Primary Cutaneous Acral CD8 Research Articles

Primary Cutaneous Acral-type CD8-positive T-cell Lymphoproliferations: Widely Divergent Clinical Outcomes Despite Nearly Identical Histomorphology

Abstract Introduction/Objective Non-epidermotropic and acral CD8(+) T-cell proliferations have recently been reclassified as lymphoproliferative disorders (LPDs) due to their indolent course clinical. Here, we describe two cases with similar histomorphology but disparate clinical outcomes, highlighting the diagnostic challenges. Methods/Case Report Case 1: An 89-year-old male developed a 2 cm erythematous papule on the forehead. Biopsy showed a non-epidermotropic pan-dermal lymphocytic infiltrate, a distinct grenz zone, and areas of necrosis. Case 2: A 53-year-old male presented with a rapidly growing, ulcerating 8.9 cm scalp lesion. Biopsy showed a deep dermal lymphoid infiltrate with complete epidermal sparing. In both cases neoplastic cells were positive by immunohistochemistry for CD2, CD3, CD5, CD7 (partial), CD8, granzyme B, TIA-1, and CD68 (perinuclear dot-like pattern). The Ki-67 proliferation index varied modestly between cases (50% in case 1 and 70% in case 2, respectively). Despite treatment, within the span of a few months, case 2 developed adjacent, widely distributed scalp nodules with extensive local tissue destruction. Pathology was consistent with recurrent disease (flow cytometry demonstrating T-cells, co-expressing CD8, CD2, CD3, CD5, CD7 and monotypic TRBC1). Results (if a Case Study enter NA) NA Conclusion CD8+ T-cell lymphoproliferative disorders, specifically primary cutaneous acral CD8+ T-cell lymphoproliferative disorder, is a rare cutaneous T-cell disorder that was re-classified, owing to its indolent clinical course, low risk of systemic dissemination, and favorable prognosis. We report two cases of nearly identical isolated cutaneous lesions that demonstrated a CD8(+)-cytotoxic phenotype with CD68-dot-like positivity. Although all morphologic findings were supportive of the diagnosis, the aggressive clinical progression in case 2 highlights the potential for the disease to defy the classically described indolent behavior. Given that few cases with aggressive clinical courses have been published, we present these cases to underscore their complexity and propose that the classification incorporate clinicopathological correlation to guide management.

Oncogenic alterations in KIR3DL1 in cutaneous acral CD8+ lymphoproliferative disorder.

Primary cutaneous acral CD8+ T-cell lymphoproliferative disorder (TLPD) is a rare and indolent lymphoma entity. Although TLPD was first identified many years ago, the molecular pathogenesis is still not fully understood. In order to better understand the molecular pathogenesis of cutaneous acral CD8+ TLPD and to identify further discriminatory markers to differentiate this lymphoma subtype from other CD8+ cutaneous lymphomas, we analysed five cases of cutaneous acral CD8+ TLPD for putative molecular alterations. Somatic alterations were assessed using whole-exome and targeted sequencing of paraffin-embedded tissue. Results were evaluated using immunohistochemical staining of respective relevant proteins. CD8+ cutaneous T-cell lymphomas (n = 12) served as control for KIR3DL1 staining. Copy number variation analysis revealed a homozygous deletion of the KIR3DL1 gene in two of the analysed cases. This resulted in loss of KIR3DL1 protein expression, which was observed in all cases of cutaneous acral CD8+ TLPD. In contrast, KIR3DL1 expression was more variable in other CD8+ cutaneous T-cell lymphomas with 50% of analysed cases (n = 12) found to be positive. In addition, one further case of acral CD8+ TLPD harboured a loss-of-function mutation in the PIK3R1 gene, presumably activating the phosphoinositide 3-kinase-AKT pathway. Alterations of the KIR3DL1 gene may be of pathogenetic relevance for acral CD8+ TLPD. Loss of KIR3DL1 protein expression may support the diagnosis of this indolent lymphoma entity; however, this is not a subtype-specific discriminative feature.

Update on primary cutaneous T-cell lymphomas rare subtypes.

