Clinical, Histologic, and Molecular Characteristics of Anaplastic Lymphoma Kinase-positive Primary Cutaneous Anaplastic Large Cell Lymphoma.

Unlike systemic anaplastic large cell lymphoma, the vast majority of primary cutaneous anaplastic large cell lymphomas (C-ALCL) do not carry translocations involving the ALK gene and do not express ALK. Expression of ALK protein therefore strongly suggests secondary cutaneous involvement of a systemic anaplastic large cell lymphoma. Recent studies described a small subgroup of ALK-positive C-ALCL, but information on frequency, prognosis, and translocation partners is virtually lacking. A total of 6/309 (2%) C-ALCL patients included in the Dutch registry for cutaneous lymphomas between 1993 and 2019 showed immunohistochemical ALK expression. Clinical and histopathologic characteristics, immunophenotype and disease course were evaluated. Underlying ALK translocations were analyzed with anchored multiplex polymerase chain reaction-based targeted next-generation sequencing. Median age at diagnosis was 39 years (range: 16 to 53 y). All patients presented with a solitary lesion. Treatment with radiotherapy (n=5) or anthracycline-based chemotherapy (n=1) resulted in complete responses in all 6 patients. Three patients developed a relapse, of whom 2 extracutaneous. After a median follow-up of 41 months, 5 patients were alive without disease and 1 patient died of lymphoma. Immunohistochemically, 3 cases (50%) showed combined nuclear and cytoplasmic ALK expression with underlying NPM1-ALK fusions, while 3 cases (50%) showed solely cytoplasmic ALK expression with variant ALK fusion partners (TRAF1, ATIC, TPM3). ALK-positive C-ALCL is extremely uncommon, has a comparable favorable prognosis to ALK-negative C-ALCL, and should be treated in the same way with radiotherapy as first-line treatment.

CD30-positive primary cutaneous anaplastic large cell lymphoma with coexistent pseudocarcinomatous hyperplasia.

CD30-positive primary cutaneous anaplastic large cell lymphoma (C-ALCL) is an indolent type of cutaneous lymphoma with favourable clinical prognosis. Pseudocarcinomatous hyperplasia (PCH) is a rare benign epithelial condition that can resemble invasive squamous cell carcinoma both clinically and histopathologically. PCH predominantly occurs in CD30-positive lymphoproliferative disorders. We report a 75-year-old woman with PCH in a multifocal C-ALCL located on the scalp and right retroauricular area, which rapidly responded to treatment with psoralen ultraviolet A photochemotherapy. Comprehensive virological analyses for potential oncogenic viruses, including Epstein-Barr virus, human herpesvirus-8, human papillomaviruses, the recently discovered cutavirus and nine different human polyomaviruses, were negative.

Brentuximab vedotin in CD30+ primary cutaneous T-cell lymphomas: a review and analysis of existing data.

BACKGROUND: The utility of brentuximab vedotin (BV) in CD30+ systemic lymphomas is established, however evidence for treating primary cutaneous lymphoma remains limited. This study aimed to evaluate BV in treating CD30+ transformed mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (PC-ALCL). METHODS: A literature review was conducted, and we analyzed data from published trials and case reports obtained via search of Ovid-MEDLINE® and PubMed databases. The search yielded 372 reports, and 10 publications met inclusion criteria. Sixty-one patients with CD30+ transformed MF and seven with PC-ALCL were included. RESULTS: Mean age at BV initiation was 60.8 years (67 - PC-ALCL; 60.1 - MF), and 4.1 therapies were attempted prior to BV (3.1 - PC-ALCL; 4.2 - MF). The overall response rate was 67.7% (100% - PC-ALCL; 63.9% - MF), with 16.2% of patients experiencing complete response (100% - PC-ALCL; 6.6% - MF). Mean time to clinical response was 5.3 and 9.3 weeks for PC-ALCL and MF, respectively. Mean response duration for patients with PC-ALCL was 7.6 and 7.8 months for MF. Peripheral neuropathy (57.2%) and fatigue (35.6%) were the most commonly reported adverse effects. CONCLUSIONS: This analysis summates the current evidence regarding the use of BV in treating CD30+ MF and PC-ALCL. Preliminary results indicate that BV is effective for CD30+ CTCL, however additional studies with larger sample sizes are necessary. The study provides clinicians with the clinical context in which BV may be appropriate as well as information regarding therapeutic expectations and outcomes.

