Spindle-cell (Sarcomatoid) Variant of Cutaneous Anaplastic Large-cell Lymphoma (C-ALCL): An Unusual Mimicker of Cutaneous Malignant Mesenchymal Tumors-A Series of 11 Cases.

Cutaneous anaplastic large-cell lymphoma (C-ALCL) represents one of the entities within the group of CD30-positive lymphoproliferative disorders of the skin. Most cases are ALK-negative, though isolated cases of ALK-positive C-ALCL have also been reported. By definition, the diagnosis of C-ALCL requires the expression of CD30 in >75% of the cells. Histopathologically, C-ALCL shows a dermal-based nodular and circumscribed proliferation of large pleomorphic cells with vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm, including hallmark cells. Since 1990, isolated case reports of a so-called "sarcomatoid" variant have been published in the literature. Herein, we present a series of 11 cases of spindle (sarcomatoid) C-ALCL, with comprehensive histopathologic, immunophenotypic, and molecular data. Spindle C-ALCL represents a potential mimicker of malignant mesenchymal or hematopoietic tumors in the skin and should always be considered in the differential diagnosis when assessing cutaneous pleomorphic spindle cell neoplasms.

Primary Cutaneous CD30+ Lymphoproliferative Disorders: a Comprehensive Review.

PURPOSE OF REVIEW: Primary cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPDs) are the second most common cutaneous lymphomas after mycosis fungoides and Sezary syndrome. They include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP), and borderline lesions. The purpose of this literature review is to consolidate the available evidence on the primary cutaneous CD30+ LPD in order to define the tools for correct diagnosis and appropriate treatment. RECENT FINDINGS: The current body of knowledge regarding the clinical features, histopathologic changes, recently described genetic alterations, and therapeutic options will be covered in this comprehensive review. Primary cutaneous CD30+ LPD represent rare cutaneous lymphomas that have significant histologic overlap within the defined group as well as with other neoplastic and reactive entities. The importance of differentiating these entities is crucial, as each one has a different clinical course and prognosis.

Diagnosis of T-cell lymphoid proliferations of the skin: putting all the pieces together.

The spectrum of T-cell lymphoid proliferations of the skin varies from indolent to highly aggressive diseases and therefore an accurate pathological diagnosis is paramount. Integration of clinical, histopathological, immunohistochemical, and molecular findings is of crucial importance in the evaluation of these processes. In this article, we discuss selected situations where difficulty may arise for the pathologist evaluating this type of skin biopsies, such as: the diagnosis of early (patch stage) mycosis fungoides, the distinction of mycosis fungoides with large cell transformation from primary cutaneous anaplastic large cell lymphoma, the recognition of new histopathological patterns of lymphomatoid papulosis and the entities they mimic, the evaluation of primary cutaneous anaplastic large cell lymphoma with expression of markers suggestive of systemic origin (such as ALK), the awareness of the wide range of clinical and pathological presentations of hydroa vacciniforme-like EBV-positive T-cell lymphoproliferative disorders, the evaluation of cases of primary cutaneous γδ T-cell lymphoma showing predominantly epidermotropic pattern of growth, and the correct interpretation of findings seen in indolent proliferations such as primary cutaneous acral CD8-positive T-cell lymphoma and primary cutaneous small/medium size CD4 + T-cell lymphoproliferative disorder.

Primary Cutaneous Anaplastic Large-Cell Lymphoma With 6p25.3 Rearrangement in a Cardiac Transplant Recipient: A Case Report and Review of the Literature.

