—  SYMPOSIUM #57  —

Cutaneous Lymphoproliferative Disorders
Moderator: Dr. Lorenzo Cerroni

Section 3 - Cutaneous Large B-cell Lymphomas

Lorenzo Cerroni


The new World Health Organization (WHO)-European Organization for Research and Treatment of Cancer (EORTC) classification of cutaneous lymphomas recognizes two main tpes of primary cutaneous large B-cell lymphomas: diffuse large B-cell lymphoma, leg-type and diffuse large B-cell lymphoma, other. Cutaneous lymphomas with predominance of large cleaved cells (large centrocytes) are classifed separately in the category of cutaneous follicle center lymphoma (diffuse type).

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCLLT) represents a type of PCBCL that is characterized by predominance of large round cells (centroblasts, immunoblasts) positive for Bcl-2. It has an intermediate prognosis, and it occurs almost exclusively in elderly patients, predominantly women. This cutaneous lymphoma is located on the leg in over 80% of cases, hence the term adopted by the WHO-EORTC classification. The prognosis of PCDLBCLLT is less favorable than that of other types of primary cutaneous B-cell lymphoma, with a 5-year survival rate of approximately 50-60%. In the past, prognosis of cutaneous diffuse large B-cell lymphomas had been linked to several factors including Bcl-2 expression, morphology of the cells, number of lesions at presentation, and location on the legs. A recent study, however, demonstrated that accurate classification according to the new WHO-EORTC categories is the single most important prognostic criterion, and that other features are of little or no relevance when cases are stratified into specific categories. Complete staging investigations are mandatory before a diagnosis of PCDLBCLLT can be established.

Clinically, patients present with solitary or clustered erythematous or red-brown nodules, located primarily on the distal aspect of one leg. In some patients, lesions may arise on both lower extremities. Ulceration is common. Small erythematous papules can be seen adjacent to larger nodules. It must be emphasized that tumors with similar morphologic and phenotypic features can arise in areas other than the lower extremities.

Histology shows dense, diffuse infiltrates within the entire dermis and subcutis. Involvement of the epidermis by clusters of large atypical cells, simulating the Pautrier's microabscesses found in cutaneous T-cell lymphoma, can be observed in some cases (B-cell epidermotropism), representing a potential diagnostic pitfall. The neoplastic infiltrate consists predominantly of immunoblasts and centroblasts (large round cells). Cases of diffuse large B-cell lymphoma with predominance of large cleaved cells are classified among the primary cutaneous follicle center lymphomas (PCFCLs). Reactive small lymphocytes are few, and mitoses are frequent. Based on the common finding of immunoglobulin gene hypermutations, it has been proposed that most cases of PCDLBCLLT represent large cell lymphomas originating from post-germinal center lymphocytes.

Neoplastic cells are positive for B-cell markers (CD20, CD79a), but there can be (partial) loss of antigen expression. MUM-1 is strongly expressed in most cases. This marker is useful in the differential diagnosis of PCDLBCLLT from PCFCL, diffuse type (in these last cases MUM-1 is usually either negative or expressed by a small minority of cells). Staining for Bcl-2 is positive in all cases. In fact, cases with prominent round cell morphology and negative staining for Bcl-2 are classified as primary cutaneous diffuse large B-cell lymphoma, other (PCDLBCLO). A rare variant of PCDLBCLLT is positive for CD30 and should not be misinterpreted as anaplastic large cell lymphoma. Expression of CD30 does not have any particular diagnostic or prognostic meaning in PCDLBCLLT .

The tumors demonstrate monoclonal rearrangement of the JH gene. The interchromosomal 14;18 translocation is not present. Phenotypic analyses as well as genetic data obtained by fluorescence in-situ hybridization (FISH) or microarray chip technologies revealed that PCDLBCLLTs show clear molecular differences from PCFCL, diffuse type, confirming the need of classifying these cases separately.

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Other
This group consists of rare cases of cutaneous large B-cell lymphoma that do not fit into the category of PCDLBCLLT, and includes cases of diffuse large B-cell lymphoma with a round cell morphology but without Bcl-2 expression (clinicopathologic features intermediate between PCFCL, diffuse type and PCDLBCLLT), intravascular large B-cell lymphoma, and rare examples of large B-cell lymphomas in the setting of immune suppression (e.g., plasmablastic lymphoma).

Cases of primary cutaneous B-cell lymphoma with predominance of large round cells but lacking Bcl-2 expression are classified in this group. Other histopathologic and immunohistochemical features of these cases are intermediate between those of PCDLBCLLT and PCFCL, diffuse type, suggesting that these cases represent a morphologic or phenotypic variant of these 2 groups. Prognosis of these patients is similar to that of PCDLBCLLT, with 5-year survival of approximately 50%.

Intravascular large B-cell lymphoma is a malignant proliferation of large B-lymphocytes within blood vessels. Most cases have a B-cell phenotype, but a T-cell variant has been reported. In rare patients, the skin may be the only affected site, although more often there is systemic dissemination from the onset, including often lesions located within the central nervous system. Clinically, patients present with indurated, erythematous or violaceous patches and plaques, preferentially located on the trunk and thighs. The clinical appearance is not typical of cutaneous lymphoma, and it may sometimes suggest a diagnosis of panniculitis or purpura. Interestingly, in some cases intravascular large B-cell lymphoma has been observed confined to lesions of cherry hemangiomas. Histopathologically it is characterized by a proliferation of large atypical lymphocytes filling dilated blood vessels within the dermis and subcutaneous tissues. It has been reported that the prognosis of intravascular large B-cell lymphoma limited to the skin is better than that of the disseminated form, but only a very limited number of cases has been studied.

Plasmablastic lymphoma is a rare lymphoma arising usually in the oral cavity in patients with severe immunosuppression, especially HIV-related. They are often associated with infection by HHV-8. It is characterized by a proliferation of plasmablasts (large eccentric nuclei, abundant cytoplasm, prominent nucleoli). The neoplastic cells are positive for CD38 and CD138, and express monotypic immunoglobulin light chains.

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