PLCγ1/PKCθ Downstream Signaling Controls Cutaneous T-Cell Lymphoma Development and Progression.

Developing mechanistic rationales can improve the clinical management of cutaneous T-cell lymphomas. There is considerable genetic and biological evidence of a malignant network of signaling mechanisms, highly influenced by deregulated TCR/PLCγ1 activity, controlling the biology of these lesions. In addition, activated signal transducer and activator of transcription 3 is associated with clinical progression, although the alterations responsible for this have not been fully elucidated. Here, we studied PLCγ1-dependent mechanisms that can mediate STAT3 activation and control tumor growth and progression. Downstream of PLCγ1, the pharmacological inhibition and genetic knockdown of protein kinase C theta (PKCθ) inhibited signal transducer and activator of transcription 3 activation, impaired proliferation, and promoted apoptosis in cutaneous T-cell lymphoma cells. A PKCθ-dependent transcriptome in mycosis fungoides/Sézary syndrome cells revealed potential effector genes controlling cytokine signaling, TP53, and actin cytoskeleton dynamics. Consistently, an in vivo chicken embryo model xenografted with mycosis fungoides cells showed that PKCθ blockage abrogates tumor growth and spread to distant organs. Finally, the expression of a number of PKCθ target genes found in mycosis fungoides cells significantly correlated with that of PRKCQ (PKCθ) in 81 human mycosis fungoides samples. In summary, PKCθ can play a central role in the activation of malignant cutaneous T-cell lymphoma mechanisms via multiple routes, including, but not restricted to, STAT3. These mechanisms may, in turn, serve as targets for specific therapies.

Diagnostic Value of Genotypic Analysis in Primary Cutaneous Lymphomas using Standardized BIOMED-2 Polymerase Chain Reaction Protocols: Experience in Daily Clinical Practice.

BIOMED-2 Concerted Action BMH4-CT98-3936 (BIOMED-2) PCR protocols are an important diagnostic tool in the evaluation of cutaneous lymphomas. The aim of this study was to assess the diagnostic value of the genotyping results obtained by these techniques in daily clinical practice. A total of 360 paraffin-embedded skin samples were retrospectively reviewed from 114 cutaneous T-cell lymphomas and 35 cutaneous B-cell lym-phomas. A total of 249 biopsies from 180 patients with benign lymphoid infiltrates served as controls. T-cell receptor and immunoglobulin gene rearrangements were assessed using the BIOMED-2 method. A combined T-cell receptor gamma and beta assay approach reliably distinguished cutaneous T-cell lymphomas from benign skin T-cell infiltrates (sensitivity 89.4%; specificity 81.5%). Analysis of complete immunoglobulin heavy chain rearrangements also differentiated cutaneous B-cell lymphomas from benign B-cell infiltrates (sensitivity 85.7%; specificity 82.4%). In conclusion, the full BIOMED-2 protocol is a useful aid combined with clinical, histological and immunophenotypical findings for assessment of lymphoid clonality in skin lymphoid proliferations.

Secondary hypereosinophilic syndrome: an unusual manifestation in a patient with syringotropic mycosis fungoides and human immunodeficiency virus infection.

Syringotropic mycosis fungoides is a very rare variant of cutaneous T-cell lymphomas characterised by prominent involvement of the eccrine glands. Hypereosinophilic syndrome refers to a rare group of conditions that are associated with persistent eosinophilia with organ involvement. It is classified into idiopathic, primary and secondary (reactive). We report herein an unusual case of hypereosinophilic syndrome with great impact on morbidity, which developed in a patient with human immunodeficiency virus infection and long-time misdiagnosed syringotropic mycosis fungoides.

Papillary Dermal Elastosis.

Papillary dermal elastosis is a rare clinicopathological entity with only 1 case reported. The authors herein report a new case. A 38-year-old woman presented with a 10-month history of slowly progressive appearance of multiple, 1-2 mm, pruritic nonfollicular papules, located on the back. The study of the biopsy with the ordinary staining revealed numerous dermal papillae showing increased elastosis. The Verhoeff elastic stain demonstrated numerous foci of clumped and curled elastic fibers in the papillary dermis. The elastic component of the reticular dermis was normal. This case report confirms this entity and can contribute to a better understanding of the spectrum of the fibroelastolytic entities.

MicroRNAs 142-3p, miR-155 and miR-203 Are Deregulated in Gastric MALT Lymphomas Compared to Chronic Gastritis.

BACKGROUND: Over the last years, our knowledge on pathogenesis of gastric MALT lymphoma has greatly improved, but its morphological diagnosis is still hampered by overlapping histological features with advanced chronic gastritis. MicroRNAs are deregulated in lymphomas, but their role and usefulness in gastric MALT lymphoma has not been extensively investigated. MATERIALS AND METHODS: We analyzed the expression of 384 miRNAs using TaqMan microRNA assay in a training series of 10 gastric MALT lymphomas, 3 chronic gastritis and 2 reactive lymph nodes. Then, significantly deregulated miRNAs were individually assessed by real-time PCR in a validation series of 16 gastric MALT lymphomas and 12 chronic gastritis. RESULTS: Gastric MALT lymphoma is characterized by a specific miRNA expression profile. Among the differentially expressed miRNAs, a significant overexpression of miR-142-3p and miR-155 and down-regulation of miR-203 was observed in gastric MALT lymphoma when compared to chronic gastritis. CONCLUSION: miR-142-3p, miR-155 and miR-203 expression levels might be helpful biomarkers for the differential diagnosis between gastric MALT lymphomas and chronic gastritis.

