ArticlePDF Available

MEN1 in a Patient With Nonsyndromic Familial Nonmedullary Thyroid Carcinoma

Authors:

Abstract and Figures

Clinical syndromes involving multiple endocrine glands have been well recognized for over a century. Multiple reports describing hereditary multiple endocrine neoplasia (MEN) syndromes involving pituitary, parathyroid, and pancreatic neuroendocrine tumors have been published. Differentiated (nonmedullary) thyroid cancer can also present as a hereditary syndrome with or without a specific genetic predisposition. We report the case of a man with nonsyndromic familial nonmedullary thyroid carcinoma, a pituitary adenoma, hyperparathyroidism, an adrenal adenoma, and pancreatic adenocarcinoma. Genetic testing did not reveal mutations in the commonly reported genes associated with MEN syndromes. MEN1 is characterized by endocrine neoplasia in at least 2 of the following glands: pituitary, parathyroid, and the gastro-entero-pancreatic (GEP) tract. Co-occurrence of MEN1 with familial nonmedullary thyroid carcinoma, however, has not been reported in the medical literature. This unique case of MEN1 co-existing in a patient with nonsyndromic familial thyroid carcinoma was not associated with any common MEN syndrome germline mutations.
Content may be subject to copyright.
JCEM Case Reports, 2023, 1, 1–4
https://doi.org/10.1210/jcemcr/luac019
Advance access publication 30 November 2022
Case Report
MEN1 in a Patient With Nonsyndromic Familial
Nonmedullary Thyroid Carcinoma
Lauren A. Fitzgerald,
1
Shelley Williamson,
2
Jawairia Shakil,
1,2,3
and Richard J. Robbins
1,2,3
1
ENMED Program, Texas A&M University, Houston, TX 77030, USA
2
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
3
Weill Cornell Medical College, New York, NY 10021, USA
Correspondence: Richard J. Robbins, MD, Houston Methodist Hospital, 6550 Fannin Street, Houston, TX 77030, USA. Email: rjrobbins@houstonmethodist.org.
Abstract
Clinical syndromes involving multiple endocrine glands have been well recognized for over a century. Multiple reports describing hereditary
multiple endocrine neoplasia (MEN) syndromes involving pituitary, parathyroid, and pancreatic neuroendocrine tumors have been published.
Differentiated (nonmedullary) thyroid cancer can also present as a hereditary syndrome with or without a specific genetic predisposition. We
report the case of a man with nonsyndromic familial nonmedullary thyroid carcinoma, a pituitary adenoma, hyperparathyroidism, an adrenal
adenoma, and pancreatic adenocarcinoma. Genetic testing did not reveal mutations in the commonly reported genes associated with MEN
syndromes. MEN1 is characterized by endocrine neoplasia in at least 2 of the following glands: pituitary, parathyroid, and the gastro-entero-
pancreatic (GEP) tract. Co-occurrence of MEN1 with familial nonmedullary thyroid carcinoma, however, has not been reported in the medical
literature. This unique case of MEN1 co-existing in a patient with nonsyndromic familial thyroid carcinoma was not associated with any
common MEN syndrome germline mutations.
Key Words: MEN1, acromegaly, familial thyroid cancer, Cushing syndrome
Abbreviations: GEP, gastro-entero-pancreatic; GH, growth hormone; IGF-1, insulin-like growth factor 1; MEN, multiple endocrine neoplasia; Tg, thyroglobulin;
TSH, thyrotropin (thyroid-stimulating hormone).
Received: 12 September 2022. Editorial Decision: 7 November 2022. Corrected and Typeset: 1 December 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/
licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For
commercial re-use, please contact journals.permissions@oup.com
Clinical syndromes involving multiple endocrine glands were
recognized as early as 1900 by Erdheim. In 1953, Underdahl
and colleagues from the Mayo Clinic reported a series of pa-
tients with tumors of the pituitary, the parathyroid glands,
and the pancreatic islets [1]. Multiple reports over the next
10 years documented that many of these syndromes were her-
editary [2]. The term multiple endocrine neoplasia (MEN)
was suggested by Steiner in 1968. MEN1 is a syndrome char-
acterized by endocrine neoplasia in at least 2 of the following:
pituitary, parathyroid, and the gastro-entero-pancreatic
(GEP) tract. Additional syndromes that may be related to
the MEN syndromes have been identied as well [3]. We re-
port the case of a man with familial nonmedullary thyroid car-
cinoma, a pancreatic adenocarcinoma, and MEN1 involving
neoplasia in 3 additional endocrine glands.
