Cyclin D1 demonstrates superior sensitivity and consistent nuclear expression compared with MiTF in cellular neurothekeoma.

Neurothekeoma and nerve sheath myxoma have long been interpreted as related tumors that share nerve sheath linage. Lack of S100 expression in neurothekeoma and similarities of gene expression profiles between neurothekeoma and fibrohistiocytic tumors have created reasonable doubt about this concept. SOX-10 represents a marker for schwannian and melanocytic differentiation, and is expressed in other tumors of nerve sheath linage. Microphthalmia transcription factor (MiTF) expression has been repeatedly reported in cellular neurothekeoma in the recent literature and was proposed as a helpful marker in this entity. We investigated 25 cases of cellular neurothekeoma, 8 cases of mixed neurothekeoma and 1 case of nerve sheath myxoma for the expression of SOX-10, MiTF, S100, NKI/C3, Melan-A and smooth muscle actin (SMA) using immunohistochemistry. A lack of SOX-10 expression was demonstrated in 100% of cellular and mixed neurothekeomas, but was present in the case of nerve sheath myxoma. More than two thirds of neurothekeomas showed very focal or no reactivity with MiTF. Our data suggest that neurothekeoma and nerve sheath myxoma are unrelated, and that cellular and mixed neurothekeoma may not be of nerve sheath lineage. In addition, MiTF should not be regarded as a useful marker in neurothekeoma.

Cellular neurothekeoma (CNT) is a benign mesenchymal tumor with uncertain cellular differentiation. Studies have found evidence of myofibroblastic differentiation and possible relation to dermatofibromas (DFs). As microphthalmia transcription factor (MITF) and NKI/C3 stains are routinely positive in CNT, we compared expression patterns of both markers in CNT and DF to assess their relationship. We assessed cases of CNT (n=25) and DFs (n=35) for histopathologic characteristics and MITF and NKI/C3 expression. Immunostaining results were classified as negative, focally positive (<50%), and diffusely positive (>50%). At least 1 additional melanocytic marker was assessed in each case of CNT. Both DFs and CNTs showed a female predilection and a wide age range. Immunostaining in CNTs for MITF was positive in the vast majority (focal 68%, diffuse 24%), as was NKI/C3 (focal 72%, diffuse 24%). All DFs were MITF positive (diffuse 74%, focal 26%), and most DFs were NKI/C3 positive (focal 57%, diffuse 3%). CNT and DF share demographic, histopathologic, and immunohistochemical features, including shared expression of MITF and NKI/C3, especially cellular DF.

CK2β Is Expressed in Endometrial Carcinoma and Has a Role in Apoptosis Resistance and Cell Proliferation

Overlapping histopathologic features of cellular neurothekeoma (CNT) and plexiform fibrohistiocytic tumor (PFHT), when both are predominantly composed of histiocytoid cells, make distinction between these entities challenging. Some have suggested that CNT and PFHT are related entities. No prior study has demonstrated a reliable immunohistochemical panel to differentiate these entities. Skin biopsies diagnosed as CNT and PFHT, from 2004 to 2010 were retrieved with accompanying pathology reports. Each case was reviewed by at least 2 dermatopathologists and 2 soft tissue pathologists for confirmation of diagnosis. All cases were then evaluated for immunohistochemical expression of PAX2, NKIC3, CD10, and microphthalmia transcription factor (MiTF). Histopathologically, the histiocytoid areas of each tumor shared similar architecture, demonstrating nests and fascicles of histiocytoid to spindled cells, with some separation of nests by collagen bands. Both CNT and PFHT were uniformly positive for NKIC3 and CD10, and both were frequently PAX2 positive. MiTF was strongly and diffusely positive in CNT and was consistently negative in the PFHT. CNT and PFHT share many histopathologic features and immunohistochemical staining patterns. Of the stains we evaluated, we found that expression of MiTF may be a reliable marker for distinguishing CNT from histiocytoid-predominant PFHT, especially in instances where only a small part of the tumor is sampled for evaluation.

