymal cells. The ependymal cells are epithelium- drugs (e.g. thalidomide), exposure to ionising radiation and
like and form a single layer of cells lining the ventricular foetal anoxia. There are a large number of developmental

malformations of the CNS but only a few important and Arnold-Chiari Malformations 873
common ones are mentioned here. Congenital hydrocephalus Arnold-Chiari malformation is the term used for a group of
is considered separately along with other types of hydro- malformations of the brain involving the brainstem and
cephalus. cerebellum. The primary defect is elongation of the medulla
and part of the vermis of the cerebellum resulting from failure
Spinal Cord Defects of the pontine flexure to form. Approximately 50% of children
with hydrocephalus have the Arnold-Chiari malformation.
Spina bifida is the term applied to the malformations of the Four types are described, of which type II malformation is
vertebral column involving incomplete embryologic closure the most common and is most frequently associated with
of one or more of the vertebral arches (rachischisis), most congenital hydrocephalus. Most patients of Arnold-Chiari
frequently in the lumbosacral region. The vertebral defect is malformation have, in addition, meningomyelocele. The
frequently associated with defect in the neural tube structures major components of type II Arnold-Chiari malformation are
and their coverings. The bony defect may be of varying as follows:
degree. The least serious form is spina bifida occulta in which 1. Elongation of the medulla with part of fourth ventricle
there is only vertebral defect but no abnormality of the spinal
cord and its meninges. The site of bony defect is marked by in the cervical canal.
a small dimple, or a hairy pigment mole in the overlying 2. Distortion of the medulla forming a characteristic S-
skin. The larger bony defect, however, appears as a distinct shaped bend at the junction with the cervical spinal cord.
cystic swelling over the affected site called spina bifida 3. Lengthening and herniation of the cerebellar vermis and
cystica. This is associated with herniation of the meninges cerebellar tonsils through the foramen magnum resulting in
or the spinal cord, or both. formation of a mass over the upper cervical cord.
Herniation of the meninges alone through the bony Combination of these abnormalities results in stenosis of
defect, meningocele, is a less common variety. The herni- the aqueduct or obstruction of the foramina of Luschka and
ated sac in meningocele consists of dura and arachnoid. Magendie causing internal hydrocephalus (discussed below).
The commonest and more serious form is, however, HYDROCEPHALUS CHAPTER 30
meningomyelocele in which the spinal cord or its roots also
herniate through the defect and are attached to the posterior Hydrocephalus is the term used for increased volume of CSF
wall of the sac. In this defect, the dura and the skin in the sac within the skull, accompanied by dilatation of the ventricles.
are deficient. A more serious variant of meningomyelocele In majority of cases of hydrocephalus, there is increased
is associated with hydrocephalus and Arnold-Chiari intracranial pressure. This type of hydrocephalus involving
malformation. ventricular dilatation is termed internal hydrocephalus. A
A rare form of the defect is myelocele or syringo- localised collection of CSF in the subarachnoid space is called
myelocele in which there is defective closure of the spinal external hydrocephalus. For better understanding of causes and
mechanisms involved in the hydrocephalus, it is essential to
canal so that the sac consists of an open flat neural tissue briefly review the source and circulation of CSF.
plate without skin covering and the CSF leaking through it. The Nervous System
Meningomyelocele and myelocele are frequently asso- Source and Circulation of CSF
ciated with neurologic defects of varying degree which CSF is mainly produced by choroid plexus in the lateral, third
include bladder and bowel dysfunction, motor and sensory and fourth ventricle, and a small part is formed on the surface
defects, and paraplegia. of the brain and spinal cord. The total volume of CSF is about
The existence of defect in bony closure in the region of 120-150 ml. CSF formed in the lateral ventricles flows through
occipital bone or fronto-ethmoid junction may result in the foramina of Munro to the third ventricle and from there
cranial meningocele and encephalocele. by the aqueduct of Sylvius to the fourth ventricle. The fluid
then passes through the foramina of Magendie and Luschka
Syringomyelia and Syringobulbia of the fourth ventricle to reach the subarachnoid space of the
These are congenital malformations which manifest clinically brain. It then spreads through the subarachnoid space over
later in life and often develop in association with certain the surface of the spinal cord. It is absorbed into the blood
acquired lesions involving the CNS. Syringomyelia and by the arachnoid villi present along the dural venous sinuses
syringobulbia are characterised by development of a syrinx (Fig. 30.2).
or a tubular cavity in the spinal cord and medulla Types and Etiopathogenesis
respectively. The cavity may be fusiform or irregular. It
usually begins in the grey matter of the spinal cord dorsal to Hydrocephalus is classified into primary and secondary
the central canal. The syrinx is usually surrounded by glial types, the former being much more common, both types have
tissue. If the cavity communicates with the spinal canal, it is distinct etiology and pathogenesis.
lined by ependymal cells. Since the fibres of lateral spino- PRIMARY HYDROCEPHALUS. Primary hydrocephalus is
thalamic tract are frequently involved in the cavity, the defined as actual increase in the volume of CSF within the
clinical effects include loss of pain and temperature sensation skull along with elevated intracranial pressure. There are 3
in the affected region. possible mechanisms of primary hydrocephalus:

874 SECONDARY HYDROCEPHALUS. Secondary hydro-
cephalus is much less common and is defined as compen-
satory increase of CSF due to loss of neural tissue without
associated rise in intracranial pressure (normal pressure
hydrocephalus) e.g. from cerebral atrophy and infarction.

MORPHOLOGIC FEATURES. Grossly, there is dilatation
of the ventricles depending upon the site of obstruction.
There is thinning and stretching of the brain. The scalp
veins overlying the enlarged head are engorged and the
fontanelle remain open.
Histologically, severe hydrocephalus may be associated
with damage to ependymal lining of the ventricles and
periventricular interstitial oedema.