Case Presentation
A 63-year-old man was referred to our medical center for evalu-
ation of jaundice secondary to a pancreatic mass. The patient
initially presented with painless jaundice. He was then sent
for imaging and a laboratory workup, which revealed a pancre-
atic mass obstructing the biliary tree and an elevated total bili-
rubin of 1.3 mg/dL (22 µmol/L). He had a stent placed
endoscopically to relieve the obstruction and was subsequently
sent to our medical center for further evaluation. His history
was signicant for papillary thyroid carcinoma resected at
age 26 followed by radioiodine remnant ablation. He subse-
quently developed acromegaly at age 51 (insulin-like growth
factor 1 [IGF-1] =776 ng/mL [101 nmol/L]; normal range:
46-219 ng/mL) and had trans-sphenoidal resection of a
13 mm adenoma which stained heavily for immunoreactive
growth hormone (GH). From age 53 to 63 he was on various
somatostatin analogs and/or pegvisomant for excessive GH
production. These were discontinued 2 months prior to his
hospitalization. Additionally, he was diagnosed with type 2
diabetes mellitus at 55 years of age. He also had a history of
recurrent kidney stones.
His family history was signicant for multiple family mem-
bers with endocrine diseases. His mother had a thyroidectomy
for differentiated thyroid carcinoma; one sister had a thyroi-
dectomy for papillary thyroid carcinoma; another sister had
parathyroid carcinoma; and a nephew had papillary thyroid
cancer. His father had a tumor (uncertain histopathology)
blocking the biliary tree with jaundice, and his daughter had
a prolactinoma (Fig. 1).
Physical examination showed central obesity, enlarged
supraclavicular fat pads, an interscapular “buffalo” hump,
and nonpigmented axillary and abdominal striae. There
were no lentigines or hyperpigmented lesions. He had no
facial features suggestive of acromegaly and no masses or
enlarged lymph nodes in the thyroid bed or cervical regions.
Magnetic resonance imaging to characterize his pancreatic
mass also revealed a 1.6-cm right adrenal mass.
Downloaded from https://academic.oup.com/jcemcr/article/1/1/luac019/6855029 by guest on 02 December 2022
2 JCEM Case Reports, 2023, Vol. 1, No. 1
Endocrinology was consulted for his uncontrolled diabetes
mellitus, history of thyroid and pituitary tumors, hyperpara-
thyroidism, concern for Cushing syndrome, and suspicion for
MEN. He had a 24-hour urine free cortisol that was 120 mcg
(324 nmol [normal range, 10-100 mcg/24 hours]) and an ele-
vated 11 PM salivary cortisol at 2.9 ng/mL (8 nmol/L).
Following a 1-mg overnight dexamethasone suppression test,
his 8 AM cortisol remained at 11 mcg/dL (303 nmol/L) and his
ACTH was suppressed at 2.5 pg/mL (0.55 pmol/L). These nd-
ings, along with the right adrenal mass seen on imaging, sup-
ported the diagnosis of adrenal Cushing syndrome. A neck
ultrasound did not reveal residual thyroid tissue or any other
abnormal masses. He had an elevated corrected calcium level
of 11.6 mg/dL (2.9 mmol/L), a decreased phosphorus level
of 2.2 mg/dL (6.8 mmol/L) and an elevated parathyroid hormone
(PTH) of 135 pg/mL (14.3 pmol/L) upon admission. A SestaMIBI
scan showed no evidence of a parathyroid adenoma. Despite this,
he still had laboratory evidence of hyperparathyroidism as well as
a history of recurrent kidney stones. Thus, 2 previously undiag-
nosed types of endocrine neoplasia were discovered upon this
admission.
Further endocrine workup revealed normal levels of GH,
IGF-1, follicle stimulating hormone, luteinizing hormone, tes-
tosterone, and prolactin. His thyrotropin (thyroid-stimulating
hormone; TSH) was 2.8 mIU/L while on levothyroxine ther-
apy; serum thyroglobulin (Tg) was detectable at 28.9 ng/mL
with negative anti-Tg antibody. Serum calcitonin and carci-
noembryonic antigen levels were within the normal reference
ranges. Gastrin and glucagon levels were also normal.
