Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC.

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

A CD56- immunoblastoid variant of blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignant hematologic neoplasm arising from plasmacytoid dendritic cells. It is a very rare tumor that constitutes less than 0.1% of all hematologic malignancies. Most patients with BPDCN present clinically with cutaneous lesions as the first sign of disease. Immunophenotypic variability with aberrant marker profiles has been reported. We report a case of a transcription factor 4 (TCF-4) + BPDCN, with negative CD56 expression in an 85-year-old woman with multiple skin nodules. A punch biopsy revealed a diffuse, monomorphous, and non-epidermotropic cell infiltrate involving the entire dermis. The infiltrate was composed of intermediate-sized cells with immunoblastoid morphology, which is an unusual morphologic variant. The neoplastic cells were strongly positive for CD45 and co-expressed CD4, CD123, TCF-4, BCL-2, and CD10. The Ki-67 proliferative rate was very high (90%). Negative immunostains included CD56, an unusual finding in BPDCN. This case illustrates the challenges encountered in the diagnosis of this entity, particularly in unusual morphologic variants and phenotypes. The elucidation of molecular signatures and development of targeted therapies for its management have been recently introduced and differ from acute myeloid leukemias. Hence, accurate diagnosis of BPDCN is critical for dermatopathologists.

Null T-cell phenotype mycosis fungoides with aberrant CD20 and CD56 expression: A diagnostic dilemma.

Mycosis fungoides (MF) represents the most common type of primary cutaneous T-cell lymphoma. Recognition of MF variants with divergent immunophenotypes is important for accurate diagnosis and appropriate management, as they can be confused with other lymphoma subtypes. We present a case of a 49-year-old male previously diagnosed with a cutaneous lymphoproliferative disorder with an unusual NK/T-cell phenotype. He presented with a 10-year history of pelvic girdle rash involving the right hip and upper thigh. The lesions were characterized as atrophic patches concentrated in sun-protected areas and involving 10% of the body surface area. Shave biopsies revealed an atypical epidermotropic infiltrate composed of hyperchromatic small to medium-sized lymphocytes with perinuclear halos and "tagging" along the dermal-epidermal junction. The immunophenotype was unusual in that the neoplastic lymphocytes showed complete loss of pan T-cell antigens along with expression of CD56, cytotoxic markers, and weak CD20. All other B-cell markers were negative. The combination of clinical findings, in addition to the histopathologic and immunophenotypic profile, were diagnostic of null T-cell phenotype MF with aberrant expression of CD56 and CD20. Null T-cell phenotype MF is very uncommon, can be diagnostically challenging, and can mislead the diagnosis of aggressive lymphoma subtypes.

Myelodysplasia cutis masquerading as granulomatous dermatitis.

Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic neoplasms resulting from mutations in stem cells. They carry a risk of transformation to acute myeloid leukemia. Cutaneous manifestations of MDS, including myelodysplasia cutis or infiltration by MDS tumor cells, are rare, but significantly associated with increased risk of progression to high-grade myeloid tumors. The clinical and histopathologic differential diagnosis for myelodysplasia cutis includes interstitial granulomatous dermatitis (IGD), a reactive granulomatous dermatitis (RGD) associated with systemic diseases including rheumatologic diseases, and hematologic malignancy like MDS. We report a patient with MDS who presented with myelodysplasia cutis masquerading as IGD both in a clinical and histopathological manner.

Apocrine Hidrocystoma of the Nail: A Unique Case.

ABSTRACT: Apocrine hidrocystomas are benign, cystic neoplastic lesions resulting from the apocrine secretory component of the sweat gland. They most commonly occur on the head and neck, with predilection to the periorbital area. Less frequent sites include the axilla, nipple, external auditory canal, foreskin, conjunctiva, lower lip, and fingers, among others. The authors report a unique case of a nail bed hidrocystoma in a 55-year-old woman, a site not previously described.

Erythema elevatum diutinum in a patient with well-controlled Crohn disease.