INFECTIONS
A large number of pathogens comprising various kinds of
bacteria, fungi, viruses, rickettsiae and parasites can cause
infections of the nervous system. The micro-organisms may
gain entry into the nervous system by one of the following
Figure 30.2 Normal circulation of CSF. routes:
1. Via blood stream. Spread of infection by the arterial route
1. Obstruction to the flow of CSF. from another focus is the most common mode of spread of
2. Overproduction of CSF. infection in the nervous system. Less often, the spread may
3. Deficient reabsorption of CSF. occur by retrograde venous route and by lodgement of septic
However, obstruction to the flow of CSF is by far the emboli in the brain.
commonest cause and is termed obstructive hydrocephalus. The 2. Direct implantation. Spread of infection by direct
terms non-communicating and communicating hydrocephalus implantation occurs following skull fractures or through
are used to denote the site of obstruction:
defects in the bony and meningeal coverings of the nervous
SECTION III
Non-communicating hydrocephalus. When the site of system.
obstruction of CSF pathway is in the third ventricle or at the 3. Local extension. Extension of infection from contiguous
exit foramina in the fourth ventricle, the ventricular system focus such as otitis media and frontal or mastoid sinusitis
enlarges and CSF cannot pass into the subarachnoid space. may occur.
This is termed as non-communicating hydrocephalus.
Among the common causes are the following: 4. Along nerve. Certain viruses such as herpes simplex,
herpes zoster and rabies spread along cranial and peripheral
i) Congenital non-communicating hydrocephalus e.g. stenosis nerves and ascend to the CNS.
of the aqueduct, Arnold-Chiari malformation, progressive
gliosis of the aqueduct and intra-uterine meningitis. In general, resultant lesions are in the form of either
ii) Acquired non-communicating hydrocephalus may occur from diffuse inflammation of the meninges (meningitis) and of
brain parenchyma (encephalitis), or combination of both
Systemic Pathology
expanding lesion within the skull. These conditions are as (meningoencephalitis). In addition, other inflammatory
under: lesions of CNS include: brain abscess, epidural abscess,
Tumours adjacent to the ventricular system e.g. subdural empyema, septic thromboembolism of dural
ependymoma, choroid plexus papilloma, medullo- sinuses and encephalomyelitis. Some of the morphologically
blastoma and others. significant lesions are described below.
Inflammatory lesions e.g. cerebral abscess, meningitis.
Haemorrhage e.g. parenchymal haemorrhage, intra- MENINGITIS
ventricular haemorrhage, and epidural and subdural Meningitis is inflammatory involvement of the meninges.
haematoma. Meningitis may involve the dura called pachymeningitis, or
Communicating hydrocephalus. When obstruction to the the leptomeninges (pia-arachnoid) termed leptomeningitis.
flow of CSF is in the subarachnoid space at the base of the The latter is far more common, and unless otherwise
brain, it results in enlargement of the ventricular system but specified, meningitis would mean leptomeningitis.
CSF flows freely between dilated ventricles and the spinal Pachymeningitis is invariably an extension of the inflam-
canal. This is called communicating hydrocephalus. The mation from chronic suppurative otitis media or from
causes of communicating hydrocephalus are non-obstructive fracture of the skull. An extradural abscess may form by
which are as follows: suppuration between the bone and dura. Further spread of
i) Overproduction of CSF e.g. choroid plexus papilloma. infection may penetrate the dura and form a subdural abscess.
ii) Deficient reabsorption of CSF e.g. following meningitis, sub- Other effects of pachymeningitis are localised or generalised
arachnoid haemorrhage and dural sinus thrombosis. leptomeningitis and cerebral abscess.

Leptomeningitis, commonly called meningitis, is usually 875
the result of infection but infrequently chemical meningitis
and carcinomatous meningitis by infiltration of the
subarachnoid space by cancer cells may occur. Infectious
meningitis is broadly classified into 3 types: acute pyogenic,
acute lymphocytic (viral, aseptic) and chronic (bacterial or
fungal).


Acute Pyogenic Meningitis
Acute pyogenic or acute purulent meningitis is acute infec-
tion of the pia-arachnoid and of the CSF enclosed in the
subarachnoid space. Since the subarachnoid space is
continuous around the brain, spinal cord and the optic
nerves, infection spreads immediately to whole of the
cerebrospinal meninges as well as to the ventricles.

ETIOPATHOGENESIS. The causative organisms vary with
age of the patient:
1. Escherichia coli infection is common in neonates with
neural tube defects. Figure 30.3 Acute suppurative meningitis.
2. Haemophilus influenzae is commonly responsible for
infection in infants and children.
3. Neisseria meningitidis causes meningitis in adolescent and 2. Elevated CSF pressure (above 180 mm water).
young adults and is causative for epidemic meningitis. 3. Polymorphonuclear neutrophilic leucocytosis in CSF
4. Streptococcus pneumoniae is causative for infection at (between 10-10,000/μl). CHAPTER 30
extremes of age and following trauma. 4. Raised CSF protein level (higher than 50 mg/dl).
5. Decreased CSF sugar concentration (lower than 40 mg/
The routes of infection in acute pyogenic meningitis are
as follows: dl).
1. Most commonly by the blood stream. 6. Bacteriologic examination by Gram’s stain or by CSF
2. From an adjacent focus of infection. culture reveals causative organism.
3. By iatrogenic infection such as introduction of micro-
organisms at operation or during lumbar puncture. Acute Lymphocytic (Viral, Aseptic) Meningitis
Acute lymphocytic meningitis is a viral or aseptic menin-
MORPHOLOGIC FEATURES. Grossly, pus accumulates gitis, especially common in children and young adults.
in the subarachnoid space so that normally clear CSF Among the etiologic agents are numerous viruses such as The Nervous System
becomes turbid or frankly purulent. The turbid fluid is enteroviruses, mumps, ECHO viruses, coxsackie virus,
particularly seen in the sulci and at the base of the brain Epstein-Barr virus, herpes simplex virus-2, arthropode-borne
where the space is wide. In fulminant cases, some degree viruses and HIV. However, evidence of viral infection may
of ventriculitis is also present having a fibrinous coating not be demonstrable in about a third of cases.
on their walls and containing turbid CSF. In addition,
purulent material may interfere with CSF flow and result
in obstructive hydrocephalus. MORPHOLOGIC FEATURES. Grossly, some cases show
Microscopically, there is presence of numerous swelling of the brain while others show no distinctive
polymorphonuclear neutrophils in the subarachnoid space change.
as well as in the meninges, particularly around the blood Microscopically, there is mild lymphocytic infiltrate in
vessels (Fig. 30.3). Gram-staining reveals varying number the leptomeninges.
of causative bacteria.
CLINICAL FEATURES AND DIAGNOSIS. The clinical
manifestations of viral meningitis are much the same as in
CLINICAL FEATURES AND DIAGNOSIS. Acute bacterial bacterial meningitis with features of acute onset meningeal
meningitis is a medical emergency. The immediate clinical symptoms and fever. However, viral meningitis has a benign
manifestations are fever, severe headache, vomiting, and self-limiting clinical course of short duration and is
drowsiness, stupor, coma, and occasionally, convulsions. The invariably followed by complete recovery without the life-
most important clinical sign is stiffness of the neck on forward threatening complications of bacterial meningitis.
bending.
The diagnosis is confirmed by examining CSF as soon as The CSF findings in viral meningitis are as under:
possible. The diagnostic alterations in the CSF in acute 1. Naked eye appearance of clear or slightly turbid CSF.
pyogenic meningitis are as under: 2. CSF pressure increased (above 250 mm water).
1. Naked eye appearance of cloudy or frankly purulent CSF. 3. Lymphocytosis in CSF (10-100 cells/μl).