Screening for carcinoid tumor showed normal range levels of
serotonin, urine 5-hydroxyindoleacetic acid, and chromogra-
nin A. Screening tests for pheochromocytoma were also nega-
tive. Laboratory results are summarized in Table 1.
We performed genetic screening due to his signicant family
history of thyroid cancer and MEN. We tested his white blood
cells for germline mutations in APC, CHEK2, DICER1,
MEN1, PRKAR1A, PTEN, RET, SDHB, SDHD, TP53,
and WRN. None of the common mutations were present in
any of these genes.
Genetic testing was performed using a commercially avail-
able Invitae genetic panel. Identication and conrmation as
needed, of signicant known mutations and their locations,
was carried out using methods established by Invitae [4].
A biopsy of the pancreatic lesion revealed adenocarcinoma.
The patient then underwent a Whipple procedure, with reso-
lution of biliary obstruction and right adrenalectomy with
resolution of hypercortisolemia. Genetic testing of the pan-
creas cancer revealed mutations in TP53, KRAS, and
ERCC2. The patient expired within 1 year due to progressive
pancreas cancer.
Discussion
Our patient had 2 of the 3 most common tumors associated
with MEN1: a GH-secreting pituitary tumor and hyperpara-
thyroidism. Like approximately 10% of MEN1 patients,
Table 1. Serum laboratory evaluation & tumor markers
Analyte Result Normal ranges
Growth hormone 1.87 ng/mL 0.05-3.00 ng/mL
IGF-1 145 ng/mL 46-219 ng/mL
Follicle stimulating hormone 7.2 mIU/mL 1.5-12.4 mIU/mL
Luteinizing hormone 9.2 mIU/mL 1.7-8.6 mIU/mL
Testosterone 311 ng/dL 300-720 ng/dL
Prolactin 14 ng/mL 4-15 ng/mL
TSH 2.8 mIU/L 0.27-4.20 mIU/L
Thyroglobulin 28.9 ng/mL 1.3-31.8 ng/mL
Thyroglobulin auto-antibody <0.9 IU/mL 0.0-4.0 IU/mL
Calcitonin <2.0 pg/mL 0.0-7.5 pg/mL
Serotonin 140 ng/mL 50-220 ng/mL
Chromogranin A 45 ng/mL 0-103 ng/mL
Urine 5-HIAA 3 mg/gCR 0-14 mg/gCR
Gastrin 15 pg/mL 0-100 pg/mL
Dopamine <20 pg/mL 0-20 pg/mL
Epinephrine 25 pg/mL 10-200 pg/mL
Norepinephrine 680 pg/mL 80-520 pg/mL
Metanephrine <10 nmol/L 0.00-0.49 nmol/L
Normetanephrine 0.58 nmol/L 0.00-0.89 nmol/L
CEA 1.4 ng/mL 0.0-3.8 ng/mL
CA 19-9 48 U/mL 0-35 U/mL
Cortisol after DST 11 mcg/dL 6-18 mcg/dL
ACTH after DST 2.5 pg/mL 6-18 pg/mL
Calcium (corrected) 11.6 mg/dL 8.8-10.2 mg/dL
Parathyroid hormone 135 pg/mL 15-65 pg/mL
Phosphorus 2.2 mg/dL 2.4-4.5 mg/dL
Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; ACTH,
adrenocorticotropic hormone; CA 19-9, carbohydrate antigen 19-9; CEA,
carcinoembryonic antigen; DST, 1-mg dexamethasone overnight
suppression test; IGF-1, insulin-like growth factor 1; TSH, thyrotropin
(thyroid-stimulating hormone).
Figure 1. Available family pedigree for the patient (proband) who had
MEN1 and familial nonmedullary thyroid carcinoma. Clinical entities are
shown by color coding in the figure. Circles = females. Squares = males.
Straight lines at 45 degrees through circles or boxes indicate family mem-
bers who have expired.
Downloaded from https://academic.oup.com/jcemcr/article/1/1/luac019/6855029 by guest on 02 December 2022
JCEM Case Reports, 2023, Vol. 1, No. 1 3
our patient had no clear mutation in the MEN1 gene.
