Clinical Approach to Medullary Thyroid Carcinoma in Pregnancy: Experience and Review of the Literature.

A 28-year-old woman with a medical history of endometriosis presented with a rapidly enlarging anterior neck mass of 2 months' duration and unintentional weight loss of 10 lb. She was 5 weeks pregnant at the time. She had no compressive symptoms nor neck pain and tenderness. Surgical history was significant for a diagnostic laparoscopy 9 years before her endometriosis diagnosis. She had no family history of thyroid cancer or endocrine neoplasia and no prior neck irradiation. She had a history of smoking marijuana, but no prior tobacco use.

Thyroid cancer is the second most diagnosed malignancy during pregnancy, second to breast cancer, with the majority being differentiated thyroid carcinomas [ 1 ]. Medullary thyroid carcinoma (MTC), arising from parafollicular C cells, is rare in pregnancy and poses unique diagnostic and management challenges due to its aggressive biology, genetic associations, and the absence of guidelines on surgical timing during gestation [ 2 ]. There is no documented incidence of MTC in pregnancy given the rarity of this histotype during pregnancy [ 3 ]. Because of the limited number of cases, the impact of pregnancy on women with MTC is not known [ 4 ]. Physiologic changes in pregnancy can influence serum hormone concentrations and tumor marker levels, including calcitonin and carcinoembryonic antigen (CEA), which are integral to the diagnosis and surveillance of MTC and related multiple endocrine neoplasia (MEN) syndromes, thereby complicating its management. We report a case of MTC diagnosed in the first trimester and successfully treated with surgery in the second trimester, accompanied by a review of previously reported cases and their outcomes. We also examine the impact of pregnancy on tumor markers critical for the diagnosis, prognostication and surveillance of MTC.

The surgery was uncomplicated. Postoperatively the patient was started on levothyroxine 88 mcg, vitamin D 2000 units, calcitriol 0.5 mcg, and calcium carbonate 2500 mg. Postoperatively, corrected calcium levels ranged from 9.5 mg/dL (SI: 2.37 mmol/L) to 11.3 mg/dL (SI: 2.82 mmol/L) (reference range, 8.5-10.1 mg/dL [SI: 2.1-2.5 mmol/L]). Doses of calcitriol and calcium carbonate were adjusted accordingly based on daily calcium measurements. Notably, PTH remained undetectable postoperatively. Hypocalcemia due to transient postoperative hypoparathyroidism improved and calcitriol was discontinued. At discharge, she was prescribed levothyroxine 112 mcg and calcium carbonate 1250 mg twice daily. Two weeks postoperatively, serum calcitonin decreased to 2 pg/mL (SI: 2 ng/L) (normal <5 pg/mL [SI:<5 ng/L]). CEA was <2 ng/mL (SI: < 2 μg/L) (normal <2.5 ng/mL [SI: < 2.5 μg/L]). Three months postoperatively, serum calcitonin was undetectable at <2 pg/mL (SI: 2 ng/L). CEA was <2 ng/mL (SI: < 2 μg/L). At 33 weeks and 3 days of gestation, the patient experienced leakage of fluid and mild, irregular contractions. She received 2 doses of betamethasone at an outside hospital. Two days later, she was admitted to another facility with a diagnosis of preterm premature rupture of membranes (PPROM). On admission, the nonstress test was reactive, and Group B Streptococcus screening was negative. She completed a 48-hour course of antibiotics. At 34 weeks, induction of labor was performed, resulting in the vaginal delivery of a viable male infant with appearance, pulse, grimace, activity, and respirations scores of 8 and 9. Maternal and neonatal outcomes were favorable.

MTC during pregnancy is rare; fewer than 10 cases are reported. Surgery in the second trimester appears safe and should be considered when tumor markers are markedly elevated or disease is aggressive. Calcitonin and CEA remain reliable tumor markers during pregnancy and should be monitored as in patients who are not pregnant. Genetic testing is essential for counseling, given the association of MTC with RET pathogenic variants and MEN syndromes. Multidisciplinary management is critical to optimizing maternal and fetal outcomes.

A multidisciplinary team including endocrinology, maternal-fetal medicine, head and neck surgery, and oncology engaged in shared decision-making with the patient. The agreed treatment plan was a total thyroidectomy with central neck dissection during the second trimester, which was performed at 19 weeks of gestation. Surgical histopathology from total thyroidectomy revealed a 4.8-cm MTC with all margins negative for carcinoma. Mitotic rate was less than 3 mitoses per mm 2 . Ki-67 labeling index was 5%. No tumor necrosis and angioinvasion was appreciated. Tumor was present in 8 of 17 regional lymph nodes, all from level VI. The largest metastatic focus measured 0.3 cm. Final staging was defined as pT3a pN1a, per the American Joint Committee on Cancer, 8th edition tumor, node, and metastasis staging classification. The right lobe was also examined, which revealed benign thyroid tissue with no carcinoma seen from the 1 lymph node extracted.

