Wayne Grayson

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.”

Pilomatrix carcinomas contain mutations in CTNNB1, the gene encoding β‐catenin

Abstract:  Mutations in β‐catenin are present in benign pilomatrixomas. β‐catenin is a downstream effector in the WNT‐signalling pathway, acting as a signal for differentiation and proliferation. Mutations in CTNNB1, the gene encoding β‐catenin, are present in a wide variety of benign and malignant neoplasms. We examined β‐catenin in a series of pilomatrix carcinomas (15 cases) by using immunohistochemistry and DNA sequencing of exon 3 from CTNNB1, and compared these to a series of benign pilomatrixomas (13 cases). All 11 pilomatrix carcinomas available for examination showed nuclear localization of β‐catenin and mutations in exon 3 similar to those demonstrated in benign pilomatrixomas. Two of 11 pilomatrix carcinomas showed significant nuclear accumulation of p53, whereas this was absent in all 13 benign pilomatrixomas. Expression of nuclear cyclin D1 was similar in both benign pilomatrixomas and pilomatrix carcinomas. Clinical follow‐up from the 15 malignant cases reported in this study and by others indicates that wide excision offers superior control of local recurrence, compared to simple excision. Immunohistochemical and molecular analysis of β‐catenin reveals that both pilomatrix carcinomas and benign pilomatrixomas harbour mutations in β‐catenin. This implies a common initial pathogenesis and is compatible with the proposition that pilomatrix carcinomas may at least on occasion arise from their benign counterparts.

Primary cutaneous apocrine carcinoma: A clinico-pathologic analysis of 24 cases

Primary cutaneous apocrine carcinoma is a rare malignancy. This study of 24 examples suggests that the prognosis is not always poor and that grading criteria devised for breast carcinoma may have utility in this group of malignancies. Furthermore, steroid receptor expression should be investigated in these tumors, particularly if a tumor is unlikely to be controlled by surgery alone.

Site and tumor type predicts DNA mismatch repair status in cutaneous sebaceous neoplasia.

Cutaneous sebaceous neoplasia is known to exhibit a high degree of DNA mismatch repair (MMR) deficiency leading to microsatellite instability and these tumors can be markers of the Muir-Torre syndrome and internal malignancy. Other tumors, such as colonic carcinoma, show tendencies toward particular histologic features and sites of involvement correlating with MMR deficiency. There are few comprehensive studies of unselected cutaneous sebaceous neoplasms. To address this gap in knowledge, we examined 94 sebaceous neoplasms from 92 patients and 17 sebaceous hyperplasia controls using immunohistochemistry for MLH1, MSH2, and MSH6. Our results indicate that MMR deficiency is significantly associated with anatomic location (more frequently in the trunk and extremities as compared with head and neck), tumor type (more often in adenoma compared with carcinoma within the head and neck region), and architecture (keratoacanthomalike). No correlation between cystic change and MMR deficiency was noted. Cutaneous sebaceous neoplasia has tendencies toward certain tumor types and anatomic distribution based on MMR status analogous to that seen in colonic carcinomas and other tumors. These may be helpful indicators for further workup for the Muir-Torre syndrome.

Primary mucinous carcinomas of the skin express TFF1, TFF3, estrogen receptor, and progesterone receptors.

Mucinous carcinoma may present at various sites, including the breast and the gastrointestinal tract. Rarely, such tumors arise within the skin. Comparatively, breast lesions are relatively common and usually associated with a good prognosis. When pure, they are typically estrogen (ER) and progesterone receptor (PR) positive and responsive to tamoxifen. The authors studied 12 mucinous carcinomas of the skin and compared the morphology with that of typical mammary lesions. The authors also evaluated for expression of estrogen receptor, progesterone receptor, and the mucus-associated peptides of the trefoil factor family (TFF), TFF1 (formerly pS2) and TFF2 (formerly SP), using immunohistochemistry. The localization of mRNAs for TFF1, TFF2, and TFF3 (formally ITF) was also studied in a subset of three tumors, using in-situ hybridization with S35 labeled riboprobes. The Grimelius stain was used to look for evidence of neuroendocrine differentiation. Eight resembled type A mucinous carcinomas of the breast, two resembled type B, and one had composite features. The 12th was a papillary neoplasm. The two type B tumors exhibited argyrophilia. All showed strong nuclear staining with the estrogen receptor antibody but a more varied pattern with antibodies to progesterone receptor and TFF1. None labeled for TFF2. The detection of TFF1 in mammalian skin is a novel finding. Cutaneous mucinous carcinoma shows strong similarities to its mammary counterpart, including expression of estrogen receptor, TFF1, and TFF3 mRNA. These observations suggest that some mucinous carcinomas of the skin might respond to antiestrogenic therapies.

Detection of integrated high risk human papillomavirus in adenoid cystic carcinoma of the uterine cervix.

