Darier disease: Histopathology revisited.

ABSTRACT: Darier disease (DD) is a rare genodermatosis. Literature on this topic is overwhelmingly dominated by case reports with rare clinical presentations, which have mentioned the histopathologic features briefly. The aim of this study was to document the histopathology of DD. Skin biopsies diagnosed as Darier disease based on clinicopathologic correlation over 12 years were reviewed for various epidermal and dermal features. There were 16 patients included, who most commonly presented in the third decade, with slight female predilection. The most common clinical presentation was hyperpigmented, hyperkeratotic, papules and plaques (91%), with 69% affecting the trunk. In addition to the classic suprabasal acantholytic clefts, we noted some unusual features: absence of parakeratosis (19%), a cornoid lamella-like pattern (62%), follicular acantholysis (13%) and multiple foci of involvement within a single biopsy (63%). Features such as the presence of dyskeratotic cells and minimal dermal lymphocytic infiltrates were concordant with previous literature. The limitation of this study was the small sample size. To conclude, pathologists must be aware of the variations in histopathology of Darier's disease, especially when challenged with atypical clinical presentations. The Darier-like pattern is met within several acantholytic diseases, and clinicopathologic correlation has the last word in arriving at a diagnosis.

Epidermodysplasia Verruciformis: A Study of Clinicopathologic Features, Biomarkers, and Associated Malignancies in Indian Patients.

BACKGROUND: Epidermodysplasia verruciformis (EDV) is a rare cutaneous manifestation of human papilloma virus infection, which has a potential for malignant transformation. The characteristic histologic features of EDV may not always be present and may often be overlooked. The use of a panel of novel biomarkers may aid in differentiating EDV from their clinical and pathologic mimics. MATERIAL AND METHODS: We reviewed 20 cases histologically diagnosed as EDV from 2013 to 2022. Sections were reviewed for histopathologic features, and immunohistochemistry for p16 and Ki67 was performed. RESULTS: There were 20 cases, ranging in age from 6 to 52 years with a male predominance. Four patients were immunosuppressed, and 4 patients had a positive family history. The most common presentation was hypopigmented papules and macules. In all the cases, epidermal keratinocytes showed dysmaturation, enlargement, and a blue-gray cytoplasm. These changes were very focal and superficial in 15 cases (75%). Associated malignancies included carcinoma in situ (1), trichilemmoma (2), and trichilemmal carcinoma (1). The trichilemmal tumors were seen in 2 siblings. p16 was expressed in the parabasal and basal layers in 7 of 17 cases (41%), in keratinocytes with and without inclusions. Ki67 was increased and localized to suprabasal and parabasal keratinocytes in 15 of 17 cases (88%). CONCLUSION: Although striking and characteristic, the keratinocyte changes are often focal and superficial, requiring multiple step-sections. Association of EDV with familial trichilemmal neoplasms is a novel finding requiring further genetic testing. In cases of clinically suspected EDV with negative histopathologic findings, p16 and Ki67 seem useful as adjunct biomarkers and could serve as cost-effective alternatives to genotyping.

Plasmacytoid Dendritic Cell Marker (CD123) Expression in Scarring and Non-scarring Alopecia.

Classification of scarring alopecia poses a major problem, as there is considerable clinicopathologic overlap, particularly between lupus erythematosus (LE) and lichen planopilaris (LPP), especially in later stages. CD123 positive plasmacytoid dendritic cells (PDC) have been shown recently to be present in all forms of LE and are touted to be useful in differentiating LE from other scarring alopecias. Their distribution in non-scarring alopecia is not well documented. This is the first study that examines the PDC in both scarring and non-scarring alopecias. Objective: To study the expression patterns of PDC in cases of both scarring and non-scarring alopecia. Materials and Methods: A total of 69 cases of alopecia (48 scarring, 21 non-scarring) were studied for CD123 expression by immunohistochemistry. Results: Among the scarring alopecias, 17/20 LE cases showed PDC in contrast to 1/22 LPP cases. This difference was statistically significant (P = 0.0001). 1/2 cases of folliculitis decalvans showed PDC. None of the cases of unclassified scarring alopecia were positive. In the non-scarring group, 19/20 cases of alopecia areata and a single case of trichotillomania lacked PDC. Conclusion: The finding of CD123 expressing PDC appears to be a promising parameter in distinguishing LE from other forms of alopecia.