Rare subtypes of cutaneous T-cell lymphomas (CTCL) include four entities, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorders, primary cutaneous acral CD8+ T-cell lymphoma, which were previously considered provisional and are now included in the new 5th World Health Organization classification of hematolymphoid tumors as distinct entities. An updated summary of the clinical, histological, and genomic characteristics of these uncommon CTCL subtypes is given in this review, with a focus on the growing body of knowledge regarding their classification and possible treatment strategies.

Cutaneous lymphoproliferative disorders: Back to the future.

In the 1980s, immunohistochemistry and clonality analyses became instrumental in the recognition and definition of new types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL) and the development of new classifications. By accepting loss of pan-T-cell antigens and clonal T-cell receptor gene rearrangements as important criteria to differentiate between benign and malignant T-cell proliferations, and monotypic immunoglobulin light-chain expression and clonal immunoglobulin gene rearrangements as crucial criteria to distinguish between benign and malignant B-cell proliferations, many cases, until then diagnosed as cutaneous lymphoid hyperplasia or pseudolymphoma, were reclassified as primary cutaneous CD4+ small/medium T-cell lymphoma (PCSM-TCL) or primary cutaneous marginal zone lymphoma (PCMZL), respectively. However, in recent years there is growing awareness that neither these immunohistochemical criteria nor demonstration of T-cell or B-cell clonality is specific for malignant lymphomas. In addition, many studies have reported that these low-grade malignant CTCL and CBCL have an indolent clinical behavior and an excellent prognosis with disease-specific survival rates of or close to 100%. As a result, recent classifications have downgraded several low-grade malignant cutaneous lymphomas to lymphoproliferative disorder (LPD). Both the 5th edition of the WHO classification (2022) and the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms reclassified PCSM-TCL as primary cutaneous CD4+ small/medium T-cell LPD and primary cutaneous acral CD8+ T-cell lymphoma as primary cutaneous acral CD8+ T cell LPD. While the 2022 ICC introduced the term "primary cutaneous marginal zone LPD," in the 5th edition of the WHO classification PCMZL is maintained. In this review we describe the background and rationale of the continually changing terminology of these conditions and discuss the clinical consequences of downgrading malignant lymphomas to LPDs.

Clinical, histopathological and prognostic features of primary cutaneous acral CD8+ T-cell lymphoma and other dermal CD8+ cutaneous lymphoproliferations: results of an EORTC Cutaneous Lymphoma Group workshop.

The differential diagnosis of atypical dermal nonepidermotropic CD8+ lymphocytic infiltrates includes a heterogeneous spectrum of lymphoproliferations with overlapping histological and phenotypic features, but divergent clinical manifestations and prognoses. As these neoplasms are rare, more data on their clinicopathological presentation and course are needed. To assess the clinical, histological and immunophenotypic features; outcomes of; and differences between dermal CD8+ lymphoproliferations. Retrospective analysis of a series of 46 patients and biopsies by the international EORTC Cutaneous Lymphoma Group. The dermal CD8+ lymphoproliferations (n = 46) could be assigned to one of three groups: (i) cutaneous acral CD8+ T-cell lymphoma (n = 31), characterized mostly by a solitary nodule arising at acral sites, a monotonous dermal infiltrate of small-to-medium-sized CD8+ lymphocytes with a characteristic dot-like pattern of CD68, a low proliferation rate and an excellent prognosis; (ii) primary cutaneous CD8+ peripheral T-cell lymphoma, unspecified/NOS (n = 11), presenting with one or multiple rapidly evolving tumours, mostly medium-sized pleomorphic CD8+ tumour cells with expression of several cytotoxic markers, and high proliferative activity; and (iii) cutaneous CD8+ lymphoproliferations (n = 4), associated with congenital immunodeficiency syndromes in two patients with persisting localized or disseminated violaceous to brownish plaques on the extremities, a histiocyte-rich infiltrate of mostly small CD8+ lymphocytes with subtle atypia and a protracted course; and papular CD8+ eruptions in two patients with acquired immunosuppression. A constellation of distinct clinical, histopathological and phenotypic features allows discrimination and assignment of dermal CD8+ infiltrates into distinct disease entities. Primary cutaneous acral CD8+ lymphoma, assigned a provisional category in current lymphoma classifications, is a distinct and reproducible entity. A correct diagnosis is essential to avoid unnecessarily aggressive treatment for indolent CD8+ lymphoproliferations and to identify cases with underlying immuno-deficiency or potential for dismal outcome.