Posttransplant lymphoproliferative disorders define an important form of lymphoproliferative disease causally linked with a state of iatrogenic immune dysregulation inherent to the posttransplant setting. Most posttransplant lymphoproliferative disorders are in the context of Epstein-Barr virus-associated B-cell lymphoproliferative disease, most notably diffuse large-cell B-cell lymphoma. A less common variant falls under the rubric of posttransplant T-cell lymphoproliferative disease, which is largely unrelated to Epstein-Barr virus infection. Anaplastic large-cell lymphoma (ALCL) is the most recognized form of posttransplant T-cell lymphoproliferative disease. Although the 6p25.3 translocation is seen in a variety of B-cell lymphoproliferative disorders, this particular translocation in the spectrum of T-cell lymphoproliferative disease is a fairly specific finding pointing toward a diagnosis of primary cutaneous ALCL and a rare subset of lymphomatoid papulosis. This translocation in the peripheral T-cell lymphoma setting serves as a favorable prognostic predictor. We report a case of an 81-year-old heart transplant recipient who developed an expansile neck mass 17 years after his heart transplant. A diagnosis of cutaneous ALCL was subsequently made with cytogenetic analysis yielding the 6p25.3 translocation. The characteristic biphasic morphology of a small-cell epidermotropic neoplastic cell populace in concert with a dermal based large-cell infiltrate characteristic for those cases of ALCL harboring this translocation was seen. After excision of the nodule, his azathioprine was withheld. He is currently alive and well without evidence of disease.

Intralymphatic Spread Is a Common Finding in Cutaneous CD30+ Lymphoproliferative Disorders.

An intralymphatic variant of the cutaneous CD30 lymphoproliferative disorders (cutaneous anaplastic large cell lymphoma [ALCL] and lymphomatoid papulosis [LyP]) has been described recently. We retrieved 60 cases of ALCL of the skin (primary cutaneous: 37; cases with concomitant involvement of 1 regional lymph node: 4; skin involvement from systemic disease: 4; cases with staging results unknown: 15) and 16 cases of LyP, to evaluate the presence of lymphatic vessel involvement by neoplastic cells. A D2-40 immunohistochemical staining was used to highlight lymphatic vessels. Lymphatic vessel involvement was found in 36 cases (60%) of ALCL (primary cutaneous: 24; concomitant: 3; secondary cutaneous: 4; staging unknown: 5), and in 6 cases (37.5%) of LyP. Follow-up data, available in 28 patients with ALCL and 11 with LyP, suggested that lymphatic vessel involvement had no negative prognostic implication. Our study demonstrates that cutaneous CD30 lymphoproliferative disorders are frequently characterized by involvement of the lymphatic vessels. The intralymphatic variant of ALCL and LyP may be explained, at least in part, by a particular lymphotropism of the neoplastic cells of cutaneous CD30 lymphoproliferative disorders.

Results of a Phase II Trial of Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and Lymphomatoid Papulosis.

PURPOSE: Brentuximab vedotin, a monoclonal antibody (cAC10) conjugated to monomethyl auristatin E, targets CD30(+) receptors. This phase II open-label trial was conducted to evaluate safety and efficacy in CD30(+) cutaneous T-cell lymphomas. PATIENTS AND METHODS: Forty-eight patients with CD30(+) lymphoproliferative disorders or mycosis fungoides (MF) received an infusion of 1.8 mg/kg every 21 days. RESULTS: Forty-eight evaluable patients (22 women and 26 men; median age, 59.5 years) had an overall response rate of 73% (95% CI, 60% to 86%; 35 of 48 patients) and complete response rate of 35% (95% CI, 22% to 49%; 17 of 48 patients). Fifteen (54%; 95% CI, 31% to 59%) of 28 patients with MF responded, independent of CD30 expression. In patients with MF/Sézary syndrome, the overall response rate was 50% (five of 10 patients) in patients with low CD30 expression (< 10%), 58% (seven of 12 patients) in patients with medium expression (10% to 50%), and 50% (three of six patients) in patients with high expression (≥ 50%). Time to response was 12 weeks (range, 3 to 39 weeks), and duration of response was 32 weeks (range, 3 to 93 weeks). All patients with lymphomatoid papulosis (n = 9) and primary cutaneous anaplastic T-cell lymphomas (n = 2) responded; time to response was 3 weeks (range, 3 to 9 weeks), and median duration of response was 26 weeks (range, 6 to 44 weeks). Soluble baseline CD30 levels were lowest in complete responders (P = .036). Grade 1 to 2 peripheral neuropathy was observed in 65% of patients (95% CI, 52% to 79%; 31 of 48 patients), is still ongoing in 55% of patients (95% CI, 41% to 69%; 17 of 31 patients), and resolved in 45% of patients (95% CI, 31% to 59%; 14 of 31 patients), with a median time to resolution of 41.5 weeks. Grade 3 to 4 events were neutropenia (n = 5), nausea (n = 2), chest pain (n = 2), deep vein thrombosis (n = 1), transaminitis (n = 1), and dehydration (n = 1). Dose reductions to 1.2 mg/kg were instituted as a result of grade 2 neuropathy (n = 6), transaminitis (n = 1), and arthralgias and fatigue (n = 2). CONCLUSION: Brentuximab vedotin is both active and well tolerated in cutaneous T-cell lymphoma and lymphomatoid papulosis, with an overall response rate of 73% and complete response rate of 35%.

