Primary cutaneous diffuse large B‐cell lymphoma,leg‐type,treated with a modified R‐CHOP immunochemotherapy – diagnostic and therapeutic challenges

Background: Primary cutaneous diffuse large B‐cell lymphoma (PCLBCL) represents a rare subtype among primary cutaneous B‐cell lymphoma exhibiting a characteristic genetic background, an aggressive clinical course and a high relapse rate under different therapeutic regimen. Therefore, PCLBCL has a rather restricted prognosis. Patients and methods: Four patients with PCLBCL were treated at our institution with age‐ and toxicity‐adapted first‐line immunochemotherapy with rituximab and modified CHOP (cyclophosphamid, vincristin, liposomal doxorubicin, prednisolon). On relapse, the same regimen with R‐CHOP or different antineoplastic strategies (radiation, polychemotherapy, immunotherapy, stem cell transplantation) were applied. Toxicity, clinical response and overall survival was documented. Results: Under this regimen, clinical response to modified R‐CHOP was achieved in all patients with tolerable toxicity – however, being characterized by a rapid disease progression with inconsistent response towards the subsequent therapeutic armentarium and unsecure impact on overall survival. Conclusions: So far, it is still unknown, if an extensive multimodal therapy for PBLBCL improves overall survival. Immunochemotherapy with R‐CHOP currently represents the most effective treatment.     

Composite cutaneous lymphoma of diffuse large B‐cell lymphoma‐leg type and subcutaneous panniculitis‐like T‐cell lymphoma

Composite lymphoma (CL) is a rare disease defined by the occurrence of two distinct lymphomas within a single tissue at the same time. We present the case of an 89‐year‐old male with a clinical history of immunoglobulin M monoclonal gammopathy of undetermined significance. The patient presented cutaneous eruption of nodules on the right bottom and arm. An excisional biopsy revealed cutaneous infiltration composed of two components. The first one consisted of large B‐cells with CD20+/MUM1+/BCL2+ phenotype whereas the second one involved the subcutaneous fat in a panniculitic manner, and was CD3+/CD8+/granzyme B+/TCRβF1+. The final diagnosis was CL of primary cutaneous large B‐cell lymphoma‐leg type (PCLBCL‐leg type) and subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL). We report and characterize for the first time coexistent PCLBCL‐leg type and SPTCL in a patient.     

Aggressive primary cutaneous B‐cell lymphomas show increased Angiopoietin‐2‐induced angiogenesis

Primary cutaneous large B‐cell lymphomas, leg type (PCLBCL/LT) are primary cutaneous B‐cell lymphoma (PCBCL) with an intermediate prognosis. Therefore, antracycline‐based polychemotherapy combined with rituximab has been recommended as first‐line treatment. Yet, despite this regimen, the 5‐year survival rate remains 50–66% only. Angiogenesis, the formation of a vascular network, is essential for the pathogenesis of nodal lymphomas. So far, no study has analysed angiogenesis and its key factors in PCLBCL/LT. The present study was aimed at characterizing angiogenesis in PCLBCL/LT to identify the angiogenic molecules as potential therapeutic targets. The intra‐tumoral microvessel density (MVD) was assessed by immunohistochemical studies of CD20 and CD31. The MVD was higher in PCLBCL/LT compared with indolent PCBCL. Analyses of open‐source microarray data showed correlation between the angiogenic molecule angiopoietin‐2 (Ang‐2) and pan‐endothelial cell markers. ELISA studies determined a shift between Ang‐2 and Ang‐1 towards Ang‐2 in the peripheral blood of PCLBCL/LT patients. Immunofluorescence costainings against the Ang receptor Tie2/angiogenic integrins/CD34 revealed that the vasculature in both aggressive and indolent PCBCL tumors harbours an endothelial cell subpopulation with reduced expression of Tie2. In contrast, the alternative Ang‐2 binding partners, angiogenic integrins, are strongly expressed in PCBCL. In line with these findings, downstream targets of Ang‐2‐integrin signalling, that is phosphorylation of focal adhesion kinase at Tyr397, and sprouting angiogenesis are enhanced in PCLBCL/LT. Our data present Ang‐2 as a promising therapeutic target and anti‐angiogenic therapy as a new line in treatment of PCLBCL/LT as a hitherto intractable disease.     

Frequent immunoglobulin G4 expression in a common variant of primary cutaneous marginal zone B‐cell lymphoma

Immunoglobulin (Ig)G4 expression was recently observed in a proportion of primary cutaneous marginal zone B‐cell lymphoma (PCMZL) with plasmacytic differentiation. IgG4‐related disease is characterised by polyclonal lymphoplasmacytic infiltration with IgG4 expression, storiform fibrosis and obliterative phlebitis in histopathology. Here we report three cases of common variants of PCMZL with predominant and varied IgG4 expression, suggesting there is an underlying clonal progression between these two entities.     

