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Monday, September 21, 2009

Hodgkin lymphoma with cutaneous involvement

Hodgkin lymphoma with cutaneous involvement
May 2009

Hodgkin lymphoma with cutaneous involvement Cyrus C Hsia MD FRCPC1, Kang Howson-Jan MD FRCPC1, Kamilia S Rizkalla MD FRCPC2Dermatology Online Journal 15 (5): 5 1. Department of Medicine, Division of Hematology2. Department of PathologyLondon Health Sciences Centre, London, Ontario, Canada.

We report a case of a 54-year-old previously healthy man with Hodgkin lymphoma who presented initially with a solitary cutaneous ulcer. Unlike non-Hodgkin lymphoma subtypes, skin involvement of Hodgkin lymphoma is extremely rare. Furthermore, the prognosis of Hodgkin lymphoma with skin infiltration is felt to be extremely poor. Contrary to other reports, this case demonstrates that a good response with standard therapy is possible.

In contrast to non-Hodgkin lymphoma subtypes, skin involvement of Hodgkin lymphoma (HL) is extremely rare [
1, 2]. Furthermore, the prognosis when cutaneous involvement is present is felt to be extremely poor in HL [2]. We report a case of a patient with HL who presented with a solitary cutaneous ulcer. Although his diagnosis was delayed, he obtained a good response with adequate standard therapy.

A 54-year-old previously healthy man noticed an ulceration in his left gluteal area. Initially, the ulcer was the size of a quarter, but subsequently enlarged to 10 cm over the course of several months. The lesion had areas of necrotic and loose granulation tissue. Marked left inguinal lymphadenopathy with associated scrotal, penile, and left leg edema developed. These were also associated with mild intermittent fevers and significant weight loss.

Two separate biopsies of the ulceration were performed and both were reported as non-specific dermatitis. However, upon review by a hematopathologist (KSR, one of the authors) the diagnosis of classical Hodgkin lymphoma, nodular sclerosis subtype, was made. The biopsies revealed multinucleated giant cells with large nuclei and several nucleoli, the characteristics of Reed-Sternberg cells, underneath a large area of ulceration and necrosis. These cells were present in the typical background of small mature lymphocytes, eosinophils, and plasma cells.

A biopsy of a left inguinal lymph node confirmed the diagnosis of nodular sclerosis HL. Similar to the skin lesion, Reed-Sternberg cells were again present and stained positively for both CD15 and CD30. The lymph node had a typical nodular pattern surrounded by broad collagen bands. Staging CT scan of the abdomen showed massive conglomerated retroperitoneal lymphadenopathy. Bone marrow was otherwise unremarkable. He was diagnosed with stage 3B disease and was started on chemotherapy with ABVD (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine) with an overall good response. After six weeks of treatment his ulcer had completely healed and his disease was deemed to be in complete remission after six cycles of therapy.

Since the first description by Sir Thomas Hodgkin in 1832, the diagnosis, classification, and management of HL have evolved dramatically [
3]. Hodgkin lymphoma represents a small but significant proportion of malignancies worldwide and has a bimodal age distribution [1, 3]. The etiology and pathogenesis of this disease remains unknown [1, 3]. A few risk factors such as familial predisposition, infections with Epstein-Barr virus or human immunodeficiency virus, and immune suppression have been implicated [1, 2, 3]. This disease has been divided into two major groups according to the World Health Organization: the rare nodular lymphocyte-predominant and classical Hodgkin lymphoma [1]. Classical HL contains four subtypes: nodular sclerosis, mixed cellularity, lymphocyte rich, and lymphocyte depleted [1]. Each subtype has its own clinical features, pathological characteristics and prognosis [1, 3].

The most common clinical manifestation of classical HL is painless lymphadenopathy; over 80 percent of involved lymph nodes are found above the diaphragm [1, 2]. Patients may also describe painful lymphadenopathy, pruritus, and constitutional symptoms [1, 2]. Rarely, extranodal regions include the spleen, liver, lung, and bone marrow [1]. It is extremely rare to have extranodal involvement of other organs, the central nervous system, or the integument – as in our patient [2-8].

