Patients with chronic lymphocytic leukemia (CLL), a B-cell malignancy characterized by impaired humoral and cellular immunity, are at increased risk of developing cutaneous squamous cell carcinoma (cSCC). Human papilloma virus (HPV) is the most common sexually transmitted infection worldwide and it has been associated with various malignancies, including cSCC. Impaired cell-mediated immunity is considered a primary risk factor in HPV-induced cSCC. We examined cSCC lesions from CLL patients with consensus review and HPV genetic analysis to further characterize the relationship between HPV and prevalence of cutaneous malignancy in this population. Eleven patients with CLL contributed 35 cSCCs. Treatment with chemotherapy shortened the latency time to first cSCC. HPV was detected in 54% of the lesions. Among the HPVpositive cSCC lesions, 84% of the lesions contained alpha-genus HPV, 42% contained beta-genus HPV, and 26% of the lesions contained both genera. There was a significant association between HPV-containing lesions and peritumoral lymphocytic inflammation, suggesting this as a future area for further characterization. The majority of the lesions, including those with alpha-genus HPV, occurred in sun-exposed areas, such as the scalp and face. These findings may lead to practice-changing recommendations for skin cancer, including the use of vaccinations to reduce HPV-associated skin cancer. K E Y W O R D S chronic lymphocytic leukemia (CLL), cutaneous squamous cell carcinoma, human papilloma virus (HPV) How to cite this article: Bhavsar-Bhakta P, Hamza M, Mehravaran S, et al. The contribution of human papilloma virus infection to cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia. eJHaem. 2021;2:228-235.

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Background: Human papilloma virus (HPV) is the most common sexually transmitted disease worldwide. α-genus HPV have oncogenic potential in anogenital skin and mucosa. Transplant patients have an increased incidence of β-genus HPV-associated cutaneous squamous cell carcinoma (cSCC). The host immune system is particularly important in the pathogenicity of HPV infection. The antibody-mediated, humoral immune response clears virus particles from body fluids and prevents re-infection. Cell-mediated immunity clears the virus from infected cells, generating immune memory. Impaired cell-mediated immunity is considered a primary risk factor in HPV-induced cSCC in the immunosuppressed population. Patients with chronic lymphocytic leukemia (CLL), a B-cell malignancy characterized by impaired humoral immunity, are at increased risk of developing cSCC. The purpose of this study is to explore the potential role of HPV in malignancies with impaired humoral response. Methods Primary cSCC tissue DNA was isolated from patients diagnosed with CLL. The tissue was analyzed for the presence of HPV. Diagnostic specimens underwent consensus dermatopathology review. Peripheral blood analytes and clinical parameters for disease course were statistically analyzed in conjunction with histopathology. Results Eleven patients with CLL contributed 37 cSCCs. In 49% of the lesions, HPV was detected. Among the cSCC lesions, 27% of the lesions contained β-genus HPV and 30% contained α-genus HPV. The most frequently reported virus was HPV-27 (α-genus), with 16% of lesions containing this variant which is frequently associated with cutaneous warts rather than cSCC. A majority of the HPV-containing lesions displayed moderate dermal lymphocytic inflammation. The lesions were often documented in sun exposed areas such as the scalp and face. Interestingly, HPV-16 and HPV-18, often found in anogenital epithelia, were detected in sun exposed skin in 14% of the lesions examined. In those patients who had documented immunoglobulins, all had hypogammaglobulinemia. Conclusions We examined clinical, histopathologic, and viral genotypes of the cSCCs in patients with CLL. It is widely accepted that CLL patients have a higher incidence and recurrence of cSCC; however, the characteristics of the lesions and the potential association to HPV has not been reported. In our cohort, the lesions were as likely to contain HPV from the α- or β- genus. HPV-27, normally associated with warts, displayed an atypical pathology. The presence of HPV-16 and -18 in sun exposed areas, suggests a novel pathology in compromised humoral immunity. Although our analysis derived some interesting associations, the role for HPV in cSCC in patients with impaired humoral immunity requires further characterization. This is particularly important as we explore the role of vaccinations in reducing HPV-associated malignancies. Citation Format: Preeya Bhavsar, Mugahed Hamza, Sepideh Mehravaran, Qin He, Steven Tyring, Peter Rady, Bhuvaneswari Krishnan, Gustavo Rivero, Daniel N. Cohen, Iberia Romina Sosa. The contribution of human papilloma virus infection to cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4898.

Introduction: Calcinosis cutis is characterized by basophilic crystalline or amorphous calcium within the dermis/subcutis. Calcinosis cutis has many different clinical subtypes and associated etiologies that may lead clinicians to consider this diagnosis. Von Kossa and/or Alizarin red special stains may be used by pathologists to highlight deposition of insoluble calcium salts, especially in histologically ambiguous or subtle cases. Case Report: We report the case of a 27-year-old male who presented with an inferior right buttock mass clinically diagnosed as epidermal inclusion cyst(s). Gross pathology revealed a gray-white pasty substance within a cyst-like structure. Histopathologic examination demonstrated pools of amorphous blue-gray material with rare deposits of admixed coarse calcifications surrounded by foreign-body giant cells. No cyst wall was seen in the specimen. Special stains, including von Kossa, were initially negative. Following additional review, it was discovered that surface decalcifying solution had been applied to the paraffin block in the histology lab prior to microtome sectioning. Hypothesizing that this could be the cause of the unusual morphology, the paraffin block was reprocessed and subsequent H and E stained sections displayed characteristic basophilic calcium deposits, which were correspondingly positive by von Kossa stain. Conclusion: The histopathologic diagnosis of calcinosis cutis is apparent by HandE in most cases, though von Kossa and/or Alizarin red special stains can be used to aid the pathologist. Given the unusual histomorphology following surface decalcification and initial lack of von Kossa stain prior to reprocessing, this report serves to make pathologists aware of this potential diagnostic pitfall.