Primary cutaneous lymphoma: the 2018 update of the WHO-EORTC classification

Primary cutaneous lymphomas are a heterogeneous group of cutaneous T-cell lymphomas (CTCL) and cutaneous B-cell lymphomas (CBCL) that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. In the last decade the 2005 WHO-EORTC consensus classification has served as a golden standard for the diagnosis and classification of these conditions. Recently, an updated version of the WHO-EORTC was published. This classification contains several new entities, including primary cutaneous acral CD8+ T-cell lymphoma and EBV-positive mucocutaneous ulcer, while other conditions were slightly modified. Herein, the characteristic features of the different types of CTCL and CBCL are presented, differences with previous classification schemes discussed and the results of more recent molecular studies with clinical implications for these conditions reviewed. In addition, an update of the frequency and survival of the different types of primary cutaneous lymphomas is provided.

Primary Cutaneous Acral CD8+ T-Cell Lymphoma—A Single Center Review of 3 Cases and Recent Literature Review

The recently published 2016 revision of the WHO classification of lymphoid neoplasms includes primary cutaneous acral CD8-positive T-cell lymphoma (PCATCL) as a provisional entity. This is a rare indolent lymphoma characterized by papules or nodules on the ear and a dermal infiltrate of CD8-positive T-lymphocytes with cytotoxic marker expression. A retrospective review of a single institutional experience with PCATCL identified 3 patients (mean age 54; range 49-62) with papules or nodules on the ear. Lesional biopsies demonstrated a dense diffuse dermal infiltrate of atypical lymphocytes with a Grenz zone in 2 cases and focal epidermotropism in 1 case. The atypical lymphocytes were predominantly CD3 and CD8 positive with expression of cytotoxic marker TIA1. Staging evaluation failed to reveal systemic disease. Two patients underwent local excision, and the third received local radiation therapy all with complete response and no disease recurrence at last follow-up 3 months (range 2-5 months). Our cases add to the existing limited literature on the clinical and histopathological features of PCATCL. We also performed an updated systematic literature view of the entity.

Cutaneous lymphomas-An update 2019.

Primary cutaneous lymphomas (CL) are the second most common form of extranodal lymphomas. Cutaneous T-cell lymphomas represent the majority. They are classified according to the WHO classification 2017 and the updated WHO-EORTC 2018 published in the fourth edition of the WHO classification for Skin Tumors monograph. Primary cutaneous acral CD8+ T-cell lymphoma and EBV-positive mucocutaneous ulcer have been listed as new provisional entities. Moreover, the histological and genetic spectrum of lymphomatoid papulosis has been expanded. Recently, prognostic subtypes were delineated for some entities and subtypes of CL such as folliculotropic mycosis fungoides and marginal zone lymphoma. Since CL show overlapping histological features, clinico-pathological correlation is of outmost importance for the diagnosis. Recent studies revealed new biomarkers and genetic alterations underlying the pathogenesis of CL. Moreover, targeted therapies have widened the treatment options particularly for aggressive lymphomas.

Primary cutaneous acral CD8+ T-cell lymphoma: report of a case

报道1例发生于左耳后的原发性皮肤肢端CD8阳性T细胞淋巴瘤，该类型为2016版WHO皮肤外周T细胞淋巴瘤分类的新增亚型，临床表现为惰性，光镜下特征为肿瘤细胞真皮及皮下弥漫浸润，但不累及表皮，瘤细胞形态单一，中等大小、核不规则，常可见到"印戒"样特征的细胞核，核分裂象少见，肿瘤细胞阳性表达CD8、CD3，CD4阴性。.

