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Primary Cutaneous CD30+ Lymphoproliferative Disorders: New Insights Into Biology and Therapy

Primary Cutaneous CD30+ Lymphoproliferative Disorders: New Insights Into Biology and Therapy

The spectrum of CD30+ lymphoproliferative diseases of the skin includes CD30+ cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, as well as borderline cases. These entities constitute the second most common group of cutaneous lymphomas according to the newly revised World Health Organization and European Organisation for Research and Treatment of Cancer consensus classification. Recent progress in immune and molecular biology, and identification of therapeutic targets have increased our understanding of these diseases and have led to novel treatment approaches. This review will provide an update on recent findings of immunologic, molecular, cytogenetic features and treatment strategies for patients with CD30+ lymphoproliferative diseases.

Clinically and biologically, cutaneous T-cell lymphomas (CTCL) represent a heterogeneous group of non-Hodgkin's lymphomas (NHL) defined by clonal proliferation of skin-homing malignant T lymphocytes. The spectrum of CD30+ cutaneous lymphoproliferative disorders includes lymphomatoid papulosis (LyP), cutaneous anaplastic large-cell lymphoma (CALCL), and borderline cases that represent the second most common types of CTCL after mycosis fungoides (MF) and comprise approximately 25% of all CTCL.[1] Their common phenotypic hallmark is the CD30 antigen, a cytokine receptor belonging to the tumor necrosis factor receptor superfamily. Other overlapping features include common spontaneous regression of the skin lesions and in general a low-grade malignant course with an excellent prognosis.[2,3]

Clinical Manifestation and Differential Diagnosis

Lymphomatoid Papulosis


Lymphomatoid Papulosis

First described in 1956 by Dupont et al as histiomonocytic reticulosis and later coined by Macaulay in 1968, LyP has been recognized as a clinically benign but often recurrent skin condition. The skin of patients is characterized by the presence of a self-healing skin eruption of erythematous papules and nodules that may become hemorrhagic, necrotic, and/or ulcerative (Figure 1).[4,5] Clinically, lesions vary from papules and nodules to, less commonly, larger plaques, and follicular, vesicular, and pustular types.[6] Oral involvement has been rarely observed.[7] While individual lesions take weeks to several months to resolve, the disease may recur for decades and is highly variable. Arthropod bites, pityriasis lichenoides et varioliformis acuta (PLEVA), prurigo nodularis, folliculitis, and various cutaneous lymphomas may clinically resemble LyP.

LyP was previously considered a benign inflammatory process comprising a spectrum with pityriasis lichenoides.[8] Both conditions are associated with crops of papules on the trunk and extremities that tend to ulcerate. However, LyP is now regarded as an indolent cutaneous lymphoma according to the new World Health Organization—European Organisation for Research and Treatment of Cancer (WHO-EORTC) classification.[1]


Key Diagnostic Criteria for Lymphomatoid Papulosis (LyP)

Three Types of Lymphomatoid Papulosis

Three histologic types have been identified, characterized as type A, B, and C (Table 1). Types A and C consist of large atypical lymphocytes resembling Reed-Sternberg cells. Type A cells are embedded in a dense inflammatory background with histiocytes, neutrophils, and eosinophils, and can resemble Hodgkin's disease, whereas type C cells are characterized by sheets of similar large atypical lymphocytes with prominent lavender nucleoli and open chromatin with fewer interspersed inflammatory cells (Figure 2). Only a few inflammatory cells are present. Type B simulates classical MF features, with epidermotropism and a dermal band-like infiltrate composed of small to medium-sized cells. It may represent an early stage in the evolution of the more conventional type A presentation.


