Early-onset chronic lymphocytic leukaemia in a young man with Cowden syndrome

Abstract

Dear Editor, Cowden syndrome (CS) is a rare autosomal dominant disorder characterised by multiple hamartomas, an increased risk of multiple solid cancers and a mutation in the PTEN gene. Although CS is strongly associated with the development of solid tumours, we are unaware of any previous reports of chronic lymphocytic leukaemia (CLL) occurring in association with CS. Here, we report the case of a 29-year-old male who developed CLL on a background of CS with a mutation in the PTEN gene (heterozygous for c.1003C > Tp. (Arg335Ter)). The PTEN gene on chromosome 10q23.2 displays tumour-suppressor function by coding for a lipid phosphate mediating cell cycle arrest and apoptosis via inhibition of the P13K/AKT pathway with 13-80 % of CS families harbouring germline nonsense, missense, and frameshift mutations in the PTEN gene [1].A 28-year-old Caucasian male patient presented with abdominal pain, and endoscopy revealed multiple small bowel and colonic polyps consistent with a hamartomatous polyposis syndrome. Further investigations revealed hypothyroidism, a large head circumference (62 cm) as well as multiple papillomatous papules, all of which are recognised features of CS. A full blood count revealed a lymphocytosis of 18.6 × 10 9 /L with morphology and immunophenotyping fully in keeping with CLL. There was no expression of CD38, and FISH analysis showed the presence of 13q deletion but no evidence of poor prognostic abnormalities (17pdel, 11qdel). Computed tomography (CT) scan did not show any organomegaly or lymphadenopathy, and remaining cell lineages (haemoglobin and platelets) were within normal range resulting in Rai stage 0 and Binet stage A disease. Thymidine kinase, ZAP-70, and IgHV mutational status were not measured. Interestingly, the patient's father also had a colonic polyposis syndrome and had undergone a total colectomy to reduce his cancer risk whilst his sister had died aged 17 from a sudden cardiac death. Genetic testing for PTEN mutation analysis revealed heterozygosity for the nonsense mutation c.1003C > Tp. (Arg335Ter), confirming a diagnosis of CS based on current criteria [2]. The patient's WCC then rose to 286 × 10 9 /L in December 2014, so anti-CLL therapy was commenced with fludarabine, cyclophosphamide, and rituximab (FCR) to which he achieved a complete morphological remission which continues.CLL is the commonest leukaemia in the Western world with a median age at diagnosis of 65-70 years. CLL is rare in younger persons with just 11 % of all US patients diagnosed with CLL in 2009 being less than 55 years of age [3]. Previous studies have shown that PTEN is mutated or inactivated in many types of cancer [4][5][6][7]; however, PTEN mutations have only been reported sporadically in haematological cancers [8][9][10]. In recent years, a high frequency of PTEN mutations/deletions was found in paediatric T cell acute lymphoblastic leukaemia (ALL) [11][12][13]; however, further studies failed to find similar PTEN mutations in CLL patients. Interestingly, low expression of PTEN has been documen...

How we approach complex vascular anomalies and overgrowth syndromes

“…Colon cancer (9%), renal cell carcinoma, melanoma (6%) also are common, and there are rare reports of osteosarcoma, 38 Ewing sarcoma, 39 mesothelioma, 40 pituitary tumors, 41 meningioma, 42 and chronic lymphocytic leukemia at an earlier age of onset than the general population. 43 Patients can develop multiple cancers serially or at the same time, mostly in the third or fourth decade. Adults with the closely related segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome (below) may be predisposed to benign ovarian, breast, and thyroid adenomas.…”

“…PHTS patients 35–37 are characterized by somatic loss‐of‐function mutations of tumor suppressor genes, most notably PTEN , which lead to cumulative lifelong risk of breast (77%–85%), endometrial (28%), and thyroid carcinomas (38%). Colon cancer (9%), renal cell carcinoma, melanoma (6%) also are common, and there are rare reports of osteosarcoma, 38 Ewing sarcoma, 39 mesothelioma, 40 pituitary tumors, 41 meningioma, 42 and chronic lymphocytic leukemia at an earlier age of onset than the general population 43 . Patients can develop multiple cancers serially or at the same time, mostly in the third or fourth decade.…”