Basal cell carcinoma arising on two variants of epidermal nevus: a case series Irene B. Cua, MD, DPDS,1 Arnelfa C. Paliza, MD, FPDS1 ABSTRACT INTRODUCTION Epidermal nevi are hamartomas of the epidermis and papillary dermis that are usually present during the first years of life. Rarely, malignant transformations develop in association with epidermal nevi. Few cases have been reported worldwide, however the lifetime risk and incidence are unknown. CASE REPORT This is a case series about basal cell carcinoma arising on epidermal nevus. The first patient is a 42-year-old Filipino female, who presented with a verrucous plaque at birth on the left temple which then developed multiple, discrete to confluent, grayish, papules and nodules on the surface. Histological examination revealed nevus sebaceus and basal cell carcinoma, pigmented type. The second patient is a 53-year-old Filipino male, who presented with a papillomatous plaque on the left temple since the first year of life which then increased in size along with the presence of a solitary bluish-black macule noted by dermoscopic examination. Histologic examination showed verrucous epidermal nevus and basal cell carcinoma, pigmented type. CONCLUSION Two rare cases of basal cell carcinoma arising on epidermal nevus are reported. Despite the rarity of malignant transformation on epidermal nevus, any suspicious growth warrants a biopsy. Knowledge of these cases is important for probing suspicious growth over an epidermal nevus that would prompt early treatment before these lesions progress in size making it harder to manage. KEYWORDS epidermal nevus, nevus sebaceus, verrucous epidermal nevus, basal cell carcinoma, malignant transformation 1Department of Dermatology, University of Santo Tomas Hospital, Manila, Philippines Corresponding author Irene B. Cua, MD, DPDS, [email protected] Conflict of interest None Source of funding None INTRODUCTION Epidermal nevi (EN) are congenital lesions that affect about 1 in 1,000 people. They appear shortly after birth as localized epidermal thickening that follow the lines of Blaschko, suggesting that they result from post-zygotic somatic mutations in the skin.1 EN have been classified historically as non-organoid or organoid. Non-organoid EN are purely keratinocytic in composition, while organoid EN are composed of keratinocytes, sebaceous glands, hair follicles, apocrine or eccrine glands, and smooth muscle cells.3 In this report, the first patient presents with the organoid type of epidermal nevus (nevus sebaceus [NS]), while the second patient has the non-organoid type of epidermal nevus (verrucous epidermal nevus [VEN]). The incidence of malignant transformation on EN varies among different reports with few data available worldwide. While malignant transformations of NS are uncommon, basal cell carcinoma (BCC) is the most frequently occurring type. According to Cribier in 2000, recent studies indicate that the rate of BCC development is less than 1%.4 In 2016, a retrospective study by Hsu et al. about secondary neoplasms arising from NS have shown that BCC represented 0.9% of the secondary neoplasms, being the most frequent malignant tumor to arise from a NS.5 Malignant transformation of VEN has been rarely reported.6 A study of Hafner, et al. in 2008 cited that approximately 10 cases of BCC associated with non-organoid EN have been reported.7 As described in various journals, BCC on top of VEN typically develops after puberty and is most common in middle-aged or elderly individuals.2,6 In the local setting, there are no reported cases of BCC arising on top of VEN. In the case of BCC arising on nevus sebaceous, there was only one (1) published case in 1989 of a 9-yearold Filipino girl.8 J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 43 CASE REPORT
This is a case series about BCC arising on two (2) types of EN. Both manifested with EN on the left temple at birth which had been asymptomatic until a few years prior when changes in the size of the nevus, coupled with the appearance of overlying nodules, prompted consultation. CASE SUMMARY PATIENT 1 A 42-year-old Filipino, female, nail technician presented with a verrucous plaque on the left temple at birth. The tumor had grown proportionately with her age and started to manifest with pruritus since puberty. Three (3) years prior to consultation, grayish nodules that are associated with bleeding on trauma appeared over the plaque. She had no J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 44 Figure 1. Clinical photo of the 42-year-old Filipino female patient. A yellowish to pinkish verrucous plaque in linear configuration measuring 8.1 x 3.0cm interspersed with multiple, grayish, transluscent, papules, and nodules. Figure 2. Histopathologic examination of the verrucous plaque of the 42-year-old Filipino female. The tumor shows epidermal hyperplasia, acanthosis, interconnecting rete ridges and proliferation of follicular papilla with presence of sebaceous glands (hematoxylin and eosin, x100). personal history of extensive sunburn nor a family history of cutaneous malignancy, or the presence of similar lesions among family members. There was no known significant exposure to chemical carcinogens and ionizing radiation. She had no other comorbidities and review of system was unremarkable. On physical examination, there was a yellowish to pinkish verrucous plaque in linear configuration measuring 8.1 x 3.0 cm interspersed with multiple, round to irregularly-shaped, grayish, translucent, papules and nodules with smooth surface on the left temporal region and lateral aspect of the left eye 0.5-2.0 cm (Figure 1). Dermoscopy findings of the nodules showed blue-gray blotches, telangiectasia, and ulceration. Skin punch biopsy specimens were taken from a representative area of the verrucous plaque and the grayish nodule. Histopathological examination of the plaque showed epidermal hyperplasia, acanthosis, interconnecting rete ridges, and proliferation of follicular papilla with presence of sebaceous glands. These findings were consistent with NS (Figure 2). Histopathology of the nodule showed orthokeratosis, irregular acanthosis, tumor islands of basaloid cells showing hyperchromatic nuclei with peripheral palisading arrangement, focally containing melanin pigments, and embedded in a mucinous stroma. These findings were consistent with BCC, pigmented type. CASE REPORT
The patient was then referred to another institution for Mohs micrographic surgery. On follow-up after five (5) months, there was no noted appearance of new lesions on the post-operative site. PATIENT 2 A 53-year-old Filipino male, geothermal engineer presented J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 45 Figure 3. Dermoscopic findings of the verrucous growth of the 53-year-old Filipino male patient. A solitary blue ovoid nest (red arrow) interspersed along the homogenous, brown, globular, cobblestone structures. Figure 4. Histopathologic findings of the blue ovoid nest. The tumor shows tumor islands of basaloid cells with hyperchromatic nuclei showing peripheral palisading arrangement focally containing melanin pigments and embedded in a mucinous stroma (hematoxylin and eosin, x100) during the first year of life with a solitary, skin-colored to brown papule on the left temple. The lesion was stable until four (4) years prior to consult, when it was noted to gradually increase in size forming a papillomatous plaque. This was not associated with bleeding or fragility. The patient claimed to have significant sun exposure given his job as a geothermal engineer. He had no known significant exposure to chemical carcinogens and ionizing radiation. He had no personal or a family history of malignancy nor presence of similar lesions among family members. He had no other comorbidities and the review of systems was unremarkable. On physical examination, there was a papillomatous, skin-colored plaque on the left temple measuring 1.1 x 1.2 cm interspersed with a 0.1 cm bluish-black macule. Dermoscopic features of the verrucous growth show homogenous, brown, globular, cobblestone appearance with a solitary blue ovoid nest (Figure 3). Shave excision biopsy of the verrucous growth showed hyperkeratosis, irregular acanthosis, mild spongiosis, dilated upper dermal blood vessels, and moderate, superficial, perivascular lymphohistiocytic cell infiltrates admixed with extravasated red blood cells. These findings were consistent with VEN. Histologic features of the solitary bluish-black macule revealed tumor islands of basaloid cells with hyperchromatic nuclei showing peripheral palisading arrangement and embedded in a mucinous stroma. The tumor cells are seen extending from the epidermis to the mid reticular dermis. The biopsy was signed out as BCC, pigmented type (Figure 4). The remaining lesions were electrocauterized with no noted appearance of new lesions on the post-operative site on follow-up after three (3) months. DISCUSSION NS is a hamartoma of the epidermis, hair follicles, sebaceous and apocrine glands usually occurring on the scalp, followed by the face. Clinically, it presents at birth as yellow-orange to pink, finely papillomatous alopecic plaque that is often oval or linear. It generally grows proportionately with age and during puberty, and has a tendency to become more verrucous, raised and greasy by the effects of the androgen hormones.4 Studies on the molecular basis for the development of BCC has shown that the genetic defect involves the human homologue of Drosophila patched (PTCH) on chromosome 9q22.3. A study by Xin et al. in 1999 provided the first evidence of the involvement of the tumor suppressor gene PTCH CASE REPORT
