Expression of growth hormone-releasing hormone receptors in apocrine adnexal tumours and apocrine glands of the skin.

Encouraged by our previous finding of growth hormone-releasing hormone receptor (GHRH-R) expression in metaplastic and neoplastic apocrine breast epithelium, we examined a small series of skin adnexal tumours with various degrees of apocrine (oxyphilic) differentiation, as well as normal axillary and anogenital apocrine sweat glands, for the expression of GHRH-R. Sections of formalin-fixed paraffin-embedded tissue blocks were immunostained for gross cystic disease fluid protein-15 (GCDFP-15) and androgen receptor (AR), to prove apocrine differentiation and correlate it with areas of GHRH-R expression. All but one of 19 tumours with apocrine epithelium and all five benign apocrine glands stained with both anti-GHRH-R antibodies used, each labelling a different domain of the receptor. Non-apocrine areas of the tumours and four eccrine tumours without oxyphilic features did not stain, but most sebaceous glands and some eccrine glands were labelled. Our data suggest that anti-GHRH-R antibodies highlight apocrine differentiation at extramammary sites also. Although GHRH-R seems to have a sensitivity comparable to classic apocrine markers such as AR and GCDFP-15, it seems to be inferior in specificity. The GHRH-R labelling of apocrine glands and neoplastic epithelium might also interfere with the emerging anti-GHRH targeted treatment of some malignancies acting on these receptors.

A Case of Trichogerminoma With Pilomatrical Differentiation and a Unique Immunohistochemical Profile.

Trichogerminomas are rare adnexal neoplasms first described by Sau et al in 1992. Including the initial report, 20 cases have been reported, all with similar histological features, namely tumor nodules composed of basaloid cells that form densely packed, round nests or "cell balls" and which demonstrate variable degrees of pilosebaceous differentiation. In this study, the authors report a case of a trichogerminoma with pilomatrical differentiation and a unique immunohistochemical profile. The patient is a 71-year-old man with a well-delineated nodule on the top of the scalp. Histologically, the lesion measured 16 mm in greatest dimension and was composed of nodules of basaloid cells with central, compact, slightly eosinophilic cells nests. Immunohistochemically, the tumor nodules diffusely expressed cytokeratins 34ßE12, AE1/3, and CK5/6. Diffuse expression of ß-catenin and nuclear expression of p63 were also evident. The peripheral basaloid cells, but not the cell balls, expressed CD10, Ber-EP4, BCL-2, and CK7, the latter a previously unreported finding. The histological findings and immunohistochemical profile are compatible with a diagnosis of a trichogerminoma.

Extramammary Paget's disease: evaluation of the adnexal status of 53 cases.

Extramammary Paget's disease (EMPD) is a distinct form of malignant skin neoplasm. The clinicopathological significance of cutaneous adnexal involvement in EMPD has not been investigated in detail. Surgical specimens were obtained from 53 patients with primary EMPD. Tumor involvement of cutaneous adnexal structures was evaluated using histological parameters. The degree of involvement was scored on a scale of 0-2: 0, no involvement; 1, involvement of the upper portion of the adnexa; 2, involvement of the lower portion of the adnexa. A score of 2 was regarded as significant. The presence of comedo necrosis was also examined. Adnexal involvement was identified in 46 cases (86.8%). Comedo necrosis was observed in 6 cases (11.3%). The proportions of each parameter in in situ cases were as follows: significant adnexal involvement (score 2) in 15/26 (57.7%), and comedo necrosis in 3/26 (11.5%). The corresponding proportions in cases with invasion were 21/27 (77.8%) and 3/27 (11.1%), respectively. No significant differences in adnexal involvement and comedo necrosis were detected between in situ EMPD and invasive EMPD (p>0.05). The current study suggests that the degree of adnexal involvement and the presence of comedo necrosis are not associated with tumor progression in EMPD.

Solid carcinoma revisited: a possible variant of microcystic adnexal carcinoma.