Erythema elevatum diutinum is a rare, chronic cutaneous leukocytoclastic vasculitis, with prominent fibrosis at its later stage. In this article, we report a case of erythema elevatum diutinum in a 23-year-old woman with well-controlled Crohn disease. To our knowledge, erythema elevatum diutinum has been reported in only three other cases of Crohn disease, in which eruptions of erythema elevatum diutinum were associated with features of active Crohn. Our patient was in clinical remission at the time of erythema elevatum diutinum onset, making this report significant not only for its uncommon presentation, but more importantly, to aid readers. diagnosis and clinical management of similar cases.

Poorly differentiated cutaneous apocrine carcinomas: histopathological clues and immunohistochemical analysis for the diagnosis of this unusual neoplasm.

Primary cutaneous apocrine carcinoma (PCAC) is a rare cutaneous malignancy that is derived from apocrine glands. Histologically, these tumours can appear well-differentiated where diagnosis should be relatively straightforward. However, occasionally these tumours can exhibit high-grade features, and in such instances the diagnosis can be challenging. A retrospective analysis of 12 cases of poorly differentiated PCAC, obtained from large academic institutions, was performed, and summarised below. Immunohistochemical studies were performed in all cases with antibodies against CK7, p63, CAM 5.2, GCDFP-15, GATA3, CEA, PR, ER, HER2, calponin, SMA, androgen receptor and EMA. All 12 cases were poorly differentiated; however, there were some histopathological clues to the diagnosis of apocrine carcinoma; namely, the presence of focal glandular formation, acrosyringial involvement and the presence of single 'pagetoid' cells within epidermis. All tumours were consistently positive for CK7, GATA3 and GCDFP-15 and negative for p63. The tumours had variable expression of CAM5.2, CEA, ER, PR, HER2, androgen receptor and EMA. In three cases, there was a preservation of the myoepithelial cell layer (with calponin and SMA), which also confirmed the primary cutaneous origin. PCAC is a difficult neoplasm to diagnose, as it can appear identical to metastatic carcinomas. We describe 12 cases of poorly differentiated PCAC, highlighting their salient clinical, histopathological and immunohistochemical features, and discuss the potential diagnostic pitfalls in distinguishing this entity from other malignant neoplasms. Our results indicate that a combination of thorough histological inspection coupled with an adequate battery of immunohistochemical stains is necessary to support the diagnosis of PCAC.

An update on Epstein-Barr virus-and human T-lymphotropic virus type-1-induced cutaneous manifestations. CME Part II.

The Epstein-Barr virus (EBV) is a DNA virus that infects 90% of the human population, is responsible for certain cutaneous lymphomas (extranodal NK/T-cell lymhoma, hydroa vacciniforme lymphoproliferative disorder, lymphomatoid granulomatosis, others), and can be associated with a variety of cutaneous manifestations (eg, infectious mononucleosis, severe mosquito bite allergy, chronic active EBV disease, Gianotti-Crosti syndrome). EBV-related skin disorders are frequent in certain populations (South and Cental America, Africa, Asia, and Oceania) and can be diagnostically challenging. The human T-lymphotropic virus type-1 is a retrovirus, which is known to be associated with adult T-cell leukemia/lymphoma, neurologic disorders, but also cutaneous non-neoplastic manifestations (infective dermatitis, infections, and infestations). We performed an updated revision of the clinical dermatologic and histopathologic findings associated with the cutaneous non-neoplastic and preneoplastic disorders occurring in association with the EBV and human T-lymphotropic virus type-1.

An update on viral-induced cutaneous lymphoproliferative disorders. CME Part I.

Viral-induced cutaneous T-cell lymphomas are an uncommon group of lymphoproliferative disorders characterized by a viral infection of T and natural killer (NK) cells. This group of cutaneous T-cell lymphomas is more commonly encountered in Asians and Native Americans from Central and South America compared with Western populations. Viral-associated lymphoproliferative disorders include a spectrum of entities that range from nonneoplastic lesions, such as chronic active Epstein-Barr virus infection and infective dermatitis to malignant diseases, such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and adult T-cell leukemia/lymphoma. This review article will focus on hydroa vacciniforme-like lymphoproliferative disorder, extranodal NK/T-cell lymphoma, adult T-cell leukemia/lymphoma, lymphomatoid granulomatosis, and Epstein-Barr virus-positive mucocutaneous ulcers. We will review the pathogenesis of these conditions and the challenges of making a timely diagnosis in early-stage disease and discuss the common clinicopathologic manifestations, mutational landscape, and approaches to treat these highly aggressive and frequently lethal types of lymphoma.

