Cutaneous Anaplastic Large Cell Lymphoma Research Articles

Transformed Mycosis Fungoides and Mimics: Exploring the Landscape of CD30+ Cutaneous T-Cell Lymphomas

Abstract Mycosis fungoides (MF) is an epidermotropic, primary cutaneous T-cell lymphoma (CTCL) with a generally indolent clinical course, although higher stage and transformed tumors can behave more aggressively. Large cell transformation may demonstrate CD30 expression and histologically resemble other CD30+ CTCLs, including lymphomatoid papulomatosis and cutaneous anaplastic large cell lymphoma. These entities are thought to exist on a spectrum with overlapping histologic features; however, it is of clinical importance that we do our best to accurately classify these entities due to the variability in treatment and prognosis. In this report, we present a case of CD30+ transformed MF and discuss the clues that allow us to make the challenging distinction between transformed MF and other CD30+ CTCLs. We review histologic and clinical features of these different disorders, with a focus on the revised World Health Organization classification of primary cutaneous lymphomas.

A case of pediatric CD30+ primary cutaneous anaplastic large cell lymphoma

A case of pediatric CD30+ primary cutaneous anaplastic large cell lymphoma

Ulcerated nodules in a sporotrichoid distribution—A rare case of primary cutaneous anaplastic large cell lymphoma

Ulcerated nodules in a sporotrichoid distribution—A rare case of primary cutaneous anaplastic large cell lymphoma

Potentials of brentuximab vedotin in the treatment of relapse/refractory cutaneous T-cell lymphomas: literature review and authors’ observation

Primary cutaneous T-cell lymphomas encompass a heterogeneous group of T-cell lymphoproliferative disorders developing primarily in the skin and characterized by a number of specific diagnostic, clinical, and therapeutic features. Mycosis fungoides accounts for more than half of all cutaneous lymphoma cases, while CD30+ lymphoproliferative diseases of the skin (primary cutaneous anaplastic large-cell lymphoma and lymphomatoid papulosis) constitute one-fourth of them and the remaining cases are rare tumour types, including primary cutaneous peripheral T-cell lymphoma, unspecified/not otherwise specified.Activation antigen СD30 is a cell membrane glycoprotein of the tumour necrosis factor family. More than 75 % of primary cutaneous CD30-positive lymphoma cells express CD30; it may be detected in other diseases as well, but to a lesser extent.Most patients with cutaneous CD30+ lymphoproliferative diseases have indolent disease and a favourable prognosis; resistant disease is observed in approximately 30 % of sufferers, and fatal outcomes occur in 8 % of cases [1].Systemic immunomodulatory therapy or chemotherapy is often used in advanced disease. Monoclonal antibodies were recently introduced into clinical practice for the treatment of cutaneous lymphomas. One of these agents is brentuximab vedotin, a CD30-monoclonal antibody conjugated to monomethyl auristatin E.We present two case reports: one of frequently recurring lymphomatoid papulosis and the other of refractory primary cutaneous peripheral T-cell lymphoma, unspecified/not otherwise specified. Targeted therapy with brentuximab vedotin, either alone or in combination with chemotherapy, resulted in a sustained, long-lasting remission in both cases.

18F-FDG PET/CT in Lymphomatoid Papulosis Mimicking Primary Cutaneous Anaplastic Large Cell Lymphoma

Lymphomatoid papulosis is a benign self-healing condition, presenting as papulonodular skin eruptions and mimicking malignant cutaneous lymphomas histopathologically. F-FDG PET/CT findings in this benign condition have not been described in detail in the literature. We present a case of lymphomatoid papulosis mimicking primary cutaneous anaplastic large cell lymphoma histopathologically and demonstrating intensely FDG-avid cutaneous lesions on F-FDG PET/CT, which disappear spontaneously in the follow-up scan.