It is known that non-specific skin involvement such as pruritus, hyperpigmentation, urticaria, erythoderma, or acquired ichthyosis occurs fairly commonly, in 17-53 percent [2, 4]. However, these are thought to be paraneoplastic syndromes rather than direct tumor infiltration [2]. Direct tumor involvement is extremely rare and reported in a number of case reports [2, 4, 5, 6, 7, 8]. In 1906, Grosz described the first case of a patient with Hodgkin disease and multiple brownish, "lentil to walnut-sized," ulcerating nodules [2, 4]. Since then, the incidence has been reported to occur in 0.5-3.4 percent of Hodgkin lymphoma patients [2, 4]. Recently, Introcaso et al. have described another case and thoroughly reviewed the literature on cutaneous HL and showed that the number of cases had reportedly diminished over time [4]. It was felt this was likely due to improved treatments and the utilization of stem cell transplantation for relapsed disease [2, 4]. Frequently in cutaneous HL, the presentation is single or multiple dermal or subcutaneous nodules that become ulcerated and involve the skin area over the chest [4, 5, 6]. The mechanism or mechanisms for the skin involvement in HL are not known but postulated to be retrograde lymphatic spread from tumor-involved lymph nodes, direct extension into skin by tumor cells in underlying lymph nodes, or hematogenous spread of the tumor [2, 4].

The diagnosis of classic HL requires careful pathological identification of characteristic binucleated tumor cells (Reed-Sternberg cells), or mononuclear cells (Hodgkin cells) within an inflammatory milieu [
1]. These malignant cells represent 0.1-10 percent of all cells in a biopsy, are derived from germinal center B cells in more than 98 percent, and are distributed in a background of reactive cells [1, 3]. Typically, these cells stain positively for CD15 and CD30 but not CD20 [1, 3]. Other than HL, cells resembing Reed-Sternberg cells may be present in other B and T cell lymphomas, carcinomas, melanomas, and sarcomas [1, 3]. In particular, HL must be distinguished from other conditions that present with cutaneous lesions such as mycosis fungoides, granulomatous slack skin disease (CTCL), lymphomatoid papulosis, and anaplastic large cell lymphoma. The latter two may also have CD30 positive cells and require the more specific CD15 positive expression to be differentiated from HL.

Overall, the prognosis in Hodgkin lymphoma is good with greater than an 80 percent five-year survival [1, 3]. However, cutaneous involvement is usually associated with diffuse lymphadenopathy, late stage disease, and poor prognosis [2, 4, 6, 8]. Our case was an exception; the outcome was favorable with a good dermatological response. Rare cases of cutaneous HL with indolent clinical courses have previously been described showing slow progression to generalized lymphadenopathy over years [6, 7]. Thus, it is important to recognize this malignancy, complete the appropriate work-up for staging, and initiate prompt treatment. There are no standardized treatments for Hodgkin lymphoma with skin lesions. Standard treatment is chemotherapy with or without involved field radiation depending on the stage and bulk of the disease [3]. Skin lesions due to Hodgkin lymphoma, as in our case, have been reported to respond to current standard treatment without further therapeutic modalities such as surgical excision, topical therapy, or local cutaneous radiation [2, 4].

Although cutaneous involvement of Hodgkin lymphoma is extremely rare, it merits consideration in the category of atypical causes of non-specific papules, plaques, and ulcers; therefore, enlisting a hematopathologist may be required. Contrary to most reported cases of HL involving skin, our case demonstrates that a good response with adequate therapy is possible.

Acknowledgements: We thank dermatologist Dr. Ronald W. Gottschalk for taking the initial picture. We thank Dr. Barbara Burrall for her constructive review and advice.

Dermatology Online

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