Compared with MEN1 patients who have an MEN1 muta-
tion, genotype-negative MEN1 patients are typically older
and usually have hyperparathyroidism and a pituitary tumor
(most commonly somatotroph adenomas) but rarely develop
a neuroendocrine GEP tumor [5]. Our patient had no evi-
dence of a neuroendocrine tumor of the GEP tract. His gas-
trin and glucagon levels were normal, and he never had
hypoglycemia or a watery diarrhea syndrome. He also had
no clinical features to suggest Carney complex or Cowden
syndrome. Carney complex patients, who often have muta-
tions in the PRKAR1A gene, present with myxomas and tu-
mors of the pituitary, adrenal, and thyroid glands. Cowden
syndrome patients have multiple hamartomas, and may de-
velop cancers of the thyroid, breast, or uterus associated
with mutations in the PTEN tumor suppressor gene. Our pa-
tient had a sister with parathyroid carcinoma; however, he
likewise had no features of hyperparathyroidism-jaw tumor
syndrome or McCune-Albright syndrome. Children with
McCune-Albright syndrome (associated with GNAS1 gene
mutations) often have polyostotic brous dysplasia and
café-au-lait pigmentation and rarely may have acromegaly,
thyroid nodules, and adrenal Cushing syndrome. There
were no other known cases of hyperparathyroidism in his
family.
The patient’s family history meets the denition of familial
nonmedullary thyroid carcinoma [6]. Medullary thyroid car-
cinoma was ruled out based on histopathology reports, and
normal serum calcitonin and carcinoembryonic antigen levels.
His measurable serum Tg could represent regrowth of a thy-
roid remnant 37 years after thyroidectomy without TSH sup-
pression. His neck ultrasound did not reveal any thyroid bed
masses or nodules and there was no lymphadenopathy. Of
course, the measurable serum Tg could also be a result of oc-
cult thyroid cancer metastases, which were not detected by the
multiple imaging studies which he underwent.
Acromegaly can be associated with other benign and malig-
nant tumors. Although many patients with acromegaly have
goiters and thyroid carcinoma, there is no well-described associ-
ation between acromegaly and familial nonmedullary thyroid
carcinoma. Acromegaly is also associated with functional and
morphological abnormalities in the adrenal glands. In 2015,
Ishikawa and colleagues reported a case with many features
similar to our case, most notably that the patient had both acro-
megaly and adrenal Cushing syndrome [7]. Approximately 30%
to 40% of MEN1 patients have functional and nonfunctional
adrenal abnormalities.
The genetic basis of nonsyndromic familial nonmedullary
thyroid carcinoma (NSFNMTC), which our patient ts, has
been a topic of considerable interest in the past 5 years. The
clinical features and secondary neoplasia in probands and
family members have been described [8]. No cases of co-
existence with MEN syndromes have been reported to data.
However, the incidence of pancreas cancer, which occurred
in our patient, seems higher in familial nonmedullary cases
than in those with sporadic differentiated thyroid carcinoma
[9]. Multiple susceptibility genes for nonsyndromic familial
nonmedullary thyroid carcinoma have been identied by
whole-exome sequencing in many unrelated families from
China, Europe, and Japan [10].
Signicant limitations in reporting this case include the in-
ability to obtain pathological tissue from his thyroidectomy
(performed 37 years prior) for genetic testing; and from his
pituitary tumor which was removed 12 years prior. Reports
of his family’s history of endocrine neoplasia also often lack
primary pathological evidence, being derived from interview-
ing multiple family members and old hospital records.
Regarding the genetic testing, Invitae’s deletion/duplication
analysis determines copy number at a single exon resolution
at virtually all targeted exons. However, in rare situations, sin-
gle exon copy number events may not be analyzed due to in-
herent sequence properties or isolated reduction in data
quality. Certain types of variants, such as structural rear-
rangements (eg, inversions, gene conversion events, transloca-
tions, etc.) or variants embedded in sequence with complex
architecture (eg, short tandem repeats or segmental duplica-
tions), may not be detected.
In summary, genetic testing and clinical features in our
MEN1 patient did not suggest a known syndrome (eg,
Carney complex, Cowden syndrome, hyperparathyroidism-
jaw tumor syndrome, or McCune-Albright syndrome).
There are sporadic case reports in the medical literature of
MEN1 with some features like our patient, but none with
familial nonmedullary thyroid carcinoma. It is possible
that features of MEN1 and nonsyndromic familial nonme-
dullary thyroid cancer in 1 individual occurred by chance
alone; however, the presence of a single hereditary genetic
predisposition in this family is also possible. Such a genetic
basis may become evident if future similar cases are
discovered.