Successful experience of combined immunochemotherapy at refractory course of primary cutaneous peripheral T-cell lymphoma, unspecified

Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of T-cell lymphoproliferative diseases that involve mainly the skin and are characterized by features of their diagnosis, clinical course and therapeutic approach. They include mainly fungal mycosis and CD30 + lymphoproliferative skin diseases (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis) which account for >50% of CTCL and primary cutaneous peripheral T-cell lymphoma, unspecified/ /not otherwise specified (PTL NOS) which occurs extremely rare. Activation antigen CD30 is a cell membrane glycoprotein that belongs to tumor necrosis factor (TNF) superfamily. Tumor cells in primary skin CD30-positive skin lymphomas express CD30 in more than 75%; in other nosological units it also can be detected but to a lesser extent. Most patients with cutaneous CD30 + lymphoproliferative diseases have an indolent the disease course of the disease with a favorable prognosis. Refractory course occurs in approximately 30% patients, and in 8% of cases lymphoma results in deaths. Recently monoclonal antibodies have been included in clinical practice for the treatment of T-cell lymphomas, one of which is brentuximab vedotin, a CD30 monoclonal antibody conjugated to monomethyl auristatin E. This article provides the clinical case of a patient with a refractory form of PTL NOS.

Response to brentuximab vedotin by CD30 expression: Results from five trials in PTCL, CTCL, and B-cell lymphomas.

7543 Background: Brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, has been evaluated in multiple trials in patients (pts) with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell lymphoma. We examined the ability of CD30 expression level to predict response to BV across these patient populations. Methods: Data were integrated from 275 pts with PTCL, CTCL, and B-cell lymphoma treated with BV from 5 prospective clinical trials. Study SGN35-012 evaluated BV plus rituximab or BV monotherapy in pts with relapsed/refractory non-Hodgkin lymphoma. The ALCANZA study compared BV to physician’s choice of methotrexate or bexarotene in pts with mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL). Three investigator-sponsored trials evaluated BV monotherapy in pts with relapsed PTCL, MF, and pcALCL (35-IST-030, 35-IST-001, 35-IST-002). Exploratory analyses were conducted to examine the relationship between CD30 expression and objective response rate (ORR) for pts with CD30 expression ≥10%, <10%, or undetectable (0%) by IHC (malignant cells or lymphoid infiltrate; local review). Results: 143 pts had tumors with CD30 <10%, including 58/143 with undetectable CD30. Activity with BV was observed at all levels of CD30 expression, including CD30=0 (Table). Analysis of the interaction between CD30 and duration of response is ongoing and will be presented in the final poster. ORR by CD30 expression, n/N (%). Clinical trial information: NCT01421667, NCT02588651, NCT01578499, NCT01352520, NCT01396070. Conclusions: CD30 expression levels ≥10%, <10%, or undetectable did not predict response to BV in a range of CD30-expressing lymphomas: Clinical responses occurred in pts with CD30 low and CD30 undetectable lymphomas. Limitations of IHC, the dynamic nature and heterogeneity of cell-surface CD30 expression, and multiple mechanisms of action of BV may all contribute to this observation.[Table: see text]

Systemic, primary cutaneous, and breast implant-associated ALK-negative anaplastic large-cell lymphomas present similar biologic features despite distinct clinical behavior.

Despite distinct clinical presentation and outcome, systemic, primary cutaneous, and breast implant-associated anaplastic large cell lymphomas (S-, PC-, BI-ALCL) ALK-negative (ALK-) show similar histopathological features including the presence of the "hallmark" cells with horseshoe-shaped nuclei and CD30 protein expression. The purpose was to better characterize these three entities using immunohistochemistry and FISH (Fluorescent in situ hybridization) to identify biomarkers differently expressed and that might be involved in their pathogenesis. Twenty-two S-ALCL ALK-, 13 PC-ALCL, and 2 BI-ALCL were included. Cases were tested for P53, P63, MUM1, MYC, GATA3, p-STAT3, PD1, and PDL1 protein expression and DUP22, TP53, TP63, MYC, and PDL1 chromosomal aberrations. As expected, S-ALCL ALK- patients had adverse outcome compare to PC and BI-ALCL. No difference was observed between the three groups concerning protein expression except for MUM1 that was significantly more frequently expressed in S-ALCL ALK- compared to PC-ALCL. In particular, constitutive activation of the STAT3 pathway and PDL1/PD1 immune-checkpoint expression was present in the three entities. TP53 deletion and PDL1 gene amplification were the commonest cytogenetic alterations and were present in the three entities. None of the studied biological parameters was associated with prognosis. Despite distinct clinical behavior, S-ALCL ALK-, PC-ALCL, and BI-ALCL share similar biological features. Larger series should be investigated with the current approach to determine more precisely the activity and the prognostic value of these biomarkers and pathways in each group.

