Prevalence and Clinical Spectrum of Nonsecretory Medullary Thyroid Carcinoma in a Series of 839 Patients with Sporadic Medullary Thyroid Carcinoma

Abstract

Background:

Medullary thyroid carcinoma (MTC) is characterized by the synthesis and secretion of calcitonin (Ct). MTC without Ct secretion has been reported on rare occasions. The aim of this study was to analyze the prevalence and clinical spectrum of nonsecretory MTC in two tertiary centers that cared for 839 patients with sporadic MTC.

Methods:

Clinical, biochemical, histological, and immunohistological findings, and somatic RET mutations were analyzed, and long-term follow-up was documented.

Results:

Seven patients with nonsecretory MTC were identified among 839 patients with sporadic MTC; thus, the prevalence rate of nonsecretory MTC was 0.83%. In these seven patients, Ct and carcinoembryonic antigen (CEA) levels were normal when MTC was initially diagnosed in the patients, despite advanced tumor stage. Ct and CEA levels remained undetectable in four patients; recurrence was indicated in one patient after 10 years of follow-up by routine anatomic imaging and increased CEA levels, and Ct levels became slightly elevated during follow-up, despite massive tumor load, in the remaining two patients. The diagnosis of MTC was confirmed by positive immunohistochemistry for Ct, CEA, and chromogranin A. A high Ki67 proliferation index (PI) (three patients) and a high proportion of RET 918-mutated cells (four patients), as well as poorly differentiated histology, were associated with aggressive biological behavior of the MTC. The prognosis for nonsecretory MTC varied between long-term survival (12.5 years) and rapid progression leading to death within 1.75 years after diagnosis.

Conclusions:

The prevalence of nonsecretory MTC was low (0.83% of patients with MTC). Diagnosis was often made at a clinically advanced tumor stage. The histological and immunohistological characteristics and the clinical course and prognosis of nonsecretory MTC are markedly heterogeneous. A high Ki-67 PI and a large proportion of cells with RET 918 mutations are associated with a poor prognosis.

Introduction

M edullary thyroid carcinoma (MTC), defined as a malignant tumor with C-cell differentiation, is of neuroendocrine origin and is characterized by the synthesis and secretion of calcitonin (Ct). Elevated basal and/or stimulated serum levels of Ct are highly sensitive and specific markers of MTC (1), and serum Ct levels have a positive correlation with MTC tumor mass (2,3). Serum Ct is the principal biochemical marker for the detection and staging of the disease, and it is also used for postoperative management and prognosis (2,4 –6). In addition to Ct, MTCs can synthesize and secrete a variety of other markers, such as carcinoembryonic antigen (CEA) and chromogranin A (CGA).

Early diagnosis of MTC is crucial, because complete operative removal of the tumor is currently the only curative therapy. Therefore, routine measurement of serum Ct in patients with nodular thyroid disease plays an important role in the early diagnosis of MTC (5,7,8). Thus, serum Ct determination is recommended in the European guidelines for the initial work-up of nodular thyroid disease (9).

The histological diagnosis of MTC is routinely confirmed by immunohistochemical detection of Ct; the vast majority of MTCs are unequivocally positive for Ct, although Ct positivity may be occasionally restricted to very few cells or small, focal areas (10 –12). Additional immunohistochemical markers of MTC are chromogranins, CEA, and synaptophysin (SPH).

Rarely, MTC without Ct secretion into the serum has been reported (13 –20). In the majority of these cases, advanced MTC with poor histological differentiation was found, which suggests that the tumor lost the ability to synthesize Ct.

In the present article, we report seven cases of nonsecretory MTC that were observed in two thyroid tumor centers; we also include long-term follow-up observations (up to 12.5 years). The aim of this study was to evaluate the histological, immunohistochemical, and molecular pathological properties of nonsecretory MTC, and to discuss the possible clinical management and prognosis for this rare variety of MTC.