Pseudoepitheliomatous Lymphomatoid Papulosis

Atypical cells exhibit a CD4+ CD8- CD30+ T-helper phenotype and frequently express cytotoxic proteins such as granzyme B, TIA-1, and perforin. Aberrant phenotypes with loss of the CD7 antigen frequently occur. The expression of CD15, a marker for Hodgkin and Reed-Sternberg cells, has been reported, but staining for CD15 is generally negative. Coexpression of CD56 is observed in rare cases, but does not appear to be associated with an unfavorable prognosis.[9,10] Pseudocarcinomatous epidermal hyperplasia was found in cases of LyP and CD30+ CALCL possibly associated with epidermal growth factor dysregulation (Figure 3).[11] Recently published immunohistochemical data suggest that fascin expression in LyP may become a predictive marker for development of a second lymphoid malignancy.[12] Low (or loss of) CD134 expression may also predict disease progression.[13]

Cutaneous CD30+ Anaplastic Large-Cell Lymphoma


Cutaneous Anaplastic Large-Cell Lymphoma

In 1985, Stein et al described a large-cell lymphoma defined by cohesive sheets of large lymphoid cells expressing the Ki-1 (CD30) antigen. This has led to the further recognition of CD30 expression as a common phenotypic hallmark for LyP and CD30+ CALCL. Most cases of CD30+ CALCL present as solitary or regional nodules and/or tumors that often show ulceration (Figure 4). The skin lesions may undergo spontaneous regression as in LyP, but often persist. Generalized or multifocal lesions are seen in about 20% of patients. Papules and plaques simulating morphea or ulcerated lesions resembling pyoderma gangrenosum have also been described.[14] Extracutaneous or regional lymph node involvement is seen in 10% of patients at presentation.


Cutaneous Anaplastic Large-Cell Lymphoma on Histology

CD30+ CALCL shows histologic and immunophenotypic overlap with LyP and may be difficult to distinguish at times. Therefore, clinical features are important in distinguishing CD30+ CALCL from LyP. A morphologic and immunophenotypic overlap with classic Hodgkin's disease has also been recognized. Histology shows a diffuse, nonepidermotropic infiltrate with cohesive proliferations of large CD30+ lymphocytes. In most cases, neoplastic cells show anaplastic features; less commonly, they have a pleomorphic or immunoblastic appearance (Figure 5). However, there is no difference in the prognosis and survival rate.

According to the WHO-EORTC system, CALCL is classified by the expression of CD30 in more than 75% of large atypical cells.[1] However, it may show a wide morphologic spectrum including neutrophil-rich tumors.[15] The atypical cells generally show an activated CD4+ T-helper cell phenotype with variable loss of T-cell markers and frequent expression of cytotoxic proteins. A CD8+ T-cell phenotype as well as coexpression of CD56 and CD30 have rarely been reported.[15] The overlying epidermis may show a variable degree of pseudoepitheliomatous hyperplasia mimicking squamous cell carcinoma, thereby leading to inappropriate diagnosis and treatment (Figure 4).[11]

In contrast to systemic anaplastic large-cell lymphoma (ALCL), primary CD30+ CALCL rarely carries the t(2;5) translocation and is usually ALCL kinase protein (ALK)-negative.[16,17] Clusterin was found to be a specific marker for ALCL, but it does not differentiate primary from secondary cutaneous ALCL, as the presence of the ALK protein apparently does.[18] Epithelial membrane antigen (EMA) and expression of c-kit receptor (CD117) is usually negative in cases of CD30+ CALCL and LyP.[19]

Borderline Cases

Borderline cases refer to those in which a difference between the clinical and histologic appearance exists. These include cases with the clinical presentation of a CD30+ CALCL but histologic features suggestive of LyP, and, conversely, cases with a recurrent, self-healing skin eruption that shows histologic features characteristic of a CD30+ CALCL. The distinction between LyP and CD30+ CALCL is not always possible based on histologic criteria. LyP type C has been described as a borderline lesion of CD30+ CALCL. Thus, the clinical appearance and the clinical course over time are used as decisive criteria for the definitive diagnosis and choice of treatment.

The presentation of CD30+ lymphoproliferative diseases can be a diagnostic challenge, as CD30 expression has been observed in cutaneous infiltrates of various reactive inflammatory and neoplastic diseases such as arthropod bites, scabies, PLEVA, Langerhans cell histiocytosis, cutaneous B-cell lymphomas with immunoblastic or large-cell features, and CD30+ large-cell transformation of MF. Therefore, clinicopathologic correlation is mandatory to establish a diagnosis and to avoid inadequate or excessive therapy.[8,20,21]


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