REFERENCES 1. Paller AS, Syder AJ, Chan YM, Yu QC, Hutton E, Tadini G, et al. Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med [Internet]. 1994;331(21):1408–15. Available from: http://dx.doi.org/10.1056/NEJM199411243312103 2. Solomon LM, Esterly NB. Epidermal and other congenital organoid nevi. Curr Probl Pediatr [Internet]. 1975;6(1):1–56. Available from: http://dx.doi. org/10.1016/s0045-9380(75)80010-7 3. Brandling-Bennett HA, Morel KD. Epidermal nevi. Pediatr Clin North Am [Internet]. 2010;57(5):1177–98. Available from: http://dx.doi.org/10.1016/j. pcl.2010.07.004 4. Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: A study of 596 cases. J Am Acad Dermatol [Internet]. 2000;42(2 Pt 1):263–8. Available from: http://dx.doi.org/10.1016/S0190-9622(00)90136-1 5. Hsu M-C, Liau J-Y, Hong J-L, Cheng Y, Liao Y-H, Chen J-S, et al. Secondary neoplasms arising from nevus sebaceus: A retrospective study of 450 cases in Taiwan. J Dermatol [Internet]. 2016;43(2):175–80. Available from: http://dx.doi.org/10.1111/1346-8138.13070 6. Viana A, Aguinaga F, Marinho F, Rodrigues R, Cuzzi T, Ramos-E-Silva M. Basal cell carcinoma arising on a verrucous epidermal nevus: a case report. Case Rep Dermatol [Internet]. 2015;7(1):20–4. Available from: http://dx.doi.org/10.1159/000380846 7. Hafner C, Klein A, Landthaler M, Vogt T. Clonality of basal cell carcinoma arising in an epidermal nevus. New insights provided by molecular analysis. Dermatology [Internet]. 2009;218(3):278–81. Available from: http://dx.doi.org/10.1159/000189209 8. Piansay-Soriano EF, Pineda VB, Jimenez RI, Mungcal VC. Basal cell carcinoma and infundibuloma arising in separate sebaceous nevi during childhood. J Dermatol Surg Oncol [Internet]. 1989;15(12):1283–6. Available from: http://dx.doi.org/10.1111/j.1524-4725.1989.tb03148.x 9. Xin H, Matt D, Qin JZ, Burg G, Böni R. The sebaceous nevus: a nevus with deletions of the PTCH gene. Cancer Res. 1999;59(8):1834–6. 10. Fazarina M, Azahsyahrina A, Moonyza A, Lee BR. Basal Cell Carcinoma Arising from an Epidermal Naevus. Medicine & Health [Internet]. 2017;12(1):109– 12. Available from: http://dx.doi.org/10.17576/MH.2017.1201.14 J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 46 in NS. The results of analysis showed that BCC and NS share 9q22.3 deletions and are therefore likely to be pathogenetically related.9 Therefore, such findings could explain the development of BCC overlying a NS. VEN are congenital cutaneous hamartomas composed of keratinocytes. While malignant transformation is observed in NS, this is even rarer in VEN.6 The link between VEN and BCC has not been fully elucidated. It remains elusive whether these skin tumors are derived directly from epidermal nevus cells, and therefore clonally related, or these secondary tumors could have arisen from other cells, such as hair follicle keratinocytes, accompanying the epidermal nevus.7 Malignant transformation of VEN commonly happens post-puberty. The oldest patient reported was a 79-year-old male.10 Furthermore, a study by Hafner in 2008 on a biopsy containing both BCC and VEN described the possible clonal relationship between both lesions based on molecular genetic findings. The study was based on the premise of mosaicism of FGFR3 and PIK3CA mutations being involved in the pathogenesis of epidermal nevus and having oncogenic potential. The hotspot PIK3CA mutation E545K was found in a biopsy containing both EN and BCC. The study concluded that both lesions may still share a common but unknown molecular genetic alteration, and that the PIK3CA mutation may then have occurred during the tumorigenesis of the BCC in terms of subclonal divergence.7 These studies provide an underlying mechanism by which VEN can theoretically give rise to BCC. However, the question of the pathogenesis of BCC arising from an EN still remains inconclusive and is subject for further study. Nevertheless, their coexistence is significant, because both may arise from the same pluripotent cells in the embryonic ectoderm. Patients with EN should be closely monitored and any changes suspicious of an evolving tumor should be sampled for pathology. In early stages, total surgical excision remains a matter of debate. Some authors suggest early period prophylactic excision for prevention of malignant development while others find this unnecessary.5 According to Viana et al., the prophylactic excision of all VEN is not recommended, given the low number of BCC and other malignancies arising from this type of nevus.6 In conclusion, two (2) rare cases of BCC arising on two (2) different variants of EN are reported. Both patients presented with an epidermal growth on the left temporal aspect of the face since birth, which manifested with new suspicious lesions on their post-pubertal years. Risk factors such as trauma and sun exposure as demonstrated in the cases could be contributory to the malignant transformation of a pre-existing nevus. Further studies could be done to explore the influence of these risk factors and relate to the molecular studies described above. Despite the rarity of malignant transformation on EN, any suspicious growth warrants a biopsy. Knowledge of these cases is important for probing suspicious growth over a pre-existing epidermal nevus that would prompt early treatment before these lesions progress in size and number making it more complicated to manage. CASE REPORT
Disseminated histoplasmosis in a 53-year-old HIV-negative Filipino male: A case report Dana Andrea D. Nery, MD1 Maria Katherina Lat-Herrin, MD, FPDS, FDSP-PDS,1 Mary Elizabeth Danga, MD, FPDS, FDSP-PDS1 ABSTRACT INTRODUCTION Histoplasmosis is a disease of global distribution with diverse manifestations caused by the dimorphic fungus Histoplasma capsulatum. It is frequently described in severely immunocompromised and Human Immunodeficiency Virus (HIV)-positive individuals. Despite being widely reported in Southeast Asia, few cases have been reported in the Philippines. CASE REPORT A 53-year-old Filipino male who presented with umbilicated papules resembling molluscum contagiosum, and a previous history of a left lung mass with initial complaints of cough and hemoptysis. Gram stain of his sputum revealed the presence of fungal elements, otherwise not specified. In relation to this, a fine-needle aspiration biopsy of the suspected lung mass was done. However, findings were negative for malignant cells and fungi. Dermoscopy revealed central ulceration and necrosis with faint peripheral arborizing telangiectasia and surrounding superficial scaling. Histopathologic analysis revealed a diffuse granulomatous dermatitis, and Periodic acid-Schiff (PAS) and Grocott methenamine silver (GMS) stains showed numerous small yeast-like structures measuring approximately 3.74µm in diameter. Tissue culture of the skin lesion on the right thigh isolated fungal elements but was not specified. As histoplasmosis is an AIDS-defining infection and often found in immunocompromised states, screening for HIV was done which revealed negative results. Interestingly, disease distribution of histoplasmosis in the Philippines was frequently found in HIV-negative patients. Due to persistent serum creatinine elevation of over 300 µmol/L, renal biopsy was also done and revealed similar fungal elements. With these findings, a diagnosis of disseminated histoplasmosis was made. After a month of treatment with oral itraconazole, there was marked improvement of the patient’s skin lesions. CONCLUSION This case highlights the importance of recognizing cutaneous manifestations and maintaining a high index of suspicion for histoplasmosis in HIV-seronegative patients. KEYWORDS systemic fungal infections, disseminated histoplasmosis, molluscum-like lesions, itraconazole 1Department of Dermatology Rizal