AIM: To investigate the role of human papillomavirus (HPV) in adenoid cystic carcinoma of the uterine cervix. METHODS: Eleven archival, paraffin wax embedded specimens were analysed by non-isotopic in situ hybridisation (NISH) for HPV types 6, 11, 16, 18, 31, and 33 using digoxigenin labelled probes. The polymerase chain reaction (PCR) was carried out on each of the cases using consensus primers to HPV. RESULTS: A total of eight adenoid cystic carcinomas harboured the HPV genome by NISH, of which five were PCR positive. Integrated HPV 16 DNA was demonstrated in seven of the eight NISH positive cases. One adenoid cystic carcinoma showed integrated HPV 31. HPV DNA was not detected in the three remaining cases. CONCLUSIONS: Integrated high risk HPV genome, in particular type 16, is associated with this uncommon type of primary cervical cancer.

The squamous variant of eccrine porocarcinoma: a clinicopathological study of 21 cases

Aim: Squamous differentiation in eccrine porocarcinoma (EPC) is an unusual phenomenon that has rarely been reported in the literature. This study describes the clinical and pathological findings in a series of 21 cases of EPC showing extensive squamous differentiation. Methods: The H&E-stained sections, epithelial membrane antigen and carcinoembryonic antigen immunohistochemical stains were reviewed for each case. The following variables were examined: age, gender, race, site and size of the EPC. The prevalence of other cutaneous lesions and/or underlying systemic disease was also documented. Results: There was an almost equal gender distribution. Mean age was 61.5 years and the average tumour size was 46.5 mm. An inordinately large number (10/21, 48%) of EPCs occurred in black patients. The tumours were located at various sites with the extremities predominating (10/19, 53%). Seven patients developed other sun-induced skin tumours, three patients were renal transplant recipients, and two patients were HIV-positive, one of whom also suffered from albinism. Six of the 11 patients in whom follow-up was available had an adverse outcome: local recurrence developed in one patient, one patient developed nodal metastases, and one patient experienced both local recurrence and nodal metastases, and of the three patients who died of disease, two developed distant metastases. Conclusion: The findings suggest a possible role for ultraviolet radiation and chronic immunosuppression in the induction of malignant squamous differentiation in a subset of EPCs. Further reports on this histological variant of EPC are required to determine whether a pathogenetic link does indeed exist or whether these tumours simply represent a unique variant of squamous cell carcinoma with divergent acrosyringial differentiation.

The HIV-positive skin biopsy

Dermatological disorders are a frequent presenting feature of HIV infection and/or AIDS. More than 90% of HIV-infected patients will suffer from one or more skin diseases during the course of their illness. This trend is reflected in the increasing number of skin biopsies from HIV-positive patients in those parts of the world where HIV infection/AIDS is highly prevalent. Histopathologists are therefore required to possess a working knowledge of the broad spectrum of cutaneous manifestations of HIV infection. These include the range of dermatoses that are specific to HIV infection, the more common dermatoses occurring with greater frequency (or modified by) HIV infection/AIDS, the spectrum of infectious diseases (often opportunistic) caused by viruses, bacteria, fungi, protozoa and even arthropods, and neoplastic conditions such as Kaposi sarcoma and B-cell non-Hodgkin lymphoma. The risk for adverse skin reactions to certain drugs is also greatly increased. Although the introduction of highly active antiretroviral therapy has resulted in a dramatic decrease in opportunistic infections, several of these drugs may result in adverse reactions in the skin. Skin biopsies play a vital diagnostic role when different diseases present with clinically similar skin lesions. Biopsy material should always be examined carefully to exclude dual pathology. The diagnosis may need to be confirmed with histochemical and immunohistochemical stains, and/or molecular studies. Where indicated, additional biopsies for microbiological culture should always be recommended. The examination of multiple serial sections often proves invaluable. A diagnostic approach is given based on the predominant histological reaction pattern, with an emphasis on clinicopathological correlation.

Ganglioneuroblastic differentiation in a primary cutaneous malignant melanoma

&NA; Ganglioneuroblastic differentiation in malignant melanomas is an exceedingly rare event. Although there has been a single report of this occurrence in a metastatic melanoma, divergent ganglioneuroblastic differentiation has not been documented previously in a primary cutaneous lesion of melanoma. The present report describes an unusual case of invasive melanoma arising on the lower leg of a 61‐year‐old woman. The 16.9‐mm thick tumor showed extensive ganglioneuroblastic differentiation, which was confirmed both immunohistochemically and ultrastructurally. Although the prognostic significance of this observation remains uncertain, the unique case reaffirms the potential morphologic diversity of melanomas and suggests a shared histogenetic origin from a common neural crest derivative.

Pemphigus vulgaris of the uterine cervix revisited : Case report and review of the literature

Pemphigus vulgaris is an autoimmune disease characterized by acantholytic blisters and erosions involving the oral mucosa, skin, and less frequently other mucosal surfaces. Although the cytology of scrapings from the cutaneous and oral lesions has been well‐documented, there are relatively few reports in the literature of the cytologic appearance of pemphigus on cervicovaginal smears. This report documents a case of pemphigus involving the cervix, in which the diagnosis was not known at the time of the cervical smear and biopsy. The cytologic features of this case and those in the literature are described in detail, highlighting the necessity of awareness of the disease and its presentation on cervicovaginal smears, in preventing an overdiagnosis of neoplasia. Diagn. Cytopathol. 2000;22:304–307.