Primary malignant apocrine and eccrine skin neoplasms are rare and their nosology is still evolving. First described in 1997, solid carcinoma is now considered a discrete entity by some, although this remains controversial. Apocrine differentiation was postulated. A single case since then was the first to include immunohistochemistry findings. The authors report an additional case of solid carcinoma, together with its immunohistochemical profile. A 63-year-old man presented with a firm nodule 3 cm in diameter on the posterior scalp. On punch biopsy, the lesion was interpreted as an adnexal neoplasm of indeterminate malignant potential. The subsequently excised tumor was initially interpreted as microcystic adnexal carcinoma with perineural invasion involving the surgical margins. Re-excision yielded clear surgical margins. After review of all the histologic material, a final diagnosis of solid carcinoma was rendered. Histologically, innumerable solid aggregations of neoplastic epithelial cells filled the dermis and extended into the subcutis. The aggregations varied in size and ranged from round or ovoid nests to elongated columns or cords embedded within a fibrotic stroma. The neoplastic cells were round and uniform in size with small nuclei and pale or clear cytoplasm. Tubular structures and mitoses were absent. Solid carcinoma is a rare skin neoplasm. Histologically, it closely resembles and may be indistinguishable from the solid areas of microcystic adnexal carcinoma. Biologically, solid carcinoma, like microcystic adnexal carcinoma, is an indolent but relentless locally destructive neoplasm that must be removed completely. The clinical, histologic, and biologic similarities suggest that solid carcinoma may be a variant of microcystic adnexal carcinoma.

Extranodal marginal zone lymphoma from ocular adnexae with subcutaneous involvement.

Extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue usually originates from cutaneous or mucosal surfaces. A rare site of involvement is the subcutaneous tissue of any location. Here, we describe a 58-year-old man who presented with bilateral extranodal MZL of mucosa-associated lymphoid tissue from ocular adnexae that involved subcutaneous tissue and subsequently extended to multiple anatomical locations in the head and neck, upper back, and arm. The neoplastic cells expressed B-cell markers, and the plasma cells expressed IgG4. The unusual pattern of infiltration of this extranodal MZL and the possible significance of IgG4 expression in this case are discussed.

PHLDA1, a follicular stem cell marker, differentiates clear-cell/granular-cell trichoblastoma and clear-cell/granular cell basal cell carcinoma: a case-control study, with first description of granular-cell trichoblastoma.

BACKGROUND: Granular-cell or clear-cell basal cell carcinomas (BCCs), and clear-cell trichoblastomas have rarely been reported in the literature. PHLDA1 is a follicular stem cell marker, the expression of which has been reported to differentiate trichoepithelioma from BCCs. We wondered whether (1) granular-cell trichoblastoma exists and (2) PHLDA1 expression can differentiate a clear- and/or granular-cell trichoblastoma and a BCC. METHODS: In the records of 2 pathology departments, 12 clear- and/or granular-cell trichoblastomas and BCCs were found. Epidemiological, histopathological, and immunohistochemical data for PHLDA1, Ki67, and AE1-AE3; and cytokeratins 17, 19, 20, and 6hf were collected. RESULTS: Trichoblastomas and clear- and/or granular-cell BCCs occurred in 7 patients (36-62 years; mean: 49) and in 5 patients (63-91 years; mean: 77), respectively. Three granular-cell trichoblastomas were identified. Both granular and clear-cell changes were present in 4 BCCs. The patterns of expression for AE1/AE3, CK17, CK19, CK6hf, and CK20 were not helpful in differentiating trichoblastoma from BCC. PHLDA1 expression was diffusely or partially present in all trichoblastomas (5/5) and absent in BCCs (0/4) (P = 0.008). CONCLUSIONS: Granular- and/or clear-cell changes are rare findings in trichoblastoma and BCC. First, we show that granular-cell trichoblastomas do occur. Second, PHLDA1 expression is a useful addition in differentiating trichoblastoma and BCC.

Melanoma arising from a long-standing pigmented trichoblastoma: clinicopathologic study with complementary aCGH/mutational analysis.

Trichoblastoma is a benign cutaneous adnexal tumor, composed mostly of follicular germinative cells. Its pigmented variant is colonized by numerous dendritic melanocytes. So far, only one case in the literature describes a combination of trichoblastoma and melanoma. We report the case of a 62-year-old man who had a slow-growing mass of the left flank present since childhood. This 8-cm mass was surgically removed when it became ulcerated and associated with axillary lymph nodes. Histologically, this tumor was strictly dermal and composed of 2 intermingled components. Large sheets of atypical, proliferating epithelioid cells predominated. Dispersed solid nests or cribriform epithelial islets encased in fibrous tissue were also seen. Some nests displayed a massive colonization by pigmented dendritic melanocytes. On immunohistochemical staining, the sheets of atypical cells expressed focally but strongly S100 protein, MelanA, HMB45, and MiTF. Epithelial structures diffusely expressed pancytokeratin AE1/AE3, KL1, and pleckstrin homology-like domain, family A, member 1. Based on these results, we diagnosed an intradermal melanoma, possibly developed from dendritic melanocytes colonizing a giant pigmented trichoblastoma. Direct sequencing of the melanoma revealed a rarely described NRAS mutation c.34G>T (G12C). Array comparative genomic hybridization displayed a complex profile somewhat divergent from standard melanoma profiles. The patient died of widespread metastatic disease 8 months after initial diagnosis.