876 4. CSF protein usually normal or mildly raised.
5. CSF sugar concentration usually normal.
6. CSF bacteriologically sterile.


Chronic (Tuberculous and Cryptococcal) Meningitis
There are two principal types of chronic meningitis—one
bacterial (tuberculous meningitis) and the other fungal
(cryptococcal meningitis). Both types cause chronic
granulomatous reaction and may produce parenchymal
lesions.
Tuberculous meningitis occurs in children and adults
through haematogenous spread of infection from tuber-
culosis elsewhere in the body, or it may simply be a mani-
festation of miliary tuberculosis. Less commonly, the spread
may occur directly from tuberculosis of a vertebral body.
Cryptococcal meningitis develops particularly in debilitated
or immunocompromised persons, usually as a result of Figure 30.4 Cryptococci in CSF as seen in mucicarmine stain.
haematogenous dissemination from a pulmonary lesion.
Cryptococcal meningitis is especially an important cause of
meningitis in patients with AIDS. malaise and vomiting. The clinical course in cryptococcal
meningitis may, however, be fulminant and fatal in a few
weeks, or be indolent for months to years.
MORPHOLOGIC FEATURES. Grossly, in tuberculous
meningitis, the subarachnoid space contains thick exudate, The CSF findings in chronic meningitis are as under:
particularly abundant in the sulci and the base of the brain. 1. Naked eye appearance of a clear or slightly turbid CSF
Tubercles, 1-2 mm in diameter, may be visible, especially which may form fibrin web on standing.
adjacent to the blood vessels. The exudate in cryptococcal 2. Raised CSF pressure (above 300 mm water).
meningitis is scanty, translucent and gelatinous. 3. Mononuclear leucocytosis consisting mostly of lympho-
SECTION III
Microscopically, tuberculous meningitis shows exudate cytes and some macrophages (100-1000 cells/μl).
of acute and chronic inflammatory cells, and granulomas 4. Raised protein content.
with or without caseation necrosis and giant cells. Acid- 5. Lowered glucose concentration.
fast bacilli may be demonstrated. Late cases show dense 6. Tubercle bacilli may be found on microscopy of centri-
fibrous adhesions in the subarachnoid space and fuged deposits by ZN staining in tuberculous meningitis.
consequent hydrocephalus. Cryptococcal meningitis is Pathognomonic capsulated cryptococci with a halo are
characterised by infiltration by lymphocytes, plasma cells, appreciated in India ink preparation of CSF in cases of
an occasional granuloma and abundant characteristic cryptococcal meningitis, while the capsule is better
capsulated cryptococci. demonstrated by mucicarmine stain (Fig. 30.4).
Table 30.1 summarises the CSF findings in the three
CLINICAL FEATURES AND DIAGNOSIS. Tuberculous important types of meningitis in comparison with those in
Systemic Pathology
meningitis manifests clinically as headache, confusion, health.



 TABLE 30.1: CSF Findings in Health and Various Types of Meningitis.
Feature Normal Acute Pyogenic Acute Lympho- Chronic (Tuberculous)
(Bacterial) cytic (Viral) Meningitis
Meningitis Meningitis
1. Naked eye Clear and colourless Cloudy or frankly Clear or slightly Clear or slightly turbid, forms
appearance purulent turbid fibrin coagulum on standing
2. CSF pressure 60-150 mm water Elevated Elevated Elevated
(above 180 mm water) (above 250 mm water) (above 300 mm water)
3. Cells 0-4 10-10,000 10-100 100-1000
lymphocytes/μl neutrophils/μl lymphocytes/μl lymphocytes/μl
4. Proteins 15-45 mg/dl Markedly raised Raised Raised
5. Glucose 50-80 mg/dl Markedly reduced Normal Reduced
6. Bacteriology Sterile Causative Sterile Tubercle bacilli
organisms present present

ENCEPHALITIS 877
Parenchymal infection of brain is termed encephalitis.
Encephalitis may be the result of bacterial, viral, fungal and
protozoal infections.

Bacterial Encephalitis

Bacterial infection of the brain substance is usually secondary
to involvement of the meninges rather than a primary
bacterial parenchymal infection. This results in bacterial
cerebritis that progresses to form brain abscess. However,
tuberculosis and neurosyphilis are the two primary bacterial
involvements of the brain parenchyma.
BRAIN ABSCESS. Brain abscesses may arise by one of the
following routes:
1. By direct implantation of organisms e.g. following
compound fractures of the skull.
2. By local extension of infection e.g. chronic suppurative
otitis media, mastoiditis and sinusitis.
Figure 30.5 Tuberculous encephalitis of the brain.
3. By haematogenous spread e.g. from primary infection in
the heart such as acute bacterial endocarditis, and from lungs dorsalis and generalised paralysis of the insane occurring in
such as in bronchiectasis. tertiary stage (page 161).
Clinically, there is usually evidence of reactivation of
infection at the primary site preceding the onset of cerebral Syphilitic meningitis. This is a form of chronic meningitis
symptoms. The features of abscess are fever, headache, characterised by distinctive perivascular inflammatory CHAPTER 30
vomiting, seizures and focal neurological deficits depending reaction of plasma cells and endarteritis obliterans.
upon the location of the abscess. Brain abscess is most Tabes dorsalis (Locomotor ataxia). There is slowly pro-
common in cerebral hemispheres and less frequent in the gressive degeneration of the posterior roots of the spinal
cerebellum and basal ganglia. nerves and the posterior columns of the spinal cord by the
spirochaetes. These changes produce loss of coordination of
Grossly, it appears as a localised area of inflammatory muscles and joints resulting in locomotor ataxia. These
necrosis and oedema surrounded by fibrous capsule. changes produce loss of coordination of muscles and joints
Microscopically, the changes consist of liquefactive resulting in locomotor ataxia. There is also loss of pain
necrosis in the centre of the abscess containing pus. It is sensation and presence of Argyll-Robertson pupils which
surrounded by acute and chronic inflammatory cells, react to accommodation but not to light. The Nervous System
neovascularisation, oedema, septic thrombosis of vessels,
fibrous encapsulation and zone of gliosis. The CSF and General paralysis of the insane. This is the result of diffuse
overlying meninges also show evidence of acute and parenchymal involvement by the spirochaetes with
chronic inflammation. widespread lesions in the nervous system. The symptoms
consist of motor, sensory and psychiatric abnormalities.
TUBERCULOMA. Tuberculoma is an intracranial mass
occurring secondary to dissemination of tuberculosis Viral Encephalitis
elsewhere in the body. Tuberculomas may be solitary or
multiple. A number of viruses can infect the CNS and produce either
aseptic meningitis (described already) or viral encephalitis,
Grossly, it has a central area of caseation necrosis but sometimes combination of both termed meningo-
surrounded by fibrous capsule. encephalitis, is present. Most viral infections of the CNS are
Microscopically, there is typical tuberculous granu- the end-result of preceding infection in other tissues and
lomatous reaction around the central caseation necrosis organs. There is usually a preceding phase of extraneural
(Fig. 30.5). A zone of gliosis generally surrounds the viral replication before involvement of the nervous system
tuberculoma. Advanced cases may show areas of occurs.
calcification. Most of the viruses reach the nervous system via blood
stream before which they enter the body by various routes
NEUROSYPHILIS. Syphilitic lesions of the CNS used to be e.g. infection of the skin and mucous membrane (in herpes
common and serious, but more recently there is evidence of simplex and herpes zoster-varicella), by the alimentary tract
atypical neurosyphilis in cases of HIV/AIDS. The lesions in (in enteroviruses including polio virus), by arthropod bite
syphilis may be in the form of syphilitic meningitis found in (in arbovirus), by transplacental infection (in cytomegalo-
secondary syphilis, and neurosyphilis consisting of tabes virus), and through body fluids in AIDS (in HIV infection).

