Analysis and therapeutic targeting of the IL-1R pathway in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK- ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK- ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK- ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.

[Primary Cutaneous Anaplastic Large Cell Lymphoma:Report of One Case].

Primary cutaneous anaplastic large cell lymphoma is a rare non-Hodgkin's lymphoma.The tumor cells have the characteristics of anaplastic cells,expressing CD30 but not anaplastic lymphoma kinase.In this study,we reported a case of primary cutaneous anaplastic large cell lymphoma in a Tibetan child and summarized the clinicopathological features,aiming to strengthen the understanding of this disease.

A Rare Case of Monomorphic T-Cell Posttransplant Lymphoproliferative Disorder Presenting as Primary Cutaneous Anaplastic Large Cell Lymphoma, ALK Negative.

ABSTRACT: Posttransplant lymphoproliferative disorders are a serious complication of hematopoietic and solid organ transplants secondary to iatrogenic immunosuppression. Most cases present as B-cell proliferations which are often Epstein-Barr virus positive; however, ∼10% of cases are T/NK cell and are less commonly associated with Epstein-Barr virus. Of these, cutaneous T/NK-cell lymphomas are exceedingly rare. We report a case of a 69-year-old male, liver transplant recipient who presented with a tender, bright red papule on the left arm during his annual skin cancer screening. Histopathologic evaluation revealed pleomorphic cells with enlarged nuclei, vesicular chromatin, and frequent mitotic figures, intercalating through the dermis. The tumor formed single strands and small cords without epidermal involvement. A patchy mild mixed inflammatory infiltrate was associated with the tumor. Tumor cells were CD2(+), CD4(+), CD30(+), CD3(-), CD20(-), ALK-1(-), and EBER(-). Molecular studies revealed a monoclonal T-cell receptor gamma gene rearrangement by polymerase chain reaction (PCR); ALK gene rearrangement was negative by fluorescence in situ hybridization (FISH). Taken together, the findings were consistent with an ALK-negative anaplastic large cell lymphoma involving skin, which, given the history of liver transplant, qualified as a monomorphic T-cell posttransplant lymphoproliferative disorder. Follow-up imaging studies showed no evidence of systemic disease, supporting an interpretation of primary cutaneous anaplastic large cell lymphoma.

[Primary cutaneous anaplastic large cell lymphoma with systemic progression responding to low-dose methotrexate therapy].

The standard therapies for primary cutaneous anaplastic large cell lymphoma (pcALCL) in an advanced stage remain undefined. A 71-year-old man presented with multiple erythema and nodules. He was diagnosed with lymphomatoid papulosis (LyP) through a skin biopsy from the left postauricular area. All skin lesions achieved complete response by electron beam irradiation. However, nodular lesions appeared in both inner canthi 5 months later. Histopathological evaluation of the lesional biopsy revealed dominant infiltration of CD30-positive large cells. Positron emission tomography/computed tomography revealed fluorodeoxyglucose-positive cervical and inguinal lymph node swelling and right tonsillitis, followed by the diagnosis of pcALCL and TNM classification T3bN3M0. Since the patient had severe chronic obstructive pulmonary disease and recurrent pneumonia, he received low-dose methotrexate (MTX) (15 mg/week) therapy. Low-dose MTX effectively debulked the lymphadenopathies over time without particular adverse effects. Although the standard therapies for pcALCL are not established, low-dose MTX was effective and considered safe for patients with frailty and compromised respiratory function. Further study is warranted on the pathophysiology of pcALCL after the development of LyP and mechanisms of action of low-dose MTX against LyP and pcALCL.

A case of primary cutaneous anaplastic large cell lymphoma on eyelid.

Primary cutaneous anaplastic large cell lymphoma is a kind of cluster of differentiation 30+ primary cutaneous lymphoproliferative disorders with a relatively good prognosis in the absence of high-stage disease. Primary cutaneous anaplastic large cell lymphoma shows a higher frequency in males and commonly affects the head and neck. Palpebral involvement is very rare. We present a 42-year-old lady patient with primary cutaneous anaplastic large cell lymphoma involving the eyelid which was initially misdiagnosed as stye. The patient underwent a total excision of the lesion and showed complete regression of the lesion after surgery without any other treatment. There was no evidence of local or systemic disease during follow-up after nine months.