Microphthalmia transcription factor and NKI/C3 expression in cellular neurothekeoma

Microphthalmia transcription factor and NKI/C3 expression in cellular neurothekeoma

Atypical cellular neurothekeoma: A lamb in wolf’s clothing

Objective: To investigate the clinicopathologic characteristics and differential diagnosis of dermal nerve sheath myxoma (DNSM) and neurothekeoma (NTK). Methods: Clinical, pathological features and immunohistochemical profiles in 9 cases of DNSM and 8 cases of NTK were comparatively studied. The literature was reviewed. Results: The involved site of 9 DNSMs included the hand/fingers (n=3), ear (n=2), face, back, abdominal wall and waist (1 case each). Two of 8 NTKs arose in the forearm (n=2), one each in the nose, lip, shoulder, supraclavicular region, leg and hand. The most common presentation was a painless cutaneous nodule or plaque which grew slowly. Grossly, DNSM was often gelatinous, whereas NTK appeared relatively solid. Microscopically, both tumors were located in the dermis and/or subcutis. DNSM was composed of well-defined multiple lobules separated by fibrous septa. NTK also exhibited lobular or multinodular architecture, but was relatively ill-defined. Besides, fascicular or whorl-like arrangement was present in 3 cases of NTK. The lobules in DNSM consisted of a paucicellular proliferation of spindled, stellate and epithelioid cells forming interconnecting cords within abundant myxoid matrix. Small syncytial-like aggregates were readily noted. The constituted neoplastic cells in NTK were composed of ovoid to round epithelioid or histiocytoid cells. Scattered multinucleated giant cells were present in 2 cases. Based on the amount of myxoid matrix, 8 NTKs were further classified into cellular (5 cases), mixed (2 cases) and myxoid (1 case). By immunohistochemistry, neoplastic cells in DNSM were diffusely positive for S-100 protein, CD68, glial fibrillary acidic protein and SOX10, whereas neoplastic cells in NTK consistently expressed CD10 and microphthalmia transcription factor, with negativity for S-100 protein and SOX10. One patient each with DNSM and NTK experienced local recurrence due to incomplete excision. Conclusions: Although DNSM and NTK share clinical and pathological features, they belong to different entities. Whereas the former is consistent with a peripheral nerve sheath tumor, the latter is more akin to fibrous histiocytic tumor. Familiarity with their cliniopathologic characteristics and distinctive immunophenotypes will help distinguishing these two entities, as well as in the differential diagnosis of cutaneous neoplasms with similar features.

Cyclin D1 Expression and Molecular Genetic Findings in Periocular Histiocytoses and Neoplasms of Macrophage-Dendritic Cell Lineage

Differential gene expression profiles of neurothekeomas and nerve sheath myxomas by microarray analysis

Superficial CD34-positive fibroblastic tumor (SCPFT) is a fibroblastic/myofibroblastic soft tissue tumor of rarely metastasizing intermediate malignancy. Some recent studies have described a relationship between SCPFT and PRDM10-rearranged soft tissue tumor (PRT) based on SynCAM3 and PRDM10 expression on immunohistochemistry. We performed CD34, cytokeratin AE1/AE3, SynCAM3, and PRDM10 immunohistochemistry in SCPFT and its histological mimics, including myxoinflammatory fibroblastic sarcoma (MIFS), superficially localized myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma. We also examined cyclin D1 expression because it is expressed in MIFS and MFS. We conducted fluorescence in situ hybridization (FISH) of PRDM10 rearrangement in SCPFT cases. On immunohistochemistry, only SCPFT showed strong and diffuse SynCAM3 expression. SCPFT also exhibited strong nuclear and weak cytoplasmic cyclin D1 expression, which was similar to that observed in MIFS. Two of five SCPFT cases exhibited nuclear PRDM10 expression. FISH revealed PRDM10 split signals in 44% and 24% of tumor cells in two SCPFT cases showing nuclear PRDM10 expression on immunohistochemistry, respectively. A minority of non-SCPFT cases showed focal SynCAM3 expression, but a combination of SynCAM3 and cyclin D1 in addition to CD34 and cytokeratin AE1/AE3 may be useful for the differential diagnosis of SCPFT and its histological mimics.