Medical Center Corresponding author Dana Andrea D. Nery, MD, [email protected] Conflict of interest None Source of funding None INTRODUCTION Histoplasmosis is a systemic mycosis caused by the thermally-dimorphic saprophytic fungus Histoplasma capsulatum and is frequently described in severely immunocompromised and Human Immunodeficiency Virus (HIV)-positive individuals. Although histoplasmosis is globally distributed, it is thought to occur more commonly in North America and is primarily endemic in Ohio and the Mississippi River Valley. It thrives in soil enriched with bird or bat guano, and humans are infected via inhalation of spores. Histoplasmosis has been widely reported in Southeast Asia; however, only 14 cases have been reported in the Philippines.1-7 We present a case of a 53-year-old HIV-seronegative Filipino male who presented with discrete umbilicated lesions on his face, trunk, and limbs. A tissue culture of the skin lesions on the right thigh showed the growth of fungi elements which prompted the investigation of an underlying infectious process. Histopathologic examination of the skin was consistent with cutaneous histoplasmosis. A biopsy of the renal interstitium confirmed the presence of fungal elements. The patient was thus managed as a case of disseminated histoplasmosis. CASE SUMMARY Three (3) months prior to consult, a 53-yearold Filipino male residing in Bulacan, a province located in the region of Central Luzon in the Philippines, presented with productive cough with minimal whitish sputum and heJ Phil Dermatol Soc • May 2023 • ISSN 2094-201X 47 CASE REPORT
moptysis, with associated exertional dyspnea, prompting hospitalization at a private institution. During this time, Mycobacterium tuberculosis infection was considered due to its endemicity in the Philippines. GeneXpert testing of a sputum sample was negative. A sputum sample was also sent for Gram stain which revealed fungal elements. No sputum culture was done at the time. A differential diagnosis of invasive candidiasis was considered, and an Aspergillus galactomannan antigen test was requested, which revealed a positive result of 5.0. Further evaluation of pulmonary findings with a computerized tomography scan of J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 48 Figure 1. Pretreatment image of multiple, well-defined skin-colored to slightly erythematous umbilicated papules on the (A) face, (B) ears, and (C) trunk measuring approximately 1.0-1.5cm x 0.8cm x 0.4-0.5cm. Figure 2. A. Dermoscopy of the ulcerated lesions on the face and trunk revealed central ulceration and necrosis, faint arborizing telangiectasias on the periphery of the lesions with surrounding superficial scaling. B. Red homogenous areas with overlying arborizing telangiectasias were more prominent on the right thigh. the chest revealed an ill-defined heterogeneously enhancing mass lesion with central air-fluid level and satellite lesions within the left lung. Fine-needle aspiration biopsy of the suspected lung mass was done which revealed findings negative for malignant cells and fungi. Physicochemical stains for microorganisms, such as Brown and Brenn, Periodic Acid-Schiff (PAS), and Ziehl-Neelsen, were done and were unable to isolate bacterial colonies, fungal elements, and acid-fast bacilli. Fungal culture of the lung mass also yielded a negative result. Serial complete blood count testing during this hospitalization showed persistent anemia and thrombocytopenia without associated symptoms such as fatigue, tachycardia, or pallor. Due to the persistence of his pulmonary symptoms, and positive Aspergillus galactomannan antigen test, he was empirically treated with sultamicillin 750mg and fluconazole 200mg daily. Eltrombopag 25mg daily was also given for persistent thrombocytopenia and the patient was subsequently discharged. Whilst taking fluconazole, the patient experienced nausea and was unable to tolerate the medication. Consequently, the medication was shifted to itraconazole 200 mg daily after two (2) weeks. Approximately a month after his initial admission, the patient presented with multiple, non-pruritic and non-painful papules on the face. The lesions increased in number to involve the trunk and extremities, with spontaneous ulcerating and crusting of lesions (Figure 1). The patient was referred to our dermatology service for assessment of his skin lesions. On physical examination, the patient had stable vital signs and had no appreciaCASE REPORT
ble lymphadenopathy. Dermatologic examination revealed multiple discrete skin-colored to slightly erythematous, monomorphic umbilicated papules measuring 1.0-1.5 x 0.8 x 0.4-0.5 cm, on the face, ears, trunk, and extremities (Figure 1A, 1B, 1C, and 1D). Red homogenous areas with overlying arborizing telangiectasia were more prominent on the right thigh. Some of the lesions had superficial ulcerations. Dermoscopy of the ulcerated lesions on the face and trunk revealed central ulceration and necrosis with faint peripheral arborizing telangiectasia and surrounding superficial scaling (Figure 2A-B). The past medical history was significant for pulmonary tuberculosis wherein the patient completed six (6) months of treatment with anti-Kochs therapy in 2016. The patient is a known hypertensive, and dyslipidemia is maintained on amlodipine, losartan with hydrochlorothiazide, and rosuvastatin (10mg, 50mg/125mg, 10mg, orally). He also has diabetes mellitus maintained on glimepiride and pioglitazone/metformin (2mg, 15/500 mg). The patient was compliant with his medications with blood pressure and fasting blood sugar controlled. Previous surgical history included a cholecystectomy and hernia repair in the 1990s. He provided no history of smoking or alcoholism. Upon further inquiry, he revealed that he had owned birds for 11 years and was an avid participant in local cockfighting: a traditional pastime in most provinces in the Philippines. He denied trauma or exposure to excavation or landscaping. History of travel included the Middle East including Israel, Jerusalem, and Egypt in 2017, and the United States, including San Francisco, Nevada, and New Jersey, in 2019. The patient is in a monogamous relationship with his wife and denies previous history of sexually transmitted infections. Further workup was done with serial blood tests revealing asymptomatic microcytic hypochromic anemia and thrombocytopenia. As bone marrow infiltration with fungi was considered, peripheral blood smear and bone marrow aspirate were done which revealed hypochromasia and anisocytosis of red blood cells, and normocellular marrow for the patient’s age (50-60%). No evidence of fungal invasion was seen. However, stains to isolate fungal organisms were not done. Serologic testing for HIV was negative. Tests to rule out other sexually transmitted infections were not requested. Due to persistent serum creatinine elevation of over 300 µmol/L, the patient was referred to nephrology service. J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 49 Figure 3. A. Histopathologic findings of 6-mm skin punch biopsies from the trunk and B. right thigh showing diffuse granulomatous infiltrates composed of multinucleated giant cells, foamy histiocytes, lymphocytes, plasma cells, and neutrophils with numerous small yeast-like structures, both extracellular and within the histiocytes and giant cells, seen as basophilic dots measuring approximately 3.74 micrometers with surrounding artefactual halo. C. Giemsa and D. Alcian Blue were negative. E. Periodic acid-Schiff and F. Grocott (GMS) methenamine silver stains positively highlighting yeast forms of Histoplasmosis. Viral hepatitis was excluded and an antineutrophil cytoplasmic antibody test (p-ANCA) was found to be negative. A renal biopsy was performed revealing IgA nephropathy with 5% cellular crescents and 24% global glomerulosclerosis. Acute interstitial nephritis was also noted with acute tubular injury, mild interstitial fibrosis, tubular atrophy, and mild hyaline arteriosclerosis. PAS staining highlighted CASE REPORT