Existing and Emerging Therapies for Cutaneous T-Cell Lymphoma.

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas characterized by an infiltration of malignant monoclonal T lymphocytes into the skin. Mycosis fungoides (MF), the most common subtype, and the rarer Sézary syndrome (SS), are considered the classical forms of CTCL, which, because of a varying presentation and lack of genetic and immunophenotypical markers, can often have a delayed diagnosis. With skin-directed topical treatment being the mainstay of therapy in the early stages, there is an absence of long-term curative therapies for advanced disease. Recent insight into the pathogenesis of CTCL has identified new potential therapeutic targets including the monoclonal antibody therapies, brentuximab vedotin and mogamulizumab. Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, received extended approval by the US FDA in 2017 to include primary cutaneous anaplastic large-cell lymphoma and CD30-expressing MF. Mogamulizumab, an anti-CCR4 antibody, received FDA approval in 2018 for relapsed or refractory MF and SS. Further targets and therapies continue to be investigated, including the monoclonal antibody therapy alemtuzumab, an anti-CD52 antibody, and the immune checkpoint blockade therapies, pembrolizumab and nivolumab. These new and emerging targets and therapies may lead to a promising broadening of CTCL treatment options in the future.

The spectrum of CD30+ T cell lymphoproliferative disorders in the skin.

Primary cutaneous CD30+ T cell lymphoproliferative disorders (pcCD30+ T cell LPDs) are a spectrum of pre-malignant to frankly neoplastic lymphoproliferations that comprise lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL), and borderline lesions. Although the atypical T cells that are the hallmark of these disorders share the expression of CD30, as the identifying marker, the clinical presentation, histological features and clinical course are vastly different. Furthermore, histopathologic features of pcCD30+ T cell LPDs may overlap with other cutaneous and systemic lymphomas. While most pcCD30+ T cell LPDs have an excellent prognosis, systemic lymphomas typically have a poorer outcome. CD30 has now been shown to be a reliable therapeutic target in pcCD30+ T cell LPDs. This review will emphasize the structure and function of CD30, along with the clinical and pathological spectrum of pcCD30+ T cell LPDs. It will also highlight other CD30+ lymphoproliferations that must be differentiated by careful clinical and pathological correlation.

47. Limb amputation of a CD30 positive cutaneous T cell lymphoma

Background: Primary cutaneous lymphomas form a spectrum of disease and the overlapping features pose a diagnostic challenge. The differential diagnosis of CD30 positive primary cutaneous lymphomas includes transformation of mycosis fungoides, lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Cutaneous involvement from systemic anaplastic large cell lymphoma is also a possibility.

Local radiation for cutaneous T-cell lymphoma other than mycosis fungoides and Sézary syndrome.

Primary cutaneous lymphoma is the second most common type of extranodal lymphoma. The clinical behavior of this lymphoma differs from that of other extranodal lymphomas and thus requires a particular pretreatment evaluation and treatment strategy. Cutaneous T-cell lymphoma (CTCL) accounts for 80% of primary cutaneous lymphoma cases and includes several confirmed disease entities as well as provisional entities. Local radiation for CTCLs is applicable for both curative and palliative intents and is based on the involved-site radiotherapy (ISRT) concept. Primary cutaneous CD30-positive lymphoproliferative disorders include primary cutaneous anaplastic large-cell lymphoma (C-ALCL), lymphomatoid papulosis (LyP), and borderline lesions, all of which exhibit indolent behavior. One half of all LyP cases show spontaneous regression and do not require active treatment. Solitary or localized C-ALCL cases are treated with surgical excision or local radiation of 24-36 Gy. The most common relapse site after local treatment is other skin areas; however, skin relapse is not associated with worsened prognosis. Subcutaneous panniculitis-like T-cell lymphoma (SPTL) without hemophagocytic syndrome exhibits indolent behavior, and localized lesions can be successfully treated with local radiation of 40 Gy or more. Extranodal NK/T-cell lymphoma, nasal type has an aggressive clinical behavior even with intensive chemotherapy and a dose of 50 Gy or higher might be required for good tumor control. Palliative local radiation of 8 Gy in one or two fractions is effective in treating refractory or relapsed CTCLs. ISRT with curative intent should encompass the original suspicious lesions plus a 2-3 cm margin, while ISRT with palliative intent should encompass visible lesions plus a 1-2 cm margin. Appropriate electron beam energy and bolus thickness should be selected according to the skin surface dose and thickness of the patch and plaque lesions. All CTCL cases should be reviewed by a multidisciplinary team to ensure an appropriate treatment strategy.

