PTLDs occur in 1% to 16% of solid organ transplantation (SOT) recipients, and the majority (70%) of them are EBV related. The risk of PTLD correlates with the level and duration of immunosuppression required for the transplanted organ, as well as the age, and EBV serostatus of the recipient.^1,2,3,4 EBV-naive patients who acquire a primary EBV infection after transplantation are at the highest risk for developing PTLD.^5,6 Furthermore, the use of T-cell depleting agents such as OKT3 and polyclonal anti-thymocyte globulins is associated with PTLD after SOT.⁷ In contrast, alemtuzumab, a monoclonal antibody directed against the CD52 surface marker found on B and T cells and other leukocytes, has not been clearly associated with an increased risk of PTLD. Thus, additional depletion of B cells may reduce the risk of B-cell proliferative disease.⁸

In a single center study, the incidence of PTLD was 0.8% for bone marrow transplants, 1.4% for renal, 1.8% for cardiac, 4.5% for lung transplants, and up to 10% in combined heart and lung transplant recipients.⁹ Since the rates of PTLD are higher in cardiac and lung transplant recipients, many of whom are pediatric patients, cutaneous PTLD has been described with some frequency in childhood.^10,11,11,12

Primary cutaneous PTLD is extraordinarily rare. Data from two transplant centers in France reported 7.5 primary cutaneous PTLDs/1,000 total primary cutaneous lymphomas/year, and 0.7 cutaneous PTLD/1000 SOT (excluding intestinal-transplant patients)/year.¹³

While PTLD may occur any time after SOT, the risk of developing PTLD is the highest in the first year after transplantation. Extranodal dissemination of PTLD is frequent and typically involves the central nervous system, lung, and liver.

Skin involvement is less common and often presents in analogy to primary cutaneous lymphomas. B-cell cutaneous lymphoproliferative PTLD presents as single or multiple macules/patches (Fig. 46-1 A and B) or nodules, with or without ulceration, and sometimes as tumors. The lesions are typically located on the legs, face, oral mucosa, and scalp.¹³ T-cell PTLD cases diagnosed as mycosis fungoides (MF)-like PTLD usually present as infiltrated plaques in the trunk, and upper and lower extremities, followed by the buttocks and the face. Some cases presented as papules, alopecia, and comedo-like lesions. Cases diagnosed as anaplastic large cell lymphoma PTLD present as tumors or plaques with frequent ulceration. The lesions are typically located in the extremities, face, buttocks, and trunk. Rare cases of Sézary syndrome usually present as generalized erythroderma.

Most of noncutaneous PTLDs are of B-cell origin, and 12.5% to 14% of cases exhibit a T-cell phenotype.^9,14 Seckin et al.¹³ showed that EBV was present in 16.6% of T-cell PTLDs and 90.9% of B-cell PTLDs in cutaneous sites. A large meta-analysis from Herreman et al.¹⁵ showed that only a third of T-cell PTLDs are related to EBV.

PTLD has been grouped by the World Health Organization (WHO) into three major morphologic categories: early PTLD, polymorphic PTLD, and monomorphic PTLD.⁴ The most recent classification scheme proposed by Knowles and colleagues divides these disorders into plasmacytic hyperplasia, polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma, non-Hodgkin lymphoma (immunoblastic or monomorphic lymphoma), and multiple myeloma.^16,17

Approximately 22% of PTLD cases show cutaneous involvement, mostly in the setting of renal transplantation.¹ A significant portion of cutaneous cases (30% to 60%) are of T-cell phenotype.^{18,19,20,21,22,23,24} Among cutaneous B-cell PTLDs, most cases are designated as diffuse large B-cell lymphoma (DLBCL) (Fig. 46-2) or plasmacytoma¹ (Figs. 46-1 and 46-3), some cases are classified as plasmablastic lymphoma,^10,12 and less frequently lymphomatoid granulomatosis (LyG).¹³ Cutaneous T-cell PTLDs are typically classified as MF, cutaneous anaplastic large cell lymphoma (C-ALCL), and rarely adult T-cell leukemia/lymphoma, lymphomatoid papulosis (Fig. 46-4), and cutaneous peripheral T-cell lymphoma.¹³ Rare cases in the skin have shown an ambiguous B- and T-cell phenotype mimicking MF.¹¹ A case with atypical Hodgkin cells and Reed–Sternberg-like cells has been also described.²⁵

