The occurrence of thyroid carcinomas with varying admixtures of MTC and differentiated carcinoma of the follicular epithelium has generated sufficient interest and controversy in terms of the histogenesis and appropriate designation for these tumors. In a comprehensive analysis, Guiu [14
] has reviewed the available literature in terms of the histogenesis of a spectrum of such tumors. The present case of a collision tumor, including a MTC, PTC and a FVPTC was identified in a lady, who did not reveal any clinical manifestations an MEN syndrome. Histologically, discrete tumor nodules were identified in the left lobe and isthmus with features of MTC and PTC. Presence of amyloid stroma with strong calcitonin positivity confirmed the diagnosis of a MTC, whereas classical nuclear features with thyroglobulin positivity were helpful in confirming a PTC as well as a FVPTC. There was no intermingling of the two types of tumor cells, barring a diagnosis of a mixed thyroid carcinoma [3
]. The lymph node deposits were of a MTC, unlike a mixed tumor, as noted earlier [9
(rearrangements in tyrosine kinase) proto-oncogene has been implicated in the development of familial and sporadic MTC [15
]. Several germline point mutations of this gene have been found to be affecting Exons 10, 11, 13, 14, 15 and 16 that have been linked with the development of MEN 2 and familial MTC. RET
somatic point mutations and gene deletions have been identified in 40–50% cases of sporadic MTC [17
]. Our case did not reveal a familial history of MTC. On genetic analysis, the patient displayed a unique G691S polymorphism that has been lately found to be associated with sporadic MTCs [18
]. It is noteworthy that the high risk mutation was absent. It has been proposed that G691S polymorphisms might be important for its putative role in the pathogenesis of sporadic MTCs. This has been found to be associated with C-cell hyperplasia in the pretumor tissue of the differentiated radiation induced thyroid tumors [20
]. As C-cell hyperplasia is considered as a preneoplastic lesion by some authors, there is a possibility that the G691S polymorphism induces C-cell hyperplasia. However, according to Elisei et al [18
], it is difficult to deduce that normal subjects harboring G691S polymorphism are at a higher risk of MTC. Nevertheless, in a recent study by Robledo et al [19
], it has been clearly suggested that the presence of G91S/S904S polymorphisms of the RET
is related to the early appearance of symptoms in MEN 2A patients, and therefore, these polymorphisms could be considered as genetic modifiers. A G691S polymorphism might be included as a low penetrance gene that might be associated with a small to moderate increased risk for the development of a MTC. Although our index case was a lady, both her daughters and a grandson, displaying the similar polymorphism could be at risk for development of an early MEN2A syndrome.
The exact mechanism by which these polymorphisms affect the age of onset for MTC is unclear. It has been explained that the G691S variant occurs in the cytoplasmic tail of the RET amidst transmembrane region and the first tyrosine kinase domain close to the residue Y687 that was found phosphorylated in all MEN 2A cases, along with few cases of MEN 2B. Even though G691S is not considered as an oncogenic mutation, its functional role has been hypothesized. Higher levels of this polymorphism have been noted in sporadic cases of MTC vs normal subjects, thereby suggesting its role as a low penetrance gene. It has also been postulated that such variants are relatively common in the population may confer a much higher attributable risk in the general population than mutations in high penetrance cancer susceptibility genes [19
Apart from a MTC, the present case also had discrete tumor nodules of PTC and FVPTC. In a literature review, Rossi et al [21
] identified 21 such cases, including 3 cases from their own study that in addition, included genetic analysis. They noted C634A substitution in the exon 11 of the RET
gene in the MTC component, while V600G BRAF
mutation in the PTC tissues, thereby suggesting the possibility of discrete mutations in both the tumors. In the present case BRAF
mutation analysis was not carried out.
Similar to ours, in their unique case of a collision tumor, Papi et al [11
] identified a mutation on the RET
gene. However, the affected Exon and codon was Exon 14 (codon 804). Recently, Melillo et al [22
], while analyzing the transforming activity of RET mutations in PC CI3 follicular cells, in case of a family with affected siblings showing a collision tumor, postulated that RET point mutants behave as conditional oncogenes, able to predispose to PTC only under specific circumstances, such as, high level expression of the mutated allele in follicular cells. However, the present case displayed occurrence of a low penetrance gene. It is possible that low penetrance genes, acting over a long time, provide a 'fertile soil' for further mutations or differential expression, leading to development of collision tumors. It is suggested that occurrence of RET polymorphisms in such cases might validate the proposed hypotheses of 'field-effect' in cases of MTC, as well as about C-cells differentiating into follicular cells [13
Therapeutically, it is important to identify whether cases of collision tumors should be given radioactive 131
Iodine. In the present case, in view of an increased radioactive iodine uptake, post surgery, the patient was subjected to radio ablation. Identification of mutations or polymorphisms as G691S in the progeny of this case opens the possibility of discussing the screening in the subsequent family members. In such cases, calcitonin (CT) levels, especially post calcium or pentagastrin infusion have been found to be useful to decide upon therapeutic interventions as the polymorphism in itself is not like a high risk mutation. While basal calcitonin level is < 30 pg/ml, levels between 30 to100 indicate C-cell hyperplasia and above 100 pg/ml indicate presence of a MTC. CT levels between 30 to100 necessitate further investigations including USG/CT scan examination for the detection of thyroid nodule [23
]. Presently, the patient's daughters have normal calcitonin levels and unremarkable thyroid. In view of unremarkable thyroids and normal calcitonin levels, therapeutic intervention has not been carried out in the patient's progeny. Nonetheless, they are on regular follow-up.
Even though screening modalities and therapeutic implications are known in cases of familial MTC, the same have not been established in sporadic MTCs. The present case of a collision tumor, displaying a unique G691 polymorphism, is suggestive of additional genetic modifiers of RET gene mutations in cases of sporadic medullary carcinoma thyroid. To our knowledge, such a polypmorphism has not been documented in any case of a collision thyroid tumor. Identification of such low penetrance genes provides a scope for genetic screening in cases of pure MTC, mixed or collision tumors. Documentation of more such cases, with a follow up is necessary to lay management guidelines for family members detected with the similar polymorphism, as of the index case.