Microsecretory adenocarcinoma of the external ear canal.

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor characterized by unique histomorphologic and immunohistochemical features as well as recurrent MEF2C::SS18 gene fusion. Since 2019, 24 cases have been reported in the literature, primarily arising in the oral cavity, with a single reported case arising in the parotid gland. Here, we present a case of MSA that arose in the external ear canal in an 89-year-old woman and was discovered during management of vertigo symptoms. Excisional biopsy of the lesion showed multiple fragments of squamous epithelium with hyperplastic changes and a distinct subepithelial infiltrating neoplasm composed of bland cells forming tubules and cords. Neoplastic cells expressed keratin, S100 protein, p63, and TLE1 and did not express p40, mammaglobin, pan-TRK, synaptophysin, or chromogranin by immunohistochemistry. SS18 gene rearrangement was shown with break-apart fluorescent in situ hybridization. Overall, the histomorphologic, immunohistochemical, and cytogenetic findings confirm a diagnosis of MSA arising in a unique extraoral location.

A case of aleukemic leukemia cutis after COVID-19 infection presenting as facial rash.

Aleukemic leukemia cutis (ALC) is a rare condition that is characterized by leukemic cells in the skin before presenting in the peripheral blood or bone marrow. We report a case of a 43-year-old woman who underwent assessment for bilateral facial nodules arising 1 month after COVID-19 infection. A punch biopsy specimen showed a malignant neoplasm primarily composed of immature blasts dissecting through the collagen in the dermis, concerning for myeloid sarcoma versus leukemia cutis. Bone marrow and blood specimens were negative for hematologic malignancy. The patient was appropriately treated with chemotherapy and is recovering well. This report highlights an interesting case of ALC following COVID-19 infection presenting as an isolated facial rash. Whether there is a true relationship between the patient's COVID-19 infection and her abrupt presentation of leukemia remains unclear, but we present this case regardless, in an effort to highlight a potentially unique association requiring further study.

Histopathologic and molecular characterization of BAP-1-inactivated melanoma.

BACKGROUND: BRCA1-associated protein 1 (BAP-1) is a deubiquitylase that functions as a tumor suppressor, regulating multiple cellular processes including cell cycle control, differentiation, cell death, and DNA repair. BAP-1-inactivated melanocytic tumors (BIMTs) have recently been described and are characterized by epithelioid cytomorphology, are often clonal in appearance, and typically do not recur or show malignant transformation on follow-up. AIM: To describe the histopathologic and molecular characterization of five cases of BAP-1-inactivated cutaneous malignant melanomas. METHODS: The archives at two separate institutions were retrospectively searched for tumors classified as melanoma with loss of BAP-1 via immunohistochemistry. Five cases were identified. These cases were classified as malignant melanoma based on cytomorphology, immunohistochemistry, and ancillary molecular testing. The clinical demographics were recorded, along with the histomorphologic features of each case. Genomic analysis for all cases was performed via OncoScan. RESULTS: The five reviewed cases consisted of two females and three males ranging from 67 to 74 years in age. Molecular characterization of each case was performed using OncoScan. Microarray assay showed that there was a complete deletion of 3p in all cases, BRAF V600E mutation in two cases, NRAS missense variant in one case, and loss of 9p in three cases. All cases showed malignant copy number alterations. CONCLUSIONS: Herein we describe five cases of BAP-1-inactivated melanomas confirmed by histomorphology and immunohistochemistry, all of which show malignant copy number profiles including loss of 3p. In addition, we provide a case of a likely BIMT showing progression to BAP-1-inactivated melanoma on a 16-year follow-up.

Acute Epstein-Barr virus infection resembling cutaneous T-cell lymphoma.

Primary, acute Epstein-Barr virus (EBV) infection is associated with a variety of cutaneous eruptions, including the viral exanthem of infectious mononucleosis and erythema multiforme. Latent, chronic EBV infection can rarely result in development of lymphoproliferative disorders with cutaneous manifestations; however, these disorders do not arise from primary infection. In this report, we present a case of primary, acute EBV infection presenting with histopathologic features closely mimicking aggressive cytotoxic cutaneous T-cell lymphoma.

