Clear cell myoepithelial carcinoma of salivary glands showing EWSR1 rearrangement: molecular analysis of 94 salivary gland carcinomas with prominent clear cell component.

This study examines the presence of the EWSR1 rearrangement in a variety of clear cell salivary gland carcinomas with myoepithelial differentiation. A total of 94 salivary gland carcinomas with a prominent clear cell component included 51 cases of clear cell myoepithelial carcinomas de novo (CCMC), 21 cases of CCMCs ex pleomorphic adenoma (CCMCexPA), 11 cases of epithelial-myoepithelial carcinoma (EMC), 6 cases of EMC with solid clear cell overgrowth, and 5 cases of hyalinizing clear cell carcinoma of minor salivary glands. In addition, 10 cases of myoepithelial carcinomas devoid of clear cell change and 12 cases of benign myoepithelioma were included as well. All the tumors in this spectrum were reviewed, reclassified, and tested by fluorescence in situ hybridization (FISH) for the EWSR1 rearrangement using the Probe Vysis EWSR1 Break Apart FISH Probe Kit. The EWSR1 rearrangement was detected in 20 of 51 (39%) cases of CCMC, in 5 of 21 (24%) cases of CCMCexPA, in 1 of 11 (9%) cases of EMC, and in 4 of 5 (80%) cases of hyalinizing clear cell carcinoma. The 25 EWSR1-rearranged CCMCs and CCMCexPAs shared similar histomorphology. They were arranged in nodules composed of compact nests of large polyhedral cells with abundant clear cytoplasm. Necrosis, areas of squamous metaplasia, and hyalinization were frequent features. Immunohistochemically, the tumors expressed p63 (96%), cytokeratin CK14 (96%), and S100 protein (88%). MIB1 index varied from 10% to 100%, with most cases in the 20% to 40% range. Clinical follow-up information was available in 21 cases (84%) and ranged from 3 months to 15 years (mean 5.2 y); 4 patients were lost to follow-up. Ten patients are alive with no evidence of recurrent or metastatic disease in the follow-up period from 3 months to 15 years (mean 5 y), 3 patients are alive with recurrent and metastatic disease, and 8 died of disseminated cancer 9 months to 16 years after diagnosis (mean 6 y). Lymph node metastasis appeared in 5 patients within 5 months to 4 years after diagnosis (mean 22 mo), distant metastases were noted in 7 patients with invasion of orbit (2 cases), and in 1 case each metastasis to the neck soft tissues, liver, lungs, mediastinum, and thoracic vertebra was noted. We describe for the first time EWSR1 gene rearrangement in a subset of myoepithelial carcinomas arising in minor and major salivary glands. The EWSR1-rearranged CCMC represents a distinctive aggressive variant composed predominantly of clear cells with frequent necrosis. Most EWSR1-rearranged CCMCs of salivary glands are characterized by poor clinical outcomes.

Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens.