Missing the Forest for the Trees - A Rare Cause of Pleural Effusion.

Neurofibromatosis type 1 (NF-1) is a genetic disorder associated with dermatological, musculoskeletal, and neurological features. Apart from these, knowledge of other uncommon manifestations, including intrathoracic and pulmonary involvement, is crucial for early diagnosis and treatment. These patients are predisposed to various sarcomatous and non-sarcomatous malignancies. We report the case of an elderly lady with NF-1 who presented with pleural effusion related to the genetic disorder, which was missed, and elaborate on the diagnostic workup done to reach a diagnosis.

Histopathology of Pemphigus Vulgaris Revisited.

ABSTRACT: Pemphigus vulgaris (PV) is a severe, potentially life-threatening autoimmune blistering disease, which is common in India. Although there is abundant literature on clinical and immunologic features, comprehensive studies on its histopathology are lacking. The aim of this study was to describe the histopathologic and immunofluorescence features as well as discuss various diagnostic pitfalls of PV. Histopathologic and immunofluorescence (DIF/IIF) findings were reviewed for 169 biopsies from 2007 to 2017 (11 years). The 169 samples included 152 skin, 16 oral mucosal, and 1 corneal biopsy. Maximum prevalence was noted in the fifth decade (57%) with a slight male preponderance. Vesicles were seen in 149 cases (88%), the level of which was suprabasal in 91(61%) and both suprabasal and intraepidermal in 50 cases (33.5%). Acantholytic cells were present in 142 cases (95%). Acantholytic keratinocytes showed rounded and polygonal acantholysis. 86 (51%) cases showed evidence of regeneration. Adnexal involvement was seen in 92 cases, commonest in the hair follicles. Unusual histologic findings included: intraepidermal bulla, absence of dermal inflammation, free floating hair shafts, multinucleated epithelial cells, eosinophil predominance; all of which are discussed. DIF was performed in 166 cases, of which 163 were positive (98%), and IgG was the commonest immunoreactant (96%). IIF was performed in 11 cases, of which 9 cases were positive for Dsg3. Although the diagnosis of PV rests on combined clinical, histologic, and IF features, histopathology as the sole means is also a powerful tool. It is important to be aware of the diagnostic pitfalls to optimize its utility.

Role of BIOCHIP Indirect Immunofluorescence Test in Cutaneous Vesiculobullous Diseases.

BIOCHIP mosaics for indirect immunofluorescence in cutaneous vesiculobullous diseases provide antibody profiles in a single run and can be an alternative to performing multistep assays. There is scanty data regarding their utility. BIOCHIP tests performed over 4 years were compared with biopsy and/or direct immunofluorescence (DIF). Of 209 BIOCHIP tests, 108 were positive. Pemphigus vulgaris and Bullous pemphigoid were the commonest. Dsg3 was the commonest positive substrate in pemphigus group (86%) with 100% sensitivity. Intercellular space pattern on BIOCHIP primate esophagus was seen only in 49%. BP 180 was the commonest positive substrate in pemphigoid (95%) with 78% sensitivity. In 68 cases, corresponding biopsy/DIF was available with concordance of 89% in pemphigus and 93% in pemphigoid groups. In 40 cases where BIOCHIP was positive without biopsy/DIF, 97.5% were concordant with clinical diagnosis. Among the negative results, 13 had biopsy/DIF that were diagnostic. The overall positivity of BIOCHIP was 92% for pemphigus and 84% for pemphigoid groups. Indirect immunofluorescence by BIOCHIP method shows good concordance with histopathology/DIF. However, the sensitivity of some of the substrates varies. It is an effective screening tool to identify cases requiring further ELISA/immunoblots or where biopsy is not feasible.