Cutaneous anaplastic large-cell lymphoma (ALCL): A comparative clinical feature and survival outcome analysis of 52 cases according to primary tumor site.

BACKGROUND: Cutaneous anaplastic large-cell lymphoma (ALCL) is primary extranodal or secondary to nodal disease. OBJECTIVE: We sought to analyze clinical features and survival outcomes by primary tumor site in patients with cutaneous ALCL. METHODS: Clinical features, survival outcomes, and prognostic factors of 52 patients with primary or secondary cutaneous ALCL to primary nodal disease were retrospectively evaluated using medical records. RESULTS: Although skin lesion characteristics did not significantly differ between groups, the head and neck location was more common in primary cutaneous ALCL, whereas cutaneous lesion extent was greater in secondary cutaneous ALCL. Skin lesion extent in primary cutaneous ALCL was indicative of extracutaneous dissemination development and skin lesion relapse. Neither anaplastic lymphoma kinase expression nor clinical stage affected skin lesion characteristics in secondary cutaneous ALCL. Patients with primary rather than secondary cutaneous ALCL demonstrated better survival outcomes. The skin lesion extent and location on the leg were associated with the tendency toward a poorer prognosis in primary cutaneous ALCL. The secondary cutaneous ALCL prognosis was not influenced by skin lesion characteristics. LIMITATIONS: This was a retrospective study in a single institution. CONCLUSION: Survival outcomes and prognostic factors in cutaneous ALCL differed by primary tumor site.

Primary Cutaneous Anaplastic Large Cell Lymphoma With Positive ALK Expression and a Rapidly Progressive Cutaneous Nodule.

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a distinct entity from systemic ALCL (sALCL). sALCL usually shows immunohistochemical positivity for anaplastic lymphoma kinase (ALK) and epithelial membrane antigen (EMA), whereas these tests are negative in pcALCL. In contrast to sALCL, pcALCL is rarely found in children and young adults. We present here a case of a rare clinical condition in a 21-year-old woman, who has pcALCL with positive ALK and patchy EMA expression. She experiences a large, rapidly growing nodule without any outside-nodule manifestation. In conclusion, both ALK and EMA expression alone cannot distinguish pcALCL from secondary skin involvement by a sALCL.

Loss of expression of 5-hydroxymethylcytosine in CD30-positive cutaneous lymphoproliferative disorders.

BACKGROUND: The methylation of DNA at position 5 of cytosine, and the subsequent reduction in intracellular 5-hydroxymethylcytosine (5-hmC) levels, is a key epigenetic event in several cancers, including systemic lymphomas. However, no studies have analyzed this epigenetic marker in cutaneous lymphomas. Therefore, we aimed to analyze the expression of 5-hmC in cutaneous CD30-positive lymphoproliferative disorders and compare it with a control group composed of reactive infectious and inflammatory disorders with CD30-positive cells. METHODS: Retrospective case series study with immunohistochemical analysis using anti-CD30 and anti-5-hmC antibodies in control (n = 19), lymphomatoid papulosis (LyP) (n = 27) and primary cutaneous anaplastic large cell lymphoma (ALCL) (n = 14) specimens. RESULTS: Complete loss of 5-hmC nuclear staining by CD30+ cells was observed in 63% of LyP cases, 57% of ALCL cases and 0% of control cases. CONCLUSIONS: The presence of 5-hmC+ and CD30+ lymphocytes was highly suggestive of a benign process. In contrast, loss of 5-hmC nuclear staining was highly suggestive of a lymphoproliferative disorder (ALCL or LyP). Under these circumstances, the use of 5-hmC staining can be a useful adjunctive tool for discriminating between neoplastic CD30+ lymphoproliferations and inflammatory/infectious simulators harboring reactive CD30+ cells.

