Primary Cutaneous Anaplastic Large T-cell Research Articles

Primary cutaneous anaplastic large T-cell lymphoma: From a lesion peculiar to its diagnosis

The authors present a clinical case of a 42-year-old woman presented to the Emergency Department for a non-pruritic skin lesion in the left lower limb with a few months of evolution.

Histopathological Markers for Target Therapies in Primary Cutaneous Lymphomas.

In recent years, targeted (biological) therapies have become available also for primary cutaneous T-cell lymphomas (PCTCLs) including anti-CD30 (brentuximab vedotin) in mycosis fungoides, primary cutaneous anaplastic large T-cell lymphoma, lymphomatoid papulosis; anti-CCR4 (mogamulizumab) in Sezary syndrome; anti-CD123 (tagraxofusp) in blastic plasmocytoid cell neoplasm. Moreover, anti-PD1 (nivolumab), anti-PDL1 (pembrolizumab, atezolizumab), anti-CD52 (alemtuzumab), anti-KIR3DL2-CD158k (lacutamab), and anti-CD70 (cusatuzumab) have been tested or are under investigations in phase II trials. The expression of these epitopes on neoplastic cells in skin biopsies or blood samples plays a central role in the management of PCTCL patients. This narrative review aims to provide readers with an update on the latest advances in the newest therapeutic options for PCTCLs.

CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA CD30+ IN ITS EXTENSIVE FORM: ABOUT A CASE

Primary cutaneous anaplastic large T-cell lymphoma CD30+ is a rare cutaneous lymphoma, which belongs to the group of cutaneous T-cell lymphoproliferations CD30+. It is characterized by an excellent prognosis and the treatment is therefore not very aggressive. However, its histological and molecular characteristics have many similarities with lymphoproliferative diseases whose prognosis is completely different. For this reason, it is important to study the patient from the anamnestic and clinical point of view in order to reach a correct diagnosis.

Lack of PRAME Expression in Cutaneous T-Cell Lymphomas.

Cutaneous T-cell lymphomas (CTCLs) are rare tumors with no established markers that can reliably distinguish between benign and malignant lesions. Preferentially Expressed Antigen in Melanoma (PRAME) is a cancer/testis antigen that is found in many solid and hematologic malignancies. PRAME overexpression typically portends a poor prognosis and lower chemotherapeutic response. To date, no studies have established a role for PRAME in CTCL. An analysis was performed on 47 cases definitively diagnosed as CTCL: 25 cases of mycosis fungoides, 2 of Sezary syndrome, 5 of CD30+ lymphoproliferative disorder, 7 of primary cutaneous anaplastic large T-cell lymphoma, 3 of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, 1 of subcutaneous panniculitis-like T-cell lymphoma, and 4 of angiocentric T-cell lymphoma. PRAME immunohistochemistry was completely negative in all cases. PRAME expression was not found in any CTCL subtypes, suggesting that the pathogenesis of CTCL is not mediated by PRAME. Further study is required to identify biomarkers that might aid in the diagnosis and prognostication of CTCLs.

Primary cutaneous CD30(+) lymphoproliferative disorders.

Primary cutaneous CD30(+) lymphoproliferative disorders are the second most common group of cutaneous T-cell lymphomas (CTCL) and include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (cALCL). Both disease entities share overlapping clinical, histopathological, and molecular features, thus representing a spectrum of cutaneous CD30(+) lymphoproliferative disorders. LyP may be distinguished from cALCL by clinicopathological correlation. In some patients, both diseases may coexist at initial diagnosis or develop over the course of the disease. Mycosis fungoides (MF), the most common CTCL, is not considered a primary cutaneous CD30(+) lymphoproliferative disorder, but may occur in some LyP patients. In addition, LyP-like lesions may develop in MF patients. However, this is frequently a manifestation of MF rather than a representation of two different disease entities. Caution also has to be taken in the setting of transformed MF with lesions expressing CD30, as they may be mistaken for either LyP or cALCL, resulting in an inadequate therapeutic approach.

Type D Lymphomatoid Papulosis: An uncommon Variant. A case report and review of the literature

Lymphomatoid papulosis (LyP) is an indolent form of primary cutaneous T-cell lymphoma, currently classified together with primary cutaneous anaplastic large T-cell lymphoma within the spectrum of CD30-positive lymphoproliferative disorders. It is characterized by presenting as a clinically benign but histopathological malignant disease. Clinical features consist in recurrent waxing and waning red papules. Histopathologically, there are 4 variants recognized, Type A or Hystiocitic type, being the most frecuent of all, Type B or Mycosis fungoides-like, Type C or Anaplastic large-cell lymphoma-like and Type D, the most recently described and uncommon variant with features similar to Cutaneous Aggressive CD8-Positive Cytotoxic T-Cell Lymphoma. We present a case of a 22-year-old female with multiple papules and nodules in trunk and limbs that after histopathological and immunochemical examination was compatible with Type D LyP. It is important to report this case, as a perfect example of an uncommon variant of LyP, with emphasis in its typical clinical, histopathological and inmunohistochemical findings and review of the literature.