What is new in adnexal tumors of the skin?

This article reviews the recent dermatopathology literature regarding cutaneous adnexal neoplasms, with emphasis on new and underrecognized entities, "old entities" with new findings, advances in immunohistochemistry, and new findings in relation to inherited disorders associated with cutaneous adnexal neoplasms.

Expression of p75 neurotrophin receptor in desmoplastic trichoepithelioma, infiltrative basal cell carcinoma, and microcystic adnexal carcinoma.

The histological discrimination between desmoplastic trichoepithelioma, infiltrative basal cell carcinoma, and microcystic adnexal carcinoma encountered in small biopsies is challenging when only morphological criteria are applied. The objective of this study is to test the use of p75 neurotrophin receptor (p75NTR) as an adjunct aid in classification of these tumors. Immunohistochemistry for p75NTR antigen was performed on routinely processed biopsies of 37 desmoplastic trichoepitheliomas, 11 infiltrative basal cell carcinomas, and 9 microcystic adnexal carcinomas diagnosed by morphological criteria in conjunction with results of CK20 immunostains. Cases were analyzed for the extent and intensity of p75NTR expression. Diffuse immunoreactivity was defined as involving >90% of tumor cells. Of the 37 desmoplastic trichoepitheliomas, 35 (94%) displayed strong diffuse immunoreactivity of tumor cells, proving high sensitivity of the marker to detect this tumor. However, despite the fact that diffuse p75NTR expression reached statistical significance in differentiating desmoplastic trichoepithelioma from infiltrative basal cell carcinoma (Fisher exact test P < 0.0001) and microcystic adnexal carcinoma (P < 0.0016), specificity of the stain is unsatisfactory because strong diffuse expression of p75NTR by neoplastic cells was observed in 4 (36%) cases of infiltrative basal cell carcinomas and 4 (44%) cases of microcystic adnexal carcinoma. This study demonstrates a significant difference in p75NTR expression in selected sclerosing neoplasms of the skin. Nevertheless, the practical value of p75NTR as an adjunct marker in the differential diagnosis of these tumors seems to be limited because of significant overlap in amount of p75NTR immunoreactivity.

Microcystic adnexal carcinoma versus desmoplastic trichoepithelioma: a comparative study.

The histologic distinction between microcystic adnexal carcinoma (MAC) and desmoplastic trichoepithelioma (dTE) can be challenging in the setting of a superficial biopsy. However, accurate diagnosis has treatment implication because the standard of care for MAC is wide local excision but more conservative care for dTE. We reviewed the histologic features of 30 MAC and 39 dTE cases and performed cytokeratin (CK) 17, CK19, and epidermal growth factor receptor (EGFR) immunostains on 20 MACs and 18 dTEs. MAC cases occurred in older patients in comparison with dTE (median, 67 years vs. 34 years). The head and neck was the most commonly involved site, 88% and 89% for MAC and dTE, respectively. In addition to features previously reported as specific for MAC, such as skeletal muscle and subcutaneous tissue invasion, perineural invasion, and ductal differentiation, we found the presence of mitotic figures to be significantly more frequent in MAC cases (P < 0.0001). In contrast, the presence of keratocyst, keratin granuloma, and calcification was significantly more frequent in dTE cases (P < 0.0001). CK19 seems to be a helpful adjunct because its expression was seen in 70% (14/20) of MAC versus 22% (4/18) of dTE cases (P = 0.0044); however, the clinical usefulness in individual cases may be limited because of the overlapping immunoprofile. CK17 and EGFR expression was seen in all the MAC and dTE cases. Low polysomy of EGFR gene was observed in only one MAC case, suggesting that molecular mechanisms other than gene amplification play a role in EGFR overexpression.

Syringocystadenocarcinoma papilliferum with transition to areas of squamous differentiation: a case report and review of the literature.

Syringocystadenocarcinoma papilliferum (SCACP) is an exceedingly rare cutaneous adnexal neoplasm, which is typically located in the head and neck, and perianal area. Very few cases have been reported in the literature. Here, we report a case of SCACP with evident transition to squamous differentiation. A 75-year-old white woman presented with 1-year history of a solitary tender nodule in the left upper arm. Physical examination revealed a single, 1.5 × 1.1-cm, erythematous ulcerated nodule within a background of red patch. Biopsy showed an adnexal carcinoma connected to the epidermis and composed of cystic papillary projections admixed with solid basaloid areas with marked cytologic atypia. The basaloid tumor cells appeared to blend with the squamous component that demonstrated ductal formation, which was highlighted by carcinoembryonic antigen. Tumor cells were reactive for both cytokeratins 5/6 and 7. This case represents SCACP arising from syringocystadenoma papilliferum in the upper arm, with distinct transition to areas of squamous differentiation.

