Metastatic squamous cell carcinoma in chronic lymphocytic leukaemia in a haematology-dermatology multidisciplinary clinic

Chronic lymphocytic leukaemia patients have a greater than a twofold increased risk of developing a second malignancy,1 and of these second cancers, non-melanoma skin cancers are the most frequent.1, 2 Basal cell carcinomas account for approximately 80% of non-melanoma skin cancers in the general population.2 However, in patients with chronic lymphocytic leukaemia, there is a reversal of this basal cell carcinoma: cutaneous squamous cell carcinoma ratio, consistent with reports in other immunocompromised states.1 Given the increased risk of non-melanoma skin cancer in chronic lymphocytic leukaemia patients, combined dermatology and haematology clinics have been established to better manage these patients.3 We aim to determine the features of metastatic squamous cell carcinoma in chronic lymphocytic leukaemia from six patients at a combined dermatology–haematology clinic in Australia. A retrospective analysis of patient presentations from 2 May 2013 to 16 April 2021 at a public tertiary clinic was conducted. Metastatic squamous cell carcinoma was defined as metastasis to locoregional areas, including lymph nodes and in-transit (local cutaneous) metastases, metastatic cutaneous squamous cell carcinomas of unknown origin and distant metastases. There were 517 patients with chronic lymphocytic leukaemia seen in our multidisciplinary clinic. Of these patients, 58 developed cutaneous squamous cell carcinomas. The overall rate of cutaneous squamous cell carcinoma was 11.2% (58/517). Of patients who had cutaneous squamous cell carcinoma, six subsequently developed metastatic cutaneous squamous cell carcinoma; thus, the overall rate of metastatic squamous cell carcinoma in the chronic lymphocytic leukaemia cohort was 1.2% (6/517) and 10.3% (6/58) of the chronic lymphocytic leukaemia cases with cutaneous squamous cell carcinoma. Table 1 depicts the characteristics of the six patients that developed metastatic squamous cell carcinoma. Table 2 outlines the metastatic squamous cell carcinoma features. All patients were male, with an average age of 65 ± 8.3 years at the time of haematological malignancy diagnosis. Two patients were on targeted therapies; one on ibrutinib, a Bruton's tyrosine kinase (Btk) inhibitor, and another on venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor. In most cases, metastatic disease developed following the institution of chronic lymphocytic leukaemia treatment, with the average time of metastatic squamous cell carcinoma development being 7 years post-chronic lymphocytic leukaemia diagnosis. The cutaneous squamous cell carcinomas and metastases were predominantly in the head and neck region. All the metastatic squamous cell carcinomas were moderate to poorly differentiated, in which two patients had perineural invasion, and another two patients had a lymphovascular invasion. Patient 2 died from Richter's transformation of the brainstem region, a rare complication of chronic lymphocytic leukaemia, patient 3 died from metastatic disease 2 years after diagnosis and patient 6 died from other comorbidities. Diffuse Large B-Cell Lymphoma treatment: Surgery Radiotherapy Immunotherapy-pembrolizumab Surgery Radiotherapy Surgery Adjuvant radiotherapy Palliative chemotherapy- carboplatin, capacitabine Surgery Pembrolizumab Surgery Radiotherapy Surgery Radiotherapy Our cohort overall observed a similar rate of metastasis of cutaneous squamous cell carcinoma in chronic lymphocytic leukaemia patients relative to overseas studies. A New Zealand study observed a 16.4% rate of cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukaemia. The rate of metastasis in these patients was 9.9% (6/61 patients).2 An American study reported a 10.7% rate of metastasis in their cohort over 5 years (3/28 patients), with a slightly older population.4 This demonstrates comparable metastatic squamous cell carcinoma rates in chronic lymphocytic leukaemia between the three countries, which is higher compared to the general community (1.9–2.6%).5 Hence, early detection for skin malignancies is paramount. The overall incidence of cutaneous squamous cell carcinoma in our chronic lymphocytic leukaemia cohort (11.2%) is markedly lower than a Canadian study (28% in 587 patients), whose patients also undergo regular review.6 This may reflect an increase in public awareness of ultraviolet exposure and skin cancer risk following government campaigns from 1988. However, given the similar metastatic rates, once a cutaneous squamous cell carcinoma has already developed, prior ultraviolet radiation avoidance may have minimal influence on rates of metastases.6 Delayed treatment for metastatic squamous cell carcinoma can result in the ongoing spread and is a higher risk with chemoimmunotherapy. The risk associated with Btk inhibitors and the BCL-2 inhibitor venetoclax remain to be determined but patients on targeted therapies still have a higher risk of skin and other second cancers.7 For many chronic lymphocytic leukaemia patients, metastatic cutaneous squamous cell carcinomas may need to be prioritised first due to the poorer 5-year survival outcome between the two cancers.8 This observational data provides a useful depiction of the general pattern and histological features of metastatic cutaneous squamous cell carcinoma in chronic lymphocytic leukaemia patients. We believe that the combined haematology–dermatology clinic model allows the patient to receive timely diagnosis and appropriate clinical care. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. SS is an investigator and advisory board member for Leo Pharma and Sanofi. SS is an editorial board member of AJD. SM notes honoraria/advisory or speaker services from Janssen, Abbvie and AstraZeneca.