878 Rabies virus travels along the peripheral nerves to reach the  TABLE 30.2. Major Forms of CNS Diseases in AIDS.
CNS. Herpes zoster-varicella is a distinct primary disease
(chickenpox) but the virus remains latent for a long time Disease Incidence
before it gets reactivated to cause severe hyperalgesia and 1. HIV-encephalopathy (AIDS-dementia complex) 25%
pain along the distribution of nerve related to acutely 2. Opportunistic infections
inflamed posterior root ganglia (herpes zoster). All these viral i) Toxoplasmosis 15%
infections enumerated so far cause acute viral encephalitis. Slow ii) Cryptococcal meningitis 9%
virus diseases are another group of CNS infections in which iii) Progressive multifocal leucoencephalopathy 4%
the agents have not only a long latent period but the disease iv) Neurosyphilis 1%
also develops slowly and may produce subacute sclerosing v) Tuberculous meningitis 1%
panencephalitis, progressive multifocal leucoence- 3. Neoplasms
phalopathy, progressive rubella panencephalopathy and i) Primary CNS lymphoma 4%
subacute spongiform encephalopathy. ii) Kaposi’s sarcoma <1%
4. Progressive multifocal leucoencephalopathy (PML) 1%
MORPHOLOGIC FEATURES. Although histologic 5. Peripheral neuropathies 70%
changes vary from one viral infection of the CNS to the 6. Myelopathy (Spinal cord disease) 20%
other but, in general, the characteristic features of viral
diseases of the CNS are as under:
1. Parenchymal infiltrate, chiefly in perivascular location, infected). PML develops in immunocompromised individual
of mononuclear cells consisting of lymphocytes, plasma like CMV and Toxoplasma encephalitis does, and is, therefore,
cells and macrophages. an important form of encephalitis due to increasing number
2. Microscopic clusters of microglial cells and presence of cases of AIDS.
of neuronophagia. PML infects oligodendrocytes and causes progressive
3. Intranuclear inclusion bodies in most viral diseases demyelination at multifocal areas scattered throughout the
and specific cytoplasmic inclusions of Negri bodies in CNS.
rabies.
Grossly, the lesions consist of focal, irregular gelatinous
areas most prominent at the junction of grey and white
HIV Encephalopathy (AIDS-Dementia Complex)
matter. Main areas affected are cerebrum, brainstem,
SECTION III
Next to knocking off of the immune system, HIV has profound cerebellum, and sometimes spinal cord.
neurovirulence but unlike tropism for CD4+ T cells of the Microscopically, the features are as under:
immune system, HIV does not have neurotropism. HIV has Focal areas of demyelination.
not been identified to infect the neuronal cells but instead Many lipid-laden macrophages in the centre of foci.
infects the cells of monocyte-macrophage cell line including Enlarged oligodendroglial nuclei containing purple
microglial cells. HIV infection then sets in a cascade of toxic viral inclusions at the periphery of the lesion.
mediators and cytokines—TNF-α,IL-1, IL-6, TGF-β,
IFN-γ, platelet activating factor (PAF) and endothelin, all of
which cause damage to the neuroglial tissues. Spongiform Encephalopathy
Important forms of CNS diseases in patients with AIDS (Creutzfeldt-Jakob Disease)
are listed in Table 30.2. Late in the course of AIDS, a group Spongiform encephalopathy, also called Creutzfeldt-Jakob
Systemic Pathology
of signs and symptoms of CNS disease appear termed HIV disease (CJD) or mad-cow disease, though included under
encephalopathy or AIDS-dementia complex. One major the group of viral encephalitis but is caused by accumulation
clinical feature of this entity is the occurrence of dementia i.e. of prion proteins. Prion proteins are a modified form of normal
fall in the cognitive ability of the individual compared to structural proteins present in the mammalian CNS and are
previous level. The condition is believed to be the result of peculiar in two respects: they lack nucleic acid (DNA or
direct effect of HIV on the CNS. Clinically, the disease RNA), and they can be transmitted as an infectious proteina-
develops in about 25% cases of AIDS while autopsy studies ceous particles (Dr Prusiner was awarded the Nobel Prize in
reveal presence of HIV-encephalopathy in 80-90% cases of medicine in 1997 for his discovery on prion proteins).
AIDS. Majority of cases occur sporadically though familial
predisposition with autosomal dominant inheritance has also
Histologically, the changes are more in subcortical area
of the brain and consist of gliosis, multinucleate giant cell been reported in 5-15% cases. Other methods of transmission
encephalitis, and vacuolar myelopathy. are by iatrogenic route (e.g. by tissue transplantation from
an infected individual) and by human consumption of BSE
(bovine spongiform encephalopathy)-infected beef, also
Progressive Multifocal Leucoencephalopathy
called as mad-cow disease.
Progressive multifocal leucoencephalopathy (PML) is a slow Clinically, CJD is characterised by rapidly progressive
viral infection of the CNS caused by a papovavirus called JC dementia with prominent association of myoclonus. CJD is
virus (not to be confused with CJ disease or mad-cow disease; invariably fatal with mean survival of about 7 months after
JC virus here stands for the initials of the patient first diagnosis.

