Frequent activating PIK3CA mutations in sporadic angiolipoma.

BACKGROUND: Angiolipoma (AL) is considered as a lipoma variant that is characterized by the combination of mature adipocytes and capillary blood vessels diffusely distributed within the tumor. With the exception of recurrent PRKD2 mutations of uncertain pathogenetic significance, the genetic abnormalities of ALs are unknown, in the absence of any of the specific chromosomal aberrations described in other lipoma variants. METHODS: Formalin-fixed and paraffin-embedded blocks of 13 conventional ALs and 5 cellular ALs from 17 individuals were retrieved and analyzed for mutations in exons 9 and 20 of PIK3CA by polymerase chain reaction and Sanger sequencing. RESULTS: Activating PIK3CA mutations were identified in 14 tumors (78%). All PIK3CA-mutated samples carried the same exon 9 mutation, c.1634A>C (p.E545A). No mutation was detected in exon 20 of PIK3CA. No significant difference between PIK3CA-mutated and wild-type samples appeared to exist based on age, gender, and location of the tumor. All 5 cellular ALs carried the p.E545A PIK3CA mutation. CONCLUSION: The high frequency of the p.E545A PIK3CA mutation in both conventional and cellular ALs suggests that activation of the PI3K/AKT pathway plays a key role in AL pathogenesis and reinforces the concept that cellular AL should be regarded as a variant of AL.

Endocrine mucin-producing sweat gland carcinoma: Clinicopathologic, immunohistochemical, and molecular analysis of 11 cases with emphasis on MYB immunoexpression.

BACKGROUND: Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare low-grade primary cutaneous sweat gland carcinoma with predilection for the periorbital skin in elderly female patients. METHODS: We describe 11 cases of EMPSGC using a broad panel of immunohistochemical markers including BerEP4, cytokeratin 7, CAM 5.2, synaptophysin, chromogranin, cytokeratin 20, Ki67, progesterone receptor, and estrogen receptor. Calponin (1A4) and p63 were used to detect surrounding myoepithelial cells. We also examined staining with a relatively new marker, MYB. Previous studies of MYB on EMPSGC remain limited. As mucin-rich basal cell carcinoma (BCC) represents a main differential diagnosis and primary cutaneous mucinous carcinoma (PCMC) could appear synchronous with EMPSGC, these lesions were also stained for MYB. RESULTS: We found strong and homogenous nuclear MYB-expression in 10 EMPSGC cases stained for MYB. MYB staining was not performed in one case. Furthermore, PCMC and mucin-rich BCCs did not express MYB. CONCLUSION: The strong nuclear MYB-positivity in EMPSGC could be useful as a new surrogate marker, especially in mucin-poor EMPSGC cases. Additionally, the staining of PCMC revealed absent MYB-expression leading to the conclusion that EMPSGC might not represent a precursor lesion for primary cutaneous mucinous carcinoma.

Cutaneous borreliosis associated with T cell-predominant infiltrates: a diagnostic challenge.

BACKGROUND: With the exception of erythema migrans, Borrelia infection of the skin manifests much more commonly with B cell-rich infiltrates. T cell-rich lesions have rarely been described. OBJECTIVE: We report a series of 6 patients with cutaneous borreliosis presenting with T cell-predominant skin infiltrates. METHODS: We studied the clinicopathologic and molecular features of 6 patients with T cell-rich skin infiltrates. RESULTS: Half of the patients had erythematous patchy, partly annular lesions, and the other patients had features of acrodermatitis chronica atrophicans. Histopathology revealed a dense, band-like or diffuse dermal infiltrate. Apart from small, well differentiated lymphocytes, there were medium-sized lymphocytes with slight nuclear atypia and focal epidermotropism. An interstitial histiocytic component was found in 4 cases, including histiocytic pseudorosettes. Fibrosis was present in all cases but varied in severity and distribution. In 5 patients, borrelia DNA was detected in lesional tissue using polymerase chain reaction studies. No monoclonal rearrangement of T-cell receptor gamma genes was found. LIMITATIONS: This retrospective study was limited by the small number of patients. CONCLUSION: In addition to unusual clinical presentation, cutaneous borreliosis can histopathologically manifest with a T cell-rich infiltrate mimicking cutaneous T-cell lymphoma. Awareness of this clinicopathologic constellation is important to prevent underrecognition of this rare and unusual presentation representing a Borrelia-associated T-cell pseudolymphoma.