Learning Points
Take a careful family history to rule out hereditary
endocrinopathies
Review the features of genetic syndromes in familial endo-
crine cases
Investigate the possibility of MEN in all patients with
acromegaly
Consider the possibility of functional adrenal tumors in
MEN patients
Funding
This study was supported in part by a grant (to R.J.R.) from
the Golfers Against Cancer organization (https://
golfersagainstcancer.org) and by the Charles and Anne
Duncan Presidential Distinguished Chair.
Author Contributions
All authors were involved in the care of this patient. All au-
thors contributed to the collection of data and construction
of the manuscript. All authors approved the nal draft of
the case report.
Disclosures
None of the authors have any conicts of interest to declare.
Data Availability
The data that support the ndings of this study are available
on request from the corresponding author, RJR.
Downloaded from https://academic.oup.com/jcemcr/article/1/1/luac019/6855029 by guest on 02 December 2022
4 JCEM Case Reports, 2023, Vol. 1, No. 1
Consent Statement
Retrospective deidentied data review and reporting was ap-
proved by our Institutional Review Board.
References
1. Underdahl LO, Woolner LB, Black BM. Multiple endocrine aden-
omas; report of 8 cases in which the parathyroids, pituitary and
pancreatic islets were involved. J Clin Endocrinol Metab. 1953;
13(1): 20-47.
2. Wermer P. Genetic aspects of adenomatosis of endocrine glands.
Am J Med. 1954;16(3):363-371.
3. McDonnell JE, Gild ML, Clifton-Bligh RJ, Robinson BG. Multiple
endocrine neoplasia: an update. Intern Med J. 2019;49(8):954-961.
4. Lincoln SE, Truty R, Lin C-F, et al. A rigorous interlaboratory
examination of the need to conrm next-generation sequencing-
detected variants with an orthogonal method in clinical genetic test-
ing. J Mol Diagn. 2019;21(2):318-329.
5. Pieterman CRC, Hyde SM, Wu S-Y, et al. Understanding the clin-
ical course of genotype negative MEN1 patients can inform man-
agement strategies. Surgery. 2020;169(1):175-184.
6. Capezzone M, Robenshtok E, Cantara S, Castagna MG. Familial
non-medullary thyroid cancer: a critical review. J Endocrinol
Invest. 2021;44(5):943-950.
7. Ishikawa M, Kato M, Sasaki H, et al. Poorly controlled acromegaly
accompanied by subclinical adrenal Cushing’s syndrome after sur-
gery for multiple endocrine tumors. Intern Med. 2015;54(6):
617-620.
8. de Carlos Artajo J, Irigaray Echarri A, García Torres J, et al.
Clinical characteristics and prognosis of familial nonmedullary thy-
roid carcinoma. Endocrinol Diabetes Nutr. 2022;69(4):262-270.
9. Capezzone M, Sagnella A, Cantara S, et al. Risk of second malig-
nant neoplasm in familial non-medullary thyroid cancer patients.
Front Endocrinol. 2022;13:845954.
10. Sánchez-Ares M, Cameselle-García S, Abdulkader-Nallib I, et al.
Susceptibility genes and chromosomal regions associated with non-
syndromic familial non-medullary thyroid carcinoma: some patho-
genetic and diagnostic keys. Front Endocrinol. 2022;13:829103.
Downloaded from https://academic.oup.com/jcemcr/article/1/1/luac019/6855029 by guest on 02 December 2022
... As prior specified, the fourth ever case of RETnegative medullary thyroid carcinoma in a MEN1-positive patient was reported in 2020, suggesting than a larger dichotomy in understanding this field should be kept in mind [128]. An additional case was reported in 2022 [142]. ...