Expression of androgen receptor in primary breast carcinoma and its relation with clinicopathologic features, estrogen, progesterone, and her-2 receptor status.

INTRODUCTION: The role of estrogen/progesterone receptors (ER/PR) is well-established with respect to therapy and prognosis of breast carcinoma. However, the role of androgen receptor (AR) expression is unclear in the Indian context. The objective is to study the following: (a) Expression of AR in resection specimens of ductal carcinomas, (b) Relationship of AR with clinicopathologic features, ER, PR, and Her-2 status. MATERIALS AND METHODS: This study included female patients with infiltrating ductal carcinoma with a minimum of 10 axillary lymph nodes, whose hormone receptor status data were available. Demographic and histopathologic details were retrieved. Immunohistochemistry for AR was done and considered positive if ≥10% of tumor cells showed nuclear staining and compared to various clinicopathologic features. RESULTS: A total of 71 cases were included in the study. AR expression was noted in 52% of cases. Of the 35 ER and/or PR expressing tumors, AR was positive in 24 cases. In contrast, of the 36 ER/PR-negative tumors, AR was expressed in only 13 cases (P = 0.006). There was no significant difference in the expression of AR between Her-2 positive and negative cases. AR positivity was noted in 23% of triple-negative tumors. Age did not show an influence on AR status. Among histopathologic parameters, low-grade tumors were significantly associated with AR expression (P = 0.018) while tumor size, lymphovascular emboli, and nodal status were not. Within the follow-up period, four patients from AR-positive group developed distant metastasis. CONCLUSION: Indian patients with breast carcinoma have a higher AR expression in low-grade and ER/PR-positive tumors, in concordance with Western studies. A good number of triple-negative tumors also express AR, which needs further evaluation.

"Joining the Spots in Adults and Young Tots": A Clinicopathological Study of Henoch-Schönlein Purpura (IgA Vasculitis).

INTRODUCTION: Henoch-Schönlein Purpura (HSP; IgA vasculitis), the most common vasculitis of childhood, has a wide spectrum of clinical manifestations ranging from palpable purpura with abdominal pain and arthritis to the more morbid renal involvement. AIMS AND OBJECTIVES: To study and correlate the clinical presentation, laboratory values, skin and renal histopathology and immunofluoroscence findings in HSP. MATERIAL AND METHODS: A total of 44 cases of HSP from March 2011 to February 2014 were studied for the above features along with their clinical outcomes. RESULTS: The mean age of the patients at presentation was 28.4 years (range 4.5-69 years) with 26.2% being children younger than 15 years. Purpura at presentation was seen in all with 77.1% cases exhibiting extracutaneous involvement. Skin biopsy revealed leukocytoclastic vasculitis in all cases, dominant IgA deposition in the papillary dermal vessels in 43 cases (97.7%), associated C3 in 10 cases (23.3%), and full-house positivity in 1 case. One case without skin immunofluorescence had renal mesangial IgA deposits. Nine cases (20.9%) with an average age of 39 years had renal symptoms and displayed varied histology from focal mesangioproliferative glomerulonephritis to crescentic. All of them had dominant mesangial IgA deposits, majority falling into International Study of Kidney Disease in Children (ISKDC) class IIIb. Peritubular capillaritis was noted in 3 cases. Two patients (4.5%) progressed to end stage renal disease, one of whom had cellular crescents at presentation. CONCLUSIONS: HSP was seen both in children and adults. Renal involvement was seen in 20.9% cases, all older than 14 years, and 66.7% with extracutaneous manifestations. The outcome in this series was favorable in 96% cases.

Multiple Eruptive Dermatofibromas Masquerading as Cutaneous Lymphoma.