Expression of T-follicular helper markers in sequential biopsies of progressive mycosis fungoides and other primary cutaneous T-cell lymphomas.

T-follicular helper (Tfh) lymphocytes represent the neoplastic cells of angioimmunoblastic T-cell lymphoma and have been observed also in several cutaneous T-cell lymphomas (CTCLs) and extracutaneous T-cell lymphomas, including peripheral T-cell lymphoma, not otherwise specified, mycosis fungoides (MF), cutaneous CD4 small/medium T-cell lymphoma (CD4SMTCL), and Sezary syndrome. We studied a large number of different types of primary CTCL for expression of Tfh markers, including 36 biopsies from 21 patients with MF (with sequential biopsies from patch stage and tumor stage of 15 patients), 13 patients with CD4SMTCL, 9 with lymphomatoid papulosis, 11 with cutaneous anaplastic large cell lymphoma (cALCL), 2 with cutaneous γ/δ T-cell lymphoma, 8 with subcutaneous panniculitis-like T-cell lymphoma, 3 with cutaneous aggressive epidermotropic CD8 cytotoxic T-cell lymphoma, 6 with cutaneous peripheral T-cell lymphoma, not otherwise specified, and 1 with Sezary syndrome. Expression of at least 3 of 5 markers (PD-1, CXCL-13, ICOS, Bcl-6, and CD10) in >10% of tumor cells was observed in 33 biopsies (MF = 20; CD4SMTCL = 11; 1 each cutaneous anaplastic large cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma, respectively). Our study shows that a Tfh phenotype is very common in MF and CD4SMTCL but can be observed rarely also in other types of CTCL. Expression of Tfh markers should not be used for classification of any entity of CTCL and may only integrate other immunohistochemical stainings for a more accurate characterization of these disorders. Precise distinction of Tfh-positive CTCLs from secondary skin manifestations of angioimmunoblastic T-cell lymphoma cannot rest on demonstration of a Tfh phenotype alone and should be achieved by a synthesis of clinical, histological, and phenotypic features.

Congenital primary cutaneous anaplastic large-cell lymphoma: a case report.

Primary cutaneous anaplastic large-cell lymphoma (C-ALCL) is the second most common type of primary cutaneous T-cell lymphoma. The median age of onset of C-ALCL is 60 years. Presented here is a case of congenital CD30-positive (CD30(+)) primary C-ALCL in a 10-day-old neonate who presented with a large erythematous indurative plaque in the right postauricular area. A systemic workup of the patient excluded other potential causes. The neonate was treated with wide excision, but chemotherapy or radiation therapy was not administered, as the patient's parents did not consent to such treatment. The patient has been monitored for 30 months after excision and there has been no disease recurrence. C-ALCL rarely occurs in children, and to the best of our knowledge, this is the first reported case of a neonate with congenital primary C-ALCL.

Primary cutaneous γδ-T-cell lymphoma (CGD-TCL) with unilateral lower extremity swelling as first-onset symptom: a rare case report.