ALK-Negative Primary Cutaneous Anaplastic Large Cell Lymphoma With Systemic Involvement or Systemic ALCL With Cutaneous Lesion. A Diagnostic Dilemma.

ABSTRACT: Primary cutaneous anaplastic large-cell lymphoma (C-ALCL) is a cutaneous CD30-positive lymphoproliferative disorder. The patients usually present with single or multiple cutaneous nodules or papules and about 10% cases present with extracutaneous manifestations, which are predominantly in the form of regional lymph nodal involvement. Visceral involvement especially pulmonary or hepatic involvement in C-ALCL is only rarely described in the scientific literature. Approximately 20%-42% cases show spontaneous regression, about 50% cases may recur; however, C-ALCL generally carries a good prognosis. We present a rare case of primary C-ALCL in a 66-year-old man with regional lymph nodal and hepatic involvement. Differential diagnostic entities are discussed in this report with the review of the literature.

Primary Cutaneous Anaplastic Large Cell Lymphoma With 6p25.3 Rearrangement and Epidermotropism.

ABSTRACT: Primary cutaneous anaplastic large cell lymphoma may harbor a 6p25.3 rearrangement, which has been associated with an epidermotropic small cell component. We report the case of a patient with said lymphoma harboring that rearrangement. It presented as a forehead nodule, histologically composed of an intermediate-to-large cell dermal component alongside a small-to-intermediate cell epidermotropic component. After multiple cutaneous and regional lymph node relapses, disease progression has been documented to a distant lymph node, despite local radiotherapy of the cutaneous lesions, chemotherapy, and anti-CD30 therapy, albeit with an indolent course over 6 years. Cases of pcALCL with nonregional lymph node involvement are unusual. Nevertheless, in this case, progression to a distant lymph node was not associated with an aggressive transformation of the disease.

Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma.

Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological neoplasm caused by skin-homing CD30+ malignant T cells, is part of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders. To date, only a small number of molecular alterations have been described in pcALCL and, so far, no clear unifying theme that could explain the pathogenetic origin of the disease has emerged among patients. In order to clarify the pathogenetic basis of pcALCL, we performed high-resolution genetic profiling (genome/transcriptome) of this lymphoma (n=12) by using whole-genome sequencing, whole-exome sequencing and RNA sequencing. Our study, which uncovered novel genomic rearrangements, copy number alterations and small-scale mutations underlying this malignancy, revealed that the cell cycle, T-cell physiology regulation, transcription and signaling via the PI-3-K, MAPK and G-protein pathways are cellular processes commonly impacted by molecular alterations in patients with pcALCL. Recurrent events affecting cancer-associated genes included deletion of PRDM1 and TNFRSF14, gain of EZH2 and TNFRSF8, small-scale mutations in LRP1B, PDPK1 and PIK3R1 and rearrangements involving GPS2, LINC-PINT and TNK1. Consistent with the genomic data, transcriptome analysis uncovered upregulation of signal transduction routes associated with the PI-3-K, MAPK and G-protein pathways (e.g., ERK, phospholipase C, AKT). Our molecular findings suggest that inhibition of proliferation-promoting pathways altered in pcALCL (particularly PI-3-K/AKT signaling) should be explored as potential alternative therapy for patients with this lymphoma, especially, for cases that do not respond to first-line skin-directed therapies or with extracutaneous disease.

Safety and Danger Considerations of Novel Treatments for Atopic Dermatitis in Context of Primary Cutaneous Lymphomas.

The impact of new and emerging therapies on the microenvironment of primary cutaneous lymphomas (PCLs) has been recently raised in the literature. Concomitantly, novel treatments are already used or registered (dupilumab, upadacitinib) and others seem to be added to the armamentarium against atopic dermatitis. Our aim was to review the literature on interleukins 4, 13, 22, and 31, and JAK/STAT pathways in PCLs to elucidate the safety of using biologics (dupilumab, tralokinumab, fezakinumab, nemolizumab) and small molecule inhibitors (upadacitinib, baricitinib, abrocitinib, ruxolitinib, tofacitinib) in the treatment of atopic dermatitis. We summarized the current state of knowledge on this topic based on the search of the PubMed database and related references published before 21 October 2021. Our analysis suggests that some of the mentioned agents (dupilumab, ruxolitinib) and others may have a direct impact on the progression of cutaneous lymphomas. This issue requires further study and meticulous monitoring of patients receiving these drugs to ensure their safety, especially in light of the FDA warning on tofacitinib. In conclusion, in the case of the rapid progression of atopic dermatitis/eczema, especially in patients older than 40 years old, there is a necessity to perform a biopsy followed by a very careful pathological examination.