A 34-year-old male came with complaints of multiple firms to hard nontender, nonitchy nodules, measuring 2 cm × 2 cm to 1 cm × 1.5 cm, present predominantly over the lower limbs. This condition started 5 years back as a single nodule over the thigh but gradually increased in number and size with time to involve both lower limbs. A differential diagnosis of cutaneous lymphoma and dermatofibroma was considered. He underwent a biopsy and immunohistochemistry for the same which were consistent with hemosiderotic histiocytoma and positive for vimentin. The patient was advised surgical excision for the same. The occurrence of multiple dermatofibromas although rare has been reported in a few case reports; however, the occurrence of multiple dermatofibromas of the hemosiderotic variant has not been documented yet.

Histopathological and immunohistochemical features of nodular podoconiosis.

BACKGROUND: Podoconiosis is a familial geochemical dermatosis which is common in Ethiopia but relatively unknown in Europe/United States. It is related to exposure of bare feet to volcanic soil and presents with extensive bilateral lymphedema of legs and feet. Histopathological and immunohistochemical features of it have not been described yet. OBJECTIVES: The objectives of this study are to characterize podoconiosis histopathologically and immunohistochemically and to increase awareness of the disease. METHODS: Ten specimens of fully developed podoconiosis were examined with hematoxylin/eosin, periodic acid-Schiff, Gram, elastica-van Gieson stainings, with immunohistochemistry (CD3,CD20,CD31,CD68,CD138, tryptase, podoplanin, collagen IV), and with polymerase chain reaction (PCR) for human papillomavirus (HPV)-specific DNA. RESULTS: All specimens showed verrucous acanthosis and papillomatosis. Eccrine ducts demonstrated hyperplasia, syringofibroadenomatous changes and miliaria. Dermal collagen bundles were thickened, and elastic fibers were dramatically reduced. A moderate lymphoplasmacytic infiltrate was joined by mast cells and scattered macrophages; neutrophils and eosinophils were sparse. Blood vessels were increased, dilated, and often sclerotic while lymphatics were reduced and largely not dilated. HPV-PCR was negative in all specimens. CONCLUSIONS: Podoconiosis demonstrates distinctive changes of chronic lymphedema with extensive sclerosis, loss of elastic fibers, verrucous acanthosis (not HPV induced) and reactive changes of eccrine structures. Mast cells, macrophages and altered blood vessels may be involved in the pathogenesis.

Lymphocytic thrombophilic arteritis: an enigma.

A 55-year-old woman presented with a 5-year history of livedo racemosa on her limbs. Histology showed vasculitis of medium-sized arteries with a circumferential, hyalinised, intraluminal fibrin ring. Her laboratory investigations did not indicate any underlying systemic disease. The findings were consistent with lymphocytic thrombophilic arteritis (LTA), alias macular arteritis, which is a recently described entity. The importance of LTA lies in the fact that it is a close clinical and microscopic mimic of polyarteritis nodosa (PAN). LTA is believed to be a distinct entity by some and as a form of PAN by others. We have discussed this case in our report.

S-100 immunostaining in the Distinction of Borderline Tuberculoid Leprosy from other Cutaneous Granulomas.