Brooke-Spiegler syndrome (BSS) is a rare, inherited, autosomal dominant disorder characterized by development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. The syndrome of multiple familial trichoepitheliomas (MFT) is considered a phenotypic variant of BSS in which patients present with trichoepitheliomas only. We studied germline and somatic mutations of the CYLD gene by direct sequencing in patients with BSS (n = 49) and MFT (n = 18) using peripheral blood and 90 samples of frozen or formalin-fixed paraffin-embedded tumor tissue selected from 379 available histology specimens. Germline CYLD mutations were found in 51 patients (76%) from 36 families (75%). Germline CYLD mutations were found in 43 of the 49 patients with BSS (88%) but in only 8 of 18 MFT cohort (44%). Twenty-one frameshift, 15 nonsense, 3 missense, and 4 splice site mutations were found in patients with BSS, whereas 1 frameshift, 5 nonsense, and 2 splice site mutations were identified in the MFT cohort. Five novel mutations were identified including 4 frameshift mutations (c.1027dupA/p.T343NfsX7, c.2155dupA/p.M719NfsX5, c.2288_2289delTT/p.F763X, and c.2641delG/p.D881TfsX32) and 1 nonsense mutation (c.2713C>T/p. Q905X). Of the 76 tumors from 32 patients with a germline CYLD mutation, 12 were spiradenomas, 15 spiradenocylindromas, 26 cylindromas, 15 trichoepitheliomas, and 7 were other tumor types. Somatic mutations were detected in 67 specimens of these 76 tumors (88%). Of the 67 somatic mutations, 21 (31%) represented a sequence alteration and 46 (69%) showed loss of heterozygosity. In the remaining 9 cases (12%), the somatic changes remained unknown. A germline CYLD mutation was not detected in 14 tumor samples from 8 patients. In these 14 tumors, somatic mutations were identified in 6 samples (43%), all consisting of sequence alterations (1 sample showed 2 different sequence alterations). In the remaining 8 samples (53%), neither germline nor somatic mutations were found in the lesional tissue. Our study increases the catalog of known CYLD mutations in patients with BSS/MFT to 86 and documents the variability of somatic mutations that may occur in them. We confirm the absence of firm genotype-phenotype correlations and the existence of a subset of patients with BSS/MFT who lack a demonstrable germline CYLD mutation. Further studies are needed to explain the reasons for this phenomenon.

Multiple (familial) trichoepitheliomas: a clinicopathological and molecular biological study, including CYLD and PTCH gene analysis, of a series of 16 patients.

Multiple familial trichoepitheliomas (MFT) constitute an autosomally inherited syndrome possibly related to Brooke-Spiegler syndrome (BSS). Although some early studies suggested a role for the PTCH gene on chromosome 9q22.3 in the etiopathogenesis of MFT, recent studies of occasional patients with the MFT clinical phenotype identified mutations in the CYLD gene on chromosome 16q12-q13, a gene responsible for BSS. A systematic investigation of PTCH and CYLD mutations in patients with MFT has never been performed. Our main objective was to collect a reasonably large series of patients with MFT to (1) study the clinicopathological spectrum of the disease, (2) determine whether the PTCH gene is implicated in the pathogenesis of MFT, and if so (3) determine the relative frequency of CYLD and PTCH mutations, (4) establish if there may be any possible genotype-phenotype correlations, and (5) study the spectrum of somatic mutations. Clinical analysis including family histories, histopathological investigations, and molecular genetic studies were performed. There were 9 female and 7 male patients ranging in age from 11 to 63 years. They presented with multiple, small, discrete and sometimes confluent, skin-colored to pink, asymptomatic nodules preferentially located on the face, being especially prominent and confluent in the nasolabial folds and inner aspects of the eyebrows. A total of 66 conventional trichoepitheliomas (TEs) were studied microscopically. Aside from typical features of TE, some also exhibited variant morphological patterns including areas reminiscent of other benign adnexal neoplasms and melanocytic hyperplasia. In none of the 9 patients tested was a germline mutation of the PTCH gene identified. Germline CYLD mutations were detected in 6 of 13 patients tested (identical in 2 unrelated patients) including 2 novel mutations, whereas the remaining 7 individuals showed wild-type alleles. Two patients with germline wild-type CYLD showed, however, a somatic mutation in the gene (1 duplication, 1 substitution mutation). Neither CYLD nor PTCH germline mutations were found in the 5 patients in whom both genes were analyzed. MFT seems to be a phenotypic variant of BSS. The PTCH gene is rarely, if ever, involved in the pathogenesis of MFT. Absence of a germline mutation of the CYLD gene in cases harboring a somatic mutation may be explained by large deletions in the gene or by mutation in intronic sequences or in the promoter region. Considering our 5 patients with no mutation in either gene, the final possibility is that another, as yet undescribed gene (neither CYLD nor PTCH) is implicated in the pathogenesis of some patients with MFT.

