Nodal Involvement by CD30⁺ Cutaneous Lymphoproliferative Disorders and Its Challenging Differentiation From Classical Hodgkin Lymphoma Open Access

Mycosis fungoides is a T-cell lymphoma, largely defined by the clinical features of its early stages, typically presenting with flat, scaly lesions or patches. When MF is limited (<10% of the body surface), lifespan is often unaffected. However, patients with disseminated plaques, tumors, or both may develop internal disease, in the form of lymph node involvement, hepatosplenomegaly, or infiltrates in other organs. A minority of patients with MF develop Sézary syndrome, with diffuse erythroderma, diffuse lymphadenopathy, and leukemic involvement.^2–4 

Cutaneous CD30⁺ lymphoproliferative disorders (CD30⁺ LPDs) include primary C-ALCL and LyP, as well as a subset of transformed MF. Lymphomatoid papulosis lesions appear as small self-healing papules, with a necrotic center that often appears in clusters and recurs in the same region of the body. Patients with C-ALCL generally present with solitary or localized ulcerating tumors or nodules. Dissemination to regional lymph nodes can develop in up to 10% to 14% of patients^3–6  and likely represents the local spread of tumor cells. Patients presenting with involvement of regional lymph nodes have a good prognosis that is similar to that of patients with only skin lesions.^2–5  Advanced-stage MF including systemic lymphadenopathy, however, has a poorer prognosis, and large cell transformation is associated with worse outcomes within this group.⁶ 

When excisional lymph node biopsy is performed, involved lymph nodes may demonstrate effacement of the nodal architecture, and a nodular appearance or fibrosis. Necrosis and adherence of the excised node to the surrounding fat, denoting extracapsular extension, can be seen.² 

Mycosis fungoides is an epidermotropic T-cell lymphoma characterized by infiltrates of small to medium-sized T lymphocytes. Histologically, early patch lesions show superficial bandlike infiltrates consisting of lymphocytes and histiocytes; typically, epidermotropism is pronounced but is not always present. Cells with a highly indented nuclei, called cerebriform cells, are characteristic and the amount present depends on the progression of the disease. Plaques of MF are raised and palpable on clinical examination; this correlates with the presence of lymphocytes in the reticular dermis, not only around vessels but also interspersed between reticular dermal collagen bundles. With progression to tumor stage, the dermal infiltrates become more diffuse, epidermotropism may be lost, and the neoplastic cells increase in number and size.^2,3 

Plaques and tumors frequently feature “transformed” cells showing large vesicular nuclei, large nucleoli, and abundant cytoplasm (Figure, A). The transformed lymphocytes may be accompanied by an inflammatory infiltrate composed of eosinophils, small lymphocytes, neutrophils, and plasma cells.

Histologic transformation is defined by presence of greater than 25% of large lymphoid cells. Transformation usually occurs in advanced disease and may have an adverse prognostic impact; involvement of lymph nodes (Figure, B and C) at this stage is common.^2,3,7 

In peripheral blood, nontransformed MF frequently demonstrates loss of CD7 and CD26. In the correct clinical setting, a population with a CD3⁺/CD4⁺/CD7⁻/CD8⁻ phenotype in which the abnormal CD7⁻/CD26⁻ cells typically show dim expression of CD3 and CD4 is highly suggestive of MF^4,8,9 ; at tissue sites, CD26 may alternately be overexpressed.¹⁰  The large cells of transformed MF, ALCL-C, or LyP are rarely represented on flow cytometry, but if present they are CD30⁺, dim CD4⁺, with or without other surface T-antigen expression.

Mycosis fungoides cells are typically CD4⁺ and CD8⁻; they also express most T-cell antigens expressed by normal peripheral blood T cells, including CD2, CD3, CD5, CD43 (Figure, D) and T-cell receptor αβ, but they are often negative for CD7 in all stages of the disease. Large cells of transformed MF express CD30 (Figure, E) in 48% to 70% of cases.^2,3,4,11  Primary cutaneous anaplastic large cell lymphoma and large cell forms of LyP are definitionally CD30⁺, often dim CD4⁺, with variable expression of other T-cell antigens. Loss of T-cell antigen expression and aberrant expression of CD15 and PAX5 is noted in a subset of cases.^12,13 

Classical Hodgkin lymphoma (CHL) is a systemic malignant lymphoma usually arising in lymph nodes; the histopathologic diagnosis of CHL is based in part on the identification of Reed-Sternberg cells (RSCs) or their variants. Diagnostic malignant cells are very large and contain 1 to multiple nuclei with a prominent nuclear membrane, pale chromatin, and a single large elongate eosinophilic nucleolus per nucleus; the cytoplasm is abundant and slightly basophilic.^2–4 

