The assessment of tumor-infiltrating lymphocytes in invasive apocrine carcinoma of the breast in relation to the HER2 status.

In the current study, we assessed the prevalence and molecular features of HER2-low phenotype in the apocrine carcinomas of the breast (ApoCa) and its relationship with tumor-infiltrating lymphocytes (TILs). A cohort of 64 well-characterized therapy-naïve ApoCa was used. The TIL distribution was assessed using the hematoxylin and eosin whole slide/scanned images following the international TILs working group recommendations. Next-generation sequencing (NGS) was performed in a subset of HER2-low ApoCa. All patients were women, with a mean age of 62 years. Forty-three carcinomas were pure apocrine carcinoma (PAC; ER-/AR+), and the remaining 21 were classified as apocrine-like carcinomas (ALCs; ER+/-, AR+/-). HER2/neu was positive (score 3+ by IHC and/or amplified by FISH) in 20/43 (47%) PAC and 4/21 (19%) ALC. The prevalence of HER2-low expression (scores 1+ or 2+ without HER2 amplification) in ApoCa was 39% without significant differences between PAC and ALC (P = 0.14); however, the HER2-low phenotype was more prevalent in triple-negative PAC than in ALC (P < 0.001). Levels of TILs were low (≤10%) in 74% of ApoCa (median 5%, range 0%-50%). TIL levels were significantly higher in ALC than in PAC (P = 0.02). HER2 status had no impact on TIL distribution (P = 0.45). The genomic profile of HER2-low ApoCa was similar to other subtypes of ApoCa. ApoCa has predominantly low TIL, particularly PAC. The prevalence of the HER2-low phenotype in ApoCa is high, which should have therapeutic and clinical implications given the recently approved therapies with antibody-drug conjugates (ADCs) for HER2-low breast cancers.

CDX2 and SATB2 positivity in pilomatrix carcinoma: Avoiding an erroneous diagnosis of cutaneous metastasis of gastrointestinal origin.

An 80-year-old female presented with a slowly growing 2-cm nodule on her shoulder over a 1-year period. Histopathologic sections of a biopsy specimen showed a multinodular, dermal-based basaloid tumor with areas of clear-cell change, stromal induction, as well as significant cytologic atypia and atypical mitotic activity. An initial investigation revealed positive staining of CDX2, a well-known marker of tumors of gastrointestinal origin. The case was referred to our dermatopathology service for consultation to determine if the lesion was in keeping with a cutaneous metastasis. On receipt of the case, an extended immunohistochemical panel was performed including SATB2, which displayed a similar pattern of staining as seen with CDX2. Although pathologists are most familiar with CDX2 and SATB2 as markers of gastrointestinal origin, the recent dermatopathology literature highlights that primary adnexal lesions of the skin also display positivity for CDX2 and can exhibit SATB2 positivity. We share a case of pilomatrix carcinoma with positive expression of nuclear CDX2 and SATB2, adding to the recent literature to (a) increase recognition of this staining pattern in hair follicle tumors, and (b) discuss briefly the shared molecular underpinnings in the tumorigenesis of gastrointestinal tumors and tumors of hair follicle origin that help clarify this underrecognized immunohistochemical pattern.

Matrical carcinoma with melanocytic hyperplasia mimicking nodular melanoma in an elderly Mexican male.

Matrical carcinoma with melanocytic hyperplasia (MCMH), previously referred to as malignant melanocytic matricoma, is a rare variant of the uncommon pilomatrical carcinoma, occurring most often on the head/neck and upper backs of middle-aged men. Nodular lesions may resemble pigmented basal cell carcinoma or melanoma clinically. We present a case of MCMH in a Hispanic patient with history of melanoma. Histopathological clues to appropriate diagnosis include basaloid cells, numerous atypical mitotic figures, matrical differentiation, shadow cells, strong diffuse nuclear and cytoplasmic expression of ß-catenin, and interspersed pigmented dendritic melanocytes.

Syringoid eccrine carcinoma: a clinicopathological and immunohistochemical study of four cases.