Brooke-Spiegler syndrome: report of 10 patients from 8 families with novel germline mutations: evidence of diverse somatic mutations in the same patient regardless of tumor type.

Brooke-Spiegler syndrome (BSS) is an inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma (cribriform trichoblastoma). BSS patients have various mutations in the CYLD gene, a tumor suppressor gene located on chromosome 16q. Our search of the literature revealed 51 germline CYLD mutations reported to date. Somatic CYLD mutations have rarely been investigated. We studied 10 patients from 8 families with BSS. Analysis of germline mutations of the CYLD gene was performed using either peripheral blood or nontumorous tissue. In addition, 19 formalin-fixed paraffin-embedded tumor samples were analyzed for somatic mutations, including loss of heterozygosity studies. A total of 38 tumors were available for histopathologic review. We have identified 8 novel germline mutations, all of which consisted of substitutions, deletions, and insertions/duplications and all except one led to premature stop codons. The substitution mutation in a single case was also predicted to disrupt protein function and seems causally implicated in tumor formation. We demonstrate for the first time that somatic events, loss of heterozygosity, or sequence mutations may differ among multiple neoplasms even of the same histologic type, occurring in the same patient.

Expression of p53 and TP53 mutational analysis in malignant neoplasms arising in preexisting spiradenoma, cylindroma, and spiradenocylindroma, sporadic or associated with Brooke-Spiegler syndrome.

We performed immunohistochemical assessment of p53 expression and TP53 mutational analysis of 15 malignant neoplasms arising from preexisting benign cylindroma, spiradenoma, and spiradenocylindroma, sporadic or associated with Brooke-Spiegler syndrome. At least weak and focal p53 positivity was present in 13 of the 15 lesions. Successful PCR and sequencing were possible in 12 of the 15 cases. In one case only there were 2 p53 mutations, one being a c.673-1G>A splice-site mutation in the 3'-end of intron 6 (position--g.15289G>A, contig gb.AY838696.1) and the second being a c.743G>A (p.R248Q) mutation in exon 7 (position--15360G>A, contig gb.AY838696.1). Single nucleotide polymorphisms were detected in all 12 malignant cases analyzed. As a control group, we included 12 randomly selected sporadic cases of spiradenoma (n = 5), cylindroma (n = 4), and spiradenocylindroma (n = 3). None of the 12 benign control group cases harbored a TP53 mutation, whereas all 12 demonstrated single nucleotide polymorphisms identical to those detected in the malignant tumor group. Immunohistochemically, 1 cylindroma and 2 spiradenomas demonstrated weak and focal p53 positivity. In conclusion, we found a fairly high rate of p53 expression in malignant neoplasms arising from preexisting benign spiradenomas, cylindromas, and spiradenocylindromas. However, the mutation rate of TP53 was low. Whereas immunostaining for p53 has been suggested as an adjunct tool to differentiate benign spiradenoma, cylindroma, and spiradenocylindroma from their malignant counterparts, its utility is limited by its heterogeneous pattern of expression, especially the sometimes lack of staining in clearly malignant areas and the occurrence of focal, weak positivity in the benign residua or in unequivocally benign neoplasms.

Fibroadenoma and phyllodes tumors of anogenital mammary-like glands: a series of 13 neoplasms in 12 cases, including mammary-type juvenile fibroadenoma, fibroadenoma with lactation changes, and neurofibromatosis-associated pseudoangiomatous stromal hyperplasia with multinucleated giant cells.

The authors present a series of 13 fibroepithelial neoplasms involving anogenital mammary-like glands, all occurring in 12 female patients, whose age at diagnosis ranged from 30 to 51 years (mean, 38 y; median, 42 y). All women presented with a solitary asymptomatic nodule in the vulva (n=8), perineum (n=2), or near the anus (n=2) ranging in size from 1.5 to 4.5 cm. Microscopically, 8 lesions were classified as fibroadenoma, and 5, including 1 recurrent tumor, as phyllodes tumor, of which 1 was benign and 4 low-grade malignant. In addition to conventional findings, we describe several hitherto unreported features including juvenile fibroadenoma-like proliferation, fibroadenoma with lactation change, and pseudoangiomatous stromal hyperplasia with multinucleated stromal giant cells in a patient with neurofibromatosis, type 1 all constituting potential diagnostic pitfalls, which are best averted by using the same approach to diagnosis as for their analogous mammary counterparts.

