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. Author manuscript; available in PMC: 2026 Jan 22.
Published before final editing as: Endocr Relat Cancer. 2025 Dec 11:ERC-24-0243. doi: 10.1530/ERC-24-0243

The Prostate is a Common Site of Disease in Patients with MEN2B and Medullary Thyroid Carcinoma

Ira L Kraft 1, Srivandana Akshintala 1, Andrea Gross 1, Eva Dombi 1, Baris Turkbey 2, Sandra Bednarova 2, John F Ward 3, Sireesha Yedururi 4, Maria Merino 5, Peter A Pinto 6, Brigitte C Widemann 1, Jack F Shern 1, Steven G Waguespack 7, John Glod 1
PMCID: PMC12823005  NIHMSID: NIHMS2129335  PMID: 41378514

Abstract

We reviewed the clinical characteristics of male patients with MEN2B associated medullary thyroid cancer (MTC) with prostate lesions and analyzed available imaging and pathology data.Patients were enrolled on a National Cancer Institute (NCI) natural history protocol (NCT01660984) and a University of Texas (UT) MD Anderson Cancer Center study (DR09–0507).Thirty-six male patients (median age of MEN2B diagnosis 12.0 years, range 1.3–25.6) with the RET p.Met918Thr germline mutation were identified.Pelvic imaging was available for 28/36 (78%) patients. Prostate lesions and/or calcifications were noted in eight patients (28.6%). Lesions were identified at a median age of 20.5 years (range 13–30.5 years). Biopsies in three patients with prostate neoplasms were histologically indistinguishable from primary MTC. Two of these patients did not have other sites of distant disease at the time of prostate biopsy. Prostate lesions in males with MEN2B and MTC are more frequent than previously described. Lesions were identified in patients as young as 14 years and often contained calcifications. The prostate is a more common site of disease in patients with MEN2B than previously appreciated and may represent a distant site of metastatic MTC metastasis or a second primary calcitonin-secreting neuroendocrine tumor. Imaging of the prostate should be considered in post-pubertal MEN2B males, especially in case of unexplained increase in calcitonin or onset of urinary tract symptoms.

Keywords: MEN2B, medullary thyroid carcinoma, prostate, metastasis

INTRODUCTION

Multiple Endocrine Neoplasia 2B (MEN2B) is a hereditary cancer predisposition syndrome caused primarily by the p.Met918Thr germline pathogenic variant in the REarranged during Transfection (RET) proto-oncogene and affecting the intracellular domain of the RET receptor tyrosine kinase1,2. Patients with MEN2B develop medullary thyroid carcinoma (MTC) in early childhood with an average age of diagnosis in the second decade of life, pheochromocytomas, and have a clinical phenotype including mucosal neuromas, chronic constipation, a marfanoid body habitus, among other manifestations3–7. MTC in MEN2B is 100% penetrant and many patients with MEN2B have persistent disease and can experience advanced, metastatic MTC7–9. The clinical course of MEN2B-associated MTC may be indolent and patients generally live into the 3rd-4th decades of life10–12.

In contrast with MEN2B-associated MTC, sporadic MTC generally occurs in the 4th-6th decades of life and is due to a heterogeneous group of somatic mutations in the RET, HRAS, or KRAS proto-oncogenes13. Sporadic MTC exhibits regional lymphatic spread and metastasis to bones, lungs, and liver6. There are also reports of metastasis to atypical locations such as axillary lymph nodes14, breast15,16, and prostate17.

Approximately 50% of patients with MEN2B develop pheochromocytomas. Although rare, other neuroendocrine tumors have been reported in patients with MEN2B including a pediatric case of lung neuroendocrine carcinoma18 and prostate neuroendocrine tumors19,20. Three cases that identified prostate tumors in MEN2B patients did not present evidence clarifying the origin of lesions19,20. In a recent report, MTC metastatic to the prostate was described in a patient with MEN2B21.

