Somatic PRKAR1A Gene Mutation in a Nonsyndromic Metastatic Large Cell Calcifying Sertoli Cell Tumor

Abstract

Large cell calcifying Sertoli cell tumors (LCCSCTs) are rare testicular tumors, representing <1% of all testicular neoplasms. Almost 40% of patients with LCCSCTs will present in the context of an inherited tumor predisposition condition, such as Carney complex (CNC) or Peutz-Jeghers syndrome. We report the case of a 42-year-old man who had presented with a right testicular mass, and was diagnosed with metastatic LCCSCT. The patient underwent radical orchiectomy, achieving initial remission of his disease. However, lymph node and hepatic metastases were identified. He received chemotherapy without response, and he died of complications of his disease 4 years after the initial diagnosis. Genetic analysis of the tumor and a lymph node metastasis identified a somatic frameshift mutation in the PRKAR1A gene (c.319delG, p.E107fs*22). The mutation was predicted to result in premature termination of the PRKAR1A protein and, thus, not be expressed at the protein level, consistent with other PRKAR1A nonsense mutations. The patient was extensively screened for signs of CNC, but he had no stigmata of the complex. To the best of our knowledge, the present report is the first of a somatic mutation in the PRKAR1A gene shown to be associated with a seemingly sporadic case of LCCSCT. Somatic PRKAR1A mutations are rare in sporadic tumors, and it is unknown whether this mutation was causative of LCCSCT in our patient who did not have CNC, or contributed to the malignancy of the tumor, which might have been caused by additional mutations.

Large Cell Calcifying Sertoli Cell Tumor

“…These cases reinforce the point that neither syndrome assures a benign clinical course and that each case must be individually evaluated. We also note that the clinically malignant tumor of one additional patient tested positive for somatic PRKAR1A mutation 3…”

Large cell calcifying Sertoli cell tumour: a contemporary multi‐institutional case series highlighting the diagnostic utility of PRKAR1A immunohistochemistry

“…The array of neoplasms associated with Carney complex frequently demonstrate bi‐allelic inactivation of PRKAR1A , even when arising in a non‐syndromic context 10,11 . In recent years, immunohistochemistry (IHC) for PRKAR1A (showing loss of expression) has emerged as a useful surrogate marker for this alteration in several of these tumour types, including atrial myxoma, 11 superficial angiomyxoma 12 and malignant melanotic nerve sheath tumour (formerly ‘melanotic schwannoma’) 13 .…”

“…As in normal tissues, PRKAR1A expression is expected to be intact in other testicular tumours, which lack PRKAR1A alterations. We therefore speculated that PRKAR1A (loss of expression) may be a potentially useful diagnostic marker for LCCSCT, as LCCSCT is similarly associated with Carney complex, while those that are sporadic can also harbour somatic PRKAR1A mutation 4,10 . Furthermore, at present there are no specific biomarkers for LCCSCT and routine IHC stains have a limited capacity to separate it from other sex cord‐stromal tumours, which have a largely similar immunoprofile.…”

Carney complex- why thorough medical history taking is so important - report of three cases and review of the literature

“… malignancy rate up to 10% (follicular, papillar cancer) [ 51 , 52 ] Breast tumors breast myxomas, myxoid fibroadenomas and ductal adenomas [ 53 , 54 ]. after puberty [ 53 , 54 ] typically, multiple Ovarian lesions common [ 55 , 56 ] ovarian cysts, serous cystadenomas and cystic teratomas after puberty rarely progress to ovarian carcinoma [ 55 , 56 ] Testicular tumors up to 75% large cell-calcifying Sertoli cell tumors (LCCSCT) [ 57 , 58 ] childhood increased risk of reduced fertility [ 59 , 60 ] and malignancy in adults [ 61 , 62 ], malignancy rate 17% [ 63 ] physicians should be aware of these very rare testicular tumors representing <1% of all testicular neoplasms [ 57 , 58 ] and their possible connection to CNC Bone lesions 1% osteochondromyxoma [ 7 ], 31.6% vertebral nodular lesions [ 64 ] osteochondromyxoma: usually early childhood [ 7 ]; vertebral lesions interpreted as osteochondromyxomas 30-40 years [ 64 ] osteochondromyxomas have the potential to be locally invasive and to recur [ 65 ] typically associated with CNC [ 66 ] Other tumors pancreatic neoplasias [ 67 ] as well as hepatic [ 68 ], colonic [ 69 ] or gastric tumors [ 70 ] …”