Adenoid cystic carcinoma-like pattern in spiradenoma and spiradenocylindroma: a rare feature in sporadic neoplasms and those associated with Brooke-Spiegler syndrome.

Spiradenoma is a benign, morphologically well-defined cutaneous adnexal neoplasm that is closely related to cylindroma. We present the rare occurrence of adenoid cystic carcinoma (ACC)-like areas in 7 spiradenomas and 1 spiradenocylindroma, not described in the English literature to date. The ACC-like areas were a minor but significant component in all lesions and were usually multifocal and blended with the conventionally appearing parts of the neoplasms. The ACC-like areas were typified by cribriform formations of epithelial cells concentrically arranged around gland-like spaces filled with mucin, homogeneous eosinophilic material, or granular basophilic material. In some neoplasms, only mucin occurred in these pseudoglandular structures, whereas in other cases, a combination of all 3 secretory products was encountered. Although well-developed bilayered glands with a demonstrable peripheral myoepithelial cell layer were not recognizable in the ACC-like areas, immunohistochemistry demonstrated myoepithelial differentiation in these portions of the tumors. When present in the ACC-like areas, ductal structures manifested a rather squamoid lining, without a recognizable peripheral myoepithelial cell layer. It is concluded that the ACC-like pattern, although a rare feature and of no clinical consequence, is a distinctive finding in a minority of cases and extends the morphological spectrum of spiradenoma and spiradenocylindroma occurring sporadically or in the setting of Brooke-Spiegler syndrome. It represents a potential diagnostic pitfall, particularly in a limited biopsy specimen where the changes may be misdiagnosed as ACC.

Pseudoangiomatous stromal hyperplasia in a complex neoplastic lesion involving anogenital mammary-like glands.

Anogenital mammary-like glands (AMLG) may give rise to various pathologic lesions identical to those known in mammary pathology. Pseudoangiomatous stromal hyperplasia (PASH), a relatively frequent hormonal change associated with different benign and malignant processes in the breast, was only once mentioned in the literature concerning the pathology of AMLG. We present here a new case of PASH in a lesion of AMLG. The present case of PASH is remarkable because of its occurrence within a complex lesion evidencing the changes identical to or reminiscent of blunt duct adenosis, fibroadenoma and hidradenoma papilliferum.

Morphologic diversity of malignant neoplasms arising in preexisting spiradenoma, cylindroma, and spiradenocylindroma based on the study of 24 cases, sporadic or occurring in the setting of Brooke-Spiegler syndrome.