Electrochemotherapy as a novel treatment for primary cutaneous marginal zone B‐cell lymphomas

In the present study, we describe the use of electrochemotherapy as alternative therapy for primary cutaneous marginal zone B‐cell lymphomas in patients unsuitable for surgery or radiotherapy. Our experience refers to three patients with primary cutaneous marginal zone B‐cell lymphomas related to Borrelia burgdorferi infection, treated with specific antimicrobial therapy and electrochemotherapy.     

Primary cutaneous T-cell-rich B-cell lymphoma in a zosteriform distribution associated with Epstein-Barr virus infection

T-cell-rich B-cell lymphoma (TRBL) is a lately recognized B-cell lymphoma variant characterized by a minor population of neoplastic B cells existing in a background of predominant polyclonal T cells. We report an 86-year-old man with primary cutaneous TRBL associated with Epstein-Barr (EB) virus infection. Clinically, palpable scaly erythemas were distributed in a zosteriform pattern on the right abdomen. Histologically, massive cellular infiltrates were located in the upper- and mid-dermis. Higher magnification showed that the cellular infiltration was composed mainly of abnormal mononuclear, large lymphoid cells with clear cytoplasm and scattered mitoses and small lymphocytes, which represented in excess of 75% of all the infiltrating cells. Immunohistochemical staining revealed that the large cells were positive for the B cell marker, CD20, but negative for the T cell marker, CD3. On the other hand, the small cells were positive for CD3, but negative for CD20. Polymerase chain reaction (PCR) revealed EB virus DNA in the skin lesion. Primary cutaneous TRBL has only been reported in 15 cases worldwide. To our knowledge, this is the first case of primary cutaneous TRBL in a zosteriform distribution reported in the literature and the second case of primary cutaneous TRBL associated with the EB virus infection. We postulate that the EB virus may be a contributory pathogenetic event leading to monoclonal B-cell proliferation.     

Primary cutaneous acral CD8+ T‐cell lymphoma of the ear: A case report

Primary cutaneous acral CD8+ T‐cell lymphoma (TCL) is a rare, distinct type of cutaneous TCL. Despite its worrisome histological appearance it has a benign clinical course. It is therefore important to recognize this as a distinct entity from other more aggressive CD8+ lymphomas, for which the management is very different.     

Acneiform primary cutaneous CD4‐positive small/medium pleomorphic T‐cell lymphoma with prominent necrosis

Primary cutaneous CD4‐positive small/medium pleomorphic T‐cell lymphoma (SMPTCL) is an indolent form of cutaneous lymphoma that usually presents in solitary fashion and is histopathologically characterized by nodular infiltration of small‐ to medium‐sized pleomorphic T‐cells. We report the case of a patient who presented with a 5‐year history of acneiform lesions on his face. Histopathologic examination of two lesions revealed a nodular infiltrate of small to medium‐sized lymphocytes with necrosis in the dermis. The proliferating cells were positive for CD2, CD3 and CD4 and negative for CD8, CD30 and CD56. They were positive for TIA‐1 and negative for perforin and granzyme B. The Ki67 proliferation index was approximately 10%. The neoplastic cells expressed programmed death‐1 and lacked expression of CXCL‐13, bcl‐6 and CD10. In situ hybridization for Epstein–Barr virus‐encoded RNA yielded a negative result. T‐cell receptor gene rearrangement showed identical T‐lymphocyte monoclonality in both lesions. In brief, we report a rare case of acneiform SMPTCL with prominent necrosis.     

Primary cutaneous follicle center lymphoma with Hodgkin and Reed‐Sternberg‐like cells: a new histopathologic variant

Primary cutaneous follicle center lymphoma (PCFCL) is the most frequent cutaneous B‐cell lymphoma. A 62‐year‐old man presented with a solitary indolent subcutaneous nodule for 3 years duration, without other abnormalities. Histological examination showed lymphoproliferation with a nodular growth pattern characterized by fibrous collagen bands surrounding nodules. The nodules were composed of medium‐sized centrocytes admixed with many large multilobulated and lacunar cells without eosinophils or granulomatous aspect. Hodgkin‐like cells were CD30+, CD15+, PAX5+, OCT2+, BOB1+, MUM1+, Ki67+, Bcl6+ and focally CD20+ and EMA?, CD79a?, Bcl2? and CD10?. The medium‐sized cells were CD20+, CD79a+, Bcl2+, Bcl6+ and CD10+, enmeshed in a network of CD21‐positive follicular dendritic cells. Epstein‐Barr virus detection was negative. Interphase fluorescence in situ hybridization showed the absence of BCL2 or BCL6 rearrangement. In such a case, the presence of Hodgkin‐like cells intermixed with the tumor population may result in a pitfall diagnosis of classical Hodgkin lymphoma (CHL). Differential diagnoses to be ruled out are secondary or primary skin localization of rather CHL, or systemic follicular lymphoma. Several clinical, radiological, histological, immunohistochemical and molecular arguments indicated the diagnosis of PCFCL. To our knowledge, this is the first report of PCFCL with Hodgkin‐like cells.     