Materials and Methods

Patients

A total of 839 patients with sporadic MTC were seen in two thyroid centers (21 –23). In all of these cases, the histological diagnosis of MTC was confirmed by immunohistochemical demonstration of Ct. RET mutations were analyzed to identify hereditary cases. Clinical diagnoses of nonsecretory MTC were based on the absence of increased serum levels of Ct and CEA in the presence of tumor tissue immunohistochemically classified as MTC. Overall, only seven nonsecretory MTC were identified in our series of 839 sporadic MTC. Demographic and clinical information was documented, including year of birth, sex, age at diagnosis of MTC, and mode of diagnosis of MTC. Informed consent for the collection of clinical, biochemical, and genetic data was obtained from all patients. Ct and CEA serum levels were measured preoperatively in six patients. In addition, before the thyroid operation, fine-needle biopsy (FNB) samples were obtained in two patients, and a lymph node biopsy was done in one patient. Ct and CEA serum levels were routinely measured postoperatively and during follow-up. Germ-line RET mutation analysis was performed routinely in six patients, and somatic RET mutation analysis was performed in all seven of the patients with nonsecretory MTC. Patient follow-up regularly included ultrasonography, computerized tomography, or magnetic resonance imaging (MRI). Reoperations due to tumor recurrence were performed in two cases, and in one case due to increased CEA serum levels.

Tumor markers

Ct serum levels were measured with different chemiluminescence immunometric assays. In the first center, between 1996 and 2006, the normal range was <10 pg/mL (Nichols Institute), and from 2007 to 2012, the normal range was <6.1 pmol/L for men and <3.6 pmol/L for women (DiaSorin). In the second center, from September 1995 until May 2004, with the ELSA-hCT solid two-site immunoradiometric Ct assay (CIS BioInternational), the normal range was <10 pg/mL, and from May 2004 to 2012, with the Immulite 2000 Ct assay (Diagnostic Products Corporation), the normal range was <5 pg/mL for women and <8.4 pg/mL for men. CEA concentrations were measured in both centers by an electrochemiluminescence immunoassay (Roche). The normal range was <4.5 ng/mL.

Mutation analysis of the RET proto-oncogene

Germ-line RET mutation analysis was performed as described previously (24). For somatic RET mutation analysis, DNA was extracted from tumor samples. For molecular analysis, a next-generation amplicon-sequencing assay (NGS) was used. Eight amplicons representing exons 5, 8, 10, 11, and 13–16 were amplified in a multiplex polymerase chain reaction (PCR) with the FastStart HighFidelity PCR System kit (Roche). The purified multiplex PCRs were pooled and sequenced according to the manufacturer's recommendations on a 454 GS Junior instrument (Roche). NGS data were analyzed using Sequence Pilot software version 3.5.1 (JSI Medical Systems). Data on primer sequences, molecular barcodes, and the PCR amplification protocol are available upon request. Sanger sequencing was used to confirm RET M918T mutations.

Histology and immunohistochemistry

The seven cases clinically classified as nonsecretory MTC were histopathologically and immunochemically re-examined by one of the authors of this study (K.W.S.). Hematoxylin and eosin staining was performed in a routine fashion. Immunohistochemical stains were done with antibodies against Ct (Dako; dilution 1:30,000), CEA (Dako; 1:2000), CGA (Novocastra; 1:100), chromogranin B (CGB) (generous gift from R. Fischer-Colbrie; 1:200), SPH (Zytomed Systems; 1:400), Ki67 (Zytomed Systems; 1:2000), thyroid transcription factor (TTF)-1 (Dako; 1:1000), and thyroglobulin (Dako; 1:20,000). Standardized indirect immunoperoxidase techniques for monoclonal or polyclonal antibodies were used (Dako Immunostainer).

The Ki67 proliferation index (PI) is indicated as the percentage of positively stained tumor cell nuclei, counted in hotspots. Tumor staging was performed according to the TNM Classification of Malignant Tumors, 7th Edition (25).

Results

Patients

The prevalence of nonsecretory MTC in our series of 839 patients with sporadic MTC patients was 0.83%. All seven patients were clinically seen for the first time between 1999 and 2010 because of thyroid nodules; subsequent clinical assessment revealed local lymph node enlargement in two patients, and distant metastases were identified in three patients (Table 1). In six out of the seven patients, Ct and CEA levels were determined preoperatively and were found to be within the normal range. Before the first surgery, pentagastrin stimulation was performed in three cases (Patients 2–4); pathological Ct stimulation was not observed in any of these three patients. FNBs of the initial thyroid nodules were performed in two cases (Patients 1 and 3); in one, cytological malignancy was suspected; in the other, the correct diagnosis of MTC had already been made based on the FNB material. In one patient (Patient 5), lymph node biopsy histologically and immunohistochemically revealed MTC metastasis. All patients underwent complete thyroidectomy and adequate lymph node dissection. The results of the histological and immunohistochemical re-evaluation of the seven cases of nonsecretory MTC identified in this study are summarized in Table 2.

