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Letters to the Editor |
Institute of Surgical Clinics University of Sienna Sienna 53100, Italy
Diana L Learoyd and Bruce G Robinson
University of Sydney Royal North Shore Hospital %St. Leonards, NSW 2065 Australia
Ret-papillary thyroid carcinoma (PTC) chimeras are rearranged forms of ret found in papillary thyroid carcinoma (PTC), which include three main isoforms, even if additional variations have also been reported (1). Ret-PTC1 and ret-PTC3 arise from chromosome 10 inversions, (fused genes: H4 and RFG/ELE, respectively), whereas the rarer ret/PTC2 arises from a chromosome 10/17 translocation. The rearrangements result in constitutive activation of ret, which is phosphorylated on tyrosine and translocated from the membrane to the cytoplasm.
The recent paper by Learoyd et al. (2), specifically analyzed the clinical outcome in patients with PTC on the basis of the presence or absence of ret/PTC expression. Unfortunately, in their series of 50 adult patients with PTC, only 4 had ret/PTC activation, as ret/PTC1 in all cases. They concluded that, in their series, "there was no significant difference between the 2 clinical patient groups (MACIS score <7 vs. >7) with respect to the presence or absence of ret/PTC in the patient’s tumor." It has been suggested that the presence of ret/PTC may be associated with a greater likelihood of metastatic spread and poorer prognosis (3, 4, 5). The prevalence of ret/PTC rearrangements in PTC series from around the world varies widely from approximately 3–85% and is influenced by several factors, including methods of detection. In particular, studies from the Chernobyl area reported a ret/PTC prevalence on the order of 70%. Most of the children in the studies had lymphonodal involvement (6, 7), and some required early re-operation for local recurrence, suggesting an aggressive behavior on the part of the tumor. Interestingly, in these case the ret/PTC3 isoform was more prevalent than ret/PTC1 (6).
On the other hand, it has recently been suggested that ret/PTC activation, namely ret/PTC1, defines a subset of PTCs lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes (8). In a series of thyroid neoplasms obtained from the files of the Department of Pathology at Yale University (New Haven, CT) 81 of 201 PTCs were positive for ret/PTC activation by immunohistochemistry (40.3%) (8). In particular, 28 of these PTCs were also examined by RT-PCR. Eight were negative and 20 were positive by immunohistochemistry. Sixteen of the 20 positive were also positive by RT-PCR: ret/PTC1 alone was detected in 10 cases, both ret/PTC1 and ret/PTC3 in 5 cases, and ret/PTC2 in 1 case. It is noteworthy that, in this series, the highest positive score for ret/PTC activation (59 of 119, or 44.5%) was observed in the subgroup "aged 40 or older" (8). Even more interestingly, we have recently observed an Italian series of PTCs associated with familial adenomatous polyposis (FAP), showing ret/PTC activation in 3 out of 4 female patients (age range 20–32); ret/PTC1 was present in all patients (9). All these patients had no recurrence, no distant metastases, and were disease free as of this writing, more than 4 yr after surgery (9, 10) despite multinodularity with lymph nodal involvement in 1 case and conservative surgery (simple lobectomy, performed with patients’ consent) in 3 of 4 cases. In addition, most of the 70 FAP associated tumors reported in the literature, regardless of ret/PTC activation, did not produce distant metastases, and the patients had a mean survival of more than 10–15 yr without recurrence (11, 12). This suggests that FAP associated tumors (showing a high incidence of ret/PTC1 activation in our series) have a relatively indolent behaviour (11). Numbers are too small, in particular, when stratified for the various PTC isoforms. Only prospective collaborative studies will determine whether specific genetic changes, such as ret/PTCs, have prognostic significance. However, cumulative data presently available suggest that ret/PTCs cannot be considered as a single entity, but as variants, namely ret/PTC1 and ret/PTC3, that could have different biological behaviors. If further confirmed, these data suggest that constitutive activation of ret in PTCs determines a different carcinogenetic pathway according to the different fused gene, with ret/PTC1 possibly having a better and ret/PTC3 a worse prognosis.
The letter (above) by Cetta et al., in response to our study of RET/papillary thyroid carcinoma (PTC) rearrangements in adult PTCs (J Clin Endocrinol Metab. 83: 3631–3635), correctly highlights the variable findings of different studies from around the world as to the clinical significance of RET/PTC in a patient’s tumor. Our study found RET/PTC1 only, in 4 of 50 adult PTCs, including patients with earlier radiation exposure. There was no association between the presence of RET/PTC and a particular clinical phenotype. The series by Cetta et al., quoted above (9), of PTCs from patients with FAP, found a high proportion of RET/PTC1 rearrangements associated with relatively indolent tumor behaviour. In contrast, Chernobyl associated PTCs have a high proportion with RET/PTC3 rearrangements and display a more aggressive phenotype.
We agree that the different RET rearrangements should be analyzed separately when an association with clinical phenotype is studied. Large collaborative studies will thus be required for sufficient numbers of patients with each of the RET rearrangements to be accrued.
Footnotes
Received February 3, 1999. Address correspondence to: Francesco Cetta, Department of Surgery, Institute of Surgical Clinics, University of Siena, Nuovo Policlinico, Viale Bracci, Siena 53100, Italy.
Received February 24, 1999. Address correspondence to: Bruce G. Robinson, Department of Endocrinology, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia.
References
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