A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders.

The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.

A case of primary cutaneous anaplastic large cell lymphoma with prominent epidermotropism.

Primary cutaneous anaplastic large cell lymphoma (PCALCL) is defined as anaplastic large cell lymphoma localized to the skin without extracutaneous involvement at the time of diagnosis. Histologically, PCALCL is characterized by a dense nodular infiltrate of large lymphocytes, extending into the deep dermis or subcutis. Epidermotropism is sometimes, but not frequently, seen. We herein report a case of PCALCL with prominent epidermotropism. A 63-year-old Japanese woman was referred to our hospital with a red nodule and indurated erythema in 1997. Histological findings of a skin biopsy specimen from a red nodule were typical of PCALCL, however, biopsy specimens from indurated erythema showed remarkable epidermotropism. Tumor cells were positive for CD4, and CD30, but negative for CD3 and CD8. She was diagnosed with PCALCL. In 2007, skin biopsy was performed again, which showed large atypical lymphocytes in the upper dermis with mild epidermotropism. Tumor cells expressed in both CC chemokine receptor 4 and CXC chemokine receptor 3, which may explain prominent epidermotropism in this case.

Nodal involvement by cutaneous CD30-positive T-cell lymphoma mimicking classical Hodgkin lymphoma.

An association between classical Hodgkin lymphoma (cHL) and mycosis fungoides (MF) or lymphomatoid papulosis has been reported in the literature. However, there can be considerable morphologic and immunophenotypic overlap between cHL and nodal involvement by CD30-positive T-cell lymphoproliferative disorders (CD30-T-LPD). To examine this potential association, biopsies from patients with a history of MF or primary cutaneous CD30-T-LPD and lymph node biopsies reported as either CD30-positive T-cell lymphoma (TCL) with Hodgkin-like cells or cHL were retrieved from the authors' institution. Of 11 cases identified, 10 were considered CD30-positive TCL with Hodgkin-like cells, whereas 1 was confirmed as cHL upon review. Five cases originally diagnosed as cHL were revised as CD30-positive TCL. Cases of CD30-positive TCL with Hodgkin-like cells showed a male predominance (M:F, 4:1) with a median age of 53 years (range, 44 to 72 y). Nearly all patients (9/10) initially presented with skin lesions. In 7/10 patients the draining lymph node was involved, whereas in 3 cases this could not be confirmed. Tumor cells morphologically resembled Hodgkin/Reed-Sternberg cells; they were uniformly strongly positive for CD30, and CD15 was expressed in 9/10 (90%) cases. A T-cell derivation was confirmed by T-cell antigen expression (7/10) and clonal rearrangement of T-cell receptor genes (9/10). In 3 cases a common T-cell clone was identified in skin and lymph node. B-cell markers (CD20/PAX5) were consistently negative. In 1 case the diagnosis of cHL followed by lymphomatoid papulosis was confirmed, with Hodgkin/Reed-Sternberg cells expressing PAX5, CD30, and CD15. In situ hybridization studies for Epstein Barr virus were negative. We show that cHL is less often associated with MF and primary cutaneous CD30-T-LPD than previously thought and that the coexpression of CD30 and CD15 in these TCLs may lead to a mistaken diagnosis of cHL.

Multiple myeloma and cutaneous anaplastic large T-cell lymphoma in the same patient: is there a causal relation?

Synchronous occurrence of lymphomatous proliferations of B and T lineage in the same patient is a very rare event and still poorly understood. All the cases reported in the English language literature are described as single case reports. We report a case of 49-year-old man, with 2-year history of multiple myeloma, presented with a raised, erythematous and ulcerated nodule in the anterior aspect of his right thigh. Histologic examination of biopsy specimen showed a dense dermic infiltrate made of large balastic cells displaying anaplastic morphology with no epidermotropism. Immunohistochemical study showed that tumor cells stained positive with CD30, EMA and CD4, and negative for CD3, CD8, CD5, CD20, CD79a, CD138 and anaplastic lymphoma kinase 1 (ALK or Ki-1).