Table 1.

Clinical Features and Follow-Up in Patients with Nonsecretory Medullary Thyroid Carcinoma

					Preoperative findings		Follow-up
Patient no.	Sex	Age at diagnosis (years)	TNM	Tumor size (mm)	Ct basal/stimulated	CEA ng/mL (normal range <4.5 ng/mL)	(years)	Outcome
1	F	61	T1 N0 M0	10	2.9^a	1.3	6	Alive, no tumor detectable
2	M	70	T4 N0 M1 (pulmonary)	80	<2/<2^b	2.1	2.25	Alive with pulmonary metastases, reoperation because of local tumor infiltration
3	F	50	T2 Nx M0	20	<0.8/1.5^a	2.8	12.5	Alive, recurrence after 10 years indicated by CEA increase; after reoperation, disease free
4	M	47	T2 N1 M0	30	2.6/5.4^c	3.1	1.5	Alive, reoperation because of local tumor infiltration
5	F	53	T3 N1 M0	45	NA	NA	1.75	Alive with lymph node metastases in the neck, bone, and brain; after first operation, Ct and CEA were normal despite multiple lymph node metastases; during follow-up, Ct became slightly elevated
6	M	45	T1 N1 M1 (pulmonary)	18	11 (normal <18)^d	NA	1.75	Dead of disease, locally invasive tumor, and pulmonary metastases; three reoperations because of local tumor infiltration, during follow-up Ct became slightly elevated
7	F	45	T3 N1 M1 (pulmonary)	55	1.5^e	1.7	3	Dead because of pulmonary failure; (metastatic MTC)

Nichols, normal range <10 pg/mL.

DiaSorin, normal range <6.1 pmol/L men, <3.6 pmol/L women.

Immulite 2000, normal range <8.4 pg/mL mEN, <5 pg/mL women.

Noncommercial calcitonin assay (normal range <18 pg/mL).

CIS, normal range <10 pg/mL.

NA, not available; TNM, TNM Classification of Malignant Tumors (25); Ct, calcitonin; CEA, carcinoembryonic antigen; MTC, medullary thyroid carcinoma.

Table 2.

Histology, Immunohistochemistry, and RET Analysis in Nonsecretory Medullary Thyroid Carcinoma Patients

Patient no.	Histology MTC	Ki67 PI	Ct	CGA	CGB	SPH	CEA	TTF-1	TG	RET mutation codon 918, % coverage
1	Well diff.^a	<2	(+)	2+	3+	(2+)	3+	3+	Neg.	0
2	Well diff.^b	<2	(+)	(2+)	3+	3+	3+	2+	Neg.	0
3	Well diff.^b	<5	(+)	3+	3+	3+	2+	3+	Neg.	39
4	Poorly diff.^b	<10	2+	3+	3+	2+	3+	3+	Neg.	0
5	Well diff.^a	>50	3+	3+	3+	3+	3+	3+	Neg.	91
6	Poorly diff.^b	>50	(+)	2+	3+	3+	3+	3+	Neg.	60
7	Poorly diff.^a	>50	(2+)	3+	3+	(3+)	3+	3+	Neg.	22

+, single cells weakly positive; 2+, focal positivity; 3+, nearly all cells positive; () indicates decreased staining intensity; Ki67 PI (proliferation index) indicates the percentage of positively labeled tumor cell nuclei.

primary tumor; ^blocal persistence or recurrence/lymph node metastasis.

CGA, chromogranin A; CGB, chromogranin B; SPH, synaptophysin; CEA, carcinoembryonic antigen; TTF-1, thyroid transcription factor; TG, thyroglobulin; diff., differentiated; neg., negative.