Cutaneous PEComa does not harbour TFE3 gene fusions: immunohistochemical and molecular study of 17 cases.

AIMS: The family of perivascular epithelioid cell tumours (PEComas) comprises a related group of mesenchymal tumours of uncertain origin that show both smooth muscle and melanocytic differentiation markers. TFE3 nuclear immunoreactivity may be viewed as a supporting marker, as it has been found in a subset of visceral PEComas. We immunohistochemically analysed 17 cases of primary cutaneous PEComas for TFE3, and five of them also for SOX-10, and also analysed them by FISH for TFE3 rearrangement. METHODS AND RESULTS: PEComas presented as skin-coloured tumours, in 12 women and five men, with a median age of 49.5 years. Tumours showed either a mixed clear cell-epithelioid cell pattern or a monomorphous clear cell pattern. None of the primary cutaneous PEComas showed detectable TFE3 or SOX-10 positivity. FISH assay for TFE3 rearrangement yielded negative results in all of the tested tumours. CONCLUSIONS: Cutaneous PEComas are mostly composed of clear cells, and, unlike a subset of visceral and deep-seated PEComas, cutaneous PEComas consistently lack TFE3 expression. Owing to the lack of SOX-10 expression, a neural crest origin could not be shown.

Primary cutaneous anaplastic large cell lymphoma with angioinvasive features and cytotoxic phenotype: a rare lymphoma variant within the spectrum of CD30+ lymphoproliferative disorders.

BACKGROUND: Primary cutaneous anaplastic large cell lymphoma (PCALCL) presents with solitary or grouped exophytic tumors and cohesive infiltrates of large CD30+ T cells. OBJECTIVE: To report an angioinvasive variant of PCALCL. METHODS: Retrospective analysis of clinicopathological features of this variant. RESULTS: The group consisted of six patients (median age 46 years) with a solitary flat necrotic lesion preferentially located on the upper extremity. Histologically, there were angiocentric and angiodestructive infiltrates of medium-sized to large pleomorphic and anaplastic cells co-expressing CD30 and CD8. Five patients were treated with surgical excision and one patient with radiotherapy. A relapse was observed in one patient with spontaneous regression of the lesions suggesting a link to the recently described angioinvasive lymphomatoid papulosis (type E). All patients were alive without evidence of disease after a median follow-up of 31 months (range 15-96), indicating an excellent prognosis. CONCLUSIONS: The angioinvasive variant of PCALCL is rare but distinctive and prone to misinterpretation as aggressive lymphoma due to its histological features.

Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests.

Cutaneous melanomas are characterized by a range of histological appearances, and several morphological variants have been described. In this study, we report a variant of superficial spreading melanoma that is characterized by large, irregular junctional melanocytic nests. The junctional nests varied in shape and size, showed focal tendency to confluence, and were often surrounded by a cuff of epidermal keratinocytes. The melanocytes comprising the nests showed variable cytological atypia. In most of the cases, scant intraepidermal or junctional single melanocytes were seen, and other well-documented diagnostic criteria for melanoma were lacking, and as a result, histological recognition of these tumors as melanoma was difficult. Some cases were associated with an invasive dermal component or showed evidence of sun damage. To provide supporting evidence for malignancy, we analyzed these tumors for genomic aberrations. Using array comparative genomic hybridization (aCGH), we identified multiple genomic aberrations in all analyzed cases. A similar pattern of genomic aberrations was seen in a control group of bona fide superficial spreading melanomas, suggesting that these 'melanomas composed exclusively or predominantly of large nests' are indeed variants of superficial spreading melanoma. Fluorescence in-situ hybridization (FISH) was positive in 40% of the cases. However, using aCGH, the FISH-negative cases showed multiple genomic aberrations in regions that are not covered by FISH. The low sensitivity of the FISH test can be explained by the fact that FISH only evaluates four genomic loci for aberrations, whereas aCGH surveys the entire genome. In summary, we present histological and molecular genetic evidence for a morphological variant of superficial spreading melanoma. Awareness of the histological features will aid in their correct diagnosis as melanoma, and in difficult cases, judicious application of ancillary tests such as aCGH (rather than FISH) will assist accurate diagnosis.

Unilesional follicular mycosis fungoides: report of two cases with progression to tumor stage and review of the literature.