We had noted a prostate lesion in one patient on the phase I/II trial of vandetanib in children with advanced MTC22. This prostate lesion was histopathologically consistent with metastatic MTC. Given this finding, we aimed to determine the prevalence of prostate lesions in males with MEN2B and better characterize prostate lesions in patients with MEN2B and metastatic MTC.

PATIENTS AND METHODS

Patients:

We retrospectively reviewed the clinical and imaging characteristics of male patients with MEN2B and prostate lesions on a National Cancer Institute (NCI) natural history protocol (NCT01660984) and a University of Texas MD Anderson Cancer Center (MDACC) ambispective study (DR09–0507). The medical records of patients at both institutions were reviewed for prostate lesions evident in radiological images that captured the pelvic region. Protocols were approved by the NCI and the MDACC Institutional Review Boards. All NCI patients or their legal guardians provided informed consent and patient assent was obtained per institutional guidelines. A waiver of informed consent was obtained for the MDACC cohort.

Imaging:

Computed tomography (CT), magnetic resonance imaging (MRI), and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging were used to evaluate lesions when available. Contrast-enhanced CT scans covering the pelvic area were reviewed by a minimum of two radiologists. Image review focused on detecting contrast enhancement and the presence of calcifications within the prostate gland. Regardless of detected CT findings, all patients with available MRIs of the pelvic area were also reviewed to detect any suspicious lesions. MRIs were acquired per standard institutional protocols. Dedicated prostate MRIs were performed with or without endorectal coil and contrast, and sequences included triplane T2 weighted MRI and ADC maps of diffusion weighted MRI.

Histopathological Staining:

Cases were processed at the NCI Laboratory of Pathology or MDACC Laboratory of Pathology and were characterized by hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC). IHC stains included calcitonin, carcinoembryonic antigen (CEA), chromogranin, synaptophysin, prostate specific antigen (PSA), thyroglobulin, thyroid transcription factor 1 (TTF-1), androgen receptor, and congo red.

Data and Statistical Analyses:

Descriptive statistics including medians, ranges, and frequencies were used. Significance was defined as p-value < 0.05 by appropriate statistical measure.

RESULTS

Clinical Characteristics

Thirty-six male patients with MEN2B and MTC (median age of diagnosis of MTC 12.0 years, range 1.3–25.6) were identified. All patients were heterozygous for the p.Met918Thr germline variant. Pelvic imaging was available for 28/36 (78%) patients and included CT (n=23), MRI (n=15), and/or FDG-PET (n=12). Prostate abnormalities were found in 8/28 patients (28.6%). Six patients had focal prostate lesions, five of which also had calcifications, and two patients had only calcifications evident within the prostate (Table 1). Of the eight patients with prostate abnormalities, median age of lesion detection was 20.5 years (range 13–30.5 years), all had elevated calcitonin levels (median 339 pg/mL, range 111–5,830), and four had other radiologically evident MTC distant metastases at the time of prostate lesion discovery (Table 1).

Table 1:

Characteristics of MEN2B Patients with Prostate Lesions

Patient # Age at MEN2B Diagnosis Prostate lesion imaging characteristics Age (years)* Prostate biopsy MTC Metastatic sites*# Dysuria or pelvic pain Serum calcitonin (pg/mL)*
2 5 Lesion/calcification 20 No bone, liver, lymph nodes No 5,565
8 8 Lesion/calcification 15 Yes lung, brain, skin, lymph nodes No 111
9 9 calcification 24 No lymph nodes No 283
14 13 Lesion/calcification 30 No bone, liver, lung, lymph nodes No 377
24 12 Lesion/calcification 14 Yes lymph nodes Yes 3,863
25 25 calcification 34 No liver, lung, bone No 5,830
27 11 Lesion 21 Yes lymph nodes Yes 339
30 13 Lesion/calcification 17 No No Yes 216
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*

Patient age, extent of disease and serum calcitonin at the time of prostate lesion identification (Normal calcitonin: male < 8.4 pg/mL),

#

Detectable on physical examination and available imaging studies around the time of identification of prostate lesion