Phenotypic Variability in Primary Cutaneous Anaplastic Large T-cell Lymphoma

Primary cutaneous anaplastic large T-cell lymphoma (pcALCL) is a well-defined entity characterized by neoplastic cells expressing CD30, CD2, CD3, CD4, and CD5. Cases with different phenotype have been reported, including variable loss of CD2, CD3, and CD5, and expression of cytotoxic phenotype (CD8⁺) and/or of cytotoxic proteins. Aberrant phenotypes represent a diagnostic pitfall and may be the cause of misdiagnoses. We reviewed 35 cases of pcALCL (M:F = 19:16; mean age, 50.8 years; range, 14-92 years), to better characterize the immunophenotypic spectrum of the disease. Twelve cases (34%) had a T-helper phenotype (CD4⁺/CD8⁻), and TIA-1 was positive in 5 of 8 stained cases. Six cases (18%) had a T-cytotoxic phenotype (CD4⁻/CD8⁺) and were also positive for TIA-1. Positivity for both CD4 and CD8 was observed in 7 cases (20%), 4 of which were stained for TIA-1 and found to be positive, whereas both CD4 and CD8 were negative in 9 cases (26%, only 1/8 tested cases being TIA-1 positive). CD2 was positive in 21 of 27 tested cases (78%), CD3 in 21 of 34 cases (62%), and CD5 in 15 of 31 cases (48%). Interestingly, 11 cases (31%) showed a profoundly aberrant phenotype lacking simultaneously several T-cell markers. Our data allow a better characterization of pcALCL with aberrant phenotypes, showing the remarkable variability in expression of different markers.

Lymphomatoid Papulosis Type D or an Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma?

Lymphomatoid papulosis (LyP) is defined as a chronic, recurrent, self-healing eruption of papules and small nodules, characterised by a waxing and waning course, and by histological features of a CD30+ cutaneous T-cell lymphoma CTCL. Classically, 3 histologic subtypes of LyP are recognised: Type A (histiocytic), type B (MFlike) and type C (anaplastic like CTCL) (1). Together with primary cutaneous anaplastic large Tcell lymphoma, LyP is classified as a part of the primary cutaneous CD30+ lymphoproliferative disorders in the WHO-EORTC classification of cutaneous lymphomas (2). Recently, a new histologic LyP variant termed type D, simulating an aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, but with the typical clinical presentation and indolent course of LyP, has been described (3–5). We describe a new case of this variant, of which diagnosis is particularly challenging and emphasises the importance of cross-disciplinary collaboration.

Aggressive Variant of Primary Cutaneous Anaplastic Large T-Cell Lymphoma

Primary cutaneous anaplastic large cell lymphoma (ALCL) represents less than 2% of all T-cell lymphomas and usually manifests as a solitary cutaneous lesion generally in older males. It is an indolent disorder with a survival rate of 90% at 10 years, and rarely shows extracutaneous dissemination. The FDG avidity of the lesions of cutaneous ALCL is the lowest reported among T-cell lymphoma subtypes. However, the available positron emission tomography (PET) literature has not taken account of a subtype of primary cutaneous ALCL that presents with extensive limb disease, has a much more aggressive course, and responds poorly to conventional therapy. We report serial F-18 FDG PET/CT imaging of a 72-year-old man with this aggressive subtype of primary cutaneous ALCL. This case demonstrates that despite the low reported sensitivity of FDG PET/CT in cutaneous ALCL, PET/CT may in fact play a vital role in identifying patients with the more aggressive extensive limb disease subtype, and help guide therapeutic decisions toward much better outcomes than currently achieved.

CD8-Positive Primary Cutaneous Anaplastic Large T-Cell Lymphoma (PCALCL): Case Report and Review of This Unusual Variant of PCALCL

Primary cutaneous anaplastic large T-cell lymphoma (PCALCL) is a well-defined CD30-positive lymphoproliferative disorder with relatively good prognosis and response to treatment. We describe a case of PCALCL expressing CD8. The patient is a 57-year-old man that clinically presented with an ulcerated nodule in his left middle finger. Histopathologic sections showed an ulcerated epidermis with a diffuse lymphocytic infiltrate in the superficial dermis with focal epidermotropism. The large cohesive atypical cells were admixed with a reactive infiltrate composed of neutrophils, eosinophils, and small lymphocytes. Immunohistochemical studies showed the tumor cells to be strongly positive for CD8, CD30, and TIA-1, focally positive for CD3, and negative for CD4, CD20, CD56, Anaplastic Lymphoma Kinase (ALK-1), and HSV. Epstein-Barr virus by in situ hybridization was negative. The diagnosis of a CD8+ PCALCL was confirmed. There is limited precedent literature regarding CD8-positive PCALCL and this case falls within the clinical and histopathologic spectrum of CD30+ lymphoproliferative disorders. CD8/CD30 coexpression is rare in PCALCL and may have important clinical and prognostic implications. To the best of our knowledge there are only 4 previously reported cases describing similar findings.