The authors present a series of 24 malignant neoplasms arising in preexisting benign spiradenoma (20), cylindroma (2), and spiradenocylindroma (2). Nineteen patients (12 females, 7 males; age range, 41 to 92 y) had a solitary neoplasm (size range, 2.2 to 17.5 cm; median 4 cm), whereas the remaining 5 (4 females, 1 male; age range, 66 to 72 y) manifested clinical features of Brooke-Spiegler syndrome (BSS), an autosomal dominantly inherited disease characterized by widespread, small, benign neoplasms on which background larger malignant lesions appeared. Microscopically, all cases showed the residuum of a preexisting benign neoplasm. The malignant components of the lesions were variable and could be classified into 4 main patterns, occurring alone or in combination: 1) salivary gland type basal cell adenocarcinoma-like pattern, low-grade (BCAC-LG); 2) salivary gland type basal cell adenocarcinoma-like pattern, high-grade (BCAC-HG); 3) invasive adenocarcinoma, not otherwise specified (IAC-NOS); and 4) sarcomatoid (metaplastic) carcinoma. In 1 case of IAC-NOS, an in situ adenocarcinoma was also found, presumed to have evolved from an adjacent adenomatous and atypical adenomatous component. Cases harboring a sarcomatoid carcinoma featured a malignant epithelial component composed of varying combinations of BCAC-HG, BCAC-LG, IAC-NOS, or squamous cell carcinoma, whereas the sarcomatoid component appeared as either a pleomorphic or spindle-cell sarcoma. Additionally, in 2 cases there were foci of heterologous chondrosarcomatous differentiation and in 1 case there was rhabomyosarcomatous differentiation. Of the 21 patients with available follow-up (range, 3 mo-15 y; average 4.8 y; median 3.5 y), 10 were without evidence of disease, 1 was alive with metastatic disease, 1 was alive with BSS, 3 developed local recurrences, 4 had died of disease, and 2 were dead of other causes. The histologic pattern of the malignant neoplasm correlated to some extent with the clinical course. BCAC-LG neoplasms showed a less aggressive course, with local recurrences but no distant metastases, whereas the BCAC-HG neoplasms typically followed a highly aggressive course resulting in the death 3 of 6 patients with BCAC-HG. Patients with sarcomatoid carcinoma had a relatively good survival. Molecular genetic investigations revealed no mutations in the CYLD gene in the 4 sporadic cases investigated. One patient with BSS revealed a novel missense germline mutation in exon 14 (c. 1961T>A, p. V654E), whereas a living descendant of another deceased patient demonstrated a recurrent nonsense germline mutation in exon 20 (c. 2806C>T, p. R936X). Given the morphologic diversity and complexity of the neoplasms in question, we propose using a more specific terminology with the precise description of the neoplasm components, rather than generic and less informative terms such as "spiradenocarcinoma" or "carcinoma ex cylindroma."

Hyperplasia of hair follicles and other adnexal structures in cutaneous lymphoproliferative disorders: a study of 53 cases, including so-called pseudolymphomatous folliculitis and overt lymphomas.

We studied 53 cutaneous lymphoproliferative disorders, all of which manifested hair follicle hyperplasia. There were 42 cases conforming to the description of pseudolymphomatous folliculitis (PLF) and 11 cases of authentic lymphomas including mycosis fungoides, CD30+ anaplastic large cell lymphoma, diffuse large B-cell lymphoma, B-cell small cell lymphoma/leukemia, and peripheral T-cell lymphoma, not otherwise specified. All patients with PLF clinically presented with a solitary nodule preferentially involving the face. Beside hair follicle hyperplasia, the typical features were a dense infiltrate of small well-differentiated lymphocytes, lymphoplasmacytoid cells, plasma cells, and epithelioid histiocytes forming tiny granulomas. Some unusual or worrisome features recognized included eccrine/apocrine duct hyperplasia, subcutis/muscle infiltration, lymphocyte "smudging," single file infiltration, and large atypical cells. Immunohistochemically, T-cell predominant cases dominated in the series. All 34 tested cases revealed a polyclonal pattern of kappa and lambda immunoglobulin (Ig) light chain expression. In 4 cases, scattered CD30+ cells were identified. Monoclonal rearrangements of T-cell receptor (TCR) and IgH genes were detected in 19 and 3 cases respectively, including 1 case with dual T-cell receptor/IgH rearrangement. Three of 30 tested cases proved positive for herpes simplex virus-1, whereas herpes simplex virus-2 always tested negative. Of 31 cases tested for Borrelia burgdorferi, 30 specimens were negative. In 9 cases, fluorescent in situ hybridization for t(11;18) and t(14;18) revealed none of the above translocations. The most common treatment modality was surgical removal. Forty patients with a mean follow-up of 3.7 years included 39 patients with no evidence of disease and 1 individual with local recurrence. The comparison of "clonal cases of PLF" and those with polyclonal population or in which clonality remained undetermined revealed no differences between the 2 groups in the clinical presentation, pathologic, and immunohistochemical features. We conclude that hyperplasia of hair follicles and other adnexa can be seen not only in the condition currently known as PLF, but also in genuine cutaneous lymphomas and may be just a happenstance secondary to a basic pathologic process.