Liver kinase B1 (LKB1) in murine erythroid progenitors modulates erythropoietin setpoint in association with maturation control.

Erythropoiesis is a tightly regulated process. It is stimulated by decreased oxygen in circulation, which leads to the secretion of the hormone erythropoietin (Epo) by the kidneys. An additional layer of control involves the coordinated sensing and use of nutrients. Much cellular machinery contributes to sensing and responding to nutrient status in cells, and one key participant is the kinase LKB1. The current study examines the role of LKB1 in erythropoiesis using a murine in vivo and ex vivo conditional knockout system. In vivo analysis showed erythroid loss of LKB1 to be associated with a robust increase in serum Epo and mild reticulocytosis. Despite these abnormalities, no evidence of anemia or hemolysis was found. Further characterization using an ex vivo progenitor culture assay demonstrated accelerated erythroid maturation in the LKB1-deficient cells. Based on pharmacologic evidence, this phenotype appeared to result from impaired AMP-activated protein kinase (AMPK) signaling downstream of LKB1. These findings reveal a role for LKB1 in fine-tuning Epo-driven erythropoiesis in association with maturational control.

Cutaneous reactive B-cell lymphoid proliferations.

Cutaneous lymphoid hyperplasia (CLH), also known as cutaneous pseudolymphoma, is a spectrum of benign conditions characterized by reactive B- and T-cell cutaneous lymphocytic infiltrates. B-cell lymphoid proliferations are a heterogenous group of non-neoplastic cutaneous diseases that must be histopathologically distinguished from cutaneous B-cell lymphomas. These proliferations can be observed as reactive phenomena to infections, medications, allergens, neoplasms, and more. Furthermore, there are many inflammatory conditions that present with reactive B-cell infiltrates, including actinic prurigo, Zoon balanitis, Rosai-Dorfman disease, and cutaneous plasmacytosis. This review summarizes multiple cutaneous B-cell lymphoid proliferations within the major categories of reactive and disease-associated CLH. Further we discuss major discriminating features of atypical CLH and malignancy. Understanding the specific patterns of B-cell CLH is essential for the proper diagnosis and treatment of patients presenting with such lesions.

Primary cutaneous anaplastic large-cell lymphoma with aberrant cytokeratin expression: An unusual mimicker of poorly differentiated carcinomas.

An 81-year-old male presented with a rapidly growing cheek nodule. Biopsy revealed a dermal infiltrate of large atypical cells, some exhibiting a horseshoe-shaped nucleus. Immunohistochemistry revealed positivity for CD4, CD3, CD45, and CD30 (>95%). Melanocytic markers, cytotoxic markers, CD20, CD56, ALK1, synaptophysin, CD1a, and ETS-related gene (ERG) were negative. Notably, there was weak but diffuse expression of pan-cytokeratin (AE1/AE3) and Oscar keratin. There was also a weak expression of epithelial membrane antigen (EMA). CAM 5.2, p40, and IRF4/DUSP22 rearrangement were negative. Further staging revealed skin-limited disease. A diagnosis of primary cutaneous anaplastic large-cell lymphoma (PC-ALCL) was rendered. We present a rare case of cytokeratin positive PC-ALCL, a finding never reported in the literature. Both PC-ALCL and systemic ALCL (S-ALCL) evoke a broad differential. CD45, EMA, and cytokeratin stains help differentiate from metastatic carcinomas. There have been rare prior reports of cytokeratin expression in S-ALCL, which tend to stain with an unusual cytoplasmic and membranous pattern like our case, have variable co-expression of EMA, and null T-cell phenotypes. These show the significant diagnostic challenges that can arise in differentiating ALCL from metastatic or primary skin carcinomas. Awareness, careful attention to morphology (e.g., hallmark cells), and considering routine CD30 can help lead the pathologist to the correct diagnosis.

Primary cutaneous follicle center lymphoma with aberrant CD8 expression.