BACKGROUND: Histopathologic diagnosis of borderline tuberculoid leprosy (BTL) is fraught with hurdles. It overlaps with other granulomas and documenting nerve involvement is the key to correct diagnosis. This is difficult on H and E sections alone. S-100 immunostaining may help in this regard. OBJECTIVES: To study the patterns of nerve involvement in BTL and other cutaneous granulomas using S-100 immunostain and compare its sensitivity with that of H and E staining, in both adequate and inadequate biopsies. MATERIALS AND METHODS: A total of 20 cases of BTL were reviewed. And, 19 biopsies from other cutaneous granulomas were taken as controls. S-100 immunostaining was done on paraffin sections. The pattern of nerve involvement was graded as intact, infiltrated and/or fragmented, intact with perineural inflammation. RESULTS: Of the 20 cases of BTL, S-100 demonstrated infiltrated and/or fragmented nerves in 15 and absent nerves in 5 cases. H and E stain identified neuritis in eight cases. The sensitivity of S-100 and H and E is 0.78 and 0.41. In the 19 controls, S-100 identified normal nerves in 16 with 7 showing perineural inflammation only and their absence in 2 cases. H and E identified normal nerves in nine cases. The sensitivity of S-100 and H and E is 0.83 and 0.41. In biopsies where subcutis was absent, the sensitivity of S-100 in identifying nerve involvement is 0.66 compared with H and E 0.33. CONCLUSION: S-100 staining is an efficient ancillary aid in distinguishing BTL from other granulomas and is superior to H and E in identifying nerve involvement, even where subcutis is absent. Infiltration and/or fragmentation of nerves by S-100 is the only reliable marker of BTL.

Papulonecrotic tuberculid-clinicopathologic and molecular features of 12 Indian patients.

BACKGROUND: Papulonecrotic tuberculid (PNT) is said to be a hypersensitivity reaction to M. tuberculosis. Some reports indicate that organisms are demonstrable by polymerase chain reaction (PCR). METHODS: We describe 12 patients with PNT over 6 years. We reviewed the histopathologic features, clinical data and follow-up. PCR for M. tuberculosis DNA was done in all cases. RESULTS: There were 7 men and 5 women. The ages ranged from 3-58 years. Upper limbs were commonly involved (8 cases). All patients had multiple papulonodular lesions, 5 showed ulceration and scarring. Mantoux test was strongly positive in all. Seven patients had systemic tuberculosis. On microscopy, necrosis was seen in 11 cases, varying from minimal to extensive. Epithelioid granulomas were common, except for 1 case with palisading and interstitial patterns. The infiltrate showed mostly lymphocytes, while 3 cases showed eosinophils. Vasculitis was seen in 8 cases. Two cases had dermal mucin, one also with interface dermatitis. This patient had concurrent LE. Mycobacterial DNA was detectable by PCR in 3 cases. Seven patients showed improvement/resolution of lesions on treatment. CONCLUSIONS: PNT is a rare disease. A positive PCR reiterates the question whether these are "tuberculids". PNT may be better classified as true cutaneous tuberculosis and patients screened for systemic disease.

Psoriasiform dermatoses: microscopic approach.

Psoriasiform dermatoses often pose challenges to both dermatologists and pathologists alike. With proper clinicopathologic correlation and a systematic approach, it is possible to arrive at a specific diagnosis in most cases. This article attempts to outline a practical, step-wise method of looking at these cases and highlights some important clues in individual conditions.

Direct immunofluorescence in cutaneous vasculitis: experience from a referral hospital in India.

BACKGROUND: Cutaneous vasculitis is commonly recognized and biopsied, owing to ease of access. Most biopsies are also subjected to direct immunofluorescence (DIF), though the rates of positivity vary. This is an attempt to assess the utility of DIF and glean data that will help optimize the test. OBJECTIVE: To assess the diagnostic utility of DIF in cutaneous vasculitis. MATERIALS AND METHODS: All cases of suspected cutaneous vasculitis submitted for DIF between 2004 and 2010 were included. Clinical data, histopathologic diagnosis, DIF findings and additional tests such as anti nuclear antibody (ANA), anti neutrophil cytoplasmic antibody (ANCA) (where done) were noted. RESULTS: There were 198 patients in the study group, with a female predominance. Purpura was the commonest clinical presentation. Extracutaneous involvement was noted in 29% of patients' i.e., joint pain, abdominal pain and hematuria. Leukocytoclastic vasculitis was the commonest histologic diagnosis. DIF showed an overall positivity of 39% (n = 77) with C3 in 26% (n = 52) and IgA in 23% (n = 46) cases. Forty one cases of suspected Henoch Schonlein Purpura (HSP) showed IgA positivity. The timing of biopsy ranged from <3 days to six months, with 38% being done within seven days. DIF was positive in 86% of biopsies performed within seven days of onset of lesions. Sixty percent of patients with extracutaneous manifestations showed deposits. Vascular deposits were also noted in dermatitis herpetiformis, dematomyositis and prurigo. CONCLUSION: DIF positivity is strongly influenced by the timing of the biopsy and the presence of extracutaneous features. Its clinical value is greatest in patients with HSP, being contributory in 90% of cases. Vascular deposits may be seen in non-vasculitic conditions and need clinicopathologic correlation.