Postoperative follow-up

Initially, postoperative Ct and CEA serum levels were negative in all seven patients. In Patients 1–4 and 7, Ct serum levels remained undetectable on subsequent follow-up visits. Increasing CEA levels (maximum 8 ng/mL) were observed in one patient (Patient 3) after 10 years of follow-up. Local recurrence was suspected, operated on, and confirmed histologically. The CEA level decreased thereafter to the normal range. This patient has been described previously (15) with up to 5 years of follow-up. As of 2012, the patient was disease free. In Patient 5, the postoperative Ct level was in the normal range despite the detection of multiple lymph node metastases. During follow-up, Ct and CEA levels started to increase after several months, and 19 months after the initial diagnosis, the patient showed a massive tumor burden in a prefinal stage of disease. At this time, the Ct levels were only slightly elevated (Ct 215 pg/mL, CEA 16 ng/L). In Patient 6, the Ct level increased during follow-up (basal Ct, 29 pg/mL; after pentagastrin, 82 pg/mL); however, the values were very low for a patient with multiple lung metastases. Four patients remained completely Ct and CEA negative during follow-up (1–6 years): Patient 1 remained disease free; Patient 4 had local tumor infiltration; Patient 2 was alive but had pulmonary metastases, and Patient 7 died of metastatic disease 3 years after the initial diagnosis.

Three patients developed additional tumors during follow-up. One woman had atypical breast cancer (Ct immunohistochemistry was negative). A second woman had schwannoma of the mediastinum and a malignant melanoma located in the labia minora. The third patient had papillary microcarcinoma of the thyroid gland in addition to MTC.

The follow-up time ranged from 1.5 to 12.5 years (mean follow-up 4.1 years). Patients 6 and 7 died 1.75 and 3 years after diagnosis, respectively, both from progressive lung metastases. All of the other patients were still alive. Two patients were disease free; one had a local tumor in the neck; one had pulmonary metastases, and one had bone and brain metastases.

Molecular genetics findings

None of the patient displayed clinical evidence of multiple endocrine neoplasia type 2 MEN 2. Family histories of thyroid carcinomas and adrenal or parathyroid tumors were negative. Biochemical findings concerning adrenal or parathyroid tumors were consistently negative in all of seven of the patients. No germ-line RET mutations were detected in six patients. Exons 5, 8, 10, 11, and 13–16 were analyzed in five patients, and exons 10, 11, and 13 of the RET proto-oncogene were examined in one patient. No germ-line RET mutation analysis was available for one patient. In this patient (Patient 6), an M918T mutation was identified in the tumor tissue. Because the patient completely lacked clinical signs and symptoms of MEN 2B, and no other RET mutations were detected, this case was also regarded as sporadic MTC.

A somatic RET mutation (M918T) was found in four of the seven patients (Table 2). In three cases, the primary tumor was available for somatic mutation analysis, and in four cases, lymph node metastases/local recurrences were examined. RET mutation analysis in the tumor tissue revealed somatic M918T RET mutations in two primary tumors and two local recurrences; the remaining three patients had no somatic RET mutation. The percentage of mutated DNA ranged from 22% to 91% (coverage 1646-fold to 3286-fold). Loss of heterozygosity was indicated in Patient 5. In this patient, loss of polymorphisms in tumor DNA compared to germ-line DNA indicates loss of one allele.

Histological findings

The MTCs of the patients described here were classified as well- (n=4) or poorly (n=3) differentiated tumors (Table 2). In four cases (three well-differentiated, one poorly differentiated MTC), weak immunohistochemical Ct staining was observed in very few cells after a thorough search. Strong focal Ct positivity was found in two patients. The remaining patient's MTC (Patient 5) consisted almost exclusively of strong Ct-positive tumor cells; in this patient, Ct serum levels became measurable during tumor progression that resulted in a massive tumor burden. Other neuroendocrine markers, such as chromogranin (CGA/CGB) and SPH, as well as CEA, were consistently strongly positive in all cases. All tumors were thyroglobulin negative and TTF-1 positive.

The Ki67 PI was <2% and <5% in two and one differentiated MTCs, respectively (all three cases showed weak Ct immunoreactivity in single cells only). The remaining well-differentiated MTC (Patient 5) had a Ki67 PI of >50%, which was associated with rapid tumor progression. Two of the three poorly differentiated MTCs also showed >50% Ki67 PI; one patient developed local tumor recurrence and lung metastases and died 1.75 years after diagnosis, and the other patient died from tumor progression (lung metastases) 3 years after MTC diagnosis. The only patient with an MTC classified as a poorly differentiated MTC, but with a Ki67 PI of <10%, had developed only local tumor recurrence.

In all three patients with a Ki67 PI >50%, a somatic RET mutation M918T was identified (mutated DNA ranged from 22% to 91%). Both findings, a high Ki67 PI and RET 918 mutation positivity, are associated with an adverse course of the disease.