B. Intracranial haemorrhage: 879
a) Haemorrhage in the brain parenchyma (intracerebral
haemorrhage)
b) Haemorrhage in the subarachnoid space (subarachnoid
haemorrhage).
The stroke syndrome is the cardinal feature of cere-
brovascular disease. The term stroke is used for sudden and
dramatic development of focal neurologic deficit, varying
from trivial neurologic disorder to hemiplegia and coma.
Other less common effects of vascular disease include:
transient ischaemic attacks (TIA), vascular headache (e.g. in
migraine, hypertension and arteritis), local pressure of an
aneurysm and increased intracranial pressure (e.g. in
hypertensive encephalopathy and venous thrombosis).
A few important forms are discussed below.

A. ISCHAEMIC BRAIN DAMAGE
Figure 30.6 Neurocysticercosis. The sliced surface of the cerebral Ischaemic necrosis in the brain results from ischaemia caused
hemisphere of the brain shows may tiny whitish nodules and cysts about by considerable reduction or complete interruption of blood
1 cm in diameter.
supply to neural tissue which is insufficient to meet its
Grossly, the changes are too rapid to become noticeable metabolic needs. The brain requires sufficient quantities of
but brain atrophy may be seen in long-standing cases. oxygen and glucose so as to sustain its aerobic metabolism,
Microscopically, the hallmark is spongiform change i.e. mainly by citric acid (Krebs’) cycle which requires oxygen.
there are small round vacuoles in the neuronal cells. These Moreover, neural tissue has limited stores of energy reserves
changes are predominantly seen in the cortex and other so that cessation of continuous supply of oxygen and glucose
grey matter areas. Spongiform changes result in neuronal for more than 3-4 minutes results in permanent damage to CHAPTER 30
loss and glial cell proliferation but significantly without neurons and neuroglial cells.
any inflammation or white matter involvement.
Deprivation of oxygen (anoxia) to the brain may occur in
4 different ways:
Fungal and Protozoal Encephalitis
1. Anoxic anoxia, in which there is low inspired pO .
2
Mycotic diseases of the CNS usually develop by blood stream 2. Anaemic anoxia, in which the oxygen-carrying haemo-
from systemic deep mycoses elsewhere in the body. They globin is reduced.
are particularly more common in immunosuppressed 3. Histotoxic anoxia, in which there is direct toxic injury as
individuals such as in AIDS, patients of lymphomas and occurs in cyanide poisoning.
other cancers. Some of the fungi which may disseminate to 4. Stagnant (ischaemia) anoxia, in which the damage is caused The Nervous System
the CNS are Candida albicans, Mucor, Aspergillus fumigatus, by cessation of blood with resultant local accumulation of
Cryptococcus neoformans, Histoplasma capsulatum and metabolites and changes in pH.
Blastomyces dermatitidis. These fungal infections may produce
one of the three patterns: fungal chronic meningitis, vasculitis In all these different forms of anoxia, the end-result is
and encephalitis. ischaemic brain damage which may have one of the following
Besides fungal infections, CNS may be involved in two patterns:
protozoal diseases such as in malaria, toxoplasmosis, 1. Global hypoxic-ischaemic encephalopathy, resulting from
amoebiasis, trypanosomiasis and cysticerosis (Fig. 30.6). generalised cerebral hypoperfusion.
2. Cerebral infarction, resulting from severe localised
CEREBROVASCULAR DISEASES reduction or cessation of blood supply.

Cerebrovascular diseases are all those diseases in which one Global Hypoxic-Ischaemic Encephalopathy
or more of the blood vessels of the brain are involved in the
pathologic processes. Various pathologic processes commonly The brain receives 20% of cardiac output for maintaining its
implicated in cerebrovascular diseases are: thrombosis, vital aerobic metabolism. A number of factors determine the
embolism, rupture of a vessel, hypoxia, hypertensive maximum length of time the CNS can survive irreversible
arteriolosclerosis, atherosclerosis, arteritis, trauma, aneurysm ischaemic damage. These are as under:
and developmental malformations. These processes can result i) Severity of the hypoxic episode.
in 2 main types of parenchymal diseases of the brain: ii) Presence of pre-existing cerebrovascular disease.
iii) Age of the patient.
A. Ischaemic brain damage: iv) Body temperature.
a) Generalised reduction in blood flow resulting in global In normal individuals, the brain continues to be perfused
hypoxic-ischaemic encephalopathy adequately up to systolic arterial pressure of 50 mmHg by
b) Local vascular obstruction causing infarcts. an auto-regulatory vascular control mechanism. However,