We report an unusual case of primary cutaneous follicle center lymphoma (PCFCL) with aberrant expression of the T-cell marker CD8. The patient is a 48-year-old male with no significant past medical history who presented with red indurated plaques on the abdomen. A punch biopsy showed abnormal lymphoid follicles in the dermis with reduced mantle zones and decreased tingible body macrophages. The epidermis was uninvolved. The follicles expressed CD20, PAX-5, and bcl-6 by immunohistochemistry. CD8, however, was strongly positive, highlighting neoplastic cells, which were negative for any additional T-cell markers. TIA and granzyme B were also negative. The patient underwent further staging workup, without evidence of nodal involvement. His course has been indolent thus far. In summary, we present a case of PCFCL with aberrant expression of the T-cell marker CD8, a finding not previously reported in the literature and a potential diagnostic pitfall.

Clonal cutaneous and neurosyphilis: A pitfall in pseudolymphoma diagnosis.

Syphilis is a sexually transmitted infectious disease caused by the bacterium Treponema pallidum and can cause a wide variety of cutaneous manifestations, most commonly, a papulosquamous eruption of the trunk and extremities. Treatment with penicillin is curative. We report a case of a 69-year-old man who presented with recent onset of blurry vision and a nonpainful, nonpruritic eruption of pink-to-violaceous dermal nodules on his upper trunk and upper extremities. Biopsies of two separate locations revealed a dense superficial and deep perivascular atypical lymphocytic infiltrate with admixed plasma cells, histiocytes, and eosinophils. Some scattered cells expressed CD30, PD1, BCL-6, and ICOS. T-cell receptor (TCR)-rearrangement showed an identical TCR-gamma clone between both biopsy specimens. The patient was subsequently seen by ophthalmology and diagnosed with acute anterior uveitis. Rapid plasma reagin was reactive and cerebrospinal fluid studies showed findings consistent with a diagnosis of neurosyphilis. A T. pallidum immunostain of the skin biopsies was performed upon re-review, and was diffusely positive for spirochetes at the dermal-epidermal junction and within injured vessels. The patient was treated with penicillin G with near-resolution of his skin lesions. This case highlights the unusual ability of syphilis to mimic a T-cell lymphoma with matching clones across two different biopsy sites.

Next-generation sequencing confirms T-cell clonality in a subset of pediatric pityriasis lichenoides.

BACKGROUND: Pityriasis lichenoides (PL) is a papulosquamous disease that affects both adults and children. Previous studies have shown a subset of this entity to have clonal T-cell populations via PCR-based assays. In this study, we sought to implement next-generation sequencing (NGS) as a more sensitive and specific test to examine for T-cell clonality within the pediatric population. METHODS: We identified 18 biopsy specimens from 12 pediatric patients with clinical and histopathologic findings compatible with PL. Patient demographics, clinical features, management, and histopathologic findings were reviewed. All specimens were analyzed for clonality with NGS of T-cell receptor beta (TRB) and gamma (TRG) genes. RESULTS: Of the 12 patients, 9 (75%) had complete resolution of lesions at the time of data collection (mean follow-up 31 months). The remaining three patients significantly improved with methotrexate (with or without acitretin). Interestingly, 7 of 12 patients (58%) and 9 of 17 biopsy specimens (53%) showed evidence of T-cell clonality. Two patients showed matching TRB clones from different anatomic sites. CONCLUSIONS: T-cell clonality is a common finding in PL, probably representing a "reactive clonality" rather than a true lymphoproliferative disorder. Clonality alone cannot be used as a means to distinguish PL from lymphomatoid papulosis or cutaneous lymphoma.

Primary Cutaneous Anaplastic Large-Cell Lymphoma With Aberrant CD20 Expression: Case Report and Review of the Literature.

ABSTRACT: Cutaneous CD20 + T-cell lymphomas are exceedingly rare. Differentiating cases of T-cell lymphoma with aberrant expression of the B-cell marker CD20 from B-cell lymphoma may be associated with misdiagnosis or delays in diagnosis. We report, to the authors' knowledge, the first case of CD20 + primary cutaneous anaplastic large-cell lymphoma and review the literature to characterize published cases of CD20 + cutaneous T-cell lymphoma (n = 40). There is no accepted explanation for this phenomenon; however, it is suspected that these cases may be due to neoplastic transformation of CD20 + T cells or that CD20 may represent a T-cell activation marker. Expression of CD20 may have clinical significance in prognostication and consideration of treatment options with anti-CD20 therapies such as rituximab.