Autoimmune Manifestations as the Harbinger of Primary Cutaneous Anaplastic Large Cell Lymphoma.

Although autoimmune manifestations can be associated with various lymphomas, they are distinctly unusual with primary cutaneous anaplastic large cell lymphoma (PCALCL). We present the case of a 76-year-old woman who, over the course of 2 years, presented with a variety of autoimmune disorders including minimal change disease and focal glomerulosclerosis, visual loss due to retinal vasculitis, immune mediated thrombocytopenia, autoimmune hemolytic anemia, and inflammatory polyarthritis in conjunction with elevated rheumatoid factor, cryoglobulins, and hypocomplementemia. She ultimately developed PCALCL that took an aggressive course and to which she ultimately succumbed. Our case adds to the growing literature demonstrating autoimmune manifestations associated with a variety of lymphoid malignancies. We propose that immune dysregulation can predispose patients to the development of both autoimmune and lymphoproliferative disease. Suspicion of underlying malignancy in patients presenting with otherwise unexplained autoimmune phenomena may prompt earlier diagnosis.

Remission of refractory granulomatous primary cutaneous anaplastic large cell lymphoma to brentuximab vedotin.

Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a rare non-Hodgkin's lymphoma that arises as a single, or multiple dome-shaped tumours on the skin. The histology is characterised by the presence of atypical lymphocytes with large irregularly shaped nuclei that express the surface marker CD30. There can be significant heterogeneity in clinical manifestation and histological pattern and in rare cases accurate diagnosis can be a challenge. Here, we present an unusual case presentation of cutaneous CD30+ anaplastic large cell lymphoma with significant granulomatous histology pattern that mimicked sarcoid. After a lack of durable response to treatments that included glucocorticoid and methotrexate, targeted treatment with anti-CD30 monoclonal antibody drug conjugate (brentuximab vedotin) yielded long-term clinical remission.

Primary cutaneous anaplastic large-cell lymphoma with 6p25.3 rearrangement exhibits a biphasic histopathologic pattern: Two case reports and literature review.

BACKGROUND: Primary cutaneous CD30+ lymphoproliferative diseases are the second most common group of cutaneous T-cell lymphomas, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large-cell lymphoma (pcALCL), and borderline cases. These diseases form a spectrum and may show overlapping histopathological, phenotypic, and genetic features. In the 2016 WHO classification, LyP with 6p25.3 rearrangement was introduced as a rare new subtype of LyP and showed distinctive clinicopathological features. The striking biphasic histopathologic pattern presented with larger transformed lymphocytes diffusely infiltrating the dermis and smaller atypical cells infiltrating the epidermis as in pagetoid reticulosis. METHODS: Herein we report two cases of pcALCL with rearrangement involving the DUSP22-IRF4 locus on 6p25.3 that show the same particular biphasic histopathologic pattern. We review the literature regarding five similar reported cases and discuss the clinical, pathologic immunotype and follow-up features. RESULTS: Our findings suggest that the biphasic histopathologic pattern is not a unique characteristic of LyP with 6p25.3 rearrangement. CONCLUSION: Cutaneous CD30+ lymphoproliferative diseases with 6p25.3 rearrangement may have the same biphasic histopathological pattern and favorable prognosis, although a variety of clinical manifestations ranging from LyP to pcALCL and even anaplastic lymphoma kinase negative systemic ALCL with secondary cutaneous involvement may be observed.

Diagnosis and Management of Cutaneous Lymphomas Including Cutaneous T-cell Lymphoma.

The cutaneous lymphomas are malignancies of T-cell and B-cell lymphocytes in which the skin is the primary organ of involvement. The cutaneous T-cell lymphomas include variants that can mimic the presentation of common skin diseases or arthropod bites. Mycosis fungoides, the most common cutaneous T-cell lymphoma, usually presents as fixed asymptomatic patches or plaques in sun-protected areas. The cutaneous B-cell lymphomas have fewer variants that often present as papules or nodules that can mimic nonmelanoma skin cancers. Some therapies for cutaneous lymphoma have unique side effects such as central hypothyroidism, hyperlipidemia, and peripheral neuropathy.