Article
Full-text available
We aimed to provide an in-depth analysis with respect to three turning points in pancreas involvement in primary hyperparathyroidism (PHP): hypercalcemia-induced pancreatitis (HCa-P), MEN1 (multiple endocrine neoplasia)-related neuroendocrine tumors (NETs), and insulin resistance (IR). This was a comprehensive review conducted via a PubMed search between January 2020 and January 2024. HCa-P (n = 9 studies, N = 1375) involved as a starting point parathyroid NETs (n = 7) or pancreatitis (n = 2, N = 167). Case report-focused analysis (N = 27) showed five cases of pregnancy PHP-HCa-P and three reports of parathyroid carcinoma (female/male ratio of 2/1, ages of 34 in women, men of 56). MEN1-NET studies (n = 7) included MEN1-related insulinomas (n = 2) or MEN1-associated PHP (n = 2) or analyses of genetic profile (n = 3), for a total of 877 MEN1 subjects. In MEN1 insulinomas (N = 77), the rate of associated PHP was 78%. Recurrence after parathyroidectomy (N = 585 with PHP) was higher after less-than-subtotal versus subtotal parathyroidectomy (68% versus 45%, p < 0.001); re-do surgery was 26% depending on surgery for pancreatic NETs (found in 82% of PHP patients). MEN1 pathogenic variants in exon 10 represented an independent risk factor for PHP recurrence. A single pediatric study in MEN1 (N = 80) revealed the following: a PHP rate of 80% and pancreatic NET rate of 35% and 35 underlying germline MEN1 pathogenic variants (and 3/35 of them were newly detected). The co-occurrence of genetic anomalies included the following: CDC73 gene variant, glucokinase regulatory protein gene pathogenic variant (c.151C>T, p.Arg51*), and CAH-X syndrome. IR/metabolic feature-focused analysis identified (n = 10, N = 1010) a heterogeneous spectrum: approximately one-third of adults might have had prediabetes, almost half displayed some level of IR as reflected by HOMA-IR > 2.6, and serum calcium was positively correlated with HOMA-IR. Vitamin D deficiency was associated with a higher rate of metabolic syndrome (n = 1). Normocalcemic and mildly symptomatic hyperparathyroidism (n = 6, N = 193) was associated with a higher fasting glucose and some improvement after parathyroidectomy. This multilayer pancreas/parathyroid analysis highlighted a complex panel of connections from pathogenic factors, including biochemical, molecular, genetic, and metabolic factors, to a clinical multidisciplinary panel.
Article
Full-text available
Introduction Familial non-medullary thyroid carcinoma (FNMTC) is defined by the presence of 2 or more first-degree family members with differentiated thyroid carcinoma (DTC). The aim of this study is to compare clinicopathological features and prognosis of FNMTC and sporadic carcinoma (SC). Materials and methods Retrospective study of DTC included in the hospital database during the period 1990–2018. Results A total of 927 patients were analyzed, 61 of them were FNMTC, with a mean follow-up of 9.7 ± 6.5 years. The prevalence of FNMTC was 6.6%, with a lower TNM staging presentation (P = 0.003) consequence of a higher proportion of tumors smaller than 2 cm (P = 0.003), combined with a greater multifocality (P = 0.034) and papillary histologic subtype (P = 0.022) compared to SC. No significant differences in age at diagnosis (P = 0.347), gender (P = 0.406), neither in other aggressiveness markers (bilaterality, extrathyroidal extension, lymph node involvement and metástasis) were detected. Rate of persistence/recurrence (P = 0.656), disease-free survival (P = 0.929) and mortality caused by the tumor itself (P = 0.666) were comparable. Families with ≥3 affected relatives, had smaller tumors (P = 0.005), more multifocality (P = 0.040) and bilaterality (P = 0.002), as well as a higher proportion of males (P = 0.020). Second generation patients present earlier FNMTC compared to those of the first generation (P = 0.001). Conclusion In our study FNMTC presents a lower TNM staging, higher multifocality and papillary variant, with similar aggressiveness and prognosis compared to SC.
Article
Full-text available
Introduction Survival rates in patients with non-medullary thyroid carcinoma (NMTC) are high, increasing the possibility to develop a second malignant neoplasm (SMN). Many studies investigated the relationship between increased risk of SMN in NMTC patients treated with radioiodine, but few data are available about the impact of family history (FH) of thyroid cancer on SMN risk. Purpose To assess the risk of SMN in a large cohort of sporadic and familial NMTC using the standardized incidence ratio (SIR). Patients and methods We studied 918 NMTC patients (73.9% female patients) followed for a median follow-up of 9 years. In 798/918 (86.9%) patients, NMTC was sporadic, while the remaining 120 (13.1%) were familial NMTC (FNMTC). Results We identified 119/918 (13%) patients with SMN in association with NMTC. NMTCs had an increased risk of SMN when compared to the general population (SIR 2.1, 95% CI 1.7–2.5). The rate of SMN for all sites was significantly higher in familial compared to sporadic NMTC (20% versus 11.9%, p = 0.01), primarily driven by families with more than two affected members. The risk of SMN was remarkably higher for breast cancer, especially in familial cases (SIR 22.03, 95% CI 14.4–41.2) compared to sporadic cases (SIR:17, 95% CI 11.9–24.6). Conclusions NMTC patients have a higher risk of SMN compared to the general population and this risk is much higher in patients with FNMTC. This observation raises the hypothesis that genetic risk factors for a first cancer may predispose to SMN, especially among individuals with familial clustering of the same or other tumors.