Pathological diagnosis of clear cell sarcoma of the kidney (CCSK) is challenging as it resembles blastemal Wilms tumor (WT) and other pediatric sarcomas, and does not have any distinctive immunophenotype. The YWHAE-FAM22 translocation t(10;17)(q22;p13) has been reported in a subset of CCSK. This translocation also occurs in high-grade endometrial sarcoma, in which it is associated with cyclin D1 overexpression. Hence we seek to determine YWHAE-FAM22 translocation status and cyclin D1 immunoreactivity in a series of local CCSK cases. Of 8 CCSK cases from 7 patients identified, no CCSK had the YWHAE-FAM22 fusion transcript by reverse transcriptase-polymerase chain reaction. Novel karyotypes were identified for 2 cases: 1 had t(2;13)(q13;q22) and the other t(3:17)(q29;p11.2). Excluding a case with poor tissue section antigenicity, 7 of 7 CCSKs (100%) showed diffuse and strong nuclear cyclin D1 staining. Cyclin D1 immunohistochemistry was also performed on tissue microarrays of other pediatric renal tumors: blastemal areas of 18 WT cases were negative; 6 rhabdoid tumors and 1 metanephric adenoma showed patchy and weak staining; 3 mesoblastic nephromas and 18 of 29 neuroblastomas had positive staining. Cyclin D1 immunohistochemistry helps distinguish CCSK from blastemal WT and metanephric adenoma and rhabdoid tumors, but not from neuroblastomas and mesoblastic nephromas. Cyclin D1 overexpression in CCSK is not contingent on YWHAE-FAM22 translocation, and cyclin D1 inhibition may potentially be explored as a targeted therapeutic strategy in CCSK.

Langerhans cell histiocytosis (LCH) is a rare disorder of unknown etiopathogenesis. Diagnosis is based on the identification of CD1a positive histiocytic infiltrate. Activation of the mitogen-activated-protein-kinase (MAPK) is constantly observed in LCH and therefore downstream markers such as cyclin D1 may be a useful marker for LCH. The aim of this study was to investigate the expression of cyclin D1 in LCH. We assessed the immunohistochemical expression of cyclin D1 (clone SP4-R) in series of 16 cases of confirmed LCH. Expression of Cyclin D1 was scored as weak, moderate, and strong nuclear staining and results were interpreted by two pathologists. The percentage of positivity was assessed. The mean age of patients was 13.7 years old with a male to female ratio of 1:3. The most common involved site was bone (n = 9; 56,3%), followed by lymph node (n = 5; 31,2%) and skin (n = 2; 12,5%). All cases showed nuclear staining for cyclin D1 with variable intensity. It was assessed moderate in 43,8% (n = 7) and strong in 56,2% (n = 9). The percentage of positive cells was >50% in 13 cases and <50% in 3 cases. Our results have shown that all cases of Langerhans cell histiocytosis from various sites express cyclin D1. This finding may be attributed to MAPK pathway activation that has been described in LCH. Otherwise, cyclin D1 is not significantly expressed in reactive Langerhans cell proliferations. Therefore, cyclin D1 immunohistochemistry may be useful as a diagnostic marker and in excluding non-neoplastic mimics of LCH.

Cellular neurothekeoma is a cutaneous tumor with a distinctive histopathologic appearance characterized by a dermal-based multinodular proliferation of epithelioid to spindled cells. Although the tumor may show varying amounts of myxoid stroma, extensive myxoid change is uncommon. The tumor typically presents as a solitary nodule with a predilection for the head and neck and upper limbs; examples of multiple cellular neurothekeomas are decidedly rare. The present report describes a unique case of multiple myxoid cellular neurothekeomas arising in a 60-year-old female with systemic lupus erythematosus. Two papular lesions were identified involving the skin inferior to the umbilicus and the left inguinal crease. Both lesions were histopathologically similar, forming a nodular mass composed of epithelioid cells in a prominent myxoid stroma. By immunohistochemistry the lesional cells expressed NKI/C3, microphthalmia transcription factor (MiTF), and CD68, with focal staining for PGP9.5, factor XIIIa, and CD10 also observed. The tumors were negative for S-100, SOX-10, epithelial membrane antigen, desmin, smooth muscle actin, glial fibrillary acid protein, and CD34. The present case confirms that cellular neurothekeoma can present clinically as multiple lesions and can have a predominantly myxoid appearance, potentially mimicking other cutaneous myxoid lesions.

Nuclear Expression of the Sox 11 Transcription Factor in Mantle Cell Lymphoma, and Cytoplasmic Expression in Follicular Lymphoma and Multiple Myeloma: Pathogenetic Implications.