Cutaneous lesions in patients with CLL are less common in comparison with T-cell leukemias or lymphomas. However, skin manifestations can occur in up to 25% of patients with CLL.² The cutaneous manifestations of the disease can be secondary to seeding by leukemic cells (leukemia/lymphoma cutis, LC) and other malignant diseases or nonmalignant disorders. Leukemia cutis generally arises months after the onset of leukemia. However, it may occasionally precede the hematologic manifestations by several months. In a study by Cerroni et al.⁵ describing 42 CLL patients, the mean duration of CLL before skin manifestation was 39 months. However, 16.7% of the patients developed skin lesions as the first sign of disease. When skin involvement does occur, it is most commonly found on the face (Fig. 34-1).^1,5,6,7 LC usually manifests as a solitary grouped or generalized papules, plaques, nodules, or large tumors. Some cases can also present as a papulovesicular (Fig. 34-2A,B) or granuloma annulare–like eruptions.^8,9 The lesions can arise at sites of scars from herpes zoster or herpes simplex virus (HSV) eruptions.¹⁰ Rare cases have occurred in association with actinic granulomas¹¹ or dermatofibromas.¹² We have also identified the association of CLL and epidermodysplasia verruciformis (EDV) on a patient undergoing treatment with the novel tyrosine-kinase inhibitor ibrutinib (data not published, Fig. 34-3). It is not uncommon to see leukemic infiltrates of CLL/SLL on excisional specimens performed for biopsy-proven carcinomas,^13,14 melanoma,¹⁵ and Merkel cell carcinomas.^16,17,18 It is also relatively common to see the coexistence of CLL/SLL in association with metastasis on sentinel or excisional biopsies of patients with melanoma (Fig. 34-4).¹⁵ Patients with coexistent CLL and Merkel cell carcinoma or melanoma have a worse prognosis, when compared to patients without CLL.¹⁹ An association between Merkel cell polyomavirus infection in T cells of CLL has also been detected.^20,21 The prognosis of LC in the course of CLL is controversial. Isolated case reports showing the coexistence of CLL and Sézary syndrome are available.²² While most authors agree that LC is associated with a worse prognosis,^23,24 others have claimed the opposite.⁵

Histologically, LC presents as a patchy perivascular and periadnexal, nodular and diffuse, and band-like types of infiltration in the skin (Fig. 34-5). Overlap of these histologic patterns can be seen. Cytologically, the leukemic cells are typically small, uniform lymphocytes, with scant cytoplasm and coarsely clumped chromatin. Prolymphocytes, cells with finely dispersed chromatin, more abundant cytoplasm, and distinctive nucleoli can also be present. Additional inflammatory cells such as eosinophils, plasma cells, and histiocytes can also be seen.^2,5,25 Walther et al.¹³ have also shown the peculiar association of CLL in the skin in association with scars.

Neoplastic B cells are CD20⁺, CD19⁺, PAX-5+ and show aberrant coexpression of CD5, CD43, and CD23. CLL cells lack CD79b, CD10, BCL-6, BCL-1 (cyclin D1), and FMC7 expression. A word of caution should be used with PAX5, as Merkel cell carcinoma and other neuroendocrine carcinomas can also express this marker. This is particularly important when PAX5 is the sole B-cell lineage specific marker such as in patients treated with rituximab (anti-CD20 mAb) whose leukemic cells lack CD20 expression.²⁶ Flow cytometry shows dim surface light chains expression and dim-to-moderate expression of CD20. Cutaneous involvement by CLL can rarely show biclonality.²⁷

The differential diagnosis includes primary cutaneous B-cell lymphomas, such as primary cutaneous follicle center lymphoma (PCFCL), and marginal zone B-cell lymphoma (PCMZL); and other systemic lymphomas with secondary cutaneous manifestations (follicular and mantle cell lymphoma among others). PCFCL has a germinal center phenotype with BCL-6 and/or CD10 expression, markers not typically seen in CLL. A rare case of PCFCL has been reported in a patient with preexistent history of CLL.²⁸ PCMZL can show substantial overlap with CLL; however, PCMZL is typically negative for CD5 and CD23. In addition, PCMZL often shows cytoplasmic light chains restriction within the plasma cell population, a feature that can be analyzed with the use of in situ hybridization studies.¹ Among the systemic lymphomas, mantle cell lymphomas (MCL) are also CD5⁺. However, as opposed to CLL, they are typically cyclin D1 (BCL-1) and SOX-11 positive and carry the t(11;14) translocation.^{29,30,31,32,33}