On physical examination, a hard, immobile 5-cm nodule was palpable in the left thyroid lobe. No cervical lymphadenopathy was detected. Neck ultrasonography (US) revealed a 4.2 × 2.7 × 2.0-cm solid, isoechoic, left thyroid nodule with punctate echogenic foci with no cervical lymphadenopathy. This corresponded to a Thyroid Imaging Reporting and Data System (TI-RADS) 4 lesion and met American Thyroid Association (ATA) high-suspicion criteria ( Fig. 1A–C ). The thyroid gland was homogeneous in echotexture and normal in vascularity. Detailed independent review of the US confirmed a 4-cm isoechoic, left lobe nodule with microcalcifications and coarse intranodular calcifications ( Fig. 1B ). The right thyroid lobe was unremarkable. Computed tomography of the neck with contrast confirmed a 3.2 × 2.8-cm left thyroid nodule without pathologic cervical lymphadenopathy or metastases. Further staging imaging was deferred due to pregnancy. (A and B) Neck US transverse view and sagittal view, respectively, of left thyroid nodule (4.2 × 2.7 × 2.0 cm). (C) Doppler (transverse view) left thyroid nodule. The patient underwent US-guided fine-needle aspiration at 6 weeks’ gestation without any complications. Fine-needle aspiration was positive for malignancy (Bethesda VI category) with features suggestive of MTC ( Fig. 2A and B ). The sample was positive for calcitonin and chromogranin by immunostaining and supported by morphology. Staining was negative for Congo Red. Features were suggestive of MTC, with a risk greater than 99%. Afirma MTC classifier was positive (risk of mortality > 99%) and parathyroid was negative. No variants or gene fusions were detected. (A) Medullary carcinoma of the thyroid showing nests of tumor cells and stromal amyloid deposition. Hematoxylin and eosin (H&E), 100× magnification. (B) High-power view of tumor cells with finely stippled chromatin. H&E, 400× magnification. Findings were consistent with sporadic MTC without evidence of metastasis. At 5 weeks of gestation, CEA and calcitonin were notably elevated ( Table 1 ). Mildly elevated plasma normetanephrines were noted at 12 weeks, so a 24-hour urine for metanephrines and catecholamines was obtained and was negative ( Tables 2 and 3 ). These levels of elevated plasma normetanephrines were interpreted as borderline, and not consistent with pheochromocytoma. Repeat plasma metanephrine level was normal ( Table 4 ). Relevant laboratory findings at 5 weeks of gestation Abnormal values are shown in bold font. Relevant laboratory findings at 12 weeks of gestation Abnormal values are shown in bold font. Relevant laboratory findings at 14 weeks of gestation Relevant laboratory findings at 16 weeks of gestation Germline testing was negative for the following hereditary thyroid cancer-related genes: APC, CHEK2, DICER1, MEN1, PRKAR1A, PTEN, RET, SDHB, SDHD, and TP53 . Table 5 showcases the full list of 40 genes that were tested and found negative. Genetic mutations tested No cancer-causing mutations were identified in all 40 genes tested (Invitae Laboratories).