Cutaneous Lymphoproliferative Disorders: What's New in the Revised 4th Edition of the World Health Organization (WHO) Classification of Lymphoid Neoplasms.

Cutaneous lymphoproliferative disorders remain a challenging aspect of dermatopathology, in part due to the rarity of the entities and extreme variability in clinical outcomes. Although many of the entities remain unchanged, the approach to some of them has changed in the new 2016 classification scheme of the World Health Organization. Chief among these are Epstein-Barr virus-associated lymphoproliferative disorders such as Epstein-Barr virus-associated mucocutaneous ulcer and hydroa vacciniforme-like lymphoproliferative disorder, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous acral CD8+ T-cell lymphoma, primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, and breast implant-associated anaplastic large cell lymphoma. In addition, translocations and gene rearrangements such as those involving the 6p25.3 locus have started to inform diagnosis and classification of anaplastic large cell lymphoma and lymphomatoid papulosis. In this review, we will examine what is new in the diagnostic toolbox of cutaneous lymphoproliferative disorders.

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary Cutaneous Acral CD8+ T-Cell Lymphoma.

Primary cutaneous acral CD8+ T-cell lymphoma is a new provisional entity in the 2016 revision of the World Health Organization classification of lymphoid neoplasms. This is a challenging diagnosis because of its rarity, as well as its morphologic and immunophenotypic overlap with other CD8+ cytotoxic lymphoid proliferations. Appropriate classification of this entity is crucial because of its indolent clinical behavior compared with other CD8+ T-cell lymphomas. Knowledge of the clinical setting, sites of involvement, and morphologic features can aid in correct diagnosis. Here, we review the clinical and pathologic features of primary cutaneous acral CD8+ T-cell lymphoma with an emphasis on the differential diagnosis among other C8+ T-cell lymphomas.

Contributions From University of Michigan 2016 New Frontiers in Pathology Conference.

Every autumn the Department of Pathology at the University of Michigan (UM; Ann Arbor, Michigan) organizes a case-based continuing medical education conference directed toward an audience of community and academic pathologists and trainees with the intent of providing up-to-date and cutting-edge information for the practicing pathologist. Last year the conference was held in Ann Arbor on October 19–21, 2016. Although we invited 3 excellent outside speakers, the meeting was primarily “homegrown,” with the majority of case studies and interactive breakout sessions presented by UM faculty. With gracious support from the editorial staff of Archives of Pathology & Laboratory Medicine, we publish 11 review articles based on topics presented at the conference. The manuscripts are published in 2 separate issues: part I in this issue and part II in the November issue.This issue (part I) contains 5 review articles that focus on surgical pathology. Reena Singh, MD, and Kathleen R. Cho, MD, present compelling evidence with molecular confirmation that the fallopian tubal epithelium can be a site of metastasis and not simply a site of origin for gynecologic cancers, especially in the face of widespread disease. Avneesh Gupta, MD, Nathan Shaller, MD, and Kathryn A. McFadden, MD, review the clinicopathologic features of pediatric thalamic brain tumors. Based upon their review of the literature, diffuse and pilocytic astrocytomas account for the vast majority of cases (80%). The authors emphasize the importance of tissue diagnosis for prognostication, therapeutic molecular targeting, and identifying tumors for which resection is likely to be beneficial. Julie M. Jorns, MD, and her colleagues from radiology and oncologic surgery, Deborah O. Jeffries, MD, and Lesly A. Dossett, MD, MPH, highlight next-generation technologies in localization for breast surgery, notably nonradioactive, nonwire localization techniques such as SAVI SCOUT (Cianna Medical, Inc, Aliso Viejo, California), which uses infrared light and microimpulse laser, and Magseed (Endomagnetics, Inc, Austin, Texas), which uses a magnetic seed for localization, both of which are also being tested and deployed at other institutions. Shula Schechter, MD, and Jiaqi Shi, MD, PhD, review the clinicopathologic and molecular features of the pancreatic simple mucinous cyst, an underrecognized lesion, which they compare and contrast with other pancreatic mucinous cysts, notably intraductal papillary mucinous neoplasm and mucinous cystic neoplasm, tumors that differ from simple mucinous cysts in that they are associated with malignant potential. Finally, in this issue Angela Wu, MD, details UM's approach to the very challenging diagnosis of oncocytic renal cell neoplasia in core biopsy and resection specimens using morphologic and immunohistochemical criteria.In next month's issue (part II), review articles will appear on additional topics presented at the UM New Frontiers Conference in hematopathology, dermatopathology, and perinatal and soft tissue pathology. There are 3 hematopathology papers. In one, Nathan J. Charles, MD, PhD, and Daniel F. Boyer, MD, PhD, review mixed-phenotype acute leukemia, an underrecognized, heterogeneous category that comprises acute leukemias with discrete admixed populations of myeloid and lymphoid blasts and ones with extensive coexpression of lymphoid and myeloid markers in a single blast population. In the second hematopathology paper, Vivian M. Hathuc, DO, Alexandra C. Hristov, MD, and Lauren B. Smith, MD, review primary cutaneous acral CD8+ T-cell lymphoma, a newly classified cutaneous lymphoma with an indolent clinical course, and compare and contrast it with other more aggressive cutaneous T-cell diseases. Steven Weindorf, MD, and John Frederiksen, MD, PhD, present a thorough yet concise review of IgG4-related disease for the practicing pathologist in the third hematopathology paper. Also in the November issue, Amer Heider, MD, reviews placental pathology of fetal vascular malperfusion in a very well-written and accessible paper; Lauren M. Stanoszek, MD, PhD, Grace Y. Wang, MD, and Paul W. Harms, MD, PhD, address diagnostic mimics of cutaneous basal cell carcinoma in their beautifully illustrated manuscript; and David R. Lucas, MD, reviews and updates myxoinflammatory fibroblastic sarcoma, a challenging soft tissue tumor that is frequently misdiagnosed by pathologists unaware of its clinicopathologic manifestations.We hope you enjoy reading these articles.