Dominance of Nonmalignant T-Cell Clones and Distortion of the TCR Repertoire in the Peripheral Blood of Patients with Cutaneous CD30+ Lymphoproliferative Disorders

The CD30-positive cutaneous lymphoproliferative disorders (CLPD) include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (cALCL). Despite the malign-appearing histology, an excellent prognosis and spontaneous regression of single lesions characterize LyP. Even after years of clinical remission newly erupting lesions often harbor a T-cell clone identical to the initial one. This fact raises the question whether the clonal T-cell population persists in the peripheral blood. Therefore we investigated genomic DNA of 126 samples of lesional skin and peripheral blood from 31 patients with CLPD, obtained during both active disease and clinical remission. We performed molecular genetic analysis by combining T-cell receptor (TCR)-gamma PCR with the GeneScan technique and assessed the TCR repertoire in selected blood samples by beta-variable complementarity-determining region 3 (CDR3) spectratyping qualitatively and quantitatively. We were able to detect a clonal T-cell population in 36/43 (84%) skin samples and in 35/83 (42%) blood samples. Comparison of the compartments in each patient demonstrated different T-cell clones in skin and blood, suggesting a reactive nature of the clonal T cells in the blood. Moreover, CDR3 spectratyping revealed a restricted T-cell repertoire in the blood, suggesting T-cell stimulation by an unknown antigen.

The morphologic spectrum of primary cutaneous anaplastic large T‐cell lymphoma: a histopathologic study on 66 biopsy specimens from 47 patients with report of rare variants

Primary cutaneous anaplastic large T-cell lymphoma (PCALCL) is a well-defined entity with prognostic differences from the nodal counterpart [nodal anaplastic large cell lymphoma (NALCL)]. Several histological variants of NALCL have been characterized (common, lymphohistiocytic and small cell). However, studies on morphological variants of PCALCLs are lacking. We analyzed retrospectively the clinicopathologic features of 66 biopsies from 47 patients (M : F = 27 : 20; median age: 53 years; mean age: 51.8 years; range: 14-82) with PCALCL, in order to better characterize the spectrum of this unusual neoplasm. The 'common variant' was the most frequent (40.4%). In contrast to NALCL, in PCALCL, marked reactive infiltrates are more commonly present. In fact, 26 cases were classified as 'inflammatory type' (15 cases) and 'lymphohistiocytic' (11 cases). Concerning the predominant cell morphology, large anaplastic cells (33%) were almost as frequent as large pleomorphic (36%) and small to medium-sized cells (26%). We reported for the first time in the skin 2 rare cases with the predominance of large cells with a 'signet-ring'-like appearance. Epidermotropism and presence of eosinophils were found in a proportion of cases in all PCALCL variants. PCALCL is characterized by variable histopathological presentations and a broad cytomorphologic spectrum.

Differential Expression of TRAF1 Aids in the Distinction of Cutaneous CD30-Positive Lymphoproliferations

Lymphomatoid papulosis (LyP), primary cutaneous anaplastic large T-cell lymphoma (cALCL), and cutaneous infiltrates of systemic anaplastic large cell lymphoma (sALCL) are CD30-positive lymphoproliferative disorders of the skin that overlap clinically, histopathologically, immunophenotypically, and genetically but differ considerably in their prognosis. In particular, lesions of LyP regress spontaneously, whereas those of cALCL and sALCL persist and may progress and spread to extracutaneous sites. In contrast to patients with cALCL, LyP patients do not benefit from an aggressive radio- and/or chemotherapeutic approach. We generated a novel tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) antibody that recognizes a formalin-resistant epitope (Ber-TRAF1A) and investigated the expression of TRAF1, an intracellular component of TNFR signaling, in LyP and ALCL. We could show a strong TRAF1 expression in the tumor cells of most LyP cases (42/49, 84%). In contrast, tumor cells of primary and secondary cALCL revealed TRAF1 expression in only a few cases (3/41, 7%) as shown for sALCL without skin manifestation. The data indicate that TRAF1 expression reliably distinguishes LyP from primary or secondary cALCL. This might be of crucial diagnostic importance and has a strong impact on the treatment decision for patients with cALCL and LyP.