Article
Full-text available
Thyroid cancer is the malignant tumor that is increasing most rapidly in the world, mainly at the expense of sporadic papillary thyroid carcinoma. The somatic alterations involved in the pathogenesis of sporadic follicular cell derived tumors are well recognized, while the predisposing alterations implicated in hereditary follicular tumors are less well known. Since the genetic background of syndromic familial non-medullary carcinoma has been well established, here we review the pathogenesis of non-syndromic familial non-medullary carcinoma emphasizing those aspects that may be useful in clinical and pathological diagnosis. Non-syndromic familial non-medullary carcinoma has a complex and heterogeneous genetic basis involving several genes and loci with a monogenic or polygenic inheritance model. Most cases are papillary thyroid carcinoma (classic and follicular variant), usually accompanied by benign thyroid nodules (follicular thyroid adenoma and/or multinodular goiter). The possible diagnostic and prognostic usefulness of the changes in the expression and/or translocation of various proteins secondary to several mutations reported in this setting requires further confirmation. Given that non-syndromic familial non-medullary carcinoma and sporadic non-medullary thyroid carcinoma share the same morphology and somatic mutations, the same targeted therapies could be used at present, if necessary, until more specific targeted treatments become available.
Article
Full-text available
Background: Familial non-medullary thyroid carcinoma (FNMTC), mainly of papillary histotype (FPTC), is defined by the presence of the disease in two or more first-degree relatives in the absence of other known familial syndromes. With the increasing incidence of PTC in the recent years, the familial form of the disease has also become more common than previously reported and constitutes nearly 10% of all thyroid cancers. Many aspects of FNMTC are debated, concerning both clinical and genetic aspects. Several studies reported that, in comparison with sporadic PTCs, FPTCs are more aggressive at disease presentation, while other authors reported no differences in the clinical behavior of sporadic and familial PTCs. For this reason, recent guidelines do not recommend screening of family members of patients with diagnosis of differentiated thyroid cancer (DTC). FNMTC is described as a polygenic disorder associated with multiple low- to moderate-penetrance susceptibility genes and incomplete penetrance. At the moment, the genetic factors contributing to the development of FNMTC remain poorly understood, though many putative genes have been proposed in the recent years. Purpose: Based on current literature and our experience with FNMTC, in this review, we critically discussed the most relevant controversies, including its definition, the genetic background and some clinical aspects as screening and treatment.
Article
Full-text available
Orthogonal confirmation of next-generation sequencing (NGS)-detected germline variants is standard practice, although published studies have suggested that confirmation of the highest-quality calls may not always be necessary. The key question is how laboratories can establish criteria that consistently identify those NGS calls that require confirmation. Most prior studies addressing this question have had limitations: they have been generally of small scale, omitted statistical justification, and explored limited aspects of underlying data. The rigorous definition of criteria that separate high-accuracy NGS calls from those that may or may not be true remains a crucial issue. We analyzed five reference samples and over 80,000 patient specimens from two laboratories. Quality metrics were examined for approximately 200,000 NGS calls with orthogonal data, including 1662 false positives. A classification algorithm used these data to identify a battery of criteria that flag 100% of false positives as requiring confirmation (CI lower bound, 98.5% to 99.8%, depending on variant type) while minimizing the number of flagged true positives. These criteria identify false positives that the previously published criteria miss. Sampling analysis showed that smaller data sets resulted in less effective criteria. Our methodology for determining test- and laboratory-specific criteria can be generalized into a practical approach that can be used by laboratories to reduce the cost and time burdens of confirmation without affecting clinical accuracy. © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology
Article
Full-text available
A 48-year-old woman diagnosed with acromegaly 21 years earlier presented at our hospital with a left adrenal tumor. Her medical history included breast cancer, thyroid cancer and an incompletely resected growth hormone (GH)-producing pituitary adenoma. Endocrinological and radiological examinations revealed subclinical adrenal Cushing's syndrome. She subsequently underwent left adrenalectomy, followed by glucocorticoid replacement therapy. Her GH and insulin-like growth factor-1 levels were insufficiently controlled, and pegvisomant was administered in addition to octreotide acetate. Following adrenalectomy, a giant hepatic hemangioma and papillary thyroid carcinoma in the residual right lobe developed, indicating the high risk of tumor development in patients with acromegaly.