Role of immunohistochemistry in diagnosing tumors of cutaneous appendages.

In recent years, there has been significant progress in immunohistochemistry as an ancillary tool in diagnostic dermatopathology. In most instances, the histologic diagnosis can be rendered with the routine histologic sections; however, immunohistochemistry can help to narrow the differential in diagnosing neoplasms of cutaneous appendages in some settings including adnexal versus epidermal origin, benign versus malignant adnexal neoplasms, and primary adnexal carcinoma versus cutaneous metastases as outlined in this review.

Expression of stem-cell markers (cytokeratin 15 and nestin) in primary adnexal neoplasms-clues to etiopathogenesis.

BACKGROUND: The overlap in histopathologic features and immunoprofile of eccrine and apocrine neoplasms confounds basic issues relating to lineage of these entities. METHODS: We evaluated expression of follicular stem-cell markers, cytokeratin (CK) 15 and nestin, in 78 benign and 23 malignant adnexal neoplasms. RESULTS: CK15 and nestin expression were noted in 39 of 78 (50%) and 36 of 78 (46%) cases in the benign group, respectively (8 cutaneous mixed tumor, 10 hidradenoma papilliferum, 9 apocrine cystadenoma, 11 cylindroma and/or spiradenoma, and 9 poroma/dermal duct tumor). CK15 and nestin expression were noted in 11 of 23 (48%) and 7 of 23 (30%) cases in the malignant group, respectively (6 microcystic adnexal carcinoma, 7 porocarcinoma, and 9 eccrine carcinoma). Except 1, both markers were negative in 4 syringocystadenoma papilliferum, 10 hidradenoma, 1 syringofibroadenoma, 10 syringoma, 1 eccrine adenoma, 8 poroma/dermal duct tumor, 5 eccrine hidrocystoma, and 1 apocrine carcinoma. CONCLUSIONS: Given that follicular germinative cells give rise to the folliculosebaceous apocrine unit, expression of CK15 and nestin in the majority of cutaneous mixed tumor, hidradenoma papilliferum, apocrine cystadenoma, and cylindroma/spiradenoma is suggestive of an apocrine origin/differentiation of these neoplasms. Reinforcing this and a novel finding of our study is the preferential expression of nestin in myoepithelial cells of these lesions.

Cutaneous adnexal tumor with an unusual presentation--discussion of a potential diagnostic pitfall.

The clinical presentation of skin adnexal tumors is nonspecific, and histologically; the differential diagnosis between primary cutaneous adnexal malignant carcinomas and metastatic tumors with a visceral origin can be challenging. We report a patient with history of invasive ductal carcinoma of the breast who presented with a 1-cm erythematous palpable lesion on her right calf. The biopsy showed an intradermal proliferation of malignant epithelioid cells with ductal differentiation, histologically compatible with metastatic breast carcinoma. However, the tumor cells labeled strongly and diffusely not only for pancytokeratin and cytokeratin (CK7) but also with p63 and CK5/6; carcinoembryonic antigen highlighted the ductal structures. No labeling was seen for mammoglobin, estrogen/progesterone, Her2-neu, S-100 protein, CK20, thyroid transcription factor-1 (TTF-1), and CDX-2. Based on the p63 and CK5/6 positivity, the differential diagnosis also included the possibility of a primary adnexal neoplasm and a complete excision was advised. The reexcision specimen revealed residual infiltrating dermal tumor and an overlying intraepithelial component with marked cytologic atypia and focal duct formation, diagnostic of a primary cutaneous adnexal tumor with ductal differentiation (porocarcinoma). Immunohistochemical studies (like p63 and CK5/6) can help to differentiate a primary cutaneous neoplasm from a metastatic lesion. This discrimination is of a paramount importance because a diagnostic error can result in profound implications for patient's assumed prognosis and subsequently applied therapy.

Angiomatoid fibrous histiocytoma with cystic structures of sweat duct origin.