Primary cutaneous γδ-T-cell lymphoma (CGD-TCL) is a distinct disease entity which is an extremely rare neoplasm with poor prognosis, characterized by the γ/δ T-cell receptor expression on atypical lymphocytes. We report the case of a 42-year-old man who first presented with a swelling in the extremities and subsequent appeared subcutaneous nodule over the body. In order to clarify the diagnosis, a biopsy of subcutaneous nodule for pathology had been done. CGD-TCL was diagnosed by histopathology, immunophenotype, in situ hybridization and analysis of TCRγ genes rearrangement. The patient was treated with chemotherapeutic regimens-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone). After one period of chemotherapy, subcutaneous nodules became small, even disappeared, swelling and ulcer in the left pedal gone away gradually. One month later after first chemotherapy, tumor relapsed with lesions growing back rapidly, also showed disease in double lungs. The patient was just 10-month survival time from the onset. To our knowledge, this case is the first report of CGD-TCL with unilateral lower extremity swelling as the first-onset symptom. If patient is presented the first symptoms such as swelling of extremities, especially when ulceration appears, it is of great significance to be considerate about the possibility of CGD-TCL.

Intralymphatic cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis: expanding the spectrum of CD30-positive lymphoproliferative disorders.

Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information.

Peripheral T cell and natural killer (NK) T cell lymphomas: a clinicopathological study from a single Australian centre.

AIMS: Using pathological and clinical review, to identify all cases diagnosed as peripheral T cell and natural killer (NK) T cell lymphoma over 10 years from one metropolitan Australian hospital. METHODS AND RESULTS: Subtyping was performed using World Health Organization (WHO) 2008 criteria and a comprehensive immunohistochemical panel. Clinical data including follow-up were obtained. There were 47 cases, including 11 peripheral T cell lymphomas, not otherwise specified (NOS), nine extranodal NK T cell lymphomas, nasal type (eight nasal), eight primary cutaneous anaplastic large cell lymphomas, seven angioimmunoblastic T cell lymphomas, three anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphomas, four ALK-negative anaplastic large cell lymphomas, three enteropathic T cell lymphomas and two subcutaneous panniculitis-like T cell lymphomas. Follow-up of 46 of 47 cases (median time 45 months) revealed that 50% (23 of 46) of patients died. Five-year survival rates were: peripheral T cell lymphoma, NOS 39%; angioimmunoblastic T cell, 43%; nasal NK T 67%; ALK-negative anaplastic large cell lymphoma 67% (at 2 years); ALK(+) anaplastic large cell lymphoma 33%; subcutaneous panniculitis-like T cell lymphomas 100%; primary cutaneous anaplastic large cell lymphoma 86%; and enteropathic T cell lymphoma 33% (at 1 year). One patient with Lennert lymphoma suffered four late cutaneous relapses. CONCLUSIONS: This first Australian clinicopathological series of peripheral T cell and NK T cell lymphoma shows epidemiological and survival data similar to those for Europe and North America.

Selective IgM deficiency in CD30+ cutaneous lymphoproliferative disorder.

Primary cutaneous anaplastic large cell lymphoma with local lymph node involvement was diagnosed in a 13-year-old boy with an ulcerative facial lesion and a history of skin lesions of lymphomatoid papulosis. The tumor regressed with chemotherapy. He continued to develop recurrent self-limited lesions of lymphomatoid papulosis , with a halo surrounding these lesions during the healing phase. He developed selective immunoglobulin M deficiency with decline in levels even 4 years after the chemotherapy with no recurrent infections noted and adequate IgG response to immunizations. Both peripheral blood IgM+ and memory B cells were low, suggesting a possible cause-effect relationship between selective immunoglobulin M deficiency and chronic CD30+ cutaneous lymphoproliferative disorders.

Pyogenic variant of primary cutaneous anaplastic large-cell lymphoma: a lymphoproliferative disorder with a predilection for the immunocompromized and the young.