Article
Background It is unclear whether genotype-negative clinical multiple endocrine neoplasia type 1 patients derive equal benefit from prospective surveillance as genotype-positive patients. Methods In this retrospective cohort study, we compared genotype-negative patients with clinical multiple endocrine neoplasia type 1 with genotype-positive index cases. Primary outcome was age-related penetrance of manifestations; secondary outcomes were disease-specific survival and clinical course of endocrine tumors. Results We included 39 genotype-negative patients with clinical multiple endocrine neoplasia type 1 (Male: 33%) and 63 genotype-positive multiple endocrine neoplasia type 1 index cases (Male: 59%). Genotype-negative patients with clinical multiple endocrine neoplasia type 1 were 65 years old at last follow-up; genotype-positive multiple endocrine neoplasia type 1 index cases were 50 (P < .001). Genotype-negative patients with clinical multiple endocrine neoplasia type 1 were significantly older at their first and second primary manifestation. Only 1 developed a third primary manifestation. No genotype-negative patients with clinical multiple endocrine neoplasia type 1 with primary hyperparathyroidism and a pituitary adenoma developed a duodenopancreatic neuroendocrine tumor. Disease-specific survival was significantly better in genotype-negative patients with clinical multiple endocrine neoplasia type 1. In genotype-negative patients with clinical multiple endocrine neoplasia type 1, primary hyperparathyroidism was single-gland disease in 47% of parathyroidectomies versus 0% in genotype-positive multiple endocrine neoplasia type 1 index cases. In genotype-negative patients with clinical multiple endocrine neoplasia type 1, 17% of duodenopancreatic neuroendocrine tumors were multifocal versus 68% in genotype-positive multiple endocrine neoplasia type 1 index cases. Genotype-negative patients with clinical multiple endocrine neoplasia type 1 had more pituitary macroadenomas, fewer prolactinomas, and more somatotroph adenomas. Conclusion Genotype-negative patients with clinical multiple endocrine neoplasia type 1 have a different clinical course than genotype-positive multiple endocrine neoplasia type 1 index cases. This may support a separate classification and a tailored surveillance regimen. Of the genotype-negative patients with clinical multiple endocrine neoplasia type 1 who had parathyroidectomy, almost half had no evidence of multigland disease and may be potential candidates for a more targeted single-gland approach.
Article
The multiple endocrine neoplasia (MEN) syndromes include MEN1, MEN2 (formerly MEN2A), MEN3 (formerly MEN2B) and the recently identified MEN4. Clinical presentations are varied and often relate to the overproduction of specific hormones. Understanding the genetics of each syndrome assists in determining screening timelines. Treatments for each manifestation are dependent on location, risk of recurrence or malignancy, hormone excess and surgical morbidity. Multidisciplinary management should include geneticists, genetic counsellors, endocrinologists and endocrine surgeons.
Article
THE occurrence of a pituitary tumor, islet-cell adenoma and parathyroid tumor or of any combination of two of these in the same patient is extremely rare. It is the primary purpose of this paper to present the total experience of the Mayo Clinic with cases of this syndrome. To date, 8 cases of multiple adenomas involving two or all three of the aforementioned endocrine organs have been studied; 5 were surgical and 3 were necropsy cases.
Article
1.1. The syndrome of adenomatosis of the anterior pituitary, the parathyroids and the pancreatic islets was observed in a family in which the father and four of nine siblings were affected. It is assumed that the syndrome in this family was caused by a dominant autosomal gene with a high degree of penetrance.2.2. The gross and microscopic findings in the parathyroids and in the pancreas differ from those seen in the more common single adenomas. The therapeutic approach therefore has to be different in the two types of cases.3.3. Peptic ulcers of the stomach and of the duodenum are frequently found in patients suffering from the syndrome of adenomatosis of the endocrine gland. This may be looked upon as another manifestation of the abnormal gene.