Merkel cell carcinoma with a follicular lymphocytic infiltrate: report of 2 cases.

Merkel cell carcinoma (MCC) with a follicular lymphocytic infiltrate of the dermis was first reported by Bastian et al in 1996. Thereafter there were no further reports of such a morphological variant of MCC. We present here 2 cases of MCC characterized by foci of a dense lymphocytic infiltrate with the formation of lymphoid follicles. This feature may produce a potential diagnostic pitfall, rendering a lymphomatous appearance to the tumor.

Hidradenoma papilliferum with a ductal carcinoma in situ component: case report and review of the literature.

Hidradenoma papilliferum (HP) is a benign cutaneous adnexal neoplasm occurring mainly in the anogenital region of adult women and has features analogous to intraductal papilloma of the breast. Malignant change in HP is extremely rare. Only a single case of ductal carcinoma in situ arising in HP has been previously reported. We present a new case of HP which, in addition to the typical appearance of HP, contained a focus of ductal carcinoma in situ that appeared as enlarged pleomorphic epithelial cells having a "blastic" appearance, exhibiting atypical mitotic figures and surrounded by myoepithelial cells. Molecular biological study identified human papillomavirus (HPV)-16, which, it may be argued, may have played a role in the development of the carcinoma.

Vascular changes in merkel cell carcinoma based on a histopathological study of 92 cases.

Although prominent vascular proliferation is a known feature of various neuroendocrine tumors, it has not been systematically studied in Merkel cell carcinoma (MCC) of the skin. The purpose of this study was to fully characterize the light microscopic, immunohistochemical, and ultrastructural features of vascular changes associated with MCC and to determine their frequency and differential diagnostic implications. Additionally, the presence of human herpesvirus 8 DNA in the lesional tissue was investigated. Of 92 studied cases of MCC, 18 cases (20%) were found to exhibit foci of prominent vascular changes which were classified into the following 6 patterns: pericyte hyperplasia, pyogenic granuloma-like, hemangioendothelioma-like, epithelioid hemangioma-like, peliosis-like, and follicular dendritic cell tumor-like pattern. In addition, Azzopardi phenomenon was observed. These changes occurred singly or in combination. Human herpesvirus 8 DNA was identified by polymerase chain reaction in none of the 18 cases. It is concluded that prominent vascular proliferations may be seen in 20% of MCC, and thereby, MCC resembles neuroendocrine tumors in other organs. When unduly prominent and encountered in a limited biopsy specimen, vascular alterations may represent a potential diagnostic pitfall, but, on the other hand, they themselves may serve as a clue to the correct diagnosis. Human herpesvirus 8 does not play a role in angiogenesis in MCC.

Syringocystadenoma papilliferum with sebaceous differentiation in an intradermal tubular apocrine component. Report of a case.

Syringocystadenoma papilliferum is a benign tumor most commonly located on the scalp or face, and it often arises within a nevus sebaceus of Jadassohn. We describe a 61-year-old man with syringocystadenoma papilliferum developing within a nevus sebaceus with sebaceous differentiation in an intradermal tubular apocrine component of the syringocystadenoma papilliferum. Although some adnexal neoplasms that develop in association with a nevus sebaceus may exhibit conjoint sebaceous, follicular, or apocrine differentiation, reflecting close embryological relations of the folliculosebaceous-apocrine unit, the feature we report on has not previously been described to the best of our knowledge.

Melanoma associated with a dysplastic nevus: report of two cases with unusual sebocyte-like melanocytes in the nevus part of the lesion.