880 fall of systemic arterial systolic pressure below this critical cortex; the loss of pyramidal cell layer is more severe than
value results in rapid fall in cerebral perfusion pressure and that of granular cell layer producing laminar necrosis.
eventual ischaemic encephalopathy. Such types of medical Longer duration: Use of modern ventilators has led
emergencies occur at the time of cardiac arrest followed by to maintenance of cardiorespiratory function in the
relatively delayed resuscitation, severe episode of hypo- presence of total brain necrosis unassociated with vital
tension, carbon monoxide intoxication and status epilepticus. reaction.
Hypoxic encephalopathy may be followed by a post-
ischaemic confusional state and complete recovery or a state
of coma and even a persistent vegetative life and brain death. Cerebral Infarction
Depending upon the proneness of different cells of the Cerebral infarction is a localised area of tissue necrosis caused
brain to the effects of ischaemia-hypoxia, three types of lesion by local vascular occlusion—arterial or venous. Occasionally,
may occur: it may be the result of non-occlusive causes such as
1. Selective neuronal damage: Neurons are most vulnerable compression on the cerebral arteries from outside and from
to damaging effect of ischaemia-hypoxia and irreversible hypoxic encephalopathy. Clinically, the signs and symptoms
injury. In particular, oligodendroglial cells are most associated with cerebral infarction depend upon the region
susceptible, followed by astrocytes while microglial cells and infarcted. In general, the focal neurologic deficit termed
vascular endothelium survive the longest. The reason for stroke, is present. However, significant atherosclerotic
undue vulnerability of neurons to hypoxia can be explained cerebrovascular disease may produce transient ischaemic
by various factors: attacks (TIA).
i) Different cerebral circulatory blood flow. 1. Arterial occlusion. Occlusion of the cerebral arteries by
ii) Presence of acidic excitatory neurotransmitters called either thrombi or emboli is the most common cause of
excitotoxins. cerebral infarction. Thrombotic occlusion of the cerebral
iii) Excessive metabolic requirement of these neurons. arteries is most frequently the result of atherosclerosis, and
iv) Increased sensitivity of neurons to lactic acid. rarely, from arteritis of the cranial arteries. Embolic arterial
2. Laminar necrosis: Global ischaemia of cerebral cortex occlusion is commonly derived from the heart, most often
results in uneven damage because of different cerebral from mural thrombosis complicating myocardial infarction,
vasculature which is termed laminar or pseudolaminar from atrial fibrillation and endocarditis. The size and shape
necrosis. In this, superficial areas of cortical layers escape of an infarct are determined by the extent of anastomotic
damage while deeper layers are necrosed. connections with adjacent arterial branches as under:
SECTION III
3. Watershed infarcts: Circulatory flow in the brain by Circle of Willis provides a complete collateral flow for
anterior, middle and posterior cerebral arteries has internal carotid and vertebral arteries.
overlapping circulations. In ischaemia-hypoxia, perfusion of Middle and anterior cerebral arteries have partial
overlapping zones, being farthest from the blood supply, anastomosis of their distal branches. Their complete
suffers maximum damage. This results in wedge-shaped occlusion may cause infarcts.
areas of coagulative necrosis called watershed or borderzone Small terminal cerebral arteries, on the contrary, are end-
infarcts. Particularly vulnerable is the border zone of the arteries and have no anastomosis. Hence, occlusion of these
cerebral cortex between the anterior and middle cerebral branches will invariably lead to an infarct.
arteries, producing para-sagittal infarction.
2. Venous occlusion. Venous infarction in the brain is an
MORPHOLOGIC FEATURES. The pathologic appear- infrequent phenomenon due to good communications of the
Systemic Pathology
ance of the brain in hypoxic encephalopathy varies cerebral venous drainage. However in cancer, due to
depending upon the duration and severity of hypoxic increased predisposition to thrombosis, superior sagittal
episode and the length of survival.
thrombosis may occur leading to bilateral, parasagittal,
Survival for a few hours: No pathologic changes are multiple haemorrhagic infarcts.
visible.
3. Non-occlusive causes. Compression of the cerebral arte-
Survival 12-24 hours: No macroscopic change is ries from outside such as occurs during herniation may cause
discernible but microscopic examination reveals early cerebral infarction. Mechanism of watershed (border zone)
neuronal damage in the form of eosinophilic cytoplasm cerebral infarction in hypoxic encephalopathy has already
and pyknotic nuclei, so called red neurons.
been explained above.
After 2-7 days: Grossly, there is focal softening. The In any case, the extent of damage produced by any of the
area supplied by distal branches of the cerebral arteries above causes depends upon:
suffers from the most severe ischaemic damage and may i) rate of reduction of blood flow;
develop border zone or watershed infarcts in the junctional ii) type of blood vessel involved; and
zones between the territories supplied by major arteries. iii) extent of collateral circulation.
Microscopically, the nerve cells die and disappear and
are replaced by reactive fibrillary gliosis. There are minor MORPHOLOGIC FEATURES. Grossly, cerebral infarcts
variations in the distribution of neuronal damage to the may be anaemic or haemorrhagic. An anaemic infarct

881

















Figure 30.7 An old cystic infarct in the brain (coronal section). There
is shrinkage of scarred area with ipsilateral ventricular dilatation.


becomes evident 6-12 hours after its occurrence. The
affected area is soft and swollen and there is blurring of
junction between grey and white matter. Within 2-3 days,
the infarct undergoes softening and disintegration.
Eventually, there is central liquefaction with peripheral Figure 30.8 An anaemic infarct of a few days duration. The histologic
firm glial reaction and thickened leptomeninges, forming changes are reactive astrocytosis, a few reactive macrophages and
a cystic infarct (Fig. 30.7). A haemorrhagic infarct is red and neovascularisation in the wall of the cystic lesion. The outer cortical layer
superficially resembles a haematoma. It is usually the is, however, intact.
result of fragmentation of occlusive arterial emboli or
venous thrombosis. CHAPTER 30
Histologically, the sequential changes are as under: Intracerebral Haemorrhage
1. Initially, there is eosinophilic neuronal necrosis and Spontaneous intracerebral haemorrhage occurs mostly in
lipid vacuolisation produced by breakdown of myelin. patients of hypertension. Most hypertensives over middle
Simultaneously, the infarcted area is infiltrated by age have microaneurysms in very small cerebral arteries in
neutrophils. the brain tissue. Rupture of one of the numerous
2. After the first 2-3 days, there is progressive invasion microaneurysms is believed to be the cause of intracerebral
by macrophages and there is astrocytic and vascular haemorrhage. Unlike subarachnoid haemorrhage, it is not
proliferation. common to have recurrent intracerebral haemorrhages.
3. In the following weeks to months, the macrophages The common sites of hypertensive intracerebral haemor-
clear away the necrotic debris by phagocytosis followed rhage are the region of the basal ganglia (particularly the The Nervous System
by reactive astrocytosis, often with little fine fibrosis putamen and the internal capsule), pons and the cerebellar
(Fig. 30.8). A haemorrhagic infarct has some phagocytes cortex. Clinically the onset is usually sudden with headache
containing haemosiderin. and loss of consciousness. Depending upon the location of
4. Ultimately, after 3-4 months an old cystic infarct is the lesion, hemispheric, brainstem or cerebellar signs will
formed which shows a cyst traversed by small blood be present. About 40% of patients die during the first 3-4
vessels and has peripheral fibrillary gliosis. Small cavi- days of haemorrhage, mostly from haemorrhage into the
tary infarcts are called lacunar infarcts and are commonly ventricles. The survivors tend to have haematoma that
found as a complication of systemic hypertension. separates the tissue planes which is followed by resolution
and development of an apoplectic cyst accompanied by loss
B. INTRACRANIAL HAEMORRHAGE of function.
Haemorrhage into the brain may be traumatic, non-trau- MORPHOLOGIC FEATURES. Grossly and micros-
matic, or spontaneous. There are two main types of copically, the haemorrhage consists of dark mass of
spontaneous intracranial haemorrhage: clotted blood replacing brain parenchyma. The borders
1. Intracerebral haemorrhage, which is usually of hyper- of the lesion are sharply-defined and have a narrow rim
tensive origin. of partially necrotic parenchyma. Small ring haemor-
2. Subarachnoid haemorrhage, which is commonly aneu- rhages in the Virchow-Robin space in the border zone are
rysmal in origin. commonly present. Ipsilateral ventricles are distorted and
In addition to hypertension and rupture of an aneurysm, compressed and may contain blood in their lumina.
other causes of spontaneous intracranial haemorrhage Rarely, blood may rupture through the surface of the brain
include vascular malformations which produce mixed into the subarachnoid space. After a few weeks to months,
intracerebral and subarachnoid haemorrhage, haemorrhagic the haematoma undergoes resolution with formation of a
diathesis and haemorrhage into tumours.