J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 50 fungal elements within the interstitium. Through collaborative efforts with infectious disease, hematology, nephrology, and dermatology services, a diagnosis of disseminated histoplasmosis was made. 6-mm skin punch biopsies were done on lesions from two (2) sites on the papule on the trunk and right thigh (Figure 3A). The dermatopathology reports from both sites with hematoxyline and eosin (H&E) staining were signed out as diffuse granulomatous infiltrates composed of multinucleated giant cells, foamy histiocytes, lymphocytes, plasma cells, and neutrophils with numerous small yeast-like structures, both extracellular and within the histiocytes and giant cells, seen as basophilic dots measuring approximately 3.74 micrometers with surrounding artefactual halo, suggestive of systemic mycosis (Figure 3B). Histopathologic differentials such as cryptococcus, coccidioidomycosis, penicilliosis, and blastomycosis were considered. We performed both Giemsa stain and Alcian Blue stain tests as they could confirm the presence of deep fungal mycoses other than histoplasmosis (Figure 3C-3D). However, the results were negative in both cases. PAS and GMS stains highlight the characteristic morphology and size of histoplasmosis described as intracellular, round-to-oval spores with narrow-necked budding and the presence of pseudocapsule described as an artefactual halo. In our patient, PAS and GMS stains aided in the visualization of yeast forms of H. capsulatum (Figure 3E-3F). Tissue culture and sensitivity of the skin lesions on the right thigh done in another institution showed growth of fungi. (as it did not specify organism/sensitivity). In summary, the presence of yeast forms in both PAS and GMS stains measuring approximately 3.74 micrometers, the positive results of fungal culture from the papule on the right thigh, the presence of unspecified lung mass, PAS-positive fungal elements from the kidney, and symptoms such as prolonged cough, were highly suggestive of disseminated histoplasmosis. Oral itraconazole 200mg twice daily was continued following the diagnosis of histoplasmosis, with ongoing monitoring of liver function. Notable improvement in skin lesions were seen four (4) weeks after initiation of itraconazole and subsequently during follow-up visits (Figure 4). DISCUSSION Histoplasmosis is primarily a pulmonary disease that can be acquired from inhalation of soil contaminated with bird and bat droppings. It may present as an acute or chronic pulmonary, cutaneous, or progressive disseminated disorder. Histoplasmosis encompasses a wide range of clinical Figure 4. Post-treatment image of skin papules on the face and trunk showing reduction in size after 4 weeks of treatment with Itraconazole 200 mg/capsule daily. manifestations, with the disseminated type being the most serious and fatal. Disseminated histoplasmosis encapsulates extrapulmonary involvement in various organs such as the lymph nodes, liver, spleen, skin, or bone marrow. It is normally seen in patients with progressive illnesses such as HIV-positive individuals, or those who are in immunocompromised states. This may arise from previous reactivation of latent histoplasmosis by residing in areas where histoplasmosis is endemic or may occur from recent exposure to high fungal load. Histoplasmosis is considered hyperendemic in the Philippines based on high histoplasmin sensitivity (26%), which is considered as above the global histoplasmin rate.8 Histoplasmin skin sensitivity is a measure of immunity of individuals that may have been exposed to H. capsulatum. The prevalence rate of sensitivity may aid in the determination of endemicity of histoplasmosis in certain regions. Thus, a high histoplasmin sensitivity may indicate high incidence of exposure to this fungus, increasing the likelihood that the total number cases of histoplasmosis may be underreported. In one study of mapping histoplasmosis in Southeast Asia, it was concluded that in the Philippines, histoplasmosis is common in HIV-negative individuals. However, few cases of disseminated histoplasmosis with cutaneous manifestations have been reported in the Philippines to date.1-7 It is possible that the disseminated type of histoplasmosis is underreported in the Philippines due, in part, to its overlap in features with tuberculosis. Mycobacterium tuberculosis infection is also endemic in the Philippines and may also present with similar pulmonary findings, as well as similar diffuse granulomatous inflammation on histology. Cutaneous manifestations of histoplasmosis may be CASE REPORT
J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 51 polymorphous and non-specific. The diagnosis of cutaneous histoplasmosis may not be achieved based on clinical findings alone as it may exhibit significant overlap with other fungal infections. Cutaneous manifestations may occur in 4-11% of cases and result as a secondary invasion of the skin due to hematologic dissemination of infected macrophages. In this case, an HIV-negative, and possibly non-immunocompetent individual (as he is having diabetes and dyslipidemia) developed unusual cutaneous lesions following a history of prolonged cough and lung lesions and was diagnosed as a case of disseminated histoplasmosis. This is an AIDS-defining disease and one of the major causes of mortality among HIV/AIDS patients. This case highlights the possibility of disseminated histoplasmosis in an HIV-negative individual. Hematologic abnormalities such as anemia and thrombocytopenia may be found in patients with histoplasmosis. In a study by Smith and Utz, among 21 adults with disseminated histoplasmosis, 38% were thrombocytopenic and anemic. In cases of severe infection, H. capsulatum can infiltrate the bone marrow and cause thrombocytopenia, anemia, and leukopenia.9 Similar to this patient who exhibited the exact same features, a high index of suspicion of bone marrow infiltration with fungi should be considered. Moreover, isolation and growth of H. capsulatum from blood or bone marrow samples via culture is the gold standard for the detection of disseminated histoplasmosis. However, bone marrow culture to isolate the organism was not done due to financial constraints. Histoplasmosis can be detected by various laboratory-based techniques, including H&E and PAS stains of tissue.7 Classic findings of histoplasmosis in H&E stains reveal the presence of small (2-4mm) budding oval yeasts that are frequently present in macrophages or in the tissues. Through histological examination, H. capsulatum var. capsulatum can be misidentified as various other fungi, including Talaromyces marneffei, Cryptococcus neoformans, Candida glabreta, and Blastomyces dermatitidis. 7 Careful examination of salient features such as spore size, spore shape, presence of capsule, structures/patterns formed (budding vs traverse septum vs binary fission), reactivity to PAS, cell wall thickness and type of inflammation (granulomatous and neutrophil infiltrate) are pivotal to differentiate H. capsulatum var. capsulatum from the aforementioned fungi. Traditional mycological techniques are the current gold standard for confirming disseminated histoplasmosis; however, non-culture-based tests have been shown to enhance the detection of Histoplasma species. A recent meta-analysis for assay analytical efficiency in histoplasmosis discovered that test sensitivities for culture was 77% with varying sensitivity linked to sample type and laboratory treatment, for antigen detection assays, it was 95%; and for polymerase chain reaction (PCR)-based DNA detection analysis, the efficiency was 95%.8 Histoplasma antigen tests were found to be the most reliable approach for diagnosing histoplasmosis. Another study found that the diagnosis of disseminated histoplasmosis in hospitalized patients was facilitated by the combined use of Histoplasma blood PCR and Histoplasma urine antigen.9 The World Health Organization (WHO) recently made recommendations for the identification, treatment, and control of disseminated histoplasmosis.10 The antigen Histoplasma detection method is the recommended diagnostic technique in this recommendation. However, in the Philippines, PCR-based analysis and Histoplasma antigen tests are not available locally for the diagnosis of histoplasmosis. Consensus guidelines on the management of moderate to severe histoplasmosis recommend the use of liposomal amphotericin B at 3.0 mg/kg daily for 1-2 weeks, followed by oral itraconazole 200 thrice daily for three (3) days, followed by 200 mg twice daily for 12 months. Itraconozole may be used as the treatment of choice for non-life-threatening histoplasmosis. The patient described in this case responded well to itraconazole 200 mg/day with lesions improving after four (4) weeks on itraconazole. CONCLUSION Disseminated histoplasmosis remains an important differential diagnosis in patients presenting with molluscum-like lesions. Due to possible fatality, if not managed promptly, it is important to have a high index of suspicion for its non-specific cutaneous lesions. Skin biopsies should always be considered in patients with cutaneous lesions of systemic mycoses, as disseminated histoplasmosis can mimic other systemic fungal infections.11 A comprehensive workup for any possible underlying systemic disease, monitoring disease course, and a thorough understanding of morphological features of various applications of fungal culture and serological procedures may prevent delays in diagnosing disseminated histoplasmosis. In conclusion, disseminated histoplasmosis remains an important considCASE REPORT