Three prostate abnormalities were discovered during investigations of pelvic pain and/or dysuria and five were discovered incidentally or during routine restaging. Patients who experienced pelvic symptoms underwent multiple investigations ruling out infectious or obstructive etiologies. Pelvic symptoms such as dysuria and/or pain were noted in 3/8 (38%) of patients prior to discovery of the prostate lesion. These three patients (#8, #24, #30) had a greater than two-year history of difficulty urinating and pelvic pain. Each was subject to multiple urinalyses that consistently provided evidence against urinary tract infection. Imaging review of the lesions showed that prostate lesions arose away from the urethral tract and would not be expected to impact urine outflow (Figure 1A–D). There was no difference in age of MEN2B diagnosis in patients with prostate abnormalities versus those without.

Figure 1. Imaging and histology of prostate neoplasms in two adolescents with MEN2B.

Figure 1.

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Axial computed tomography (A) and T2-weighted magnetic resonance images of prostate tumors (B) in patient #8; axial computed tomography (C) and axial T2-weighted magnetic resonance images (D) of prostate tumor in patient #24. Lesions are marked with red asterisks. H&E stained specimens for patient #8 of the primary MTC (E) and MTC metastatic to lymph node (F), prostate (G), and skin (H). H&E stained specimens from patient #24 of the primary MTC (I) and metastatic MTC to the prostate (J), both of which stained positively for calcitonin (K and L, respectively); the prostate tumor was negative for prostate specific antigen (M) and thyroglobulin (N).

Figure 1 shows CT and T2-weighted MRI images of prostate lesions in patients #8 (A, B) and #24 (C, D). Images of the prostate lesion in patient #8 was described as “an enlarging prostate lesion approximately 3.8 × 2.0 cm with evidence of calcifications” (Figure 1). Images of the prostate lesion in patient #24 was described as “stable prostate lesion measuring approximately 1.1 × 1.1 cm with evidence of calcifications” (Figure 1). Interestingly, patient #27 had multifocal lesions in the prostate (Figure 2). Three patients (#8, #24, #27) had ultrasound-guided, core biopsies of their prostate lesions and histopathological analyses were performed on these samples.

Figure 2. Multifocal prostate tumors in a patient with MEN2B.

Figure 2.

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Coronal T2-weighted magnetic resonance imaging (MRI) of the prostate of patient #27 exhibiting multifocal lesions. Lesions are marked with red asterisks.

Histopathology

H&E stains of biopsies from patient #8 are shown in Figure 1E–H. The biopsies were taken from the primary MTC, metastatic MTC to the lymph node and skin, and prostate tumor. H&E stains of biopsies from patient #24 from the primary MTC and the prostate tumor are shown in Figure 1I–J. Morphologically, the prostate neoplasms were indistinguishable from the primary MTC. The primary MTC and prostate lesions of patient #8 and #24 (Figure 1K–L) were positive for calcitonin by IHC. The prostate lesion of patient #24 was negative for thyroglobulin and PSA (Figure 1M–N). The prostate lesion of patient #27 stained positive for calcitonin, chromogranin and synaptophysin, and negative for PSA, thyroglobulin, TTF-1, androgen receptor, CEA, and congo red (data not shown).

DISCUSSION

In this two-center study, we identified prostate neoplasms in 8/28 (28.6%) males with MEN2B and pelvic imaging, including patients who did not have other radiographically evident disseminated MTC at the time of prostate lesion discovery. This finding raises the question of the importance of the prostate as a disease site in these patients.

Comparison of data from patients #8, #24, and #27 illustrates the range of clinical characteristics of patients with prostate lesions. Patient #8 experienced widespread, progressive metastatic disease requiring systemic therapy with vandetanib and rising tumor markers throughout his disease course23. In contrast, patient #24 experienced minimal MTC disease burden with only cervical lymph node metastasis present on imaging and less aggressive disease. The prostate lesion in patient #27 was multifocal and histologically consistent with other patients reviewed. To the best of our knowledge, multifocal, cancer metastasis to the prostate have not been reported.