Discussion

Prevalence of nonsecretory MTC

Nonsecretory MTC is apparently a very rare disease; to date, only nine cases have been described in the literature (13 –20) (Table 3). In this article, we report seven additional cases of nonsecretory MTC, which we identified in a large series of 839 patients with sporadic MTC; this corresponds to a prevalence of 0.83%. To our knowledge, this is the first time that prevalence data for nonsecretory MTC have been presented. Previously described cases of nonsecretory MTC were observed only for sporadic MTC, which is supported by our findings. A diagnosis of nonsecretory MTC was established only recently; the first explicit report was published in 2000 (14), concurrent with the development of more sensitive Ct immunoassays and routine application of Ct immunostaining. In our series, nonsecretory MTC was diagnosed in the first two patients in 1999.

Table 3.

Nonsecretory Medullary Thyroid Carcinoma: Comparison of Patients in the Present Study with Patients Published in the Literature

	Patients in the literature [Refs. (13 –20)]	Present study
Number of patients (n)	9	7
Age, years (range)	48.4 (16–73)	53 (45–70)
pTNM (n)
T1–4 N0 M0	1	1
T1–4 Nx Mx	4	1
T1–4 N1 M0	1	2
T1–4 N1 M1	3	3
Follow-up, years (range)	1.8 (0.1–5)	4.1 (1–12.5)
Dead (n)	2	2
Ct immunohistochemical staining	All	All
Ct inadequate secretion (n)	1 [Ref. (18)]	2
CEA inadequate secretion (n)	2 [Refs. (18,19)]	1
Ki67 proliferation index (n)
<10% of tumor cell nuclei	−	4
>50% of tumor cell nuclei	−	3
RET 918 (somatic mutation) (n)	−	4

Tumor markers

The seven cases described here were identified as nonsecretory MTC from a large series of histologically or immunohistochemically confirmed sporadic MTCs, because they lacked increased serum Ct and CEA levels, despite demonstrable tumor tissue. In these patients, routine anatomic imaging is of paramount importance. In one patient, an MRI of the neck, in addition to increased CEA levels, after 10 years of follow-up indicated recurrent disease. Ct serum levels were negative during the entire follow-up period of 12.5 years in this patient, despite two histological verifications of tumor tissue. In the literature, in two nonsecretory MTC cases, CEA was elevated at baseline, despite negative Ct serum levels (18,19), supporting the use of this complementary marker in the management of MTC. In two of our patients, Ct levels became slightly elevated only when a massive tumor load was present; the measured Ct levels were abnormally low compared to secretory MTC cases with similar tumor masses. Similarly, a preoperative Ct level of 38 pg/mL was described previously in a patient with a 6.5-cm MTC with a 5-cm metastasis in the neck (18). Therefore, in some cases, nonsecretory tumor behavior may be associated with lower tumor burden, and minor secretion may become obvious only with a massive tumor load. During follow-up, an initial nonsecretory MTC may become a secretory MTC, which argues for the inclusion of regular Ct and CEA measurements in the follow-up of nonsecretory MTC patients.

Nonsecretory MTC cannot be detected by serum Ct screening as an integral part of the diagnostic evaluation of thyroid nodules. Thus, nonsecretory MTC may be detected more often at advanced tumor stages.

Immunohistochemistry

Immunohistochemical re-evaluation of the seven cases of nonsecretory MTC in this series revealed that four tumors contained only a few weakly Ct-positive tumor cells; two of these tumors showed focal Ct positivity, and one tumor was strongly Ct positive in almost all tumor cells. All of the tumors completely lacked thyroglobulin. However, all seven cases showed unequivocal immunoreactivity for both CGA and CEA, the combination of which is accepted as a diagnostic criterion for MTC even in cases that completely lack Ct immunoreactivity (12). We thus have no doubt that all seven cases in the present series represent true MTC; in four cases, the demonstration of a somatic RET mutation (M918T) additionally confirmed MTC. Neuroendocrine tumors of the thyroid gland that lack both Ct and CEA (26) have been described and are denoted as atypical MTC (12); these neuroendocrine-differentiated tumors may represent intrathyroidal parathyroid tumors or a metastasis of a neuroendocrine carcinoma. It was also suggested that thymic remnants may give rise to primary non-MTC neuroendocrine tumors of the thyroid (12). Rarely, metastases from extrathyroidal neuroendocrine tumors to the thyroid may simulate MTC or stain positive for Ct (27,28).