Mycosis fungoides (MF) is the most common type of cutaneous lymphoma and has protean clinicopathological manifestations. Follicular or folliculotropic MF (FMF) is a rare variant, which histopathologically is characterized by pronounced folliculotropism of neoplastic T cells, with or without follicular mucinosis, and clinically by an impaired prognosis compared to classic MF. In contrast, unilesional MF is a very rare variant with an excellent prognosis, with a single case of large-cell transformation reported to date. The combination of folliculotropic and unilesional MF is very unusual, with only two cases reported to date. Here we report two patients with unilesional folliculotropic MF with progression to tumor stage in both patients. To the best of our knowledge, this is the first report on the disease evolution with large-cell transformation and progression of unilesional FMF. Complete remission was achieved by local radiation therapy in both patients. The differential diagnoses, classification and implications for the treatment of unilesional FMF as well as the pertinent literature are discussed.

A proposal for improving multicolor FISH sensitivity in the diagnosis of malignant melanoma using new combined criteria.

Fluorescence in situ hybridization (FISH) for the diagnosis of melanoma makes use of specific fluorescent probes to detect selected chromosomal alterations on paraffin-embedded tissue samples. To date, interpretation of FISH data has been based on numerical values generated by 2 different computational algorithms that of Abbott and that of Gerami. To further evaluate the value of FISH in the diagnosis of malignant melanoma, we selected 163 clinically and histologically unequivocal cases of malignant melanoma in a cohort of 575 melanocytic tumors and analyzed FISH data using the criteria of Abbott, Gerami, and new combined criteria. Depending on the used criteria, FISH was positive in the unequivocal malignant melanoma in 69.3% (113/163) of cases using the Abbott criteria, 74.2% (121/163) of cases using the Gerami criteria, and 82.2% (134/163) of cases using the combined criteria of Abbott and Gerami. Although use of all 3 criteria was associated with 100% FISH negativity in a cohort of 30 unequivocal benign melanocytic nevi, use of the combined criteria revealed more FISH-positive cases in ambiguous benign melanocytic lesions than the criteria of Abbott or Gerami alone: Abbott, 125 of 367; Gerami, 146 of 367; combined, 161 of 367. Furthermore, we show that 66% (8/12) of FISH-negative cases of unequivocal melanoma are positive when analyzed by array comparative genomic hybridization (aCGH), demonstrating that false-negative results remain despite the usage of the combined criteria for evaluation of FISH data. In these 8 FISH-negative aCGH-positive cases, copy number alterations were often located on chromosomes 9p, a chromosomal locus that is not targeted by the FISH probes currently used. In conclusion, the existing criteria for the evaluation of multicolor melanocytic FISH are limited by a nonnegligeable rate of false negativity that can be reduced by using newly proposed combined criteria but at the cost of increased detection of FISH positivity in ambiguous benign melanocytic lesions.

EWSR1 gene rearrangement occurs in a subset of cutaneous myoepithelial tumors: a study of 18 cases.

Cutaneous myoepithelial tumors form a clinicopathological spectrum ranging from mixed tumor to myoepithelioma and myoepithelial carcinoma. Recently, EWSR1 rearrangement has been described in a subset of soft tissue myoepithelial tumors, whereas the cutaneous counterparts showed this aberration in a minority of cases. This raises the question whether cutaneous myoepithelial tumors have comparable genetic alterations. We examined 18 cases of cutaneous myoepithelial tumors arising in 7 female and 11 male patients (age range, 34-86 years; mean, 58 years). Eight mixed tumors occurred at the head, and one at the scrotum. Six myoepitheliomas arose at the extremities, and one case each at the back and head. One myoepithelial carcinoma occurred at the cheek. The tumor size ranged from 0.3 to 1.7 cm (mean, 1.0 cm). All mixed tumors and three myoepitheliomas were limited to the dermis. Four myoepitheliomas and the myoepithelial carcinoma involved the subcutis. Mixed tumors and myoepitheliomas were composed of myoepithelial cells with a variable cytomorphology, architecture and stromal background. Ductal structures were seen by definition in mixed tumors. The myoepithelial carcinoma represented an infiltrative dermal neoplasm consisting of atypical spindle cells. Immunohistochemically, all cases tested were positive for EMA and calponin, whereas S100, CK, ASMA and GFAP were expressed in 90%, 80%, 78% and 50% of the cases tested, respectively. By fluorescent in situ hybridization analysis, 7 out of 16 cases (44%) exhibited EWSR1 rearrangement. Four of them were mixed tumors, two were myoepitheliomas and one was a myoepithelial carcinoma, confirming that these lesions represent a spectrum of dermal myoepithelial tumors. Follow-up information, available for five patients (including the patient with a myoepithelial carcinoma), revealed no evidence of disease in all cases (range, 6-72 months). Our study provides a genetic relationship of myoepithelial tumors of the skin with their counterparts in soft tissue, bone and visceral localization by sharing EWSR1 rearrangement.