Two patients in our cohort had calcifications in biopsy-proven tumors of the prostate, and only one of the eight patients had no calcifications identified. While prostatic calcifications are common in men greater than 40 years of age, they are unusual in young adults and children, identified by abdominal ultrasound in only 9% of men between the ages of 18 and 29 years 24. Urinary tract symptoms were reported by three patients with a prostate lesion in our cohort, and calcifications of the prostate can be associated with chronic pelvic pain25. The pathophysiology of isolated prostate calcifications in patients with MEN2B is not yet completely defined and further study will be required to understand the clinical significance of this finding.

Metastases of solid tumors to the prostate are generally uncommon with reported occurrence in less than 1% of prostatic surgical specimens and in 3% of postmortem prostate samples in patients with disseminated cancer26–28. Anecdotally, in our practice we have not identified prostate metastases in patients with sporadic MTC or MEN2A and to our knowledge only one case, a 73-year-old with sporadic MTC with a prostate metastasis, has been reported17. Prostate lesions have been reported in four patients with MEN2B including three cases that were characterized as primary neuroendocrine tumors of the prostate and one as metastatic MTC19–21. It is interesting to note that in two cases the patients presented with urinary symptoms including persistent dysuria, nocturnal outflow obstruction, and acute urinary retention20. In our patient cohort 3 of 8 patients with prostate lesions had a history of pelvic pain, however, the lesions arose away from the urethral tract and would not be expected to impact urine outflow (Figure 1A–D). Overall, the relationship between prostate lesions and pelvic symptoms in MEN2B is not clear.

Our data suggest that neoplastic lesions of the prostate are common in patients with MEN2B. While the clinical implications are not yet defined the prostate should be considered as a possible site of disease in MEN2B patients with abnormal calcitonin levels. In some patients with widespread MTC, this may reflect a site of distant metastasis, but in others (such as patients #24 and #27) a distinct primary prostate calcitonin-secreting neuroendocrine tumor cannot be ruled out. Interestingly, none of the patients in this cohort had lymphatic metastases below the diaphragm at the time the prostate lesion was identified. The possibility of a primary neuroendocrine tumor of the prostate has potential prognostic and therapeutic implications that remain to be explored.

These findings suggest that male MEN2B patients with abnormal biomarkers may benefit from dedicated imaging of the prostate. Because there is no clear relationship between prostate lesions and urinary symptoms, we have not limited prostate imaging to symptomatic patients. We recommend dedicated biparametric (bpMRI) which includes three plane T2-weighted MRI and diffusion weighted MRI (including high b value sequence) and ADC maps. Longer follow-up is necessary to clarify the natural history of these prostatic neoplasms.

ACKNOWLEDGEMENTS

We thank all the participating patients, families, investigators, nurses, study coordinators, and research staff. Additionally, this research was made possible by the National Institutes of Health (NIH) Medical Research Scholars Program (MRSP) (https://clinicalcenter.nih.gov/training/mrsp), a private-public collaboration dedicated to training the next generation of physician scientists.

DISCLOSURES and FUNDING STATEMENT

None of the authors have financial interests or other conflicts to disclose. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

Research Support:

This project has been funded in whole or in part with federal funds from the National Cancer Institute, Center for Cancer Research and the National Institutes of Health, under Contract No. HHSN261200800001E.

Footnotes

Clinical Trial Registration Numbers: NCT01660984 and MD Anderson study DR09-0507

Previous Presentation(s): Kraft IL, Gross A, Akshintala S, Bradford D, Killian KJ, Lei H, Zhu Y, Stevenson H, Bednarova S, Turkbey B, Derse-Anthony C, Merino MJ, Waguespack SG, Widemann BC, Shern JF, Glod JW. Clinical and genomic characterization of prostate lesions in multiple endocrine neoplasia 2B. The American Society for Pediatric Hematology and Oncology Annual Meeting, Montreal, Quebec, April 26–29, 2017.

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