This case highlights the complexity of managing MTC during pregnancy. Fewer than 10 cases have been reported in the literature. We have compiled the available reports and summarized the key clinical characteristics of each case ( Table 6 ). Most underwent surgery in the second trimester, with favorable outcomes [ 4 ]. Deferred surgery until postpartum was used for late diagnoses or indolent disease. Receptor tyrosine kinase ( RET ) pathogenic variants were reported in several Multiple Endocrine Neoplasia type 2A (MEN2A) cases, underscoring the need for genetic testing. Maternal and fetal outcomes across cases have been largely favorable when care was coordinated by a multidisciplinary team [ 12 ]. Reported cases of MTC diagnosed during pregnancy showing patient demographics, clinical presentation, management, outcome (maternal and fetal), and genetics/pheochromocytoma/paraganglioma Abbreviations: LN, lymph node; MTC, medullary thyroid carcinoma; PPROM, preterm premature rupture of membranes; PTU, prophylthiouracil. In this case, the patient's diagnosis of PPROM was found to be secondary to cervical shortening and funneling. Another risk factor was her history of marijuana use. There is no known association between MTC and PPROM. An uncomplicated thyroidectomy at 19 weeks is unlikely to be related to preterm rupture of membranes at 34 weeks, especially given the time interval. Since her hypothyroidism was well controlled during the pregnancy, the 2 events are almost certainly unrelated. Key clinical decision-making factors to consider in the management of MTC during pregnancy are described here. Imaging: Because pregnancy restricts the use of ionizing radiation and contrast-based imaging, neck US remains the primary modality for evaluation. It should be performed during each trimester in patients undergoing active surveillance to monitor disease progression while ensuring maternal and fetal safety [ 4 ]. Cross-sectional and functional imaging—including radionuclide scintigraphy—should generally be postponed until after delivery. Calcifications are present in a substantial proportion of MTCs [ 5 ]. While microcalcifications (punctate echogenic foci) are classically associated with papillary thyroid carcinoma, MTC more frequently demonstrates macrocalcifications, often accompanied by posterior acoustic shadowing [ 5 , 6 ]. Nonetheless, punctate echogenic foci have also been reported in MTC and metastatic nodes, and multiple small punctate calcifications can coalesce into larger, coarse aggregates both pathologically and on US, as observed in this case. Although the presence of microcalcifications is strongly associated with papillary thyroid carcinoma, the malignancy risk associated with macrocalcifications on thyroid US is less well-defined. In our prior work, we observed that macrocalcifications occurred in 70% of malignant nodules and were significantly associated with an increased risk of malignancy [ 13 ]. These findings underscore the importance of considering coarse calcifications as a potential indicator of MTC, warranting further evaluation and management. Biochemical markers in pregnancy: Data on reliability of calcitonin and CEA measurements during pregnancy are limited [ 4 ]. Some reports suggest false elevations, without correlation to serum calcium or phosphate [ 9 , 14 ]. Silva et al state that calcitonin can be elevated 100 to 200 points higher than normal, depending on the trimester, and suggest that the hormone elevation could be protective of maternal skeleton during gestation [ 14 ]. The dramatic postoperative decline and total normalization of calcitonin and CEA, which was observed in this case, supports the continued use of these biomarkers as reliable indicators of tumor burden of MTC in pregnancy. Published literature on the accuracy of plasma and 24-hour urine metanephrines is only discussed in the context of pheochromocytomas in pregnancy [ 15 , 16 ]. Plasma and urine metanephrines are not known to be affected by pregnancy. However, they are still the primary test and most reliable laboratory assessment for pheochromocytoma diagnosis. In this case, plasma normetanephrines were slightly elevated, but the urine catecholamines and repeat plasma metanephrine level was normal. Studies have shown that common factors such as physiological or physical stress, suboptimal sampling conditions, and recent physical activity can lead to false or transient elevations in plasma metanephrines and catecholamines [ 17 ]. Genetic testing: MTC can be either hereditary (25%) or sporadic (75%). In hereditary MTC, RET pathogenic variants are found 95% to 98% of cases, as opposed to 24% to 40% of cases in sporadic MTC [ 18 ]. RET pathogenic variants are critical for counseling offspring. Germline testing was negative for our patient, aligning with sporadic disease ( Table 5 ). Timing of surgery: In contrast to differentiated thyroid cancer, where low-risk cases may defer surgery until postpartum, MTC is more aggressive and lacks consensus guidelines on its management during pregnancy. In this case, high levels of tumor markers and rapid growth supported surgery in the second trimester, aligning with obstetric safety standards and the 2017 Guidelines of ATA [ 4 , 5 ]. Per guidelines, surgery should be strongly considered during the second trimester, but there is low-quality evidence to support this recommendation [ 4 ]. However, if a patient is diagnosed with MTC during the third trimester, surgery is recommended to be delayed until postpartum. No other therapies are recommended given the rarity of newly diagnosed MTC in pregnancy. Management of MTC: For MTC in general, surgery remains the mainstay of treatment. Total thyroidectomy with lymph node dissection is the standard approach. Radioactive iodine has no role because MTC cells do not take up iodine [ 19 ]. Radiation therapy (external beam radiation therapy) is not routinely used. External beam radiation therapy may be considered in cases of unresectable local disease, residual microscopic disease with high risk of locoregional recurrence (eg, extensive nodal involvement, extrathyroidal extension), or palliation of bone or brain metastases [ 20-22 ]. Traditional cytotoxic chemotherapy has shown very limited benefit in MTC and is rarely used today [ 23 ]. Targeted systemic therapy with tyrosine kinase inhibitors (eg, vandetanib, cabozantinib) are Food and Drug Administration-approved for progressive, metastatic, or unresectable MTC [ 24-26 ]. Selective RET inhibitors (eg, selpercatinib, pralsetinib) for RET -mutated MTC showed higher efficacy with fewer side effects [ 23 ]. These agents have largely replaced conventional chemotherapy in advanced disease.