Common origin of sequential cutaneous CD30+ lymphoproliferations with nodal involvement evidenced by genome‐wide clonal evolution

This study sought to clarify the molecular pathways underlying the putative evolution from lymphomatoid papulosis (LyP) to cutaneous anaplastic large-cell lymphoma (c-ALCL) and lymph node invasion (LNI). We analysed nine sequential tumours from the same patient presenting with parallel evolution of LyP (n=3) and c-ALCL (n=1) with LNI (n=1), combined with systemic diffuse large B-cell lymphoma (DLBCL) (n=4). Clonality analysis showed a common clonal T-cell origin in the five CD30+ lesions, and a common clonal B-cell origin in the four DLBCL relapses. Array-comparative genomic hybridisation and targeted next-generation sequencing analysis demonstrated relative genomic stability of LyP lesions as compared with clonally related anaplastic large-cell lymphoma (ALCL) tumours, which showed 4q and 22q13 deletions involving the PRDM8 and TIMP3 tumour suppressor genes, respectively. The three analysed CD30+ lesions showed mostly private (specific to each sample) genetic alterations, suggesting early divergence from a common precursor. In contrast, DLBCL tumours showed progressive accumulation of private alterations, indicating late divergence. Sequential cutaneous and nodal CD30+ tumours were clonally related. This suggests that LyP, c-ALCL and LNI represent a continuous spectrum of clonal evolution emerging from a common precursor of cutaneous CD30+ lymphoproliferations. Therefore, nodal ALCL tumours in the context of LyP should be considered as a form of transformation rather than composite lymphoma.

Outcome and survival in children with Non-Hodgkin’s lymphoma

Background Non-Hodgkin lymphoma is the third most common malignant tumor in children. It includes four major subtypes: Burkitt Lymphoma (BL), Lymphoblastic Lymphoma (LL), Diffuse Large B-cell Lymphoma (DLBL) and Anaplastic Large Cell Lymphoma (ALCL). The use of multidrug chemotherapy, radiation therapy, biologic agents, and improved diagnostic and supportive care resulted in better cure rates. Objective This study is to report prognosis and outcome of Non-Hodgkin lymphoma (NHL) patients at tertiary health care facility in King Faisal Specialist Hospital and Research Center, Jeddah (KFSHRC-J). Materials and Method A retrospective cross-sectional study of all eligible patients with Non-Hodgkin lymphoma (NHL), admitted, diagnosed and managed at King Faisal Specialist Hospital and Research Center, Jeddah from Jan 2005 to December 2016, previously untreated, with biopsy proven NHL and Age ≤ 15 years at diagnosis. Clinical data Research Form used to collect patient’s data from medical records. Demographic, Clinical and Survival data analysed using Statistical Package for Social Sciences. Results Thirty-one pediatric patients with biopsy proven Non-Hodgkin lymphoma (NHL) fulfilled the inclusion criteria. Twenty-six (80.6%) were males. Nineteen (61.3%) patients were ≤ 10 years of age at diagnosis, while 12 (38.7%) were>10 years of age. The mean age at diagnosis was 8.1years. The commonest primary site is abdomen (n=19, 61.3%), followed by Head & Neck (n=9, 28.1%), mediastinum (n=1, 3.1%), primary CNS (n=1, 3.1%), bone (n=1, 3.1%) and skin (n=1, 3.1%). Regarding histology 19 (61.3%) had Burkitt Lymphoma (BL), 6 (19.4%) had Diffuse Large B-cell Lymphoma (DLBL), 2(6.4%) had T-cell Lymphoblastic Lymphoma, 2 (6.4%) had T-cell rich B Cell Lymphoma, 1 (3.1%) had B-cell Lymphoma not otherwise specified and 1 (3.1%) had Cutaneous Anaplastic Large Cell Lymphoma (ALCL). Predominantly, patients presented in advanced stages III (n=18, 60%) and IV (n=10, 33%).Twenty-five (77.8%) patients completed treatment and are well to date while six of the patients (18.6%) died during the study period. Conclusion Children admitted to the (KFSHRC-J) appeared affected by non-Hodgkin Lymphoma at a younger age, with a higher incidence of Burkitt's Lymphoma. The predominant presenting site is abdomen followed by head/neck. They present mostly with advance disease. Survival rates are similar to those described in the literature of developed countries.