BACKGROUND: Syringoid eccrine carcinoma (SEC) is a rare malignant adnexal tumour with variable presentations. AIM: To examine the clinicopathological and immunohistochemical features of SEC. METHODS: Four cases were reviewed by three dermatopathologists and the immunohistochemical profile was examined using antibodies against CK5/6, CK7, CK14, CK20, LMWK, HMWK, EMA, mCEA, p63, ER, PR, AR, S-100 and Ber-EP4. RESULTS: The cases occurred in two men and two women, ranging in age from 61 to 87 years (mean 68.5). Two of the lesions were from the face and two from the trunk. All four lesions were composed of an atypical infiltrative mass with syringoma-like tadpole morphology with ductular differentiation and prominent desmoplasia. Three cases demonstrated perineural invasion and two had positive lymph node metastases. Immunostaining was variable. Immunohistochemistry positivity was as follows: three out of four cases were positive for CK5/6, CK7 (2/4), CK14 (1/3), CK20 (0/2), HMWK (0/2), LMWK (1/2), EMA (3/4), mCEA (4/4), p63 (2/3), ER (2/3), PR (1/2), AR (0/3), S-100 (0/3) and Ber-EP4 (2/2). CONCLUSION: SEC can present on the trunk and are not limited to the head and neck region. In addition to syringoma-like tadpole structures and glandular differentiation, these tumours can also exhibit squamoid and cribriform growth patterns. Immunostaining in SEC is variable and this variability is believed to stem from this tumour's ability to differentiate along multiple routes, including sweat secretory and/or ductal differentiation.

Primary cutaneous neuroendocrine carcinoma within a cystic trichoblastoma: a nonfortuitous association?

Merkel cell (primary cutaneous neuroendocrine) carcinoma is a rare neoplasm of the skin. Its occurrence has been reported in association with other cutaneous neoplasms (Bowen disease, squamous cell carcinoma) in cases regarded as collision tumors. It has recently been described in association with cysts of the follicle apparatus. We present a unique case of rapidly growing nodular tumor on the left forearm of an 84-year-old woman, which proved to be a Merkel cell carcinoma located within a cystic trichoblastoma. The malignant component located in the center of the lesion had typical histopathological and immunohistochemical features of Merkel cell carcinoma. It was surrounded by an epithelial proliferation, made of K17-positive basaloid cells, whose aspects where those of trichoblastoma in a retiform pattern. Both lesions were intertwined, suggesting that the Merkel cell carcinoma had developed within a previously existing trichoblastoma and that it derived from the follicular Merkel cells present in the trichoblastoma. The unique features of this case, together with the reported cases of Merkel cell carcinoma arising within follicular lesions, and the fact that numerous Merkel cells are normally localized in the adult hair follicle, further support the hypothesis of a histogenetic link between normal follicular Merkel cells and Merkel cell carcinoma.

Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl.

The mechanism by which Wnt receptors transduce signals to activate downstream beta-catenin-mediated target gene transcription remains incompletely understood but involves Frizzled (Fz) receptor-mediated plasma membrane recruitment and activation of the cytoplasmic effector Dishevelled (Dvl). Here, we identify the deubiquitinating enzyme CYLD, the familial cylindromatosis tumor suppressor gene, as a negative regulator of proximal events in Wnt/beta-catenin signaling. Depletion of CYLD from cultured cells markedly enhances Wnt-induced accumulation of beta-catenin and target gene activation. Moreover, we demonstrate hyperactive Wnt signaling in human cylindroma skin tumors that arise from mutations in CYLD. At the molecular level, CYLD interacts with and regulates K63-linked ubiquitination of Dvl. Enhanced ubiquitination of the polymerization-prone DIX domain in CYLD-deficient cells positively links to the signaling activity of Dvl. Together, our results argue that loss of CYLD instigates tumor growth in human cylindromatosis through a mechanism in which hyperubiquitination of polymerized Dvl drives enhancement of Wnt responses.

CD10 for the distinct differential diagnosis of basal cell carcinoma and benign tumours of cutaneous appendages originating from hair follicle.

AIMS: Differential diagnosis between the group of trichoadenoma, trichofolliculoma, trichoepithelioma, trichoblastoma and basal cell carcinoma has been creating some difficulties for the pathologist and the clinicians, particularly in the presence of small specimens. MATERIAL AND METHODS: A total of 30 cases of benign tumours of cutaneous appendages originating from the hair follicle and 30 cases of basal cell carcinoma were retrieved from the archives deposited from 2004 to 2008. RESULTS: The expression of CD10 in both tumours was graded from [0] to [2+] for each case. The immunoreactivity of CD10 was comparatively examined among the groups and each subgroup. The stromal CD10 immunopositivity of benign tumours of cutaneous appendages originating from the hair follicle was stronger than the other (p = 0.003) regarding both the numerical and the degree of expression. However, peripheral CD10 of basal cell carcinoma was stronger than the other for [1+] immunopositivity (p = 0.03). It was exact opposite for [2+] (p = 0.013). Besides, central CD10 immunopositivity and CD10 reactivity for the subgroups was not significant. CONCLUSIONS: CD10 may be very useful for the differential diagnosis between them particularly in the small and superficial biopsies and it may be even a life-saving method in some selected cases.