We present two cases of melanoma arising in a dysplastic nevus that contained intradermal sebocyte-like melanocytes characterized by a scalloped dark-staining nucleus surrounded by the pale multivacuolated cytoplasm imitating sebaceous differentiation. Both patients were women, aged 49 and 55 years. Location included the back and temporal area. Microscopically, both cases had the following features in common: the melanoma in situ, which was of the superficially spreading type, was associated with a dysplastic compound nevus, in which the sebocyte-like cells were identified in the intradermal nevus part of the lesion. The sebocyte-like cells comprised a minor component but were immediately recognizable and appeared as cells with multivacuolated neoplasm and scalloped nuclei arranged in nests. Some contained melanin in the cytoplasm. They stained positively for S-100 protein and melan A but were EMA and HMB-45 negative. The conventional part of the nevi demonstrated the same phenotype, with the exception of the melanocytic nests located at the dermoepidermal junction that were HMB-45 positive. The cases are discussed in the context of the pertinent literature.

Human papillomavirus in lesions of anogenital mammary-like glands.

Long considered as ectopic breast tissue, anogenital mammary-like glands (MLGs) have recently been suggested to represent distinctive structures located in the anogenital area. We studied 16 neoplasms of anogenital MLG for human papillomavirus (HPV) DNA using INNO-line probe assay (LiPA) HPV Genotyping kit, GP5+/6+, CP(SGB), and FAP 6085-6319 primer sets. The lesions included 3 fibroadenomas, 2 adenosis tumors, 1 invasive ductal carcinoma, 1 tubulolobular carcinoma, 2 hidradenoma papilliferum with prominent cystic change rendering a cystadenoma appearance and oxyphilic metaplasia, and 7 cases of extramammary Paget disease. All 3 fibroadenomas, both adenosis tumors, both hidradenoma papilliferum, and the tubulolobular carcinoma proved negative for HPV DNA. HPV-31 was detected by LiPA in the case of invasive ductal carcinoma. In 2 of the 7 patients with extramammary Paget disease, there was HPV DNA present in the lesional tissue, typed as HPV-6 (LiPA) and a type which was closely related to HPV-21 and HPV-24 (FAP 6085-6319), whereas the remaining 5 cases tested negative. These results coupled with those obtained from literature review suggest that HPV plays no causative role in lesions of anogenital MLG.

Tubular adenoma and syringocystadenoma papilliferum: a reappraisal of their relationship. An interobserver study of a series, by a panel of dermatopathologists.

Tubular adenoma (TA) and syringocystadenoma papilliferum (SCAP) may show histopathological overlap, with some lesions having features of both neoplasms (SCAP + TA). TA has been recently suggested to represent a carcinoma. Four observers blindly assessed 67 cases of TA, SCAP, and their lookalikes (poroma, apocrine adenoma, apocrine carcinoma; all lesions focally featuring a pseudopapillary pattern), and classified the lesions into one of four categories: (1) TA, (2) SCAP, (3) SCAP + TA, and (4) others. Lesions were also classified as benign or malignant. In only 29 cases was there unanimous agreement among the four observers, who classified 22 lesions as TA, three as SCAP, and four cases as others. Of the 38 cases where there was interobserver diagnostic variation, in 30, the diagnosis varied between TA or SCAP or SCAP + TA; the remainder fell in the others category. Analysis of the factors leading to interobserver variability indicated that diagnostic problems occurred when there were any of the following: epidermal acanthosis, papillomatosis, connection of the neoplastic tubules to the overlying epidermis and/or follicular infundibula, and plasma cell infiltration. These features accounted for the morphological overlap between TA and SCAP. All observers agreed that the lesions were benign; the only apocrine carcinoma included was recognized as such by all observers. From the study, it was concluded that TA may arise in the deep dermis without any epidermal connection, or, in other cases, it may be more superficially located with or without an epidermal connection. It may be reasonably inferred that, possibly as a response to infection, there may be accompanying plasma cells and variable acanthosis and papillomatosis, such that the appearances are those of "pure" SCAP, or lesions may have features "intermediate" or overlapping between TA and SCAP.