CD30⁺ T-cell lymphoproliferative disorders (CD30⁺ T-LPDs), including transformed MF and primary cutaneous CD30⁺ LPDs, may secondarily involve regional or, at advanced stages, systemic lymph nodes. The large anaplastic cells can resemble RSCs and their variants. Of possible aid in their distinction, anaplastic cells in CD30⁺ LPDs vary in size and may have multiple nucleoli, whereas RSCs and their variants are more uniformly large and have 1 or 2 large eosinophilic nucleoli.⁵  Reed-Sternberg–like cells of CD30⁺ T-LPDs may be set in a polymorphic inflammatory background with eosinophils, neutrophils, plasma cells, and histiocytes similar to mixed cellularity or nodular sclerosis–type CHL. In addition, the RSC-like cells can coexpress CD30 (Figure, F), CD15, and PAX5, whereas CHL may have aberrant T-antigen expression and is CD15⁻ in a subset of cases.^7,12,13  Consequently, CHL represents a pitfall in the diagnosis of lymph node involvement by CD30⁺ T-LPDs and vice versa. A correct diagnosis has a direct impact on the patient's disease evolution by guiding the selection of therapy. Clinically, the presence of B symptoms and extensive nodal disease, particularly with mediastinal involvement, favors CHL. A previous history of CTCL, particularly within the draining region of the involved node, favors CTCL (Table 1).

Owing to the multiple overlapping histologic features, distinguishing nodal involvement by CD30⁺ T-LPDs from CHL, based on morphology, is difficult. If present, sinusoidal involvement by the large cells favors CD30⁺ T-LPDs.⁷  Architecturally, the presence of thick fibrous bands is most consistent with CHL nodular sclerosis subtype, although cases of nodal involvement by primary cutaneous T-cell lymphoma with extensive fibrosis in a nodular pattern have been described (Figure, A).⁷  Flow cytometry shows an increased CD4:CD8 ratio in both cases. While multiple and overt immunophenotypic aberrancies in background small T cells would favor MF, we note that loss of CD7 and CD26 alone is nonspecific.

In CHL, RSCs show variable expression of B-cell markers.^1,3,7  PAX5 plays an important role in the differential diagnosis, since it is expressed in some 90% to 95% of cases¹⁴ ; aberrant expression of PAX5 in CTCL is reported but rare.¹³  CD30⁺ CTCLs coexpress CD15 in a subset of cases, ranging from 9% in transformed MF to 40% in ALCL-C.¹²  Epstein-Barr virus is negative in transformed MF, LyP, and ALCL-C but can be positive in CHL (up to 75% of mixed cellularity CHL and 10% to 25% of nodular sclerosis CHL). Aberrant expression of T-cell markers in RSCs is rare but well documented and it has been correlated with a worse prognosis; CD4 is the most commonly expressed T-cell marker in CHL.¹⁵  CD43 is rarely aberrantly expressed in CHL (<5%)¹⁶  but is one of the most sensitive markers for T-cell lymphoma, making it an especially useful marker in the immunophenotypic distinction between CHL and CD30⁺ CTCL. The RSCs of CHL commonly lack the common leukocyte antigen CD45,³  and strong CD45 expression is an argument against the diagnosis of CHL. Distinguishing immunophenotypic features of a basic immunohistochemical panel are presented in Table 2.

Molecular studies should be considered early in the workup of difficult cases, as results may take weeks to arrive. Standard gene rearrangement studies performed according to the BIOMED-2 protocol demonstrate immunoglobulin gene rearrangement in a subset of CHL cases,¹⁷  whereas T-cell receptor gene rearrangement supports T-cell lymphoma origin (Table 1).^1,2,3,7  Comparing molecular studies from the different patient's specimens (skin biopsies versus lymph node) is valuable, as identifying clonal peaks of identical size supports involvement by the same process. In contrast to these standard polymerase chain reaction–based molecular techniques, high-throughput sequencing¹⁸  of amplified immunoglobulin or T-cell receptor loci has the advantage of allowing comparison of aberrant sequences and more precise delineation of clonal relationships.

The therapy for CD30⁺ T-LPDs, including transformed MF and primary cutaneous CD30⁺ LPDs, differs greatly from therapy for CHL; CD30⁺ LPDs with local lymph node involvement often respond to local treatment, including local radiotherapy or surgical excision.⁵  However, in CHL, combined modality treatment (chemotherapy plus radiotherapy) is the standard.¹⁹  In MF, by contrast, a stage-adapted conservative therapeutic approach is recommended.¹  Multiagent systemic chemotherapy is only indicated for patients with effaced lymph nodes or visceral involvement or for patients with widespread tumor. Both C-ALCL and LyP have an excellent prognosis, with a 10-year survival of 90% and almost 100%, respectively. Patients with localized C-ALCL are typically treated with local radiotherapy or surgical excision. Patients with C-ALCL presenting with multifocal skin lesions can be best treated with low-dose methotrexate. Recent preliminary studies report high response rates in patients with C-ALCL as well as patients with MF expressing CD30. Novel targeted therapies such as brentuximab vedotin are in trials for CD30⁺ lymphomas, both CHL and CTCL.¹ 

Differentiating nodal involvement by CD30⁺ T-LPDs from CHL is a challenging task. Communication with clinicians to obtain their clinical impression and a detailed clinical history is of crucial importance. Judicious use of immunohistochemistry studies plays an essential role in arriving at the correct diagnosis; awareness of aberrant expression of CD15 by CTCL and T-cell markers by CHL is crucial. Review of the patient's previous specimens is important. Molecular gene rearrangement studies should be initiated early in difficult cases, and comparison of clonal abnormalities in prior diagnostic biopsies is especially valuable.