882 slit-like space called apoplectic cyst which contains The remaining 15% cases of subarachnoid haemorrhage
yellowish fluid. Its margins are yellow-brown and have are the result of rupture in the posterior circulation, vascular
haemosiderin-laden macrophages and a reactive zone of malformations and rupture of mycotic aneurysms that occurs
fibrillary astrocytosis. in the setting of bacterial endocarditis. In all types of
aneurysms, the rupture of thin-walled dilatation occurs in
Subarachnoid Haemorrhage association with sudden rise in intravascular pressure but
Haemorrhage into the subarachnoid space is most comm- chronic hypertension does not appear to be a risk factor in
only caused by rupture of an aneurysm, and rarely, rupture their development or rupture.
of a vascular malformation. Clinically, berry aneurysms remain asymptomatic prior
A general discussion of aneurysms is given on page 405. to rupture. On rupture, they produce severe generalised
Of the three types of aneurysms affecting the larger headache of sudden onset which is frequently followed by
unconsciousness and neurologic defects. Initial mortality
intracranial arteries—berry, mycotic and fusiform, berry from first rupture is about 20-25%. Survivors recover
aneurysms are most important and most common.
completely but frequently suffer from recurrent episodes of
BERRY ANEURYSMS are saccular in appearance with fresh bleeding.
rounded or lobulated bulge arising at the bifurcation of
intracranial arteries and varying in size from 2 mm to 2 cm MORPHOLOGIC FEATURES. Rupture of a berry aneu-
or more. They account for 95% of aneurysms which are liable rysm frequently spreads haemorrhage throughout the
to rupture. Berry aneurysms are rare in childhood but subarachnoid space with rise in intracranial pressure and
increase in frequency in young adults and middle life. They characteristic blood-stained CSF. An intracerebral
are, therefore, not congenital anomalies but develop over the haematoma may develop if the blood tracks into the brain
years from developmental defect of the media of the arterial parenchyma. The region of the brain supplied by the
wall at the bifurcation of arteries forming thin-walled saccu- affected artery frequently shows infarction, partly
lar bulges. Although most berry aneurysms are sporadic in attributed to vasospasm.
occurrence, there is an increased incidence of their presence
in association with congenital polycystic kidney disease and TRAUMA TO THE CNS
coarctation of the aorta. About a quarter of berry aneurysms
are multiple. Trauma to the CNS constitutes an important cause of death
In more than 85% cases of subarachnoid haemorrhage, and permanent disability in the modern world. Important
the cause is massive and sudden bleeding from a berry causes of head injuries are: motor vehicle accidents,
SECTION III
aneurysm on or near the circle of Willis. The four most accidental falls and violence. Traumatic injuries to the CNS
common sites are as under (Fig. 30.9): may result in three consequences which may occur in
1. In relation to anterior communicating artery. isolation or in combination:
2. At the origin of the posterior communicating artery from epidural haematoma;
the stem of the internal carotid artery. subdural haematoma; and
3. At the first major bifurcation of the middle cerebral artery. parenchymal brain damage.
4. At the bifurcation of the internal carotid into the middle
and anterior cerebral arteries. A. Epidural Haematoma
Epidural haematoma is accumulation of blood between the
dura and the skull following fracture of the skull, most
Systemic Pathology
commonly from rupture of middle meningeal artery. The
haematoma expands rapidly since accumulating blood is
arterial in origin and causes compression of the dura and
flattening of underlying gyri (Fig. 30.10). The patient
develops progressive loss of consciousness if haematoma is
not drained early.

B. Subdural Haematoma
Subdural haematoma is accumulation of blood between the
dura and subarachnoid and develops most often from
rupture of veins which cross the surface convexities of the
cerebral hemispheres. Subdural haematoma may be acute
or chronic.
Acute subdural haematoma. Acute subdural haematoma
develops following trauma and consists of clotted blood,
often in the frontoparietal region. There is no significant
compression of gyri (Fig. 30.11). Since the accumulated blood
Figure 30.9 The circle of Willis showing principal sites of berry
(saccular) aneurysms. The serial numbers indicate the frequency of is of venous origin, symptoms appear slowly and may
involvement. become chronic with passage of time if not fatal.

883


















Figure 30.10 Epidural haematoma often results from rupture of Figure 30.11 Subdural haematoma often results from rupture of
artery following skull fracture resulting in accumulation of arterial blood veins crossing the cerebral convexities and is characterised by
between the skull and the dura. accumulation of venous blood between the dura and the arachnoid.