Cutaneous anaplastic large-cell lymphoma belongs to the class of primary cutaneous CD30-positive lymphoproliferative disorders. The pyogenic variant is marked by a neutrophil rich inflammatory background. We describe 2 cases (one which clinically presented as cellulitis, and another arising in a patient with Hodgkin lymphoma) and review the clinicopathologic features of cases reported in the literature. In all cases, the male to female ratio is 1.2:1. The average age at presentation for patients with this variant is 47 years old with 15% of patients being 25 years old or younger. Thirteen percent of patients are immunocompromized. Ten percent of patients experience extracutaneous disease progression and 18% of patients are dead at 10 months. Immunophenotypically, the anaplastic large cells demonstrate loss of pan-T cell antigens, CD2, CD3, CD5, and CD7, with 65% of cases expressing CD4 and 29% of cases expressing CD8. Epithelial membrane antigen expression is reported in over half of the cases. In the clinical context of a progressive ulcerating lesion in younger or immunocompromized patients, it is important for the pathologist when presented with a skin specimen demonstrating a neutrophil-rich inflammatory background to include the pyogenic variant of anaplastic large-cell lymphoma. We hope to increase awareness of this rare CD30-positive lymphoproliferative disorder subtype by better defining the clinical spectrum in which this entity can present.

Neutrophil/eosinophil-rich type of primary cutaneous anaplastic large cell lymphoma: a clinicopathological, immunophenotypic and molecular study of nine cases.

AIMS: To elucidate the clinicopathological, immunophenotypic and molecular features of neutrophil/eosinophil-rich primary cutaneous anaplastic large cell lymphoma (CALCL), and to emphasize the cutaneous manifestations, differential diagnosis and prognosis of this peculiar entity. METHODS AND RESULTS: We described the clinical presentations, histopathology, immunophenotype, molecular features and follow-up courses of nine neutrophil/eosinophil-rich CALCL cases. Various clinical lesions including multiple nodules, plaques and solitary exophytic masses with or without ulceration or crusting were noted in nine patients. Two patients died of disease progression, with one developing multiple lymph node involvement. Histologically, cohesive sheets or small clusters of neoplastic cells were admixed with large numbers of neutrophils and/or eosinophils, representing 10-40% of cells per high-power field. All nine cases showed T-cell phenotypes. The frequency of rearranged TCRB, TCRG and TCRD genes in six cases with available paraffin-embedded tissue was 100%, 83% and 33%, respectively. CONCLUSIONS: Neutrophil/eosinophil-rich CALCL should be differentiated from various infectious and non-infectious diseases, especially from non-neoplastic cutaneous CD30+ infiltrates rich in neutrophils and eosinophils. Precise correlation of clinical presentation, morphological features, phenotypic and molecular analysis can help to establish the correct diagnosis. Whether this rare variant has a significantly different prognosis from classical CALCL needs further investigation.

Diagnostic and prognostic evaluation of phenotypic markers TRAF1, MUM1, BCL2 and CD15 in cutaneous CD30-positive lymphoproliferative disorders.

BACKGROUND: CD30 is expressed in various types of cutaneous lymphomas, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (C-ALCL), some cases of mycosis fungoides showing large cell transformation (MF-TR) and skin localizations of systemic anaplastic lymphoma kinase (ALK)-positive or ALK-negative ALCL. Differentiation between these entities is often not possible on the basis of histology alone, but several markers, including TRAF1, MUM1 and BCL2, have been reported to provide additional diagnostic information. OBJECTIVE: To evaluate the diagnostic and prognostic significance of these markers in a large group of cutaneous CD30-positive lymphoproliferations. METHODS: An immunohistochemical study on the expression of TRAF1, MUM1, BCL2 and CD15 was performed on skin biopsies from 28 patients with C-ALCL, 39 patients with LyP, 11 patients with CD30-positive MF-TR, two with ALK-positive ALCL and six with ALK-negative ALCL. In addition, the prognostic significance of these markers was evaluated. RESULTS: TRAF1 was expressed in roughly 70-80% and MUM1 was expressed in 70-100% of all the groups of cutaneous CD30-positive lymphoproliferations. Highest levels of BCL2 were expressed in MF-TR (73%), in contrast to 21% in C-ALCL and 36% in LyP. Highest levels of CD15 were expressed in C-ALCL (43%), compared with 18% in LyP and 9% in MF-TR. A relationship with survival was not clear. CONCLUSIONS: The results of the present study suggest that TRAF1, MUM1, BCL2 and CD15 cannot be considered as useful diagnostic or prognostic marker in cutaneous CD30-positive lymphoproliferations. Differentiation between these different conditions should be based on a combination of clinical, histological and immunophenotypical criteria.