Although three of the cases of nonsecretory MTC were weakly positive for Ct in a few tumor cells, our results indicate that there is only a limited association between the immunoreactivity of Ct within the tumor tissue and serum levels of Ct. One patient had distinct focal Ct positivity without Ct secretion into the serum. In another patient, strong Ct immunostaining was associated with the development of a low amount of secretion during follow-up. The same was true for CEA levels; all patients showed distinct and strong immunohistochemical CEA positivity, but only one patient developed elevated CEA serum levels during follow-up.

Biological implications

In thyroid C cells, the Ct/calcitonin gene-related peptide (CGRP) gene is expressed in a tissue-specific manner by alternative splicing, which favors Ct over CGRP. The Ct mRNA transcript is translated into pre-proCt, which after proteolytic cleavage gives rise to three distinct peptides, N-proCt, mature Ct, and C-proCt; these are normally also found in tumor cells and can be secreted (29). Several molecular forms of Ct are present in the blood, but modern two-site immunometric assays that use monoclonal antibodies measure only monomeric Ct. It is possible that more complex forms of Ct, such as premature, polymeric, or altered forms (aberrant post-translational modification), are secreted in nonsecretory MTC and are not detected by the two-site assays. In nonsecretory MTC, the complex mechanism of Ct synthesis appears to be disturbed, but not entirely stopped, as shown by Ct immunochemical staining; alternatively, the storage or secreting machinery in the tumor cells could be impaired. Therefore, the typical correlation between tumor size and basal Ct levels found in other patients with MTC was not observed in the patients with nonsecretory MTC. We would have expected to find Ct preoperative values of >1000 pg/mL, because there were lymph node metastases in five patients and distant metastases in two cases (3). Nonsecretory MTC is apparently characterized by a complete lack of or inadequate amounts of Ct and CEA secretion.

Follow-up and prognosis

The prognosis for our seven patients with nonsecretory MTC was heterogeneous and did not differ substantially from that of patients with secretory sporadic MTC. Although diagnosis was performed in the patients at advanced stages in most cases (Table 3), and a cure was thus highly unlikely, the prognosis varied between long-term survival (12.5 years) and rapid progression, leading to death within 1.75 years after diagnosis.

The presence of somatic RET mutations in tumor tissue is associated with a worse prognosis (30,31). A recent study showed that combined RET and Ki67 analysis could be useful for risk stratification in patients with sporadic MTC (32). Even in this small series of nonsecretory MTC cases, high expression of Ki67 and large numbers of cells carrying the RET M918T mutation were associated with an adverse course of the disease. Moreover, poorly differentiated histology may be of predictive importance: two out of three patients with high Ki-67 died; two out of four patients with the RET M918T mutation died, and two out of three patients with poorly differentiated tumors died. Similarly, two out of three patients with both high Ki-67 and RET 918 died; two out of two patients with poorly differentiated tumors and high Ki-67 died, and two out of two patients with poorly differentiated tumors and the RET M918T mutation died. Survival in the two deceased patients was 1.75 and 3 years. In fact, only the two patients with all three features died. In this series of patients with nonsecretory MTC, neither Ct immunostaining nor serum Ct levels were prognostic factors. Some patients with progressive MTC had an increase in serum CEA, while serum Ct levels declined. This has been considered to be a sign of tumor dedifferentiation and poor prognosis (33).

Conclusions

The prevalence of nonsecretory MTC was low in our series. Because of the lack of elevated tumor markers such as Ct and CEA, which may serve as screening markers, nonsecretory MTC is often diagnosed at clinically advanced tumor stages. In some cases, Ct or CEA levels may rise during follow-up, but to an extent that is entirely inadequate in relation to tumor mass. In our series, Ct immunostaining was scarce in most cases. In some cases, nonsecretory MTC showed strong immunohistochemical Ct expression in the tumor cells, demonstrating a poor association between serum Ct levels and immunohistochemical Ct staining. Neither Ct immunostaining nor the development of low levels of Ct or CEA secretion allows for conclusions to be drawn regarding the prognosis of patients with nonsecretory MTC. The prognosis varies between long-term survival and rapid tumor progression, and the latter is associated with poorly differentiated histology, high Ki-67 levels, and somatic RET-mutated cells (in our patients, only the M918T mutation was found). In summary, our results show that nonsecretory MTC is a rare disease that is markedly heterogeneous in its histological and immunohistological appearance and in its clinical course and prognosis.

Footnotes

Disclosure Statement

The authors have nothing to disclose.

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