Clonality in sarcoidosis, granuloma annulare, and granulomatous mycosis fungoides.

The histological discrimination of granulomatous cutaneous T-cell lymphomas (CTCLs) from reactive granulomatous disorders such as sarcoidosis and granuloma annulare (GA) may be difficult due to overlapping histological features. We analyzed the T-cell receptor gene rearrangement in sarcoidosis and GA to investigate the value of the detection of clonal T cells as an adjunctive diagnostic marker in the differentiation between sarcoidosis and GA versus granulomatous CTCLs. Rearrangement of T-cell receptor γ genes was examined by the use of automated high-resolution polymerase chain reaction fragment analysis in 35 cases of sarcoidosis and 15 cases of GA and compared with a series of 19 cases of granulomatous CTCLs. A monoclonal T-cell population was found in none of the cases of sarcoidosis and in 2 of 15 cases of GA (13%). In granulomatous CTCLs, a neoplastic T-cell clone was detected in 94%. Presence of clonal T cells argues in favour of a granulomatous CTCL, while a polyclonal T-cell population makes the presence of a sarcoidosis or a GA more likely. The analysis of T-cell clonality is a useful diagnostic adjunct in the differentiation between sarcoidosis and GA from granulomatous CTCLs.

Well-differentiated spindle cell liposarcoma ('atypical spindle cell lipomatous tumor') does not belong to the spectrum of atypical lipomatous tumor but has a close relationship to spindle cell lipoma: clinicopathologic, immunohistochemical, and molecular analysis of six cases.

Well-differentiated spindle cell liposarcoma represents a rare atypical/low-grade malignant lipogenic neoplasm that has been regarded as a variant of atypical lipomatous tumor. However, well-differentiated spindle cell liposarcoma tends to occur in subcutaneous tissue of the extremities, the trunk, and the head and neck region, contains slightly atypical spindled tumor cells often staining positively for CD34, and lacks an amplification of MDM2 and/or CDK4 in most of the cases analyzed. We studied a series of well-differentiated spindle cell liposarcomas arising in two female and four male patients (age of the patients ranged from 59 to 85 years). The neoplasms arose on the shoulder, the chest wall, the thigh, the lower leg, the back of the hand, and in paratesticular location. The size of the neoplasms ranged from 1.5 to 10 cm (mean: 6.0 cm). All neoplasms were completely excised. The neoplasms were confined to the subcutis in three cases, and in three cases, an infiltration of skeletal muscle was seen. Histologically, the variably cellular neoplasms were composed of atypical lipogenic cells showing variations in size and shape, and spindled tumor cells with slightly enlarged, often hyperchromatic nuclei. Multivacuolated lipoblasts were present in three neoplasms. Focal myxoid stromal changes were seen in three cases. Immunohistochemically, CD34 was at least focally positive in all cases, whereas scattered tumor cells only showed a nuclear expression of MDM2 in two neoplasms. FISH analysis revealed a deletion of the Rb-1 gene in all six cases, whereas no MDM2/CDK4 amplification was identified in all cases tested. Follow-up information was available in four cases (range from 4 to 24 months), and revealed a local recurrence in one case. Although well-differentiated spindle cell liposarcoma and atypical lipomatous tumor behave clinically similar, it can be speculated on the basis of clinicopathologic and molecular findings that well-differentiated spindle cell liposarcoma may constitute an independent entity rather than a morphologic variant of atypical lipomatous tumor, and may represent the atypical/low-grade counterpart of spindle cell lipoma.

Classifying ambiguous melanocytic lesions with FISH and correlation with clinical long-term follow up.