Chronic subdural haematoma. Chronic subdural haema- 4. Traumatic intracerebral haemorrhage. On trauma to the
toma occurs often with brain atrophy and less commonly CNS, the parenchymal vessels of the hemispheres may get
following trauma. Chronic subdural haematoma is composed torn and cause multiple intracerebral haemorrhages.
of liquid blood. Separating the haematoma from underlying 5. Brain swelling. Head injury may be accompanied by
brain is a membrane composed of granulation tissue.
localised or diffuse brain swelling.
C. Parenchymal Brain Damage
DEMYELINATING DISEASES
Trauma to the CNS may result in damage to brain paren- Demyelinating diseases are an important group of
chyma and includes the following forms: CHAPTER 30
neurological disorders which have, in common, the
1. Concussion. Concussion is caused by closed head injury pathologic features of focal or patchy destruction of myelin
and is characterised by transient neurologic dysfunction and sheaths in the CNS accompanied by an inflammatory
loss of consciousness. Invariably, there is complete neurologic response. Demyelination may affect peripheral nervous
recovery after some hours to days. system as well. Some degree of axonal damage may also
occur but demyelination is the predominant feature. The
No significant morphologic change is noticed but more exact cause for demyelination is not known but currently
severe concussion may cause diffuse axonal injury viral infection and autoimmunity are implicated in its
(discussed below).
pathogenesis.
Loss of myelin may occur in certain other conditions as The Nervous System
2. Diffuse axonal injury. Diffuse axonal injury is the most
common cause of persistent coma or vegetative state well, but without an inflammatory response. These
following head injury. The underlying cause is sudden conditions have known etiologies such as: genetically-
angular acceleration or deceleration resulting in widespread determined defects in the myelin metabolism (leucodys-
axonal shearing in the deep white matter of both the trophies), slow virus diseases of oligodendrocytes (pro-
hemispheres. gressive multifocal leucoencephalopathy), and exposure to
toxins (central pontine myelinolysis). All these entities are
Grossly, the changes are minimal to small multiple currently not classified as demyelinating diseases. Only those
haemorrhages. conditions in which the myelin sheath or the myelin-forming
cells (i.e. oligodendrocytes and Schwann cells) are primarily
3. Contusions and lacerations. Contusions and lacerations injured and are associated with considerable inflammatory
are the result of direct damage to the brain parenchyma, exudate are included under the term ‘demyelinating
particularly cerebral hemispheres, as occurs in the soft diseases’. Pathologically and clinically, two demyelinating
tissues. Most often, they are the result of blunt trauma. The diseases are distinguished:
overlying skull may or may not be fractured. Traumatic 1. Multiple or disseminated sclerosis
subarachnoid haemorrhage invariably accompanies cerebral 2. Perivenous encephalomyelitis.
contusions.
Multiple (Disseminated) Sclerosis
Microscopically, brain parenchyma at the affected site is
haemorrhagic, necrotic and fragmented. On healing, these Multiple or disseminated sclerosis is the most common of
lesions appear as shrunken areas with golden brown the CNS demyelinating diseases. The usual age at onset is
haemosiderin pigment on the surface. 20 to 40 years. The disease presents as recurrent attacks of
focal neurologic disorder with predilection for involvement

884 of the spinal cord, optic nerve and brain. The first attack These groups along with the list of diseases included in each
usually begins with a single sign or symptom, most group are briefly outlined below without going into the
commonly optic neuritis, followed by recovery. As the details of individual diseases for which the interested reader
disease becomes more progressive, remissions become may consult pertinent text on neuropathology and neurology.
infrequent and incomplete. The etiology of multiple sclerosis
remains unknown but a role for genetic susceptibility, Degenerative Diseases
infectious agent and immunologic mechanism has been Degenerative diseases are disorders of unknown etiology
proposed. and pathogenesis, characterised pathologically by prog-
ressive loss of CNS neurons and their processes accom-
MORPHOLOGIC FEATURES. The pathologic hallmark panied by fibrillary astrocytosis. The identification of these
is the presence of many scattered discrete areas of diseases depends upon exclusion of diseases with known
demyelination termed plaques.
etiologies such as metabolic disturbances, vascular
Grossly, plaques appear as grey-pink, swollen, sharply diseases, nutritional deficiencies or infection. A consider-
defined, usually bilaterally symmetric areas in the white able proportion of degenerative disorders are genetic in
matter. origin, with either dominant or recessive inheritance;
Microscopically, the features vary according to the age others occur sporadically. Family history is, of course, of
of the plaque: great importance.
1. ln active enlarging plaques, the histologic features are The degenerative disorders usually begin insidiously and
accumulation of lymphocytes and macrophages around have a gradual progressive course over many years. In
venules and at the plaque margin where demyelination virtually all cases, the lesions have characteristic bilaterally
is occurring. In addition, there is loss of oligodendrocytes symmetric distribution. Another striking characteristic of the
and presence of reactive astrocytosis with numerous lipid- degenerative disorders is that particular anatomic or
laden macrophages (microglia) in the plaque. The axons physiologic system of neurons may be selectively affected,
in the plaque are generally intact. leaving others entirely intact.
2. In old inactive plaques, there is no perivascular inflam- Classification of degenerative diseases into individual
matory cell infiltrate and nearly total absence of syndromes is based on clinical aspects and anatomic
oligodendrocytes. Demyelination in the plaque area is distribution of the lesions. Some of the more common
complete as there is only limited regeneration of myelin. degenerative diseases are listed in Table 30.3. Two of the
SECTION III
Gliosis is well-developed but astrocytes are less important examples—Alzheimer’s disease and parkin-
prominent. Some axonal loss may be present. sonism, are considered below.
ALZHEIMER’S DISEASE. Alzheimer’s disease is the most
Perivenous Encephalomyelitis common cause of dementia in the elderly. The condition
Perivenous encephalomyelitis includes two uncommon occurs after 5th decade of life and its incidence progressively
diseases: acute disseminated encephalomyelitis and acute increases with advancing age. The exact cause is not known
necrotising haemorrhagic leucoencephalitis. Both are monophasic but a few factors are implicated in its etiology which include
diseases characterised by perivenous mononuclear positive family history and deposition of Aβ amyloid derived
inflammatory cell infiltration. Both diseases occur following from amyloid precursor protein (APP) forming neuritic ‘senile’
a viral infection, vaccination or a respiratory illness. Both plaques and neurofibrillary tangles.
these conditions are looked upon as human counterpart of Grossly, the brain is often reduced in weight and
Systemic Pathology
experimental allergic encephalomyelitis (EAE) and are bilaterally atrophic.
considered to be allergic reaction against myelin antigen. Microscopically, the main features are as under:
Acute disseminated encephalomyelitis occurs usually i) Senile neuritic plaque is the most conspicuous lesion and
following viral infection (measles, mumps, rubella, consists of focal area which has a central core containing
chickenpox), whooping cough or vaccination. The disease Aβ amyloid.
begins abruptly with headache and delirium followed by ii) Neurofibrillary tangle is a filamentous collection of
lethargy and coma. Signs of meningeal irritation and fever neurofilaments and neurotubules within the cytoplasm
may be present. Prognosis for recovery is generally good. of neurons.
Acute necrotising haemorrhagic leucoencephalitis is a iii) Amyloid angiopathy is deposition of the same amyloid
rare disease occurring more often after a respiratory infection. in the vessel wall which is deposited in the amyloid core
The clinical course is similar to that of acute disseminated of the plaque.
encephalomyelitis except for its suddenness of onset and iv) Granulovacuolar degeneration is presence of multiple,
rapidity of progression, sometimes leading to death within small intraneuronal cytoplasmic vacuoles, some of which
48 hours. contain one or more dark granules called Hirano bodies.
PARKINSONISM. Parkinsonism is a syndrome of chronic
MISCELLANEOUS DISEASES
progressive disorder of motor function and is clinically
Included under the heading of miscellaneous diseases of the characterised by tremors which are most conspicuous at rest
CNS are degenerative, metabolic and nutritional diseases. and worsen with emotional stress; other features are rigidity