Case of primary cutaneous peripheral T‐cell lymphoma,not otherwise specified,with characteristics of follicular helper T cells

We report a case of an 88‐year‐old woman with a decalvant, erythematous, ulcerated tumor extending from the right temporal to occipital region. Histopathological analysis revealed a dense infiltration of medium‐to‐large‐sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T cells expressed programmed death‐1 (PD‐1), Bcl‐6 and CXCL13. Flow cytometry analysis showed that CD4⁺ PD‐1^hi T cells also expressed CD10, inducible T‐cell co‐stimulator and CXCR5. On the basis of the clinical appearance and the histopathological findings, we diagnosed the patient with primary cutaneous peripheral T‐cell lymphoma, not otherwise specified. Recently, the concept of primary cutaneous follicular helper T (TFH)‐cell lymphoma was proposed, and in this case, tumor cells clearly expressed TFH‐cell markers. Therefore, we considered this case to be a variant of the entity. Although this entity is still provisional, this case supports the new concept.     

Primary cutaneous CD4 positive small/medium T‐cell lymphoma with high proliferation index and CD30‐positive large lymphoid cells

Primary cutaneous CD4 positive small/medium pleomorphic T‐cell lymphoma (SMPTCL) represents a provisional subtype of primary cutaneous T‐cell lymphoma with indolent clinical course. A few aggressive fatal cases with increased proliferation rate and few infiltrating CD8 positive T‐cells have been reported. We describe a case of SMPTCL with an increased proliferation rate, admixed CD30‐positive large lymphoid cells, and few infiltrating CD8 positive T‐cells. The lymphoma cells were positive for CD3, CD4, CD2 and CD5, and negative for CD8. A subset of the lymphoma cells was positive for follicular helper T‐cell markers bcl‐6 and PD‐1. There were approximately 20% CD30‐positive large lymphoid cells, and Ki‐67 showed a moderately high proliferation rate (～40%), mostly in the large lymphoid cells. CD8 infiltrating T‐cells were few (<5%). The patient had an indolent disease with complete response to radiation therapy. To the best of our knowledge, this is the first reported case of SMPTCL with an increased proliferation rate and large CD30+ cells that followed an indolent clinical course.     

Primary cutaneous follicle center cell lymphoma of the scalp successfully treated with anti CD20 monoclonal antibody and CHOP combination therapy with no subsequent permanent loss of hair

We present a primary cutaneous follicle center cell lymphoma (PCFCCL) patient who was successfully treated with Rituximab, a new anti-CD20 monoclonal antibody. A thirty-two-year-old male developed two asymptomatic tumors on the scalp. Histopathologically, the tumors were composed of diffuse and nodular infiltration of centrocytes and centroblasts. Immunohistopathologically, the tumor cells stained positively with anti-CD20 antibody and anti-kappa antibody, but not with anti-CD5, anti-CD10, or anti-Bcl-2 antibody. Radiation therapy is effective in treating PCFCCL; however, it usually results in the permanent loss of hair. This patient was treated with Rituximab and CHOP, and achieved a complete remission. He has had no recurrence in more than 12 months and no permanent loss of hair on the scalp.     

Primary cutaneous marginal zone lymphoma associated with juxta‐articular fibrotic nodules in a teenager

Primary cutaneous marginal zone lymphoma (PCMZL) has rarely been reported in teenagers and is occasionally associated with Borrelia burgdorferi infection. Juxta‐articular fibrotic nodules represent a unique, localized fibrosing response to spirochete infections, namely Borreliosis. Herein, we report a 15‐year‐old healthy boy who presented with a 4‐year history of progressive acquisition of asymptomatic, erythematous nodules, ≤3 cm, beginning with his right forearm (3), then right arm (1) and lastly his right inner thigh (1). Biopsy showed PCMZL in three of five samples, and inflamed, fibrotic nodules, near the elbow in two. The bottom heavy lymphomatous nodules consisted of mostly small CD20+ CD43+ lymphocytes, some with plasmacytoid features. Mature plasma cells were lambda light chain restricted by in situ hybridization. The juxta‐articular fibrotic nodules were located in the deep dermis and subcutis, had peripheral plasma cell‐rich infiltrates, and showed nodular sclerosis (morphea profunda‐like) in one, and lamellar and angiocentric sclerosis in the other reminiscent of quiescent lesions of chronic localized fibrosing leukocytoclastic vasculitis. Immunohistochemistry for B. burgdorferi revealed rare positive organisms; however, polymerase chain reaction (PCR) and serology were negative for B. burgdorferi as were serologic and/or PCR assays for Bartonella henselae, Ba. quintana, Ehrlichia chaffeensis, Treponema pallidum, Helicobacter pylori and Babesia microti. No evidence of extracutaneous disease was found by the review of systems and imaging studies. A 4‐week trial of doxycycline therapy failed, whereas intralesional (IL) corticosteroid therapy induced rapid regression of his nodules. After two local recurrences, also treated with IL corticosteroids, he is well, without cutaneous disease, 20 months later. A literature review of 19 pediatric cases PCMZL reveals a similar natural history as adult PCMZL. Despite negative serology and PCR for B. burgdorferi, the occurrence of ipsilateral juxta‐articular fibrotic nodules, positive B. burgdorferi immunohistochemistry and rapid response to IL corticosteroids implicate the presence of a replicative or non‐replicative infectious (spirochetal) antigen in the initiation and promotion of this teenager's PCMZL.     