CD30-positive primary cutaneous lymphoproliferative disorders: molecular alterations and targeted therapies.

Primary cutaneous CD30-positive T-cell lymphoproliferative disorders are the second most common subgroup of cutaneous T-cell lymphomas. They include two clinically different entities with some overlapping features and borderline cases: lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Molecular studies of primary cutaneous anaplastic large cell lymphoma reveal an increasing level of heterogeneity that is associated with histological and immunophenotypic features of the cases and their response to specific therapies. Here, we review the most significant genetic, epigenetic and molecular alterations described to date in primary cutaneous CD30-positive T-cell lymphoproliferative disorders, and their potential as therapeutic targets.

Molluscum contagiosum infection with features of primary cutaneous anaplastic large cell lymphoma

CD30+ T cell pseudolymphomas (CD30+ PSL) are a group of benign inflammatory cutaneous disorders that can develop in settings of viral infections or drug reactions. Owing to their histological similarities to malignant lymphomas, these benign infiltrates are occasionally misdiagnosed as malignant, causing significant concerns for patients and physicians. Herein, we report a patient with CD30+ PSL associated with molluscum contagiosum whose initial biopsy revealed atypical large CD30-expressing cells, leading to a misdiagnosis of primary cutaneous anaplastic large cell lymphoma and referral to our cutaneous lymphoma clinic. We report this case to demonstrate that reactive CD30+ infiltrate associated with molluscum contagiosum can be mistaken for T-cell lymphomas and patients should be reassured in these cases.

050 - Clinical, histological and molecular characteristics of ALK-positive primary cutaneous anaplastic large cell lymphoma

050 - Clinical, histological and molecular characteristics of ALK-positive primary cutaneous anaplastic large cell lymphoma

A case of primary cutaneous anaplastic large cell lymphoma presenting with ulcers on the sole

A case of primary cutaneous anaplastic large cell lymphoma presenting with ulcers on the sole

085 - Brentuximab vedotin (BV) versus physician’s choice (PC) of methotrexate or bexarotene in adult patients with previously treated CD30-positive cutaneous T-cell lymphoma (CTCL; mycosis fungoides [MF] or primary cutaneous anaplastic large cell lymphoma [pcALCL]): final time to next therapy (TTNT) results from the phase 3 ALCANZA study

085 - Brentuximab vedotin (BV) versus physician’s choice (PC) of methotrexate or bexarotene in adult patients with previously treated CD30-positive cutaneous T-cell lymphoma (CTCL; mycosis fungoides [MF] or primary cutaneous anaplastic large cell lymphoma [pcALCL]): final time to next therapy (TTNT) results from the phase 3 ALCANZA study

011 - A retrospective analysis of patients with co-existent mycosis fungoides and primary cutaneous anaplastic large cell lymphoma from the Australian Cutaneous Lymphoma Network database

011 - A retrospective analysis of patients with co-existent mycosis fungoides and primary cutaneous anaplastic large cell lymphoma from the Australian Cutaneous Lymphoma Network database