ACKNOWLEDGMENTS The authors would like to acknowledge Maria Isabel Beatriz Puno-Gomez, MD, FDSP-PDS, Consultant of Department of Dermatology Rizal Medical Center, for her invaluable insights and contribution for this case. REFERENCES 1. Azar MM, Malinis MF. Disseminated histoplasmosis with skin lesions and osteomyelitis in a patient from the Philippines. Am J Trop Med Hyg [Internet]. 2016;95(1):70–4. Available from: http://dx.doi.org/10.4269/ajtmh.16-0063 2. Palencia RJ, Aniceto EG, Pena AC. Fever of unknown origin with hepatomegaly due to Histoplasma capsulatum: Case report. Phil J Microbiol Infect Dis. 1990 Jul;19:63-7. 3. Mendoza JT. Histoplasmosis: Report of a Case. Monthly Bulletin of the Philippine Health Service. 1947;23(1):33-40. 4. Natividad-Santos E. A case of progressive disseminated histoplasmosis. Chest Dis. 1974;9:15-9. 5. Lin-Kleiner HF. Disseminated Histoplasmosis in a Two-Month Old Filipino Infant: A Preliminary Report. 6. Navarro EE, Tupasi TE, Verallo VM, Romero RC, Tuazon CU. Disseminated histoplasmosis with unusual cutaneous lesions in a patient from the Philippines. The American journal of tropical medicine and hygiene. 1992 Feb;46(2):141-5. 7. Marquez-Protacio FV. Disseminated histoplasmosis in an HIV-positive Filipino. J Phil Dermatol Soc. 2019;28(1), 54-8 8. Fandiño-Devia E, Rodríguez-Echeverri C, Cardona-Arias J, Gonzalez A. Antigen Detection in the Diagnosis of Histoplasmosis: A Meta-analysis of Diagnostic Performance. Mycopathologia. 2016 Apr;181(3-4):197-205. doi: 10.1007/s11046-015-9965-3. Epub 2015 Nov 11. PMID: 26559429. 9. Falci, DR. The era of histoplasmosis in Brazilian endemic mycoses The Lancet Regional Health – Americas, Volume 3, 100037. Available from: https://doi.org/10.1016/j.lana.2021.100037 10. World Health Organization (WHO). WHO. Guidelines for diagnosing and managing disseminated histoplasmosis among people living with HIV. Available from: http:// https://www.who.int/publications/i/item/9789240006430 11. Baker J, Setianingrum F, Wahyuningsih R, Denning DW. Mapping histoplasmosis in South East Asia - implications for diagnosis in AIDS. Emerg Microbes Infect [Internet]. 2019;8(1):1139–45. Available from: http://dx.doi.org/10.1080/22221751.2019.1644539 12. Smith JW, Utz JP. Progressive disseminated histoplasmosis. A prospective study of 26 patients. Ann Intern Med [Internet]. 1972;76(4):557–65. Available from: http://dx.doi.org/10.7326/0003-4819-76-4-557 J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 52 eration, even in non-endemic areas. Histoplasma urine antigen and PCR assay are complementary to standard mycologic procedures and crucial in our clinical setting.12 Therefore, further research should be explored in terms of newer diagnostic modalities to establish their efficacy and applicability in the local setting. CASE REPORT
CASE REPORT The great mimicker: A case report of an extensive pyoderma gangrenosum in a 39-year-old Filipino female treated with systemic corticosteroids and antibiotics Camille Joyce J. Crisostomo, MD, DPDS,1 Niña A. Gabaton, MD, FPDS1 ABSTRACT INTRODUCTION Pyoderma gangrenosum (PG) is a rare inflammatory disease with unknown etiology. Ulcerative PG presents with a rapidly enlarging painful ulcer with erythematous and undermined border often misdiagnosed as infection, vascular disorder, malignancy, and other inflammatory disease. Hence, this poses a diagnostic challenge for clinicians leading to a delay in the management and significant morbidity. The treatment of PG is equally challenging due to the rarity of the disease and the scarcity of clinical trials. Currently, there are no clinical practice guidelines for the management of PG. CASE REPORT Our patient presented with multiple large ulcers with erythematous and undermined borders over the chest, abdomen, and the lower back. Cribriform scars and contractures were noted as well. She underwent several sessions of surgical debridement and was given different broad-spectrum antibiotics with noted worsening of the lesions. Due to extensive involvement of the disease, her quality of life has been significantly affected. A diagnosis of PG was made after the biopsy showed predominantly neutrophilic infiltrate. Prednisone 1mg/kg/day and clobetasol propionate ointment were initiated with significant decrease in pain and size of the ulcers after one month of therapy. Doxycycline was used as an adjunct therapy with excellent response. CONCLUSION Pyoderma gangrenosum is a rare, debilitating disease that remains a diagnostic dilemma. The worsening of ulcers despite surgical debridement and antibiotics is a clue that should prompt clinicians to consider PG. This case highlights the important role of dermatology in individuals who present with non-healing chronic ulcers because as seen in this case, not all ulcers are just ulcers. KEYWORDS pyoderma gangrenosum, neutrophilic dermatosis, ulcers 1Department of Dermatology, Southern Philippines Medical Center, J. P. Laurel Ave., Bajada, Davao City, Philippines Corresponding author Camille Joyce J. Crisostomo, MD, DPDS [email protected] Conflict of interest None Source of funding None INTRODUCTION Pyoderma gangrenosum (PG) is a rare, chronic inflammatory disease with an estimated incidence of 3-10 cases per million of the population per year.1 It is classified under the group of neutrophilic dermatoses. Although the etiology is still unknown, abnormalities of the immune system have been suggested to play a role in the pathogenesis of the disease.2 The classic or ulcerative PG begins as papules, pustules, or nodules rapidly progressing to ulcers with violaceous and undermined borders commonly affecting the lower extremities. This is accompanied by significant pain that is usually out of proportion to the appearance of the lesion.3 Despite these distinctive features, the diagnosis of pyoderma gangrenosum remains challenging due to lack of a specific laboratory test. In addition, several other diseases can mimic the presentation of PG leading to misdiagnosis. The scarcity of research trials for pyoderma gangrenosum is due to the low incidence of the disease. Hence, evidence-based therapeutic guidelines for PG are still currently lacking, making it difficult to manage this disease. Herein we report a case of an extensive pyoderma gangrenosum initially diagnosed as an infection and was managed several times with surgical debridement and broadspectrum antibiotics with worsening of the condition. The patient was treated with oral prednisone and doxycycline with excellent response. CASE SUMMARY This is a case of a 39-year-old Filipino female who presented with a 3-year history of rapidly enlarging painful ulcers on the chest, abdomen and back. The lesions would begin as J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 53
CASE REPORT a papule with central suppuration, which would rupture spontaneously evolving to a very painful ulcer. At the onset of the initial lesion on the abdomen three (3) years prior to consult, the patient immediately sought consult in a private hospital and was prescribed with clindamycin with no apparent improvement. During the interim, there was development of new lesions on the chest, right leg, back, and left arm. The patient sought consult with internists and surgeons at different hospitals where wound cultures taken at different times revealed different bacterial species including Pseudomonas, Morganella, and Staphylococcus. Despite antibiotic coverage for these organisms and a series of surgical debridements, there was no apparent improvement of the ulcers leading to an impaired quality of life. Past medical history was unremarkable. There was no intake of any medications nor any trauma over the area prior to the onset of the lesions. Physical examination revealed multiple, well-defined, ulcers with a base J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 54 Figure 1. A. Multiple, well-defined ulcers surrounded by erythematous, undermined borders over the chest (largest measuring 18 cm x 10 cm), abdomen (15 cm x 10 cm and 9 cm x 2.5 cm), and the B. lower back (1 cm x 1 cm). C. Cribriform scars on the right lower leg. Figure 2. A. Scanning view (H&E; 4x) of the biopsy of the ulcer edge. B. There’s a superficial dermal edema (H&E; 40x) and C. diffuse predominantly neutrophilic infiltrates (H&E; 40x). D. Foci of epidermal necrosis was noted in another section (H&E; 40x). containing purulent discharge surrounded by erythematous, undermined borders over the chest, abdomen, and the lower back (Figure 1A-B). There were three (3) chest ulcers, two (2) abdominal ulcers, and a small ulcer on the lower back, ranging from 1-18 cm in size. Cribriform scars with fibrotic strands and contractures were noted on the chest, abdomen, back, left arm, gluteal area extending to the left thigh, and right leg (Figure 1C). Blood investigations showed anemia, neutrophilia, and elevated ESR. No atypical cells or blasts were seen on peripheral blood smear but neutrophilic leukocytosis was noted. Wedge incision biopsy was done on the ulcer edge. Histopathology revealed a mildly acanthotic and spongiotic epidermis overlying a dermis with superficial edema and diffuse predominantly neutrophilic inflammatory infiltrate (Figure 2A-C). Another section showed foci of epidermal necrosis (Figure 2D). These are findings consistent with a neutrophilic dermatosis. Based on the clinical and histopathologic findings, a diagnosis of pyoderma gangrenosum (PG) was made. The patient was started on prednisone at a dose of 1 mg/kg/ day, clobetasol propionate ointment over the periphery of the ulcers, and hydrocolloid dressing for wound care. There was a significant decrease in the size of the ulcers with formation of granulation tissue after one (1) month of treatment while some ulcers healed with cribriform scarring (Figure 3A). Doxycycline 100 mg twice daily was given as an adjunct treatment. Complete control of the condition was achieved on the fourth month (Figure 3B) for which oral prednisone and doxycycline were gradually tapered and discontinued on the sixth month of treatment. By this time, the majority of the patient’s ulcers had completely healed (Figure 3C). Patient is still in remission four
(4) years after treatment (Figure 3D). DISCUSSION Pyoderma gangrenosum (PG) remains a diagnosis of exclusion despite the several proposed diagnostic criteria in the literature. The clinical presentation commonly mimics other diseases including infections, vasculopathies, malignancies, and other inflammatory disorders.3 Infectious differential diagnoses that can mimic PG include atypical mycobacteria, cutaneous tuberculosis, cutaneous leishmaniasis, ecthyma gangrenosum, and other deep fungal infections. The histopathologic findings do not confirm the diagnosis but rather aid in excluding the other differential diagnoses. There are several subtypes of PG depending on the clinical presentation and morphology. The most common type is the ulcerative or the classic PG, which presents initially with a solitary or multiple pustules or nodules that rapidly ulcerate with a violaceous and undermined border. This type commonly affects the lower extremities and is frequently associated with arthritis, inflammatory bowel disease, monoclonal gammopathy, and malignancy.3 A large case series of PG revealed that 77.7% of the lesions present on the leg, with the remaining involving the trunk (11.7%), peristomal site (8.7%), upper extremities (8.7%) , and head and neck (7.8%).4 Another study by Pereira et al., revealed that out of 17 patients with ulcerative PG, 13 patients had involvement of the lower limbs (76%) while the remaining four (4) had abdominal lesions (23.5%).5 The most recent diagnostic criteria of PG based on a Delphi Consensus of International Experts in 2018 include a major criterion which is a biopsy finding of ulcer edge demonstrating a neutrophilic infiltrate and eight (8) minor criteria which include the following: (1) exclusion of infection, (2) pathergy, (3) history of inflammatory bowel disease or inflammatory arthritis, (4) history of papule, pustule or vesicle J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 55 Figure 3. A. After 1 month of treatment, there was a decrease in the size of the ulcers. B. At 4 months, the majority of the ulcers have healed. C. No ulcers but with cribriform scarring 6 months after treatment. D. Complete remission 4 years after treatment. ulcerating within four (4) days, (5) peripheral erythema, undermining border, and tenderness at ulceration site, (6) multiple ulcerations, at least one (1) on an anterior lower leg, (7) cribriform or “wrinkled paper” scar(s) at healed ulcer sites; and (8) decreased ulcer size within one (1) month of initiating immunosuppressive medication. To make a diagnosis of PG, a patient must meet the major criterion and four (4) out of eight (8) minor criteria. These are the only diagnostic criteria that makes PG not a diagnosis of exclusion and has been reported to have a sensitivity and specificity of 86% and 90%, respectively.6 The patient fulfilled the major criterion and five (5) out of eight (8) minor criteria. Hence, the diagnosis of ulcerative pyoderma gangrenosum (PG). The management of PG is likewise difficult due to the lack of clinical practice guidelines. Treatment is based on the severity of the disease, as well as patient response. In mild PG, local therapy such as intralesional or topical high-potency corticosteroids and topical calcineurin inhibitors may be adequate. A mainstay of treatment for PG is oral corticosteroids. Prednisone 1 to 2 mg/kg/day is often used to induce remission of the disease with gradual tapering and addition of steroid-sparing agents. Similar efficacy is seen with cyclosporine given as a monotherapy or in combination with other therapies. Other adjunctive treatment modalities include minocycline, dapsone, methotrexate, mycophenolate mofetil, cyclophosphamide, and thalidomide.7 Antibiotics, such as doxycycline, can also be used due to its anti-inflammatory and antimicrobial effect.8 One patient with partial immunoglobulin A deficiency who was diagnosed with PG on the leg was treated with prednisolone 40 mg and doxycycline 100 mg once daily for three (3) months with complete resolution of lesion.9 Another case of a female patient with superficial granulomatous pyoderma gangrenosum, who was initially given systemic immunosuppressives but eventually developed complications, responded well with oral doxycycline.10 Combination therapy should be tailored based on the response of the patient.7 In this case, there was a significant improvement with a decrease in size of the ulcers after one (1) month of initiating treatment with oral prednisone and clobetasol propionate ointment. Doxycycline was used as an adjunct therapy in our patient with excellent response. In conclusion, pyoderma gangrenosum (PG) is a rare, debilitating disease that often remains a diagnostic dilemma. The diagnosis of PG can be extremely challenging. However, the important clues that supported the diagnosis of PG likely were non-response to both broad-spectrum antibiotics and surgical debridement. Histopathologic findings are CASE REPORT
REFERENCES 1. Monari P, Moro R, Motolese A, Misciali C, Baraldi C, Fanti PA, et al. Epidemiology of pyoderma gangrenosum: Results from an Italian prospective multicentre study. Int Wound J [Internet]. 2018;15(6):875–9. Available from: http://dx.doi.org/10.1111/iwj.12939 2. Ahn C, Negus D, Huang W. Pyoderma gangrenosum: a review of pathogenesis and treatment. Expert Rev Clin Immunol [Internet]. 2018;14(3):225–33. Available from: http://dx.doi.org/10.1080/1744666X.2018.1438269 3. Powell F, Hackett B, Wallach D. Pyoderma Gangrenosum. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller A, Leffell DJ, Wolff K. Fitzpatrick’s dermatology in general medicine, eighth edition, 2 volume set. 8th ed. New York, NY: McGraw-Hill Medical; 2012: 371-379. 4. Gunawan H, Maharani RH, Achdiat PA, Hindritiani R. A case report of extensive pyoderma gangrenosum on the upper third of the body. Clin Cosmet Investig Dermatol [Internet]. 2021;14:1645–9. Available from: http://dx.doi.org/10.2147/CCID.S337508 5. Pereira N, Brites MM, Gonçalo M, Tellechea O, Figueiredo A. Pyoderma gangrenosum--a review of 24 cases observed over 10 years: PG over 10 years. Int J Dermatol [Internet]. 2013;52(8):938–45. Available from: http://dx.doi.org/10.1111/j.1365-4632.2011.05451.x 6. Maverakis E, Ma C, Shinkai K, Fiorentino D, Callen JP, Wollina U, et al. Diagnostic criteria of ulcerative pyoderma gangrenosum: A Delphi consensus of international experts. JAMA Dermatol [Internet]. 2018;154(4):461–6. Available from: http://dx.doi.org/10.1001/ jamadermatol.2017.5980 7. Prajapati V, Man J, Brassard A. Pyoderma gangrenosum: common pitfalls in management and a stepwise, evidence-based, therapeutic approach. J Cutan Med Surg [Internet]. 2009;13 Suppl 1(3_suppl):S2-11. Available from: http://dx.doi.org/10.2310/7750.2009.00002 8. Alonso-León T, Hernández-Ramírez HH, Fonte-Avalos V, Toussaint-Caire S, E Vega-Memije M, Lozano-Platonoff A. The great imitator with no diagnostic test: pyoderma gangrenosum. Int Wound J [Internet]. 2020;17(6):1774–82. Available from: http://dx.doi.org/10.1111/ iwj.13466 9. Demirel S, Shetty M, Patel M, Mahmood K. First presentation of pyoderma gangrenosum in a patient with partial immunoglobulin A deficiency. JRSM Open [Internet]. 2022;13(4):20542704221086384. Available from: http://dx.doi.org/10.1177/20542704221086386 10. Sullivan N. Conservative management of superficial granulomatous pyoderma gangrenosum with oral doxycycline. J Am Acad Dermatol [Internet]. 2016;74(5):AB293. Available from: http://dx.doi.org/10.1016/j.jaad.2016.02.1130 J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 56 confirmatory. Doxycycline, a treatment adjunct used for its anti-inflammatory properties, can be used in patients with PG to lessen the possible long-term side effects of corticosteroids. A timely referral to a dermatologist is vital to prevent further delays in the diagnosis and management of PG, as well as to avoid long-term scarring and sequelae of the disease that can significantly affect the patient’s quality of life. This case highlights the important role of dermatology in individuals who present with non-healing chronic ulcers because as seen in this case, not all ulcers are just ulcers. CASE REPORT
