Subcutaneous panniculitis-like T-cell lymphoma in a 14-year-old female homozygous for HAVCR2 mutation.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma preferentially involving subcutis. A link between patients with SPTCL and HAVCR2 mutations has recently been discovered. We present a 14-year-old girl of Chinese heritage who was diagnosed with SPTCL in the context of homozygous HAVCR2 status for c.245A>G p. (Tyr82Cys) and achieved complete remission after treatment with cyclosporin and steroids. Dermatologists should be aware of the diagnostic, management and familial genetic counselling utility of HAVCR2 for investigating and managing patients with SPTCL.

Complete remission of stage IV erythrodermic mycosis fungoides with large cell transformation through combination of pralatrexate and romidepsin followed by allogeneic hematopoietic stem cell transplantation.

We report the case of a 59-year-old woman with stage IV erythrodermic mycosis fungoides (MF) and large cell transformation who, despite failing multiple previous treatments, achieved complete remission through a combination of pralatrexate and romidepsin followed by allogeneic hematopoietic stem cell transplantation (alloSCT). Further studies are needed in focussing on this combined regimen in treating cutaneous T-cell lymphoma (CTCL) and its efficacy as a bridging regimen in facilitating successful alloSCT.

Sebaceous Neoplasms With Rippled, Labyrinthine/Sinusoidal, Petaloid, and Carcinoid-Like Patterns: A Study of 57 Cases Validating Their Occurrence as a Morphological Spectrum and Showing No Significant Association With Muir-Torre Syndrome or DNA Mismatch Repair Protein Deficiency.

Sebaceous neoplasms with an organoid pattern (rippled, labyrinthine/sinusoidal, carcinoid-like, and petaloid) are rare. Previous studies suggested that the above patterns likely represent variations along a morphological continuum. The objectives of this study were to (1) validate this proposition by studying a large number of cases, (2) determine whether there are specific associations with clinical features, (3) establish their frequency, and (4) determine whether they have any association with Muir-Torre syndrome. Fifty-seven sebaceous neoplasms (54 sebaceomas and 3 sebaceous carcinomas) with organoid growth patterns were studied. These occurred in 36 men and 18 women (sex unknown in 3), with ages at diagnosis ranging from 22 to 89 years (mean, 63 years). All patients presented with a solitary nodule (mean size, 11 mm) on the head and neck area. Of the 57 tumors, 24 manifested a single growth pattern, 23 had a combination of 2 patterns, and 10 a combination of 3 patterns, indicating that these patterns are part of a morphological continuum of changes. The carcinoid-like pattern was the most frequent in the "monopatterned" neoplasms (13 cases), whereas the labyrinthine/sinusoidal pattern comprised most of the "polypatterned" lesions, in which various combinations occurred. Immunohistochemically, mismatch repair protein deficiency was detected in 3 of the 22 cases studied, whereas 5 of the 33 patients with available follow-up had an internal malignancy/premalignancy. In conclusion, sebaceous neoplasms with organoid growth patterns are predominantly sebaceomas having a predilection for the scalp, occurring as solitary lesions in elderly patients (male to female ratio of 2:1). Such patterns are expected to be found in a quarter of sebaceomas. In most cases, more than one of the organoid patterns is present. These lesions do not appear to be associated with internal malignancy or mismatch repair deficiency in most cases. However, confirmation of the absence of any significant association with Muir-Torre syndrome syndrome will require genetic studies.

Anogenital Mammary-Like Glands: A Study of Their Normal Histology With Emphasis on Glandular Depth, Presence of Columnar Epithelial Cells, and Distribution of Elastic Fibers.