Benign vs. Malignant Skin Adnexal Neoplasms: How Useful are Silhouettes?

BACKGROUND: Skin adnexal tumors are daunting diagnostic problems. Cytologic atypia does not always imply malignancy and "typia" does not underscore a benign course. Bernard Ackerman first described criteria on silhouettes that enable distinction between the two. AIMS: To evaluate the histologic features on silhouettes of benign and malignant skin adnexal tumors. To identify overlaps and confounding features. MATERIALS AND METHODS: A blinded retrospective review of all skin adnexal neoplasms between 1995 and 2007 was done, with a total of 68 cases. We studied 16 histologic parameters on scanner view and categorized them as benign or malignant. They were compared with the final histologic diagnosis. Statistical analysis was performed using chi-square test. RESULTS: 15 criteria attained statistical significance. Features that proved highly sensitive and specific were: Circumscription, ulceration, uniform size of cell aggregates, discrete arrangement, preserved adnexae and necrosis. Criteria that were sensitive but not very specific include: Symmetry, V-shape, vertical orientation, smooth margins, compressed fibrous tissue, type of clefting, shelling out and geometric shapes. Presence of epithelial cells in singles was not helpful. CONCLUSION: Malignant skin adnexal tumors are differentiated accurately from benign ones by their contrasting silhouettes. Pathologists should heed the impression formed on scanner view, before evaluating cytologic features.

Origin Use of CD4, CD8, and CD1a Immunostains in Distinguishing Mycosis Fungoides from its Inflammatory Mimics: A Pilot Study.

UNLABELLED: Patch-stage/early mycosis fungoides (MF) is difficult to differentiate from benign dermatoses, despite several robust histologic criteria. Most studies include advanced lesions and data about early disease is limited. OBJECTIVES: (1) To compare the CD4:CD8 ratio in patch-stage MF versus inflammatory mimics. (2) To study patterns of CD1a expression in the epidermis and dermis in the two groups. MATERIALS AND METHODS: Twenty cases each of early MF and inflammatory dermatoses were selected. The diagnoses were established after clinicopathologic correlation, repeat biopsies, and follow-up. The inflammatory group included pityriasis lichenoides chronica, actinic reticuloid, lichenoid purpura, and various psoriasiform dermatoses. Immunohistochemistry was done for CD4, CD8, and CD1a. Epidermal CD4, CD8 cells were quantified and CD1a was graded semi-quantitatively in the epidermis and dermis. RESULTS: The average CD4:CD8 ratio was 4.2 in MF (range: 1-16.8), and 0.9 in inflammatory diseases (range: 0.43-5), which was statistically significant (P < 0.0001). None of the MF cases had a ratio <1. Four cases of pityriasis lichenoides chronica had a ratio >1. CD1a cells had a continuous or confluent epidermal pattern in almost all cases of MF, while they occurred as small or large groups in the dermis. In inflammatory dermatoses, there were either isolated or scattered CD1a+ cells in both epidermis and dermis. CONCLUSIONS: Elevated CD4:CD8 ratio favors MF. But there is an overlap in the lower range with pityriasis lichenoides chronica. These cases require good clinicopathologic correlation and follow-up. Patterns of CD1a expression are more reliable. Immunostains buttress morphology and are a valuable addition.