Recently, initial studies describing the use of multicolor fluorescence in situ hybridization (FISH) for classifying melanocytic skin lesions have been published demonstrating a high sensitivity and specificity in discriminating melanomas from nevi. However, the majority of these studies included neither histologically ambiguous lesions nor a clinical long-term follow up. This study was undertaken to validate a special multicolor FISH test in histologically ambiguous melanocytic skin lesions with known clinical long-term follow up. FISH was scored by three independent pathologists in a series of 22 melanocytic skin lesions, including 12 ambiguous cases using four probes targeting chromosome 6p25, centromere 6, 6q23, and 11q13. The FISH results were compared with array comparative genomic hybridization data and correlated to the clinical long-term follow up (mean: 65 months). Pair-wise comparison between the interpretations of the observers showed a moderate to substantial agreement (kappa 0.47-0.61). Comparing the FISH results with the clinical behavior reached an overall sensitivity of 60% and a specificity of 50% (chi(2)=0.25; P=0.61) for later development of metastases. Comparison of array comparative genomic hybridization data with FISH analyses did not yield significant results but array comparative genomic hybridization data demonstrated that melanocytic skin lesions with the development of metastases showed significantly more chromosomal aberrations (P<0.01) compared with melanocytic skin lesions without the development of metastases. The FISH technique with its present composition of locus-specific probes for RREB1/MYB and CCND1 did not achieve a clinically useful sensitivity and specificity. However, a reassessment of the probes and better standardization of the method may lead to a valuable diagnostic tool.

Molecular diagnostics of parapox virus infections.

BACKGROUND: The diagnosis of parapox virus infections relies primarily on a history of contact with infected animals. The clinical presentation is usually a non-specific necrotic ulcer. The histology may also be non-specific, especially with older lesions. Negative-staining electron microscopy (EM) is a fast and reliable diagnostic tool, but is not widely available. Serological tests and the time-consuming viral culture are also rarely used in Europe. PATIENTS AND METHODS: The diagnostic procedure in two patients with ecthyma contagiosum and milker's nodule using polymerase chain reaction specific for orthopox, parapox and Orf virus is explained. Diagnostics included bacterial culture, viral culture, histology and EM. In addition to these, a polymerase chain reaction (PCR) was performed in both cases. RESULTS: The patient with ecthyma contagiosum was negative for ortho-, parapox-, and orf-virus on PCR, whereas the patient with milker's nodule had a PCR positive for parapoxvirus. CONCLUSIONS: PCR is a simple, fast, and standardized method of diagnosis that can distinguish between the subgroups of parapoxviruses. A diagnosis can be made even in cases of ambiguous history or unspecific clinical presentation. The method is limited by the necessity to sample native material or to use neutrally buffered formalin in case of PCR from paraffin material.

Mutations in exon 3 of the CTNNB1 gene (beta-catenin gene) in cutaneous adnexal tumors.

Previous studies suggested that mutant beta-catenin gene cells in cutaneous adnexal tumors with matrical differentiation contribute to their tumorigenesis. Except for pilomatricoma and pilomatrical carcinoma, only a handful of other cutaneous adnexal tumor types have been studied. DNA was extracted from 86 lesions including 17 proliferating tricholemmal and trichilemmal tumors, 15 trichoblastomas, 7 trichoadenomas, 4 pilomatricomas, 1 pilomatrical carcinoma, 4 basal cell carcinomas (BCCs) with shadow cells, 2 trichofolliculomas, 3 BCCs with sebaceous differentiation, 9 sebaceous adenomas, 6 sebaceomas, 14 sebaceous carcinomas (both ocular and extraocular forms), 2 gigantic horns, and 2 apocrine mixed tumors with shadow cells and subjected to polymerase chain reaction with newly designed primers encompassing glycogen synthase kinase-3beta phosphorylation sites of the CTNNB1 gene. Also, 3 craniopharyngiomas were studied. Sequenced polymerase chain reaction products for possible beta-catenin gene mutations showed a total of 8 alterations. These included 5 different point mutations, 3 of them identified in 2 different tumors: S23N (cribriform trichoblastoma), D32Y (pilomatricoma and craniopharyngioma), G34R (pilomatrical carcinoma and craniopharyngioma), S37F (2 BCCs with shadow cell differentiation), and G34V (craniopharyngioma). This study broadens the list of cutaneous adnexal tumors harboring CTNNB1 mutations and extends the listing of the mutations occurring in these neoplasms.

Mixed-type liposarcoma: clinicopathological, immunohistochemical, and molecular analysis of a case arising in deep soft tissues of the lower extremity.

A rare case of mixed-type liposarcoma arising in deep soft tissue of the right thigh of a 45-year-old female patient is reported. The neoplasm was completely excised and was composed of an irregular admixture of areas of atypical lipomatous tumor/well-differentiated liposarcoma of the lipoma-like subtype with areas of myxoid/round cell liposarcoma. An amplification of the MDM2 and CDK4 genes respectively in the atypical lipomatous tumor/well-differentiated liposarcoma areas was detected by fluorescence in situ hybridization (FISH) analysis, and translocations of the CHOP and FUS genes were detected by FISH analysis in the myxoid/round cell liposarcoma areas.

