Dense lymphocytic infiltrates associated with non-melanoma skin cancer in patients with chronic lymphocytic leukemia
1. Department of Dermatology
Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy associated with an increased risk of non-melanoma skin cancer. Basal cell carcinomas and squamous cell carcinomas in these patients may have an associated dense peritumoral leukemic infiltrate. This infiltrate can lead to the diagnosis of CLL and may also obscure tumor margins and pose a challenge in the assessment of perineural tumor spread. Immunohistochemical stains are useful in distinguishing leukemic B-cell infiltrates from tumor-reactive T-cell infiltrates. Leukemic cells of CLL are CD20+/CD23+/CD5+/CD43+/CD3-, whereas benign reactive infiltrates are composed of CD20-/CD23-/CD5+/CD43+/CD3+ T-cells. Given the paucity of symptoms in early stages of CLL, a dense lymphoid infiltrate surrounding a cutaneous neoplasm may serve as the first indication of CLL. We report a series of three cases of SCC with a coexisting infiltrate of CLL, including one with perineural involvement, one involving metastatic SCC, and one in which this histologic finding spurred the initial diagnosis of CLL.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in western nations . Patients with CLL are reported to have an eight-fold increased risk of developing nonmelanoma skin cancer (NMSC) [2, 3]. Following Mohs surgical excision, CLL patients have a seven-fold and fourteen-fold increase in rate of recurrence of squamous cell carcinoma  and basal cell carcinoma , respectively.
Dense peritumoral lymphocytic infiltrates composed of leukemic B-cells have been described in CLL patients with squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) [6, 7, 8]. Recognition of this phenomenon may lead to the diagnosis of CLL [6, 9, 10].
Such infiltrates are also of significance because they may obscure histological margins. We report three cases and discuss histological differentiation from a reactive lymphoid infiltrate. In one of our cases, the infiltrate was present in a perineural pattern. Because reactive perineural lymphoid infiltrates can be a marker for perineural tumor extension, failure to identify the infiltrate as leukemic may result in larger postoperative defects .
An 84-year-old man presented to Mohs surgery for treatment of a biopsy-confirmed, well-differentiated SCC in the left infra-auricular area. The final Mohs stage revealed a dense inflammatory infiltrate, raising concern of obscured, residual SCC within the infiltrate. Cytokeratin stains failed to reveal residual tumor, confirming adequate margins.
At follow-up, an SCC of the right superior helical rim was treated via the Mohs technique. Again, a significant peritumoral inflammatory response was noted on Mohs sections (Figure 1). Cervical and axillary lymphadenopathy were identified, which, according to the patient, had been present for years. Due to suspicion of a lymphoproliferative disorder, a CBC was obtained, revealing a WBC count of 54,400 with 89 percent lymphocytes. A tentative diagnosis of CLL was made, and consultation with the hematology service was recommended. However, the patient declined further evaluation or treatment.
A 77-year-old man with a 10-year history of CLL and multiple NMSCs presented to Mohs surgery for excision of a biopsy-proven SCC of the right scalp. During Mohs excision, a dense peritumoral inflammatory infiltrate and a similar infiltrate around a deep peripheral nerve were identified (Figures 2 and 3). Tissue was sent for immunohistochemical stains to differentiate perineural SCC-associated inflammation from a leukemic infiltrate. The infiltrating cells were noted to express CD20, CD23 and CD5, consistent with the patient’s known CLL (Figure 2). Cytokeratin stains failed to reveal perineural SCC (Figure 3).
An SCC of the forehead was excised from a 76-year-old man. However, multiple cutaneous and nodal metastases developed two months later. Radiation therapy and chemotherapy were only partially helpful. Palliative excision of the metastatic nodules over the right temple was performed and microscopic examination showed moderately to poorly differentiated metastatic SCC with dense perivascular lymphoid aggregates (Figure 4A). The lymphoid cells were CD20 and CD5 positive (Figures 4B and 4C), but CD3 negative. The dermatopathologist, concerned about a cutaneous leukemic infiltrate, consulted the clinician, who confirmed a known history of CLL.
