Gamma‐delta T‐cell lymphoma arising in a long‐standing cutaneous plaque

The precise classification and characterization of primary cutaneous gamma‐delta T‐cell lymphoma (PCGD‐TCL) has been hindered by clinical and morphologic features that overlap with other lymphomas, especially subcutaneous panniculitis‐like T cell lymphoma (SPTCL). The recent World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification distinguishes the more aggressive PCGD‐TCL from the usually indolent SPTCL, however. We report a 30‐year‐old woman with an indurated violaceous plaque on the left cheek that had been present for several years. Biopsies showed a dense lymphocytic infiltrate involving the subcutis and dermis that consisted mostly of small and medium‐sized lymphocytes, some with irregular nuclear contours and dense chromatin. These cells were positive for TIA‐1, TCR‐gamma and CD8, but negative for beta‐F1 and granzyme‐B. Staging with positron emission tomography–computed tomography (PET/CT), CBC and bone marrow with flow cytometry identified lymphadenopathy as well as blood and marrow involvement by an abnormal TCRgd‐positive T‐cell proliferation (Ann Arbor Stage IV). The patient's history of a long‐standing lesion in this case is unusual, in that gamma‐delta T‐cell lymphomas are typically rapidly progressive neoplasms. As such, it raises the possibility of ‘transformation’ of a long‐standing inflammatory process into an overt lymphoma.     

A review of the solitary cutaneous T‐cell lymphomas

Cutaneous T‐cell lymphomas (CTCL) account for almost 65‐92% of all cutaneous lymphomas, many of which usually present with multiple lesions. However, a number of well‐recognized and rare types of CTCL, including mycosis fungoides, can present in isolated fashion. These solitary lesions often run a relatively indolent clinical course but often pose diagnostic difficulties. We review histopathologically challenging solitary cutaneous T‐cell lymphomas, including criteria for diagnosis, clinical course and prognosis, particularly for primary cutaneous CD4+ small/medium pleomorphic lymphoma and indolent CD8+ lymphoid proliferation of acral sites. In addition, we suggest an algorithm and nomenclature to aid in the diagnosis of such problematic lesions.     

In vivo reflectance confocal microscopy assessment of the therapeutic follow‐up of cutaneous T‐cell lymphomas causing scalp alopecia

Cutaneous T‐cell lymphomas involving the scalp and determining scarring alopecias are difficult to be followed up during treatment because of the peculiar anatomical site of onset. In vivo reflectance confocal microscopy has already been reported to be useful for cutaneous T‐cell lymphoma evaluation and for therapeutic follow‐up in inflammatory skin conditions. We describe a case of a 26‐year‐old man affected by cutaneous T‐cell lymphoma affecting the scalp in which reflectance confocal microscopy demonstrated to be useful for in vivo evaluation of the therapeutic response to topical and systemic treatment.     

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.     

Primary cutaneous T cell lymphomas: photochemotherapy immunomodulation with analysis of the inflammatory‐expansive cellular dynamic

Primary cutaneous T cell lymphomas (CTCLs) are characterized by hyperproliferation of malignant CD4+ T cells with primary localization on the skin. The common characteristics are the migration of the malignant mature T‐lymphocytes into the epidermis, with hyperproliferation of malignant CD4+ T cells and epidermotropism. Sézary syndrome (SS) is the leukemic variant. It was established that CTCLs arise from a clonal expansion of CD4+ T cells with an identical rearrangement of the T cell receptor. The purpose of this study was to evaluate the immunomodulation effect of photochemotherapy‐A (psoralen plus ultraviolet A (PUVA)). Pre‐ and post‐PUVA punch skin biopsies of nine patients were stained immunohistochemically for CD34+, CD8+, CD7+, CD16+, CD56+, CD1a+, Bcl2+, p53+, CD45RA+, and CD45RO+ cells. The results showed a pre‐PUVA cells/mm² without significant difference among expansive or reactive cells. Post‐PUVA analysis showed a significant decrease in the mean of expansive‐reactive cells. PUVA immunomodulated decreasing cellular infiltrate. These findings could contribute to the comprehension of how PUVA acts. We achieved ectoscopic clearance of the lesions, although post‐PUVA, there still was a mononuclear pathological infiltrate. This result demonstrates that the PUVA treatment should only be withheld when the histological analysis is normal.     

T‐cell receptor gene rearrangement analysis of sequential biopsies in cutaneous T‐cell lymphomas with the Biomed‐2 PCR reveals transient T‐cell clones in addition to the tumor clone

Detection of a dominant T‐cell clone by T‐cell receptor (TCR) gene rearrangement analysis is often essential for the diagnosis of cutaneous T‐cell lymphomas (CTCL). The occurrence of T‐cell clones in addition to the diagnostic T‐cell clone during the course of CTCL has been reported, but the data of these studies have been contradictory. We retrospectively evaluated the data of 114 lesional skin biopsies from 26 patients with Mycosis fungoides and two patients with primary cutaneous anaplastic large cell lymphoma, which were analysed with the standardized Biomed‐2 PCR for the TCRγ and TCRβ locus. A dominant T‐cell clone was repetitively detected in 93% (26/28) of patients. Additional T‐cell clones appeared temporarily in 39% (11/28) of patients. Correlation with the clinical data did not show an association of the presence of additional T‐cell clones with age, number of treatments, progression of disease or survival. Our findings demonstrate that a persistent T‐cell clone, most likely the disease causing tumor clone, is detectable in almost all CTCL patients. In addition, transiently appearing T‐cell clones frequently occur during the course of disease. The biological relevance of these additional clones has still to be determined. However, it is important to take the possibility of additional T‐cell clones into account for diagnostic analyses.     