A Case of Large Meningeal Epithelioid Hemangioendothelioma With WWTR1-CAMTA1 Gene Rearrangement and Slow Growth Over 15 Years.

Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm predominantly occurring in the soft tissue. A majority of EHE cases is driven by a WW domain containing transcription regulator protein 1 (WWTR1)-calmodulin-binding transcription activator 1 (CAMTA1) gene fusion. The clinical course of EHE ranges from long-term favorable to rapidly aggressive. Few cases of intracranial EHE have been reported, none of which has been molecularly proven. We report a case of left parietal meningeal EHE, which was resected 15 years after initial radiological detection. Four years prior to surgery, a second atlantooccipital lesion and pulmonary nodules were detected, which remained constant in subsequent radiological controls. The tumor infiltrated the cranial bone. Histology showed an isomorphic tumor with epithelioid cells forming vacuoles that contained erythrocytes. Necrosis was absent and anaplasia and proliferative activity were scant. Immunohistochemistry showed expression of the endothelial markers CD34, CD31, vascular endothelial growth factor, and factor VIII and predominantly nuclear overexpression of CAMTA1. Fluorescence in situ hybridization showed WWTR1-CAMTA1 gene fusion. Our report provides the first case of intracranial EHE with molecular proof of WWTR1-CAMTA1 gene fusion. The slowly progressive clinical course of 15 years is the longest so far reported for intracranial EHE.

Histiocytoid Sweet syndrome: a dermal infiltration of immature neutrophilic granulocytes.

OBJECTIVE: To describe a series of 41 patients with fresh lesions of Sweet syndrome in which the histopathologic study demonstrated an inflammatory infiltrate mostly composed of histiocytoid mononuclear cells. DESIGN: Histopathologic, immunohistochemical, and cytogenetic studies of the inflammatory infiltrate in a case series of histiocytoid Sweet syndrome. SETTING: University departments of dermatology and a private laboratory of dermatopathology. METHODS: Conventional histopathologic study as well as immunohistochemical investigations were performed using the alkaline phosphatase antialkaline phosphatase technique with a large panel of antibodies. In some cases, fluorescent in situ hybridization studies were performed to investigate the presence of the bcr/abl gene fusion. RESULTS: Immunohistochemical studies demonstrated that most cells of the infiltrate showed immunoreactivity for CD15, CD43, CD45, CD68, MAC-386, HAM56, and lysozyme, which is consistent with a monocytic-histiocytic immunoprofile. However, intense myeloperoxidase reactivity was detected in most of the cells with histiocytic appearance, which raised the possibility of specific cutaneous involvement by myelogenous leukemia. Nevertheless, cytologic peripheral blood examinations, fluorescent in situ hybridization studies to investigate the bcr/abl gene fusion, and follow-up of the patients, taken all together, ruled out this possibility. CONCLUSIONS: This case series demonstrates that some fresh cutaneous lesions of Sweet syndrome are histopathologically characterized by an infiltrate mostly composed of cells that may be misinterpreted as histiocytes, when in fact they are immature myeloid cells. We named this histopathologic variant histiocytoid Sweet syndrome, which should not be mistaken with leukemia cutis or other inflammatory dermatoses that are histopathologically characterized by histiocytes interstitially arranged between collagen bundles of the dermis.

Mutations of the BRAF gene in benign and malignant melanocytic lesions.

A single-point mutation in exon 15 of the BRAF gene has recently been reported in a high percentage in cultured melanoma cells and in 6 of 9 primary melanomas examined. To evaluate the impact of the T1796A BRAF mutation, we screened primary melanomas, various types of nevi and lesions where a melanoma developed in an underlying nevus. We could detect the mutation in 28 of 97 (29%) melanomas and in 39 of 187 (21%) nevi, including blue nevi (0/20) and Spitz nevi (0/69), which did not carry the mutation. In melanomas with an underlying nevus, either the mutation was present in both the laser-microdissected nevus cells and the laser-microdissected melanoma cells (3/14) or both lesions were negative for the BRAF mutation except one case. In conclusion, mutations in exon 15 of the BRAF gene are nonspecific for progression of a nevus to a melanoma. Other so far unknown cofactors seem to be of importance.