The normal histology of anogenital mammary-like glands (AGMLG) has been studied previously, but some aspects, including glandular depth, presence of columnar epithelium resembling columnar cell change/hyperplasia as defined in mammary pathology, and distribution of elastic fibers, have not been previously investigated. To address these issues, we studied 148 AGMLG identified in 133 paraffin blocks sampled from 64 vulvar wide excision or vulvectomy specimens (64 patients, various indications for surgery). The depth of AGMLG ranged from 0.64 to 3.9 mm. Epithelial columnar cell change was noted in 33.1% of all AGMLG, whereas columnar cell hyperplasia was detected in 10.1%. Occasionally, combinations of cuboidal epithelium and columnar cell change were seen within 1 histological section. Of 22 specimens stained for elastic fibers, in only 6 (27.3%) cases were elastic fibers found around glands. Periductal elastic fibers were demonstrated around 3 of the only 5 ducts, which were available for analysis in slides stained for elastic fibers. The depth of AGMLG should be taken into account when planning topical and surgical therapies for lesions derived or evolving from AGMLG. Alterations identical to columnar cell change may represent a normal variation of AGMLG.

Molecular alterations in lesions of anogenital mammary-like glands and their mammary counterparts including hidradenoma papilliferum, intraductal papilloma, fibroadenoma and phyllodes tumor.

Lesions affecting anogenital mammary-like glands (AGMLG) are histopathologically very similar to those seen in the breast but whether this morphological similarity is also reflected at the genetic level is unknown. To compare the underlying molecular mechanisms in lesions of AGMLG and their mammary counterparts, we analyzed the mutational profile of 16 anogenital neoplasms including 5 hidradenomas papilliferum (HP), 1 lesion with features of HP and fibroadenoma (FA), 7 FA, 3 phyllodes tumors (PhT)) and 18 analogous breast lesions (6 intraductal papillomas (IDP), 9 FA, and 3 PhT) by high-coverage next generation sequencing (NGS) using a panel comprising 50 cancer-related genes. Additionally, all cases were analyzed for the presence of a mutation in the MED12 gene. All detected mutations with allele frequencies over 20% were independently validated by Sanger sequencing (concordance: 100%). Mutations in PIK3CA, AKT1, MET, ABL1 and TP53 genes were found in lesions of AGMLG and also their mammary counterparts. The PI3K-AKT cascade plays a role in tumors arising at both sites. It appears that some histopathologically similar anogenital and breast lesions develop along similar molecular pathways.

Hidradenoma Papilliferum: A Clinicopathologic Study of 264 Tumors From 261 Patients, With Emphasis on Mammary-Type Alterations.

Hidradenoma papilliferum (HP), also known as papillary hidradenoma, is the most common benign lesion of the female anogenital area derived from anogenital mammary-like glands (AGMLG). HP can be viewed conceptually as the cutaneous counterpart of mammary intraductal papilloma. The authors have studied 264 cases of HP, detailing various changes in the tumor and adjacent AGMLG, with emphasis on mammary-type alterations. In many HP, the authors noticed changes typical for benign breast lesions, such as sclerosing adenosis-like changes, usual, and atypical ductal hyperplasia. Almost in a third of cases, remnants of AGMLG adjacent to the lesion were evident, manifesting columnar changes reminiscent of those seen in breast lesions. This study shows that the histopathological changes in HP run a broad spectrum comparable with that in the mammary counterpart and benign breast disease.

Depth and Patterns of Adnexal Involvement in Primary Extramammary (Anogenital) Paget Disease: A Study of 178 Lesions From 146 Patients.

Extramammary Paget disease (EMPD) is a rare neoplasm usually presenting in the anogenital area, most commonly in the vulva. Adnexal involvement in primary EMPD is a very common feature and serves as a pathway for carcinoma to spread into deeper tissue. The depth of carcinomatous spread along the appendages and the patterns of adnexal involvement were studied in 178 lesions from 146 patients with primary EMPD. Hair follicles and eccrine ducts were the adnexa most commonly affected by carcinoma cells. The maximal depth of involvement was 3.6 mm in this series. When planning topical therapy or developing novel local treatment modalities for EMPD, this potential for significant deep spread along adnexa should be taken into account.

Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome.

Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). Although RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the preexisting CLL, the mechanisms leading to RS have not been clarified. To better understand the pathogenesis of RS, we analyzed a series of cases including 59 RS, 28 CLL phase of RS, 315 CLL, and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell-cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL phase, being present in approximately one half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. Although RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL phase preceding RS had not a generalized increase in genomic complexity compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions.