"Squamoid eccrine ductal carcinoma": an unusual low-grade case with follicular differentiation. Are these tumors squamoid variants of microcystic adnexal carcinoma?

Squamoid eccrine ductal carcinoma is a rare primary cutaneous tumor exhibiting both squamous and adnexal ductal differentiation. The cell of origin of these tumors is unknown, and they have been classified both as variants of cutaneous squamous cell carcinoma and as a type of eccrine carcinoma. Only 6 of these tumors have been reported in the literature to date. We report an additional case of a slow-growing tumor, occurring on the great toe of a 61-year-old woman, which was unusual as it showed follicular differentiation in addition to squamoid and ductal areas. The lesional cells were positive for cytokeratins 7 and 17, carcinoembryonic antigen (which highlighted the ductal structures), and p63 (favoring a primary cutaneous tumor) and showed low levels of staining with Ki-67 and p53, consistent with a low-grade tumor. We postulate that these tumors may be closely related to microcystic adnexal carcinoma and similarly show differentiation along both follicular and ductal lines, likely indicating folliculosebaceous-apocrine, rather than eccrine, origin or differentiation.

Spiradenocylindrocarcinoma. Report of a case with a low-grade component of spiradenocarcinoma and an immunohistochemical study.

Spiradenocylindrocarcinoma is a very rare malignant cutaneous neoplasm of the folliculosebaceous-apocrine unit. We report a case of this hybrid tumor in a 42-year-old woman. The tumor consisted of 2 circumscribed nodules with areas of cylindrocarcinoma and low-grade spiradenocarcinoma. In the overlapping areas, both spiradenomatous and cylindromatous features were observed. Expansion of the tumor beyond the fibrous pseudocapsule into the adjacent tissue was present. Furthermore, tumor cells were demonstrating mild to moderate pleomorphism and an increased mitotic index. p53 and ki-67 were among the positive immunohistochemical markers. A relatively small number of tumor cells expressed estrogen receptors. The aim of this study was to investigate the nature of this rare tumor of the skin appendages.

Differential expression of mucin core proteins and keratins in apocrine carcinoma, extramammary Paget's disease and apocrine nevus.

BACKGROUND: Apocrine carcinomas are rare, the immunohistochemical characterizations that are incomplete. The purpose of this study was to determine the immunohistochemical characteristics of mucin core proteins and keratins in apocrine carcinoma, extramammary Paget's disease (EMPD) and apocrine nevus. METHODS: We report four cases of apocrine carcinomas along with immunohistochemical analyses: (i) an axillary apocrine carcinoma with an apocrine nevus, (ii) an inguinal apocrine carcinoma, (iii) a vulvar apocrine carcinoma with EMPD and (iv) an axillary apocrine carcinoma with EMPD and an apocrine nevus. RESULTS: The tumor cells of apocrine carcinomas, EMPD and apocrine nevi displayed a positive reaction to MUC-1 and CK7 and a negative reaction to CK20. Apocrine carcinomas had high molecular weight (HMW) cytokeratin(+)/CK5(+)/CK14(-)/MUC5AC(-), EMPD with underlying apocrine carcinoma had HMW cytokeratin(-)/CK5(-)/CK14(-)/MUCA5AC(-) and the apocrine nevi had HMW cytokeratin(+)/CK5(+)/CK14(+)/MUCA5AC(+). CONCLUSION: The immunohistochemical findings suggest that apocrine carcinomas, apocrine nevi and EMPD with underlying apocrine carcinomas are quite different, even though they are all derived from apocrine glands.

Apocrine hidradenocarcinoma showing Paget's disease and mucinous metaplasia.