The role of AHI1 and CDKN1C in cutaneous T‐cell lymphoma progression

Cutaneous T‐cell lymphoma (CTCL) is the most common lymphoma of the skin. Recent reports suggest that AHI1 is overexpressed in a subset of CTCL‐derived cell lines, where it downregulates the expression of CDKN1C tumor suppressor gene. In the current work, we test the expression of these genes in 60 patients with Mycosis Fungoides and Sezary Syndrome by RT‐PCR and correlate our findings with 6 years of clinical follow‐up. These findings reveal that AHI1 and CDKN1C exhibit opposite expression patterns, where AHI1 is expressed in poor and intermediate prognosis patients, while CDKN1C is expressed in favourable prognosis patients. Kaplan–Meier analysis documents that downregulation of CDKN1C is associated with poor disease outcome in patients with CTCL, while upregulation of AHI1 shows a weak association with aggressive disease course.     

Primary cutaneous CD8+ cytotoxic T‐cell lymphoma involving the epidermis and subcutis in a young child

CD8+ cytotoxic T‐cell lymphoma involving the skin represents a heterogeneous group of diseases that include subcutaneous panniculitis‐like T‐cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T‐cell lymphoma, and ‘type D’ lymphomatoid papulosis. In this report, we describe a case of CD8+ cytotoxic T‐cell lymphoma involving both the epidermis and subcutis. The patient was a 6‐year‐old girl who presented with a 3‐year history of multiple plaques on her trunk and legs. The lesions had relapsed twice but responded well to prednisone. Histopathologic examination showed the proliferation of atypical lymphocytes in the epidermis, dermis and subcutaneous tissue. On immunohistochemical analysis, the atypical lymphocytes were positive for βF1, CD3, CD8, perforin, granzyme B and TIA‐1, but negative for T‐cell receptor (TCR) γ, CD4, CD30 and CD56. It was difficult to classify this tumor in terms of the known types of cutaneous lymphoma, and this case should be differentiated with subcutaneous panniculitis‐like T‐cell lymphoma and primary cutaneous aggressive epidermotropic CD8+ T‐cell lymphoma.     

Acitretin combined with NB‐UVB in the treatment of cutaneous CD30‐positive anaplastic large cell lymphoma

Cutaneous CD30⁺ lymphoproliferative disorders represent a spectrum of skin lymphatic reticular proliferative diseases, including lymphomatoid papulosis (LYP), primary cutaneous anaplastic large cell lymphoma (PC‐ALCL), and borderline lesions between them. Although they all express CD30 as a phenotypic marker and share overlapping immunophenotypic features, they differ in clinical manifestations, pathological features, treatment, and prognosis. LYP is a kind of benign disease characterized by recurrent papules and nodules, and may spontaneously regress. PC‐ALCL presents with solitary tumor or local grouped nodules characterized by large T‐cells and may completely or partially resolve in fewer than half of cases. We reported a case of patient with clinical manifestation and pathologic features consistent with LYP in its early stages, which later turned into PC‐ALCL. This patient was treated with acitretin combined with NB‐UVB and had an obvious response.     

CD8‐positive peripheral T‐cell lymphoma with aberrant expression of CD20 and concurrent in situ follicular lymphoma

A case of a 78‐year‐old woman with a CD8‐positive peripheral T‐cell lymphoma with aberrant expression of CD20 associated with follicular lymphoma in situ (FLIS) is reported. The neoplasm presented initially as cutaneous macules, papules, plaques and nodules. A skin biopsy was performed and the diagnosis of peripheral T‐cell lymphoma (PTCl) with aberrant expression of CD20 was made. The staging procedures included an excisional inguinal lymph node biopsy that showed findings similar to those of the previous diagnosis. In addition, FLIS was identified. The clinicopathologic features of PTCLs with aberrant CD20 expression involving the skin as well as this uncommon association are reviewed.