Population-based screening for Lynch syndrome in Western Australia.

We showed earlier that routine screening for microsatellite instability (MSI) and loss of mismatch repair (MMR) protein expression in colorectal cancer (CRC) led to the identification of previously unrecognized cases of Lynch syndrome (LS). We report here the results of screening for LS in Western Australia (WA) during 1994-2012. Immunohistochemistry (IHC) for loss of MMR protein expression was performed in routine pathology laboratories, while MSI was detected in a reference molecular pathology laboratory. Information on germline mutations in MMR genes was obtained from the state's single familial cancer registry. Prior to the introduction of routine laboratory-based screening, an average of 2-3 cases of LS were diagnosed each year amongst WA CRC patients. Following the implementation of IHC and/or MSI screening for all younger (<60 years) CRC patients, this has increased to an average of 8 LS cases diagnosed annually. Based on our experience in WA, we propose three key elements for successful population-based screening of LS. First, for all younger CRC patients, reflex IHC testing should be carried out in accredited pathology services with ongoing quality control. Second, a state- or region-wide reference laboratory for MSI testing should be established to confirm abnormal or suspicious IHC test results and to exclude sporadic cases by carrying out BRAF mutation or MLH1 methylation testing. Finally, a state or regional LS coordinator is essential to ensure that all appropriate cases identified by laboratory testing are referred to and attend a Familial Cancer Clinic for follow-up and germline testing.

Extramedullary hematopoiesis associated with organizing peritoneal hemorrhage: a report of 5 cases in patients presenting with primary gynecologic disorders.

Extramedullary hematopoiesis (EMH) usually occurs in patients with severe anemia or myelofibrosis, and involvement of the serous cavities is uncommon. A total of 5 cases of peritoneal EMH are presented in patients presenting with primary gynecologic pathology including endometrial adenosarcoma (n=2), ovarian leiomyosarcoma, and ovarian endometrioid adenocarcinoma (each n=1), all of which were associated with peritoneal metastases; the remaining patient had a hemorrhagic benign ovarian cyst. All cases were associated with organizing peritoneal hemorrhage, and EMH was localized to the reactive granulation tissue. EMH was not identified within the tumor tissue in the 4 neoplastic cases. Erythroid precursors were present in all cases and granulocytic precursors and megakaryocytes were identified in two and three cases, respectively. There was no evidence of EMH in the corresponding peritoneal fluid cytology preparations examined in 4 cases. None of the patients had a significant hematological abnormality at the time of presentation or during a mean follow-up period of 35 mo (range, 2-66 mo). The mechanism of peritoneal EMH in these cases is uncertain but most likely related to tissue hemorrhage and repair as described in other sites such as dura, myocardium, and synovium. Pathologists should be aware that EMH may involve the peritoneum to avoid misinterpretation of the findings, particularly in small biopsy or cytology samples.

Aggressive and nonaggressive translocation t(6;11) renal cell carcinoma: comparative study of 6 cases and review of the literature.