Angiomatoid fibrous histiocytoma is an unusual soft tissue tumor, mostly arising in the subcutaneous fibro-adipose tissue of children and young adults and measuring a few centimeters in greatest dimension. Reported herein is a unique case of angiomatoid fibrous histiocytoma containing epithelium-lined cystic structures. This large tumor (12 cm) was located in the subcutaneous tissue of the left leg of a 28-year-old woman. The cystic structures were variably sized and were lined by a double cell layer with areas of squamous metaplasia. Their overall histological features suggested a sweat duct origin. Immunohistochemical stains confirmed such origin, demonstrating an inner epithelial and an outer myoepithelial (smooth muscle actin and cytokeratin 17 positive) cell layer. The present case is illustrative of a mechanism of sweat duct dilatation that may occur during the growth of neoplasms involving the dermis and subcutis, resulting in formation of tumors with unusual histological features.

Oculocutaneous oncocytic tumors: clinicopathologic and immunohistochemical study of 2 cases with literature review.

Oculocutaneous oncocytic tumors (OCOTs) are uncommon neoplasms that have been reported only rarely in the dermatopathology literature and whose immunophenotypic profile has not been well characterized. The clinical, histologic, and immunophenotypic features of 2 cases seen by the authors were assessed, and relevant publications in the literature were reviewed. Both patients with OCOTs were adult women with gradually enlarging, asymptomatic lesions involving the caruncle; they were locally excised. Histologically, the tumors were well-circumscribed nodules comprised of large oxyphilic cells arranged in confluent sheets and forming glandular spaces with secretory material. Microcystic areas and sparse intermingled goblet-cells were also apparent. Nuclear atypia and infiltrative growth were absent. Mitotic activity was absent in one case; a single mitotic figure was identified in the other. Immunostains demonstrated uniform expression of pankeratin and mitochondrial antigens. Both neoplasms were also labeled for markers associated with cutaneous adnexal, lacrimal, and minor salivary glandular tissue, including alpha-1-antitrypsin, gross cystic disease fluid protein-15, carcinoembryonic antigen, lysozyme and MUC1; each case expressed 4 of the 5 substances. Some cells expressed cytokeratins 5/6 and p63 consistent with the presence of basal-type differentiation in a subset of cells. No definite evidence of myoepithelial differentiation was demonstrated, as stains for smooth muscle actin, muscle-specific actin, and S100 protein were negative. Estrogen and progesterone receptor proteins were absent; strong cytoplasmic immunoreactivity for androgen receptor protein was evident, but nuclear staining was absent. The authors conclude that OCOTs show glandular differentiation. A review of the literature disclosed that none of these lesions arising in the caruncle behaved aggressively, in contrast to occasional tumors in other oculocutaneous sites.

Vulvar trichogenic tumors: a comparative study with vulvar basal cell carcinoma.

Trichogenic tumors are very rare in genital skin and often cause diagnostic problems because they are mitotically active and they share some histologic features with basal cell carcinomas (BCCs). We present the clinical and histologic features of 16 vulvar trichogenic tumors (6 plaque-like, 10 nodular; average age, 65 years) in comparison with 16 BCCs (11 plaque-like, 5 nodular; average age, 78 years). All trichogenic tumors, except 1 case with HSV infection, were nonulcerated tumors. Superficial plaque-like trichogenic tumors featured basal keratinocyte proliferations with peripheral nuclear palisading but no clefting at the epithelial-stromal interface. Nodular trichogenic tumors consisted of solid lobules of squamous cells and anastomosing cords and reticulations of follicular germinative cells with mitoses and apoptosis. Large pink cells with trichohyaline granules and melanocytes resembling the inner hair sheath, and clear cells resembling the outer root sheath were common. Most cysts were keratinized, but some fluid-filled cysts showed apocrine and sebaceous differentiation. The well-defined mesenchymal component of trichogenic tumors was pale and mucinous, and contained fibrocytes and fibrillary collagen bundles. All BCCs showed surface ulcerations and clefting at the stromal-epithelial interface. BCCs showed no trichogenic differentiation and lacked an organized mesenchymal tumor component. The tumor stroma of BCCs was paucicellular, mucinous, or granulation tissue-like with an inflammatory infiltrate.

Cylindroma of the breast of skin adnexal type: a study of 4 cases.

Four cases of solitary cylindroma of the breast of skin adnexal type are described. The tumors were morphologically and immunophenotypically identical to their dermal counterparts. They arose in close proximity to the nipple, such as the retroareolar area of the breast and in intimate association with the lactiferous ducts, suggesting an origin from the latter structures. One case occurred in a woman with hereditary multiple cylindromatosis (Brooke-Spiegler syndrome). This is the second reported case of this hereditary syndrome with extracutaneous manifestations and the first case in which the breast is involved.