Concurrent lymph node metastases of medullary and papillary thyroid carcinoma in a case with RET oncogene germline mutation

Abstract

We report the case of a 72 yr-old woman who underwent total thyroidectomy and resection of neck lymph nodes because of a firm nodule in the right lobe, which was consistent with medullary thyroid carcinoma (MTC) on cytological examination. Histology showed multifocal bilateral MTC; a 2 mm papillary thyroid carcinoma (PTC) was also detected in the right lobe, next to a focus of MTC; five cervical lymph nodes contained MTC. In one right perithyroidal lymph node, concurrent metastases of MTC and PTC were demonstrated. DNA analysis showed a point mutation in exon 14 at codon 804 of the RET proto-oncogene locus, as frequently found in cases of familial MTC (FMTC). To our knowledge, this case represents the first documented case of concurrent lymph node metastases of MTC and PTC in a patient with RET proto-oncogene germline mutation. We report this unique case, discuss related thyroid malignancies, and suggest possible underlying pathogenetic mechanisms.

Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumour: report of three cases with molecular analysis and review of the literature

“…FNA biopsy was performed in 11 cases (Lamberg et al 1981, Ishida et al 1985, Gero et al 1989, Gonzalez-Campora et al 1992, Darwish et al 1995, Kobayashi et al 1995, Pastolero et al 1996, Tseleni-Balafouta et al 1997, Mazziotti et al 2001, Papi et al 2003: in one case cytology provided the exact diagnosis of concurrent MTC and PTC (Kobayashi et al 1995) while in the others it was, respectively, compatible with a follicular proliferation or nodule (Lamberg et al 1981, Gonzalez-Campora et al 1992, with PTC (Gero et al 1989, Fugazzola et al 2002, with MTC (Darwish et al 1995, Tseleni-Balafouta et al 1997, Mazziotti et al 2001, Papi et al 2003 or non-diagnostic (Pastolero et al 1996). All cases were treated with surgery and metastatic disease in regional lymph nodes was detected in eight cases (Ishida et al 1985, Gero et al 1989, Lax et al 1994, Kobayashi et al 1995, Pastolero et al 1996, Macak et al 1997: histology of metastatic deposits revealed PTC in two cases (Gero et al 1989, Kobayashi et al 1995, MTC in three (Lax et al 1994, Pastolero et al 1996, Macak et al 1997, and a mixed PTC and MTC in two (Ishida et al 1985, Papi et al 2003. One case was reported well and alive with a lung metastasis 3 years after treatment (Lax et al 1994)...…”

“…Genetic analysis of RET oncogene in cases of concurrent PTC and MTC has so far provided conflicting results (TseleniBalafouta et al 1997, Mazziotti et al 2001, Brauckhoff et al 2002, Fugazzola et al 2002, Papi et al 2003. In fact, of the seven cases studied by genetic analysis only two showed germline point mutations in exon 14 (codon 804) (Papi et al 2003) and in exon 13 (codon 790) (Brauckhoff et al 2002) respectively. No somatic mutations of the RET gene have been found in the tumour tissue in any case.…”

The Oncogenic Activity of RET Point Mutants for Follicular Thyroid Cells May Account for the Occurrence of Papillary Thyroid Carcinoma in Patients Affected by Familial Medullary Thyroid Carcinoma

“…4 Nonetheless, there are rare patients carrying germ-line RET point mutations of the type associated with FMTC and MEN2 syndromes with both MTC and PTC in their thyroid gland (this study). [12][13][14][15] This suggests that point mutations in RET can predispose to PTC, as well. Should this be true, however, the question remains of why RET point mutations are so rarely associated with PTC.…”

“…DNA was extracted from white blood cells from the three patients and DNA sequencing was performed for exons 10,11,13,14,15, and 16 of RET according to standard procedures. 21 One single mutation changing codon 634 from TGC to TCC (cysteine to serine) in exon 11 was found in the three patients.…”

“…9 -11 Similarly to MEN2 carriers, the rare kindreds affected by both MTC and PTC carry germ-line point mutations in RET. Accordingly, K603Q, 12 M918T, 13,14 and V804L 15 point mutations have been described in such families. Given its familial distribution, it is unlikely that PTC occurs in these families simply by chance.…”