UNLABELLED: t(6;11) renal cell carcinoma (RCC) has been recognized as a rare and mostly nonaggressive tumor (NAT). The criteria for distinguishing aggressive tumors (AT) from NATs are not well established. A total of 6 cases were selected for the study. Five cases of t(6;11) RCCs behaved nonaggressively, and 1 was carcinoma with aggressive behavior. The tumors were analyzed morphologically using immunohistochemistry and by molecular-genetic methods. The specimen of aggressive t(6;11) RCC was from a 77-year-old woman who died of the disease 2.5 months after diagnosis. The specimens of nonaggressive t(6;11) RCCs were from 3 women and 2 men whose ages range between 15 and 54 years. Follow-up was available in all cases (2.5 months-8 years). The tumor size ranged from 3 to 14 cm in nonaggressive t(6;11) RCC. In the aggressive carcinoma, the tumor size was 12 cm. All tumors (6/6) were well circumscribed. Aggressive t(6;11) RCC was widely necrotic. Six (100%) of 6 all tumors displayed a solid/alveolar architecture with occasional tubules and pseudorosettes. Pseudopapillary formations lined by bizarre polymorphic cells were found focally in the aggressive t(6;11) RCC case. Mitoses, though rare, were found as well. All cases (AT and NAT) were positive for HMB-45, Melan-A, Cathepsin K, and cytokeratins. CD117 positivity was seen in 4 of 5 NATs, as well as in the primary and metastatic lesions of the AT. mTOR was positive in 2 of 5 NATs and vimentin in 4 of 5 NATs. Vimentin was negative in the primary lesion of the AT, as well as in the metastasis found in the adrenal gland. Translocation t(6;11)(Alpha-TFEB) or TFEB break was detected in 4 of 5 NATs and in the AT case. Aggressive tumor showed amplification of TFEB locus. Losses of part of chromosome 1 and chromosome 22 were found in 1 of 5 NATs and in the AT. CONCLUSIONS: (1) Aggressive t(6;11) RCCs generally occur in the older population in comparison with their indolent counterparts. (2) In regard to the histologic findings in ATs, 3 of 5 so far published cases were morphologically not typical for t(6;11) RCC. Of the 3 cases, 2 cases lacked a small cell component and 1 closely mimicked clear cell-type RCC. (3) Necroses were only present in aggressive t(6;11) RCC. (4) Amplification of TFEB locus was also found only in the aggressive t(6;11) RCC.

Rosai-Dorfman disease presenting as choroidal melanoma: a case report and review of the literature.

BACKGROUND: Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare non-malignant proliferation of histiocytes of unknown aetiology. It was first recognised as a distinct clinicopathologic entity in 1969, and is classified as an idiopathic non-Langerhans cell histiocytosis. The disease process is usually self-limiting and often involves lymph nodes, but extranodal involvement is well-described and any anatomic site can be involved. METHODS: We describe a unique case of a 40-year-old male who presented with a fundus mass diagnosed clinically as choroidal melanoma. The tumour showed rapid growth. The patient developed a total retinal detachment and underwent enucleation. The globe contained a choroidal tumour with histologic and immunophenotypic features characteristic of RDD. The literature of ocular Rosai-Dorfman disease was reviewed. RESULTS: This is the first case in the English literature of intraocular choroidal RDD, mimicking choroidal melanoma. CONCLUSIONS: Rosai-Dorfman disease can present as a mass-producing lesion in the choroid and may mimic other choroidal tumours. The case emphasises the need to consider diagnostic biopsy prior to definitive treatment of choroidal tumours.

A clinicopathologic and molecular biologic study of patients presenting with few adnexal tumors (two to four) from the morphological spectrum of Brooke-Spiegler syndrome.

We report 11 individuals, each presenting with few (2-4) adnexal neoplasms histologically confirmed as belonging to the spectrum of lesions typical for Brooke-Spiegler syndrome (BSS) and/or multiple familial trichoepitheliomas. These include spiradenoma, cylindroma, spiradenocylindroma, and trichoblastoma variants. Our objective was to clarify whether this is merely a sporadic, albeit unusual, occurrence of multiple neoplasms in these patients or whether they are related to BSS and its phenotypic variant, multiple familial trichoepithelioma. Six patients presented with 2 neoplasms, 4 had 3 lesions and the last had 4 lesions. In none was there any family history of similar lesions. The 28 neoplasms consisted of 7 spiradenomas, 6 cylindromas, 5 spiradenocylindromas, and 11 trichoblastomas (6 trichoepitheliomas and 5 with mixed patterns). In 1 patient only with 2 spiradenomas, both tumors harbored identical CYLD sequence alterations (c.1112C>A/S371X) in the CYLD gene and both showed loss of heterozygosity on chromosome 16q. The remaining cases yielded neither germ line nor somatic alterations in CYLD. It is concluded that the presentation with few (2-4) cylindromas, spiradenomas, spiradenocylindromas, and trichoepitheliomas is a sporadic occurrence, and that these patients do not have any relationship to BSS.