Distinction between asymptomatic monoclonal B-cell lymphocytosis with cyclin D1 overexpression and mantle cell lymphoma: from molecular profiling to flow cytometry.

PURPOSE: According to current diagnostic criteria, mantle cell lymphoma (MCL) encompasses the usual, aggressive variants and rare, nonnodal cases with monoclonal asymptomatic lymphocytosis, cyclin D1-positive (MALD1). We aimed to understand the biology behind this clinical heterogeneity and to identify markers for adequate identification of MALD1 cases. EXPERIMENTAL DESIGN: We compared 17 typical MCL cases with a homogeneous group of 13 untreated MALD1 cases (median follow-up, 71 months). We conducted gene expression profiling with functional analysis in five MCL and five MALD1. Results were validated in 12 MCL and 8 MALD1 additional cases by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in 24 MCL and 13 MALD1 cases by flow cytometry. Classification and regression trees strategy was used to generate an algorithm based on CD38 and CD200 expression by flow cytometry. RESULTS: We found 171 differentially expressed genes with enrichment of neoplastic behavior and cell proliferation signatures in MCL. Conversely, MALD1 was enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 were differentially expressed between MCL and MALD1 and confirmed by flow cytometry (median CD38, 89% vs. 14%; median CD200, 0% vs. 24%, respectively). Assessment of both proteins allowed classifying 85% (11 of 13) of MALD1 cases whereas 15% remained unclassified. SOX11 expression by qRT-PCR was significantly different between MCL and MALD1 groups but did not improve the classification. CONCLUSION: We show for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. Assessment of CD38/CD200 by flow cytometry is useful to distinguish most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment.

Sclerotic fibroma (storiform collagenoma)-like stroma in a fibroadenoma of axillary accessory breast tissue.

Accessory breast tissue is a subcutaneous remnant persisting after normal embryological development of the breast. It occurs most frequently in the axilla. Fibroadenomas in axillary breast tissue are rare. We report the case of a 29-year-old female patient who presented a fibroadenoma arising in the accessory breast tissue of the right axillary fossa. The neoplasm showed foci of sclerotic fibroma-like stroma. The patient had no signs of Cowden's syndrome. To the best of our knowledge, a lesion of this kind has not been previously reported. This stromal change suggests an uncommon involutional phase of the fibroadenoma with production of sclerotic and hypocellular collagen. The lesion should be differentiated from extraneural perineuroma, from the changes in fibroadenomas in Cowden's syndrome, from sclerosing lobular hyperplasia (fibroadenomatoid mastopathy) and from pseudoangiomatous stromal hyperplasia.

Localized eosinophilic (Langerhans' cell) granuloma of the lower lip. A lesion that may cause diagnostic error.

Eosinophilic (Langerhans' cell) granuloma is most common in children and is unusual in the elderly. A cutaneous lesion as the sole manifestation of adult Langerhans' cell histiocytosis is rare. We report an 81-year-old man who presented with a noduloulcerative lesion on the lower lip. A punch biopsy suggested a lymphoepithelioma-like carcinoma. In the absence of immunohistochemistry, the large pale cells with atypical lobular nuclei and patent nucleoli, with an overlying ulceration, were interpreted as carcinoma cells. Definitive diagnosis was established after complete resection of the lesion aided with the use of immunohistochemistry. The proliferating cells were S100, CD1a and CD207 (langerin) positive and cytokeratin, epithelial membrane antigen, CD15, CD30, melan A and carcinoembryonic antigen negative. To our knowledge, eosinophilic (Langerhans' cell) granuloma of the lip has not been described. The case constituted a diagnostic challenge because of its unusual clinical presentation and its histopathological similarity to certain other benign and malignant entities. Because there was no other organ involved, the patient was treated with complete surgical excision without recurrence or other organ involvement in the 4-month follow-up period. Labial eosinophilic (Langerhans' cell) granuloma should be considered in the histological differential diagnosis in cases with atypical polymorphous infiltrates including large pale cells.

Pedunculated polypoid lymphangioma of the anal canal.

Lymphangioma is a rare benign lesion of the gastrointestinal tract, in which the large intestine is the least commonly involved site. To the authors' knowledge a lymphangioma of the anal canal has not been reported. Described herein is a case of pedunculated polypoid lymphangioma of the right lateral wall on the transitional zone of the anal canal measuring 1.7 x 1.3 x 1 cm in a 40-year-old woman. A pedicle does not exclude the endoscopic diagnosis of lymphangioma. Lymphangioma must be included in the differential diagnosis of polypoid lesions of the anal canal.

Pilonidal sinus associated with cellular blue nevus. A previously unrecognized association.

A neoplasm associated with a pilonidal sinus (PS) is a rare occurrence in the course of a common disease. Early detection is imperative. To our knowledge, pilonidal disease associated with a cellular blue nevus (CBN) has not been reported. There is a 10% diagnostic error rate with this last lesion. Here we report the case of a 19-year-old man with recurrent sacrococcygeal PS infection associated with an indurated dome-shaped blue-black nodule 1.7 cm in diameter. Clinical diagnosis of the nodule was uncertain suggesting a pigmentary or a vascular tumor. A complete resection of the two lesions was achieved. Pathological study showed a CBN showing a predominantly alveolar pattern associated with a chronic pilonidal disease. The tumor cells showed diffuse strong reactivity for melan-A and HMB-45, and focal reactivity for S-100 protein. Staining for Ki-67 (MIB1) was virtually negative. Differential diagnoses included atypical CBN, borderline melanocytic tumor and malignant melanoma. Radical excision provides a good prognosis for the rare association consisting of a common disease such as PS with the uncommon CBN.