CASE REPORT Plasma cell cheilitis in an elderly female: A case report Maria Isabel M. Belizario, MD,1 Jolene G. Dumlao, MD, FPDS,2 Johannes F. Dayrit, MD3 ABSTRACT INTRODUCTION Plasma cell cheilitis (PCC) is a rare, chronic inflammatory dermatitis of unknown etiology. Due to the limited number of cases reported, no guidelines have been established for its treatment. We present a case of PCC clinically similar to actinic cheilitis or mucosal lichen planus, and squamous cell carcinoma but showed response to topical tacrolimus 0.1% ointment. CASE REPORT A 62-year-old female with extreme fondness to piping hot food presented with a solitary painful ulceration with some pustules and bleeding on the lower lip with three (3) months duration. Skin punch biopsy revealed a dense band-like infiltrate of plasma cells which is consistent with Plasma cell cheilitis. The patient was given tacrolimus 0.1% ointment and showed significant improvement after a month of treatment. CONCLUSION PCC is a rare condition that should still be considered in patients presenting with persistent cheilitis. Clinical and histological correlation is advised for proper management and prognostication. KEYWORDS cheilitis, persistent ulceration, plasma cell, tacrolimus 1Belizario Dermatology Clinic, 82 E. Rodriguez Jr. Avenue, Bagumbayan, Quezon City, Philippines 2Baguio General Hospital and Medical Center, Gov. Pack Rd, Baguio, 2600 Benguet, Philippines 3De La Salle University Medical Center, Gov, D. Mangubat St, Avenue, Dasmariñas, 4114 Cavite, Philippines Corresponding author Maria Isabel M. Belizario, MD, [email protected] Conflict of interest None Source of funding None INTRODUCTION Plasma cell cheilitis (PCC) is a rare, chronic inflammatory dermatitis of unknown etiology. It is commonly found in elderly males presenting as an erosive plaque or patch with fissures, bleeding, and crusting on the lip mucosa.1,2 Due to similar presentation to other causes of cheilitis, misdiagnosis is common. Differential diagnoses noted in literature include common causes of cheilitis like infective cheilitis (bacterial, fungal, herpes simplex virus) due to immunocompromised states, actinic cheilitis, squamous cell carcinoma and those associated with systemic diseases such as lichen planus.3 Due to the limited number of cases reported, no guidelines have been established for the management of this condition and use of traditional topical steroids has shown varying results.1 Aside from treatment with oral steroids, intralesional steroid injections, systemic griseofulvin, and topical tacrolimus and pimecrolimus have been explored.4,5 We present a case of PCC clinically similar to actinic cheilitis, mucosal lichen planus, and squamous cell carcinoma. Our case showed partial remission with topical tacrolimus 0.1% ointment. CASE SUMMARY A 62-year-old, non-smoker, businesswoman from Santo Tomas, Pampanga, who came in due to a painful ulceration (8/10 pain scale) with pustules and bleeding on the lower lip of three (3) months duration. Her medical and sexual history was generally non-contributory and the patient noted frequent consumption of piping hot food. The patient claimed to stay mainly indoors and did not use any form of sun protection daily. The initial presentation was a solitary, well-defined erosion with pustules and pinpoint bleeding on the lower lip (Figure 1A). The patient was initially treated by another physician for herpes simplex infection with fungal superimposition. She was initially given oral acyclovir 400mg every eight (8) hours for seven (7) days, 0.9% sodium chloride compress, miconazole cream, and betamethasone cream twice a day for two (2) weeks. There was a noted complete resolution of pain, however, only partial improvement on the lesions on the lower lip was observed. Hence, the patient decided to seek J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 57
CASE REPORT for a second opinion. Upon consultation, physical examination showed a solitary and well-defined erythematous erosion on the lower lip with no Wickham striae (Figure 1B). Skin punch biopsy and syphilis serology was advised. However, due to financial constraints, the patient was lost to follow-up. Two (2) weeks after initial consult, the patient came back for follow-up due to an increase in the size of the erosion and recurrence of pain (7/10) (Figure 1C). Dermoscopy of the lower lip showed a well-defined erosion with milky red structureless areas and multiple linear vessels on the periphery (Figure 1D). These findings were consistent with the diagnosis of PCC. Rapid plasma reagin (RPR) and venereal disease research laboratory (VDRL) test results were nonreactive. Histopathological examination showed a dense band-like infiltrate of plasma cells, lymphocytes, scattered neutrophils and eosinophils seen in the upper dermis. No hypergranulosis, colloid bodies, solar elastosis, squamous islands, or atypical cells were seen (Figure 2). Histologic findings were consistent with PCC. The patient was subsequently treated with tacrolimus 0.1% ointment twice a day. After a month of daily treatment, significant improvement was observed on the lesions on the lower lip (Figure 3). J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 58 Figure 1. A. Initial clinical presentation before seeking consultation. B. Partial response to initial treatment (given by another physician) with oral antiviral, 0.9% sodium chloride, miconazole cream, and betamethasone cream. C. Clinical photo prior to biopsy. D. Dermoscopy prior to biopsy. DISCUSSION PCC is a rare benign inflammatory condition that was first identified by Zoon in 1952 as the oral counterpart of plasma cell balanitis. PCC may also develop in other orofacial areas such as the vulva, buccal mucosa, tongue, epiglottis, and larynx.6 PCC commonly affects the lower lip and presents clinically as erosions, ulcerations, or fissures with crusting or bleeding.1,6 In a study done by Lee et al, in 2017, the most common primary presentation was a patch accompanied by erosion and the most common symptom reported was pricking.2 Our patient presented a history of painful erosion on the lower lip for three (3) months similar to the findings described in the literature. However, due to its general appearance, symptoms, and rarity, the diagnosis of PCC may be missed initially. Dermoscopy is a useful tool that can help further investigate cheilitis. Findings of a well-defined border, milky red areas and radial distribution of linear vessels on the periphery, absence of stellate border, and scales at the periphery (suggestive of actinic cheilitis) or Wickham striae (pathognomonic of oral lichen planus) have been identified as important clues in the diagnosis of PCC.7,8 Our patient presented with a histology of dense bandlike infiltrates with mature plasma cells on the subepithelia consistent with the established literature.1,9 Plasma cells seen in histopathological findings may also be found in conditions like oral lichen planus, syphilis, and lymphoma. It is important to note that our patient did not show features of hypergranulosis, subepithelial chronic lymphocytic inflammatory infiltrate, and colloid bodies on biopsy. These findings, if present, may point more to a diagnosis of oral lichen planus.10 Direct immunofluorescence (DIF) can be done to highlight the presence of colloid bodies in these cases. For lymphomas, if a high index of suspicion is present, special Figure 2. A-C. Histopathology showing dense band-like infiltrate of plasma cells, lymphocytes, and scattered neutrophils and eosinophils.