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.

Cutaneous intravascular anaplastic large T-cell lymphoma: a case report and review of the literature.

Intravascular lymphoma (IVL) is a rare subtype of extranodal lymphoma. In the 2008 WHO classification of tumors of the hematopoietic and lymphoid tissues intravascular large B-cell lymphoma is included as a distinct entity. IVL of T-cell type is not included as a diagnostic category and is only mentioned in passing by Nakamura et al. as "a different entity" in their discussion of intravascular large B-cell lymphoma. T-cell IVL is rare, the majority of cases being of natural killer/T-cell phenotype. Exceptionally rare is primary cutaneous intravascular anaplastic large T-cell lymphoma. We present such a case in an otherwise well 39-year-old female having disease limited to the skin established after detailed staging investigations. This is only the third such case described in the literature. We report the clinicopathological features of this case and also review previously documented cases of cutaneous intravascular anaplastic large cell lymphoma.

Lesions of anogenital mammary-like glands: an update.

Long considered to be ectopic breast tissue representing the caudal remnants of the milk ridges, anogenital mammary-like glands are nowadays thought to represent a normal constituent of the anogenital area. Lesions involving these glands, benign or malignant, epithelial or stromal manifest a striking similarity to their mammary counterparts. This review addresses the recent literature on lesions of anogenital mammary-like glands and our personal experience with various lesions related to these structures. Discussed are the normal anatomy and histology of these glands as well as the clinical presentation, histopathological and immunohistochemical features, molecular biological aspects, and differential diagnosis of various lesions involving anogenital mammary-like glands, including lactating adenoma, hidradenoma papilliferum, hidradenocarcinoma papilliferum, fibroadenomas, phyllodes tumor, pseudoangiomatous stromal hyperplasia, extramammary Paget disease, and other carcinomas. In addition, "nonspecific" epithelial or stromal changes some of which can be likened to similar changes occurring in a range of benign breast disease, including sclerosing adenosis, columnar cell lesions, ductal lesions and various metaplastic changes affecting epithelium and myoepithelium are discussed. Although lesions of anogenital mammary-like glands are often discussed in many dermatopathology textbooks in the context of cutaneous adnexal neoplasms we advocate that the best approach to the diagnosis of these lesions is to relate them to analogous well recognized lesions occurring in the breast, that is, through the eyes of a breast pathologist. This will enable their recognition, precise classification and should introduce greater uniformity in how they are reported in the literature so that more meaningful clinicopathological comparisons and correlations may be made.

Cutaneous adenolipoma: extending the spectrum of changes in the lipomatous and epithelial components.

Adenolipoma refers to a variant of a lipoma with entrapped eccrine or, rarely, apocrine units. We present 5 cases of cutaneous adenolipoma to demonstrate the spectrum of changes in the lipomatous and epithelial components. The cases include 3 lesions having a conventional lipomatous element and 1 with a spindle cell lipomatous component, each additionally featuring entrapped minimally altered eccrine units. In the remaining case, the epithelial component manifested a combination of hyperplastic and metaplastic changes (clear cell and squamous metaplasia) and unusually altered polarity of luminal cells with expression of myoepithelial cell markers on the luminal cells while focal absence of basal/myoepithelial cell in the corresponding area as evident microscopically and immunohistochemically.

Cutaneous type adnexal tumors outside the skin.

Cutaneous adnexal neoplasms are complex lesions, including benign and malignant neoplasms in addition to malformations and hamartomas. They show one or several features of differentiation along follicular, sebaceous, apocrine, and eccrine lines. Rarely, cutaneous adnexal neoplasms or their mimics may arise outside the skin. In some organs, such as the parotid gland, a number of tumors comprise well-established entities, whereas in the majority of cases an extracutaneous occurrence of cutaneous-type adnexal lesions is a rare and often diagnostically challenging finding. This review discusses various authentic cutaneous-type adnexal neoplasms or related lesions presented according to the organ involved.

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.