Chronic lymphocytic leukemia accounts for 22-30 percent of all leukemias . After excision with microscopically controlled margins, the rate of recurrence in patients with CLL is 7 times higher for SCC  and 14 times higher for BCC  than in similar patients without CLL. This increased occurrence and recurrence of cutaneous neoplasms in CLL patients is likely related to immune dysfunction, although recurrence may also result from positive margins obscured by the dense infiltrates.
Immune defects in CLL are numerous and include hypogammaglobulinemia, leukemic cell production of circulating IL-2 receptor with consequent removal of endogenous IL-2, down-regulation of CD40-ligand (CD154) on activated T-cells, defective expression of costimulatory antigens CD40 and CD80 on dendritic cells, decreased NK cell activity, decreased neutrophil function, and hypocomplementemia . Treatment with chemotherapeutic agents in advanced chronic leukemia may further compromise immunity.
Given their increased incidence of skin cancer, patients with CLL frequently present to dermatologists and dermatologic surgeons for diagnosis and treatment. Evaluation of biopsy specimens from these patients may be complicated by the presence of dense, monomorphic lymphocytic infiltrates associated with the cutaneous neoplasms. Mehrany et al.  found dense lymphocytic infiltrates associated with SCC and BCC in 36 percent of patients with CLL, compared with 1 percent of controls.
The finding of such infiltrates can pose a significant difficulty for those interpreting the histological sections. Cutaneous malignancies are frequently associated with reactive inflammatory infiltrates; in patients with CLL, it may not be clear whether a lymphocytic infiltrate is part of the leukemic process or part of a reaction to residual carcinoma. During Mohs surgery, this has led to the resection of additional tissue and increased size of postoperative surgical defects . This infiltrate may also obscure or simulate perineural tumor extension, requiring cytokeratin stains for clarification [14, 15], as demonstrated in case 2 above.
In the study by Mehrany et al. , 75 percent of the peritumoral dense lymphocytic infiltrates in patients with CLL were B-cell leukemic infiltrates. Differentiation of a leukemic infiltrate from a reactive inflammatory infiltrate is based on immunohistochemical characterization. The immune response to cutaneous malignancies in immunocompetent individuals is comprised predominantly of CD3+/CD43+/CD5+/CD20- T lymphocytes [16, 17], whereas the leukemic infiltrate of CLL typically consists of CD20+/CD23+ B-lymphocytes, which are negative for the T-cell marker CD3, but show aberrant (positive) expression of T-cell markers CD43 and CD5 [6, 7, 10, 18]. A complete panel of immunostains is necessary to avoid misinterpreting aberrant CD5 staining as evidence of T-cell lineage. As in case 1 above, dense lymphocytic infiltrates around epithelial neoplasms may be encountered in patients with no known history of leukemia, and this finding should stimulate further evaluation for CLL.
The pathophysiology of the dense peritumoral infiltrates in patients with CLL and NMSC is poorly understood, but this occurrence appears not to affect the staging or prognosis of the CLL . Smoller and Warnke  proposed that the leukemic B-cells may respond specifically to tumor antigens, or, alternatively, may be part of a nonspecific immunologic response, which is dominated by neoplastic B-cells as a reflection of the composition of the circulating leukocyte pool. Dargent  suggested that neoplastic B-cells are recruited to the SCC interface by adhesion molecules and cytokines, but upon arrival, do not express adequate MHC and costimulatory molecules to provide the necessary signals for T cell activation, leading to a defective T-cell response. This may in part explain the increased aggressiveness of SCC in patients with CLL .
In conclusion, dense lymphocytic infiltrates associated with epithelial neoplasms may represent a leukemic infiltrate. Immunohistochemical stains for CD20, CD23, CD3, CD5, and CD43 are useful in making this distinction. The presence of a dense tumor-associated infiltrate in a patient with no history of leukemia should prompt further evaluation for hematologic malignancy.
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