Cutaneous CD8+ Cytotoxic T-Cell Lymphoma Infiltrates: Clinicopathological Correlation and Outcome of 35 Cases.

IntroductionCytotoxic CD8+ T-cell lymphomas are only rarely encountered and thus remain only poorly characterized. Our aim was to collect and correlate clinical and histological data of CD8+ skin lymphoma infiltrates to obtain a proper subtype assignment of CD8+ skin lymphoma infiltrates and to derive putative prognostic markers thereof.MethodsFormalin-fixed and paraffin-embedded (FFPE) tissue of 35 patients with CD8+ cytotoxic cutaneous T-cell lymphoma infiltrates was retrieved from the archives of the Institute of Pathology and the Department of Dermatology, University Hospital Wuerzburg, dating back from 1998 until 2015. Cytological, histological, immunohistochemical and molecular genetic features were assessed and correlated with respective clinical data.ResultsThe identified cases of CD8+ cytotoxic atypical lymphoproliferative infiltrates of the skin (n = 35) comprised 13 cases of mycosis fungoides (MF)/Sézary syndrome (SS), 4 cases of subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 5 cases of primary cutaneous acral CD8+ lymphoma [formerly indolent CD8+ lymphoid proliferation (ILP)] and 1 case of aggressive epidermotropic primary cutaneous T-cell lymphoma (AECTCL). Moreover, nine cases were classified as primary cutaneous peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and three cases as systemic PTCL-NOS. Multiple skin lesions, a high proliferative index and especially a final subtype attribution to AECTCL or systemic PTCL-NOS were associated with a worse survival. Coexpression of CD68 by tumor cells was exclusively observed in indolent acral CD8+ T-cell lymphoma and thus indicated an invariably benign clinical course. No further distinctive markers could be derived from our analysis.ConclusionCutaneous infiltrates of CD8+ cytotoxic T-cell lymphoma comprise clinically and histologically heterogeneous entities of either primary cutaneous T-cell lymphomas or secondary infiltrates of otherwise systemic peripheral T-cell lymphomas. A thorough clinicopathological correlation with respective staging examinations remains the mainstay for correct subtype assignment and proper prognostication as long as no better markers have been defined.