A 54-year-old man presented with a solitary, erythematous, rapidly growing 1-cm nodule on his scalp that had arisen over the previous 3 months. He had no history of skin cancer. An excisional biopsy of the lesion showed a fairly well-circumscribed but focally invasive tumor consisting of areas of typical-appearing clear cell hidradenoma as well as areas with mucinous goblet-type cells and cells with eosinophilic cytoplasm and decapitation-type secretion. There was marked cellular atypia, numerous atypical mitotic figures and focal necrosis. The tumor cells focally involved the overlying epidermis (Paget's disease). Large areas of mucin were identified throughout the lesion. The tumor cells stained with markers for cytokeratin 7 and focally for EMA and CEA, confirming ductal differentiation. The goblet cells and mucinous areas stained with mucicarmine and PASD. The patient was diagnosed with hidradenocarcinoma with mucinous differentiation. Associated Paget's disease has only rarely been reported, and mucinous metaplasia is a previously unreported feature in hidradenocarcinoma.

Secretory carcinoma in the axilla: probable origin from axillary skin appendage glands in a young girl.

Invasive carcinoma in the axilla may arise from skin appendage glands or ectopic breast tissue or it may be a metastasis. Carcinomas of the skin adnexal glands and breast can be difficult to distinguish from each other as they often display the same patterns of growth. Tubular, cribriform, papillary, apocrine, mucinous, and adenoid cystic are histologic types of carcinoma seen in the breast and skin appendage glands. To our knowledge, secretory carcinoma, the most common form of mammary carcinoma in children, has not yet been described as a morphologic pattern of skin adnexal carcinoma, although we cannot exclude the possibility that such a case was reported with a different diagnosis. We report a case of a young girl with secretory carcinoma that seems to have arisen from skin appendage glands in the skin of the axilla in the absence of demonstrable ectopic breast tissue.

Proliferating tricholemmal cystic carcinoma: a case containing differentiated and dedifferentiated parts.

A 46-year-old man had a cystic mass on the right side of his scalp. Histological examination revealed a cystic dermal nodule composed of relatively circumscribed lobules of proliferating squamous epithelium, with atypical mitoses and dyskeratotic cells of invasive structure, which was diagnosed as proliferating tricholemmal cystic carcinoma (PTCC). Most of the cyst was composed of thick layers of highly proliferating, atypical, dedifferentiated epithelium (dedifferentiated part), which was attached to a highly proliferative but mildly differentiated part. A completely differentiated, tricholemmal cyst (TC)-like part was also attached to the main cyst, which supports the idea of PTCC beginning in a pre-existing TC. The dedifferentiated and mildly differentiated parts exhibited a high frequency of proliferating cell nuclear antigen (PCNA)-positive cells both in the basal and the suprabasal layers, while PCNA staining was almost negative in the TC-like part. Expression of cytokeratin (CK)10 and CK16 suggested disturbed epidermal differentiation in dedifferentiated part, while TC-like part showed well-differentiated trichilemmal epithelium and the mildly differentiated part was in the middle of these two.

CYLD mutations in familial skin appendage tumours.

BACKGROUND: Germ-line mutations in CYLD are found in patients with familial skin appendage tumours. The protein product functions as a deubiquitinase enzyme, which negatively regulates NF-kappaB and c-Jun N-terminal kinase signalling. Brooke-Spiegler syndrome (BSS) is characterised by cylindromas, trichoepitheliomas and spiradenomas, whereas in familial cylindromatosis (FC) patients present with cylindromas and in multiple familial trichoepitheliomas (MFT) with trichoepitheliomas as the only skin tumour type. Although described as distinct entities, recent studies suggest that they are within the spectrum of a single entity. OBJECTIVE: To investigate the mutation spectrum of CYLD and possible genotype-phenotype correlations. METHODS: 25 families including 13 BSS, 3 FC, and 9 MFT families were examined and evaluated for mutations in the CYLD gene. RESULTS: In total, 18 mutations in CYLD, including 6 novel mutations, were identified in 25 probands (72%). The mutation frequencies among distinct phenotypes were 85% for BSS, 100% for FC, and 44% for MFT. The majority of the mutations were insertions, deletions or nonsense mutations leading to formation of truncated proteins. All mutations were located between exons 9 to 20, encoding the NEMO binding site and the catalytic domain. Genotype-phenotype analysis failed to reveal a correlation between the types of mutations and their location within the gene and the patients' phenotypes and disease severity. CONCLUSIONS: This study provides further evidence on the role of CYLD in the pathogenesis of skin appendage tumours characterised by cylindromas, trichoepitheliomas and/or spiradenomas, but the molecular mechanisms of CYLD in skin tumorigenesis and the reasons for phenotypic variability remain to be explored.

Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity.