stains for CD 19, CD 20, CD 5, and CD 10 may be done.11 As for syphilis, the patient presented with a clinically non-contributory sexual history as well as non-reactive RPR-VDRL results. However, a biopsy specimen could be sent for further testing with Warthin-Starry stain to visualize spirochetes if present. Our patient’s specimen was not sent for further testing as the correlation of history, physical examination with dermoscopy, results of syphilis serology, and biopsy findings all pointed strongly to clinching the diagnosis of PCC. Lugović-Mihić et al., proposed a classification for cheilitis that can help simplify the approach to the diagnosis and management of similar cases.12 The timing, reversibility, and association with other systemic diseases must be carefully considered. Given the presentation and development of persistent cheilitis seen in our patient, there is a need to take into account the following differential diagnoses: actinic cheilitis, squamous cell carcinoma, and PCC. A biopsy is warranted in order to come up with a definitive diagnosis. Finding a band-like infiltration of mature plasma cells in the upper dermis is necessary for the diagnosis of PCC.2,6,12 The etiology of PCC is still unknown. However, there have been studies that suggest associations with mechanical damage or accumulated solar damage.9 As seen similarly in other published studies, our patient presented with lesions on the lower lip. The lower lip is commonly the focal point of accumulated sun damage or mechanical trauma.6 Although our patient claimed to have no significant occupational or recreational sun exposure, her frequent consumption of piping hot food may have contributed to accumulated mechanical damage to her lower lip, leading to this condition. T-cells and macrophages have been identified to influence cellular differentiation leading to this nonspecific inflammatory response.5 The exact mechanism of action that tacrolimus may have on plasma cells remains unexplained. However, its known influence on immunomodulation of inflammatory cytokines J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 59 such as mast cells, Langerhans cells, T-cells, and eosinophils have been identified. It is suggested that the eroded nature of the lesions contributes on tacrolimus’ enhanced efficacy.2 Although PCC is a benign condition, treatment may be challenging and clinical outcomes may vary. Topical therapeutic options include the use of topical corticosteroids and immunomodulators among others.1 A 2017 case series done with 13 patients from 2011 to 2016 in Seoul Korea, 8 out of 13 patients used topical tacrolimus 0.1% and intralesional steroid injections. Five (5) patients were given additional methylprednisolone (0.5-1.0mg/kg/day) due to poor response and continued progression of symptoms. Other patients in the case series received topical steroids, pimecrolimus, and cryotherapy. Of the 13 patients, 23.1% of patients experienced complete resolution and 38.5% experienced partial remission. However, 38.5% of patients relapsed after complete or partial remission with a median follow-up duration of 11.2 months.6 In a case series in Chosun University Hospital involving 20 patients from 2012 to 2019, 90% of the patients received intralesional triamcinolone injections and 60% additionally received topical tacrolimus while the rest were given methylprednisolone (0.1mg/kg/day), dapsone (100mg/day), and cryotherapy. Of the 20 patients, 45% experienced complete resolution with no recurrence, 40% of patients experienced relapse (average time for relapse was 10.75 months), while 15% did not respond to treatment.9 Our patient experienced partial improvement with the use of betamethasone cream for two (2) weeks. However, the patient was shifted to topical tacrolimus 0.1% ointment twice a day for maintenance therapy. The patient did not report any adverse events, burning, or irritation during the entire duration of the one-month treatment period. There was no reported recurrence of symptoms after 12 months of partial remission as well. Performing dermoscopy and skin punch biopsy play an important role in finalizing the diagnosis for patients who present with recalcitrant cheilitis. Although rare, PCC must be considered for patients who present histopathological findings with a dense band-like infiltration of mature plasma cells. An accurate diagnosis is important for proper patient counselling and improved patient outcomes. Currently, there have been no studies that reported on the malignant potential of this condition. However, given its relapsing nature, it is therefore important to counsel patients regarding the probability of recurrence. Thus, regular follow-up amidst initial control of symptoms is important. CASE REPORT Figure 3. A. 1 week post treatment B. 2 weeks post treatment C. 1 month post treatment
REFERENCES 1. Dos Santos HT, Cunha JLS, Santana LAM, Trento CL, Marquetti AC, de Albuquerque-Júnior RLC, et al. Plasma cell cheilitis: the diagnosis of a disorder mimicking lip cancer. Autops Case Rep [Internet]. 2019;9(2):e2018075. Available from: http://dx.doi.org/10.4322/ acr.2018.075 2. Hanami Y, Motoki Y, Yamamoto T. Successful treatment of plasma cell cheilitis with topical tacrolimus: report of two cases. Dermatol Online J [Internet]. 2011;17(2):6. Available from: http://dx.doi.org/10.5070/d34rd1p1js 3. Lugović-Mihić L, Pilipović K, Crnarić I, Šitum M, Duvančić T. Differential diagnosis of cheilitis - how to classify cheilitis? Acta Clin Croat [Internet]. 2018;57(2):342–51. Available from: http://dx.doi.org/10.20471/acc.2018.57.02.16 4. White JW Jr, Olsen KD, Banks PM. Plasma cell orificial mucositis. Report of a case and review of the literature. Arch Dermatol [Internet]. 1986;122(11):1321–4. Available from: http://dx.doi.org/10.1001/archderm.122.11.1321 5. da Cunha Filho RR, Tochetto LB, Tochetto BB, de Almeida HL Jr, Lorencette NA, Netto JF. “Angular” plasma cell cheilitis. Dermatol Online J [Internet]. 2014;20(3). Available from: http://dx.doi.org/10.5070/d3203021759 6. Lee JY, Kim KH, Hahm JE, Ha JW, Kwon WJ, Kim CW, et al. Plasma cell cheilitis: A clinicopathological and immunohistochemical study of 13 cases. Ann Dermatol [Internet]. 2017;29(5):536. Available from: http://dx.doi.org/10.5021/ad.2017.29.5.536 7. Truffello D, Cevallos C, Escanilla C, Morgan P. Dermoscopic findings in a case of plasma cell cheilitis. An Bras Dermatol [Internet]. 2022;97(6):827–9. Available from: http://dx.doi.org/10.1016/j.abd.2020.12.019 8. Litaiem N, Mansour Y, Jones M, Zeglaoui F. Dermoscopic signs of lichen planus. BMJ Case Rep [Internet]. 2016 [cited 2023 May 3];2016:bcr2015213923. Available from: https://casereports.bmj.com/content/2016/bcr-2015-213923 9. Choi H, Shim DH, Na CH, Kim MS, Shin BS. Clinicohistological analysis of plasma cell cheilitis: 20 cases [Internet]. Medcomhk.com. [cited 2023 May 3]. Available from: https://medcomhk.com/hkdvb/pdf/2021v29n005-012.pdf 10. Anitua E, Piñas L, Alkhraisat MH. Histopathological features of oral lichen planus and its response to corticosteroid therapy: A retrospective study: A retrospective study. Medicine (Baltimore) [Internet]. 2019 [cited 2023 May 12];98(51):e18321. Available from: http://dx.doi.org/10.1097/MD.0000000000018321 11. Mansour AT, Shandiz AE, Zimmerman MK, Roth TD, Zhou J. Concomitant lymphoplasmacytic lymphoma and plasma cell myeloma, a diagnostic challenge. Am J Blood Res. 2017;7(2):10–7. 12. Lugović-Mihić L, Blagec T, Japundžić I, Skroza N, Delaš Adžajić M, Mravak-Stipetić M. Diagnostic management of cheilitis: an approach based on a recent proposal for cheilitis classification. Acta Dermatovenerol Alp Panonica Adriat [Internet]. 2020;29(2):67–72. Available from: https://acta-apa.mf.uni-lj.si/journals/acta-dermatovenerol-apa/papers/10.15570/actaapa.2020.16/actaapa.2020.16.pdf J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 60 CASE REPORT
J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 61 CONTINUING MEDICAL EDUCATION CME QUIZ ANSWER KEY 1. Which correctly describes male skin? a. Skin is 25% thicker than females b. More subcutaneous fat than females c. Sebum production decreases during menopause d. Less dense collagen than females 2. This is a minimally invasive cosmetic procedure in which specialized sutures are used to lift and reposition the skin of the face, neck, and body: a. Dermal filler b. Neurotoxin c. Thread lifting d. Liposuction 3. Which of the following statements is correct? a. Women’s lips tend to be thinner and less curved b. The upper and lower facial dimensions of males are proportionally equal c. Women’s expression lines are more profound because they have greater muscle mass d. As a result of androgen hormones, women produce more sebum than men 4. Around how many months do the effects of Botulinum Toxin A typically last? a. 1-2 months b. 3-4 months c. 1 year d. 5-6 months 5. Which products are considered pigment lightening agents that can be used to treat hyperpigmentation in male patients including dark spots and melasma? a. Hydroquinone b. Kojic acid c. Azelaic acid d. All of the above _