This varies according to the PTLD subtype. Primary cutaneous plasmacytoma-like PTLD shows strong CD79 expression, plasma cell marker expression (CD138, CD38), light chain restriction, and Epstein–Barr virus-encoded RNA (EBER) but not HHV-8 positivity (Fig. 46-3). DLBCL-PTLD is positive for B-cell markers (CD20, CD19, CD79a, PAX5), and shows a nongerminal center phenotype (MUM1+, variable BCL-6, CD10⁻) (Fig. 46-2). Plasmablastic lymphomas are negative for B-cell surface antigens (CD20, CD19), while positive for plasma cell markers (CD138, CD38, CD79a, MUM1) and have a very high Ki67 labeling index (>90%).^1,4,15,22 EBV/EBER expression is seen in almost all B-cell-type PTLDs corresponding to DLBCL, plasmacytoma, plasmablastic lymphoma, and LyG.¹³

MF-like PTLD characteristically shows a CD4⁺ phenotype, with expression of CD2, CD3, and CD5, but variable loss of CD7. C-ALCL-like PTLD is often CD4⁺ as well, with variable expression of CD3, CD5, and CD7. Most cases are positive for CD2 and CD30. Some cases can be EMA positive. C-ALCL-like PTLD characteristically shows expression of the cytotoxic markers TIA-1 and Granzyme-B. Rare cases show EBV/EBER expression.¹³

Early PTLD lesions are polyclonal, while monomorphic PTLDs exhibit clonal B-cell or T-cell gene rearrangement. Polymorphic PTLDs are usually monoclonal and rarely oligoclonal. Several nonrandom chromosomal alterations involving lymphoma-associated oncogenes such as BCL-1, BCL-2, MYC, and RAS TP53 had been described in polymorphic and monomorphic PTLDs but not in early PTLD lesions.²⁶ The presence of somatic hypermutation within the BCL-6 gene have been associated with shortened disease survival and refractoriness to reduced immunosuppression or surgical excision.²⁷

Early lesions are most often seen in children or young adults, and respond well to immunosuppression reduction.²⁸ In contrast, monomorphic PTLD does not respond to decrease in immune-suppression and requires cytotoxic therapies. In localized disease, radiation or surgical excision may lead to remission. Other treatment strategies include antiviral therapy, systemic chemotherapy, and rituximab. In general, PTLDs presenting in the skin usually respond well to reduction of immunosuppression and show a favorable prognosis. However, aggressive neoplasms warrant additional therapy like chemotherapy and antiviral therapy.^9,17,29

EBV-MCU had been described in patients with immunosuppression secondary to azathioprine, cyclosporine, or methotrexate (MTX) or in patients with age-related immunosenescence.^{30,31,32,33,34} Recently, cases have also been reported in patients after solid and allogeneic bone marrow transplantation.^35,36 EBV-MCU is slightly more frequent in women with a mean age of 80.

Patients typically present with solitary, sharply demarcated ulcers in the oropharyngeal mucosa (buccal mucosa, tongue, tonsils), and less frequently in the large bowel, rectum, or skin lesions in the lips, arms, and chest (Fig. 46-5). Isolated regional lymphadenopathy can occur but systemic adenopathy is never present. Spontaneous resolution of the lesions occurs in approximately 25% of cases. Disease-associated mortality has not yet been reported.³³

Microscopic examination shows shallow, sharply circumscribed mucosal or cutaneous ulcers with adjacent mucosal or epidermal acanthosis including pseudoepitheliomatous changes. The underlying polymorphous infiltrate includes a mixture of lymphocytes, atypical large B-cell immunoblasts with Hodgkin-like morphology, plasma cells, histiocytes, and eosinophils (Fig. 46-6). The presence of Hodgkin-like cells, plasmacytoid apoptotic cells, and tissue necrosis is pathognomonic. The lesion is usually delineated by a rim of small lymphocytes.^33,34,37,38

Large cells are PAX-5+, OCT-2+, MUM-1+, BOB-1 +/−, and CD45^+/−. Reduced or absent expression of CD20 can be seen in a third of cases. The Hodgkin-like cells are CD30⁺ with CD15 coexpression in 43% of cases. Rimming reactive lymphocytes are CD3⁺ T cells. All cases are EBV positive (Fig. 46-7).

B- and T-cell clonality is present in 39% and 38% of cases, respectively.

Ulcerating cutaneous and mucosal lesions might be encountered in advanced stages of classical Hodgkin lymphoma (cHL), DLBCL, and LyG. In contrast to cHL, EBV-MCU shows plasmacytoid apoptotic cells, tissue necrosis, and CD30⁺CD15⁻ large cells that are more frequently positive for CD45 and B-cell markers. Perilesional expansion of CD8⁺ T cells is more characteristic of EBV-MCU than cHL.^{33,36,39,40,41} LyG is an angiocentric and angiodestructive lymphoproliferative disease of B-cell origin. The infiltrate has a significant histiocytic and T-cell component along with scattered atypical EBER+ B cells.