[Cutaneous anaplastic large cell lymphoma: clinicopathologic, immunohistochemical and prognostic study of 44 cases].

OBJECTIVE: To study the clinicopathologic features, immunophenotype and prognosis of primary cutaneous anaplastic large cell lymphoma (CALCL). METHODS: Histopathologic evaluation and immunohistochemical study by Envision method were carried out in 44 archival cases of CALCL. The clinical information and follow-up data were analyzed. RESULTS: The patients presented with skin nodules, masses or plaques, sometimes associated with ulceration. The commonest sites of involvement were the extremities. Follow-up data were available in 39 patients. The overall survival rate was 87.2% (34/39). Disease relapses were detected in 46.2% (18/39) of the patients. Statistical analysis indicated that patients older than 50 years of age or with no less than two involved anatomic sites were more likely to have disease relapses (P < 0.05). Histologically, 31 cases were classified as common variant, 6 cases as small cell variant and 7 cases as neutrophil/eosinophil-rich variant. Immunohistochemical study showed that the rates of expression of CD30, CD45, CD45RO, CD43, CD3, cytotoxic protein and epithelial membrane antigen were 100% (44/44), 91.2% (31/34), 82.6% (19/23), 94.7% (18/19), 70.0% (28/40), 73.3% (22/30) and 31.8% (7/22), respectively. The CD4(+)/CD8(-), CD4(-)/CD8(+) and CD4(-)/CD8(-) immunophenotypes were found in 58.3% (21/36), 22.2% (8/36) and 19.4% (7/36) of the CALCL cases, respectively. Only one case (3.7%) expressed CD56. CONCLUSIONS: CALCL is a form of low-grade primary cutaneous T-cell lymphoma with a wide spectrum of clinicopathologic pattern. Special variants of CALCL should not be confused with other types of cutaneous lymphomas and inflammatory lesions. CALCL patients older than 50 years of age or with no less than two involved anatomic sites are more likely to have disease relapses.

Neutrophil/eosinophil-rich type of primary cutaneous anaplastic large cell lymphoma: a clinicopathological, immunophenotypic and molecular study of nine cases.

AIMS: To elucidate the clinicopathological, immunophenotypic and molecular features of neutrophil/eosinophil-rich primary cutaneous anaplastic large cell lymphoma (CALCL), and to emphasize the cutaneous manifestations, differential diagnosis and prognosis of this peculiar entity. METHODS AND RESULTS: We described the clinical presentations, histopathology, immunophenotype, molecular features and follow-up courses of nine neutrophil/eosinophil-rich CALCL cases. Various clinical lesions including multiple nodules, plaques and solitary exophytic masses with or without ulceration or crusting were noted in nine patients. Two patients died of disease progression, with one developing multiple lymph node involvement. Histologically, cohesive sheets or small clusters of neoplastic cells were admixed with large numbers of neutrophils and/or eosinophils, representing 10-40% of cells per high-power field. All nine cases showed T-cell phenotypes. The frequency of rearranged TCRB, TCRG and TCRD genes in six cases with available paraffin-embedded tissue was 100%, 83% and 33%, respectively. CONCLUSIONS: Neutrophil/eosinophil-rich CALCL should be differentiated from various infectious and non-infectious diseases, especially from non-neoplastic cutaneous CD30+ infiltrates rich in neutrophils and eosinophils. Precise correlation of clinical presentation, morphological features, phenotypic and molecular analysis can help to establish the correct diagnosis. Whether this rare variant has a significantly different prognosis from classical CALCL needs further investigation.

Current management of primary cutaneous CD30+ T-cell lymphoproliferative disorders.

Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PCLPDs) are the second most common type of cutaneous T-cell lymphoma. These disorders comprise a spectrum of clinically benign lymphomatoidpapulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma (ALCL). The peak incidence of LyP is in the 5th decade of life, and the incidence of primary cutaneous ALCL peaks in the 6th decade, but children are also affected. Both LyP and primary cutaneous ALCL have an excellent prognosis. However, LyP is associated with development of malignant lymphoma (mycosis fungoides, Hodgkin lymphoma, or ALCL) in 20% of cases, and also with an increased risk of non-lymphoid cancers. The diagnosis of LyP is difficult and often delayed. Primary cutaneous ALCL must be distinguished from secondary skin lesions in systemic ALCL, which confer a poor prognosis. Correlation of clinical findings with histopathology and immunopathology (stains for ALK kinase, epithelial membrane antigen, and cutaneous lymphocyte antigen) are important to achieve a correct diagnosis. When a diagnosis of CD30+ PCLPD is established, minimal clinical staging is required. Low-dose methotrexate (10-25 mg weekly) is the most effective therapy for PCLPD but is usually reserved for aggressive cases of LyP and multifocal lesions of cutaneous ALCL Many patients with LyP can be followed expectantly, with special attention to changes in character of the skin lesions or development of lymphadenopathy. Patients with localized cutaneous ALCL can be treated with irradiation. Extracutaneous spread of disease is an indication for multiagent chemotherapy. Other treatment alternatives are discussed.

[Primary cutaneous anaplastic large cell lymphoma: a clinicopathologic analysis of 8 cases].

OBJECTIVE: To study the clinicopathologic features, immunophenotype and prognosis of primary cutaneous anaplastic large cell lymphoma (C-ALCL). METHODS: Eight cases of C-ALCL were enrolled into the study. The clinicopathologic features, immunohistochemical findings and results of in-situ hybridization for EBER 1/2 were analyzed. RESULTS: Three of the 8 patients were males and 5 were females. The median age was 49.5 years. C-ALCL often presented with solitary skin nodule, without systemic symptoms. Histologically, the lymphoma cells infiltrated the dermis and subcutis in a sheet-like pattern. They were of large size and showed conspicuous nuclear atypia. Immunohistochemical study showed that more than 75% of the lymphoma cells were positive for CD30. All cases expressed one to three T cell markers (CD3, CD5 or CD45RO) and cytotoxic granule-associated antigens (TIA-1, granzyme B or perforin). The staining for leukocyte common antigen was positive in all cases, while the expression of CD5, CD8, ALK-1 and epithelial membrane antigen was noted in 5, 1, 1 and 3 cases, respectively. The staining for CD15, CD20, CK and HMB45 was negative. In-situ hybridization for EBER 1/2 was also negative in all the cases studied. Follow-up information was available in 6 patients. Five of them were still alive and 1 died of unclear cause. CONCLUSIONS: C-ALCL has distinctive clinicopathologic and immunophenotypic features. It is not Epstein-Barr virus-related and often carries a favorable prognosis.

Primary cutaneous eosinophil-rich anaplastic large cell lymphoma: report of an unusual case and literature review.

BACKGROUND: Cutaneous, neutrophil-rich anaplastic large cell lymphoma (ALCL) is an uncommon variant of ALCL that may be confused with inflammatory dermatoses. OBJECTIVE AND METHODS: We describe an eosinophil-rich variant of ALCL occurring on the left ear without systemic involvement. The lesion had inflammatory characteristics, which led initially to a histological diagnosis of an inflammatory process. Two months later, a second biopsy diagnosed eosinophil-rich variant of ALCL. The patient underwent radiation therapy, but due to the extensive deformation and mutilation of the ear, the patient elected to have the ear amputated. We discuss the clinicopathological findings and the differential diagnosis CONCLUSIONS: To the best of our knowledge, the occurrence of a cutaneous, eosinophil-rich variant of ALCL has not been previously reported. It is important to alert pathologists to this variant of ALCL so that this possibility may be considered in the early differential diagnosis of inflammatory cutaneous conditions.