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.     

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.     

T‐cell receptor γ gene rearrangement in cutaneous T‐cell lymphoma: comparative study of polymerase chain reaction with denaturing gradient gel electrophoresis and GeneScan analysis

Background The usefulness of T‐cell receptor gene rearrangement (TCR‐GR) analyses for differentiating cutaneous T‐cell lymphoma (CTCL) from benign inflammatory disorders (BID) has been insufficiently studied to date. Objectives To evaluate the diagnostic value of TCR‐GR analyses, comparing polymerase chain reaction (PCR) with denaturing gradient gel electrophoresis (DGGE) analysis and BIOMED‐2 standardized protocol PCR with GeneScan analysis (BIOMED‐2‐GS). Methods Both types of PCR were performed in 157 patients evaluated for initial features suggestive of CTCL between 1996 and 2007. After clinical and histological review, the final diagnosis was CTCL in 77 cases and BID in 80 cases. Results DGGE and BIOMED‐2‐GS had a similar diagnostic value for distinguishing CTCL from BID, with a sensitivity of 74% and 77%, respectively, and a specificity of 86%. The observed concordance between both methods was 90% and the kappa coefficient was 0·79. Positivity rates did not depend on the PCR method but varied according to the type of CTCL (73–75% in mycosis fungoides, 90–100% in Sézary syndrome, 40–60% in lymphomatoid papulosis and 100% in other types). The positivity rate in BID was 14% with both methods. The most frequent BID with a monoclonal pattern were drug‐induced cutaneous lymphoid hyperplasia, erythrodermic psoriasis and pityriasis lichenoides chronica. Conclusions BIOMED‐2‐GS analysis of the TCRγ gene is as sensitive and specific as DGGE for CTCL diagnosis. In addition, BIOMED‐2‐GS is less time‐consuming and gives more information concerning the size and nature of TCR‐GR.     

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.     

CD20‐Positive nodal natural killer/T‐cell lymphoma with cutaneous involvement

CD20‐positive natural killer (NK)/T‐cell lymphoma is extremely rare. We describe a case of a CD20‐positive nodal NK/T‐cell lymphoma with cutaneous involvement in a 32‐year‐old man. The patient presented with fever, night sweats, right inguinal lymphadenopathy and multiple violaceous to erythematous nodules and plaques on the back and bilateral legs. Immunohistochemical analysis showed diffusely and strongly positive staining for CD3, CD3 epsilon, CD43, CD56, TIA‐1 and CD20 but negative staining for other B‐cell markers, including CD79a and PAX‐5 and T‐cell markers CD5 and CD7. The tumor cell nuclei were diffusely positive for Epstein–Barr virus‐encoded RNA in situ hybridization. A partial clinical response was observed after chemotherapy, indicated by the decreased size of the lymph nodes and skin lesions. It is a diagnostic challenge to deal with lymphoma cells that present with the surface proteins of both T‐ and B‐cells.     

Generalized fixed drug eruption mimicking CD8+ cutaneous T‐cell lymphoma in HIV

We present a case of a widespread fixed drug eruption histologically mimicking CD8 positive cutaneous T‐cell lymphoma (CTCL). CTCL has several potential histological and clinical mimics, and accurate diagnosis relies on a combination of clinicopathological correlation and molecular studies. We add generalized fixed drug eruption to the list of possible CTCL mimics.     

Primary cutaneous acral CD8 positive T‐cell lymphoma with extra‐cutaneous involvement: A long‐standing case with an unexpected progression

Primary cutaneous acral CD8+ T‐cell lymphoma (acral CD8+ TCL) is a new provisional entity characterized by acral skin lesions and an indolent course. We describe an extraordinary case characterized by relapsed nodules with CD8+ cytotoxic infiltrates on the left ear. After 35 years, the skin lesions spread to other acral sites, and a mass with the same histological features as the other skin lesions appeared on the nose. Multiple courses of chemotherapy led to stable disease. Histological examinations carried out at different times showed the gradual transformation of the neoplastic cells, with an increased proliferation index. Genomic analysis revealed losses in the regions harboring the genes involved in cell cycle control. This is the first case of an acral CD8+ TCL with a very long history of indolent nodular lesions progressing to extra‐cutaneous sites.     

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.     

Distinct age‐matched serum biomarker profiles in patients with cutaneous T‐cell lymphoma

Immunological functions decline with age. Because MS/SzS predominately affects the elderly, it is important to distinguish age‐related from cancer‐specific changes. Also, MF and SzS are malignancies of CD4⁺ T‐lymphocytes, further compromising an immune state of the patients. The objectives of this study were to distinguish disease‐specific immunological deterioration by performing comparative age ‐ matched Luminex multiplex assessment of 34 serum biomarkers between patients with MF/SzS, HIV‐infected individuals and normal controls. Controlling for age, expression level appears to significantly differ between patients with MF/SzS and controls for the following biomarkers: G‐CSF, IL‐5, MIP‐1β, TNF‐α, VEGF, EOTAXIN, IL‐8, IL‐12, IL‐2R, IP10, MCP‐1, MIG, TNFR1 and TNFR2 (P < 0.05), while others showed normal age‐related changes. Interestingly, cluster analysis placed MF/SzS profiles closer to HIV. This further underscores an immunologically compromised state of patients with MF/SzS and suggests its potential self‐perpetuating role in disease progression.