Brooke-Spiegler syndrome, familial cylindromatosis, and familial trichoepithelioma are autosomal-dominant genetic predispositions for benign tumors of skin appendages caused by mutations in the CYLD gene localized on chromosome 16q12-q13. The encoded protein functions as ubiquitin-specific protease (UBP), which negatively regulates NF-kappaB and c-Jun N-terminal kinase (JNK) signaling. We investigated five families affected with these skin neoplasms and identified four premature stop codons and the novel missense mutation D681G in a family in which 11 of 12 investigated tumors were trichoepitheliomas. CYLD protein harboring this missense mutation had a significant reduced ability to inhibit TNF receptor-associated factor (TRAF)2- and TRAF6-mediated NF-kappaB activation, tumor necrosis factor-alpha (TNFalpha)-induced JNK signaling, and to deubiquitinate TRAF2. CYLD-D681G was coimmunoprecipitated by TRAF2, but was unable to cleave K63-linked polyubiquitin chains. Aspartic acid 681 is highly conserved in CYLD homologues and other members of the UBP family, but does not belong to the Cys and His boxes providing the CYLD catalytic triad (Cys601, His871, and Asp889). As reported previously, the homologous residue D295 of HAUSP/USP-7 forms a hydrogen bond with the C-terminal end of ubiquitin and is important for the enzymatic activity. These results underline that D681 in CYLD is required for cleavage of K63-linked polyubiquitin chains.

Monoclonal antibody Ber-EP4 reliably discriminates between microcystic adnexal carcinoma and basal cell carcinoma.

BACKGROUND: Sclerosing cutaneous neoplasms often represent a diagnostic challenge. The monoclonal antibody Ber-EP4 recognizes two glycopolypeptides found in most human epithelial cells. It is diagnostically highly reliable in the differentiation between basal cell carcinoma and cutaneous squamous cell carcinoma. In this study, we report its application in the differential diagnosis of microcystic adnexal carcinoma, desmoplastic trichoepithelioma and basal cell carcinoma. METHODS: Biopsy samples from 28 sclerosing and infiltrating basal cell carcinomas, 13 microcystic adnexal carcinomas and 16 desmoplastic trichoepitheliomas were examined after immunohistochemical staining with Ber-EP4. RESULTS: Ber-EP4 did not label any of the microcystic adnexal carcinomas, whereas all 28 basal cell carcinomas were Ber-EP4 positive. Twenty-seven of the 28 showed moderate or strong staining intensity, with the majority being strong. Only one basal cell carcinoma was weakly positive. Twelve of the 16 desmoplastic trichoepitheliomas were immunoreactive with Ber-EP4 and the staining was more variable than those of basal cell carcinomas. CONCLUSIONS: Ber-EP4 reliably differentiates microcystic adnexal carcinoma from basal cell carcinoma to the same extent as it distinguishes the latter tumor from squamous cell carcinoma. While it stains the majority of desmoplastic trichoepitheliomas, these tumors still have to be considered in the differential diagnosis with microcystic adnexal carcinoma, when Ber-EP4 is applied.

Expression of class II beta-tubulin in non-melanoma cutaneous tumors.

BACKGROUND: Different combinations of beta-tubulin isotypes contribute to the diverse functions of microtubules (MTs). Class II beta-tubulin (class II tubulin) is up-regulated in differentiated keratinocytes. In contrast, the expression of class II tubulin in follicular differentiation and cutaneous tumors has not been studied. METHODS: The immunohistochemical expression of class II tubulin was investigated in 117 cutaneous tumors: 30 squamous cell carcinomas (SCCs), seven keratoacanthomas (KAs), 57 basal cell carcinomas (BCCs), 23 trichoepitheliomas (TEs), and in the adjacent non-neoplastic skin. RESULTS: Class II tubulin was expressed in the keratinocytes of the granular layer, melanocytes, hair cortical and cuticular cells, inner root sheath (IRS), companion layer (CL) of the outer root sheath (ORS), and mesenchymal cells with Schwannian or myogenic differentiation. Moreover, class II tubulin expression was increased in the areas of squamous or follicular differentiation in cutaneous tumors. On grading the follicular differentiation or myofibroblastic response with anti-class II tubulin, TE showed follicular differentiation more frequently (p < 0.001) with less of a myofibroblastic response (p = 0.001) than BCC. CONCLUSIONS: Class II tubulin expression is closely related to squamous or follicular differentiation and may be helpful in distinguishing most SCCs from KAs and BCC from TE. However, it does not reliably distinguish well-differentiated, crateriform SCC from KA.