Cutaneous Involvement by Hodgkin Lymphoma

Alejandro A. Gru

András Schaffer

DEFINITION

Hodgkin lymphoma (HL) is a clonal lymphoproliferative disease of germinal center B-cell origin. Lymph nodes of the cervical (75% of cases), mediastinal, axillary, and paraaortic regions are the commonest sites of involvement. HL lesions contain a small number of large mononuclear or multinuclear neoplastic cells, which are admixed with nonneoplastic inflammatory and accessory cells. HL is composed of two separate disease entities: classic HL (CHL) and nodular lymphocyte predominant HL (NLPHL). These groups differ in their clinical presentation and histologic, immunophenotypic, and genetic features. Cutaneous dissemination is exceedingly rare and had been described only for CHL, not for NLPHL. Isolated case reports of “primary HL” are anecdotal. Diagnosing cutaneous HL is problematic as it shows morphologic and immunophenotypic overlap with primary cutaneous CD30⁺ lymphoproliferative diseases, such as lymphomatoid papulosis (LyP) or cutaneous anaplastic large-cell lymphoma (cALCL). Furthermore, nodal extension of CD30⁺ lymphoproliferations should be differentiated from CHL.

EPIDEMIOLOGY

HL accounts for about 15% to 30% of all lymphomas.¹^,²^,³ The age-adjusted incidence rate in the United States is approximately 3 to 4 per 100,000 population.⁴ CHL accounts for about 90% to 95% of HLs in Western countries and displays a characteristic bimodal age distribution curve with peaks at 15 to 35 years of age and in the elderly.¹^,²^,³ NLPHL comprises about 3% to 8% of HLs and occurs in all age groups with a peak in the third decade.²^,³

The incidence of CHL is higher in patients with history of infectious mononucleosis (4-fold) or HIV (6- to 20-fold).⁵^,⁶^,⁷ Furthermore, a paradoxical increase in HL incidence had been observed in HIV patients receiving combination antiretroviral therapy, or in patients receiving allogeneic bone marrow transplantation, suggesting that immune reconstitution may underpin the pathogenesis in some cases.⁷^,⁸

ETIOLOGY

Epstein–Barr virus (EBV) is detected in 25% to 75% of CHLs, while NLPHL is generally considered EBV negative.⁹^,¹⁰ Rare cases of NLPHL may be EBV positive in both children and adults.¹¹ Evidence of EBV infection is more prevalent in the mixed cellularity and lymphocyte-depleted variants, in HIV-associated cases and in patients from tropical countries.¹^,¹²^,¹³^,¹⁴

CUTANEOUS DISSEMINATION

First described by the German physician Grosz in 1906, cutaneous HL is an exceedingly rare manifestation of the nodal disease¹⁵. The incidence of cutaneous HL decreased over the last decades in part owing to improved therapy, including autologous stem cell transplantation for systemic disease.¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹ Cutaneous dissemination is associated with an aggressive clinical course.²²

The pathomechanism of cutaneous dissemination is unclear. While hematogenous spread and direct extension from involved lymph nodes had been proposed, the likeliest route of spread is retrograde lymphatogenous. This is supported by the predilection of skin lesions for anatomical sites such as axilla and chest, which overlie affected draining lymph nodes that lack histologic evidence of extranodal extension.²² Cutaneous dissemination had been described only for CHL, most commonly for the nodular-sclerosis variant.

The isolated case reports of “primary HL” are anecdotal and most likely represent examples of LyP or ALCL, rather than de novo cutaneous disease.²³^,²⁴^,²⁵^,²⁶

CLINICAL PRESENTATION

Cutaneous dissemination of CHL typically affects the skin of the chest and axilla, which are the draining areas of the most commonly affected lymph nodes. The clinical presentation includes single or agminated papules,²²^,²⁷ plaques,²⁸ sinus tracts,²⁹^,³⁰ nodules,³¹ or tumors (with or without ulceration).³² Cases with generalized erythroderma had been described.³³^,³⁴^,³⁵

Paraneoplastic dermatoses are found in 3% and 50% of patients and include hyperpigmentation,³⁶ pruritus,³⁷ acquired ichthyosis,³⁸ herpes zoster,³⁹ alopecia,⁴⁰ and disseminated granuloma annular.⁴¹^,⁴²

ASSOCIATION WITH OTHER MALIGNANCIES

A significant subset of patients with CD30⁺ lymphoproliferative disorders (LPDs), such as LyP, has a higher risk for the development of CHL.⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷ Conversely, patients with CHL might develop other malignancies including melanoma,⁴⁸ granulomatous slack skin, and follicular mucinosis.⁴⁹^,⁵⁰^,⁵¹

HISTOPATHOLOGY

The hallmark cell of CHL is the Reed–Sternberg (RS) cell. The classic RS cell is large with hyperlobulated nucleus that might appear multinucleated. Mono- or binucleated forms also exist. The mononuclear variant is called the Hodgkin cell. The nuclei of these variants show pale chromatin, thickened nuclear membrane, and large, eosinophilic, viral inclusion–like nucleolus (owl’s eye appearance) (Fig. 36-1). Additionally, mummified cells with collapsed basophilic nucleus and lack of nucleolus are invariably found (Fig. 36-1). They are thought to represent degenerate RS and Hodgkin cells. RS cells and their variants are sparsely dispersed among numerous bystander inflammatory cells, most commonly small lymphocytes, plasma cells, neutrophils, histiocytes, and eosinophils (Fig. 36-1).¹^,⁵²^,⁵³ RS-like cells and variants can be seen in a range of different disorders, particularly in LyP and cALCL (see Differential Diagnosis), and therefore they are not diagnostic of HL.

FIGURE 36-1. Cutaneous involvement by Hodgkin disease. A and B. Nodular dermal infiltrate with sparing of the epidermis. C. RS-cell variants include mononuclear Hodgkin cells, binucleated RS cells with owl’s eye appearance (white arrow), and multinucleated mummified cells (black arrow). Hodgkin cells contain a single, centrally placed eosinophilic nucleolus. Background inflammatory cells include small lymphocytes, neutrophils, histiocytes, and eosinophils.

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