Originally described by Liebow⁴ in 1972 in the lungs, it primarily affects adults in the fourth to sixth decades of life, and has a male predominance of 2:1. Unlike other LPD, many patients with LyG have no clearly defined underlying immunodeficiency. In a large multicenter case series of cutaneous posttransplant LPD (PTLD), only one case of LyG was found.⁵

LyG is linked to EBV infection. LyG patients have serologic evidence of past EBV exposure and low viral loads by PCR analysis (∼18 copies/10⁶ genome equivalents). On the contrary, patients with PTLD usually show high EBV viremias. The typical latency pattern of EBV infection in LyG is type III.^6,7 EBV-infected B cells may avoid immune surveillance due to dysfunctional T-cell or NK-cell responses.² Patients with an underlying acquired or inherited immunodeficiency syndrome may be diagnosed with LyG (e.g., Wiskott–Aldrich syndrome, X-linked lymphoproliferative syndrome, HIV/AIDS, solid organ transplant) under the current WHO classification. Electron microscopy reveals features of endothelial necrosis and regeneration.⁸ The angiocentric and angiodestructive infiltrate is characterized by numerous T-helper memory cells.⁹ EBV-induced chemokines, such as IP-10 and Mig, have been implicated in mediating the vascular damage in pulmonary LyG and most likely the skin.^10,11

Most patients present with respiratory symptoms, and usually show multiple, bilateral lung infiltrates or nodules.¹² The lungs are virtually always involved.¹ Skin involvement is present in approximately 40% to 50% of cases.^{12,13,14,15,16} Other organs such as kidneys, CNS, and GI tract are less commonly affected. The lymph nodes¹⁷ and bone marrow are usually spared. Cutaneous lesions of LyG have been seen in association with Wiskott–Aldrich syndrome, myeloproliferative disorders, and in posttransplant settings.^18,19,21 A history of lymphoma, leukemia, biliary cirrhosis, chronic hepatitis, and others can be seen in some patients.^1,22 Constitutional symptoms, including fever, weight loss, fatigue, and/or night sweats, are common complaints (80% of cases).^11,23 The clinical lesions can precede, coincide, or follow the pulmonary disease with the latter two scenarios being the most typical.

The cutaneous lesions of LyG are typically dermal or subcutaneous nodules. A third of these cases show ulceration.²⁴ Plaques (Fig. 29-1) or lichen sclerosus-like presentations had been reported in 15% and 10% of the cases, respectively.¹¹ More uncommon clinical presentations include alopecia,¹¹ necrobiosis lipoidica-like,²⁵ facial edema, papules, folliculitis-like lesions,²⁶ annular lesions,²⁷ angioedema,²⁸ and eschar-like violaceous nodules.²⁹ Rarely, the disease can present in children.^20,30 Cases secondary to azathioprine, imatinib, and methotrexate therapy have been described.^31,32,33,34 A rare isolated cutaneous form with indolent clinical course had been also reported following heart–lung transplantation.²¹ An unusual EBV-cutaneous LyG in a patient with coexistent EBV+ lung LyG had been also seen.³⁵

The clinical course of LyG is variable, ranging from spontaneous regression^36,37 to progression to EBV+ diffuse large B-cell lymphoma (DLBCL). Overall, the survival rate for LyG is poor with an average of 2 years of survival following the initial diagnosis.^1,2,13 Death typically results from progressive pulmonary insufficiency.¹¹

Cutaneous LyG is histologically characterized by a lymphocytic or lymphohistiocytic infiltrate, with or without multinucleated giant cells. The infiltrates have a periadnexal and/or perivascular–angiocentric distribution. The subcutaneous tissue shows a lymphohistiocytic panniculitis, often with poorly formed granulomas. Sarcoidal or necrotizing granulomas are not present.¹¹ Occasional mild reactive lymphocyte exocytosis can be seen in the epidermis, but without the histologic atypia associated with mycosis fungoides. The dermal infiltrate often has a superficial and deep distribution. Angiodestruction, necrosis, and atypical lymphoid cells surrounding the vessels are seen (Fig. 29-2). Occasional large atypical cells with nuclear hyperchromasia, pleomorphism, and prominent nucleoli, reminiscent to Hodgkin-like cells are seen. The histologic grading is based on the number of large atypical cells. In low-grade lesions they are few and scattered, while in the high-grade lesions they form aggregates or sheets. Angiodestruction is not typical in papular lesions, but is often seen in nodules.¹¹ Admixed plasma cells, histiocytes, and occasional eosinophils can be seen. LyG in extracutaneous sites shows similar angiocentric, atypical lymphohistiocytic infiltrates. Infarcts in the lungs are common^1,22 (Figs. 29-3 and 29-4).