Thyroid collision tumor and Graves’ disease: A case report and review of literature

Abstract

BACKGROUND

Collision tumors of the thyroid are rare entities, defined by the coexistence of two histologically distinct tumors within the same organ, separated by intervening normal tissue. Graves’ disease (GD) is a well-known risk factor for papillary thyroid cancer but has not been associated with thyroid collision tumor or medullary thyroid cancer (MTC).

CASE SUMMARY

A 37-year-old female presented with palpitations, weight loss, and tremors. Thyroid function tests showed suppressed thyrotropin and slightly elevated free thyroxine. A thyroid ultrasound was performed with a report of a nodule in the right thyroid lobe. Thyroid scintigraphy revealed a goiter with increased radiotracer uptake. Ultrasound-guided fine needle biopsy suggested an MTC, Bethesda VI. Immunohistochemistry was positive for synaptophysin and negative for thyroglobulin. Calcitonin levels were elevated. Total thyroidectomy with central lymph node dissection was performed. Pathological exam revealed a medullary carcinoma in the right thyroid lobe and a 3-mm papillary microcarcinoma in the left lobe. Lymph nodes showed reactive hyperplasia without evidence of tumor involvement. The final diagnosis was synchronous medullary thyroid carcinoma and papillary thyroid microcarcinoma, staged as T1N0M0. Sequencing of the rearranged during transfection (RET) oncogene revealed no pathogenic variants, and multiple endocrine neoplasia was ruled out.

CONCLUSION

Collision tumors are rare entities but thyroid collision tumors in GD are even more infrequent despite the known association between GD and differentiated thyroid cancer. The mechanisms by which this clinical entity occurs are unclear. Because it is a rare pathology, there are currently no guidelines for its treatment. Treatment must be guided separately or based on the more aggressive neoplasm.

Key Words: Thyroid neoplasms; Thyroid cancer; Papillary; Thyroid cancer; Medullary; Graves’ disease; Thyroid cancer; Follicular; Collision tumor; Case report

Core Tip: Collision tumors of the thyroid are rare entities, characterized by the presence of two histologically distinct tumors within the same organ, separated by normal intervening tissue. Graves’ disease is a well-established risk factor for papillary thyroid cancer but has not been associated with thyroid collision tumors or medullary thyroid carcinoma. In this review, we evaluate the available evidence on thyroid collision tumors.

INTRODUCTION

The embryological origin of medullary thyroid carcinoma is distinct from that of differentiated thyroid carcinoma. C cells arise from the neural crest of ectodermal origin, while follicular cells are of endodermal origin[1,2]. Although rare, the coexistence of medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC) has been reported as thyroid collision tumors[3,4]. Collision tumors are rare entities characterized by the presence of two distinct neoplastic histologies within the same organ, separated by normal tissue and lacking histological admixture[5,6]. Graves’ disease (GD) has been associated with an increased prevalence of PTC[7]. However, its association with MTC remains unclear, largely due to the extremely low incidence of this malignancy. While the increased detection of PTC may be attributed to intensified screening and incidental findings, MTC remains exceedingly rare in this setting. Consequently, reporting such cases is essential to better characterize this unique patient population. In this review, we evaluate the available evidence on thyroid collision tumor and in the context of GD and present the case of a 37-year-old female with GD and a thyroid collision tumor composed of both PTC and MTC.

CASE PRESENTATION

Chief complaints

A 37-year-old female Latin American female presented with palpitations, weight loss, and tremors. Thyroid function tests demonstrated suppressed thyrotropin (TSH) (0.0001 µU/mL) and a mildly elevated free thyroxine (FT4) (1.73 ng/dL, normal 0.92-1.70). Thyroid ultrasound revealed a 13 mm × 10 mm ovoid nodule in the right thyroid lobe, classified as TIRADS 3.

History of present illness

The diagnosis of GD was established based on positive TSH receptor antibodies (TRAb) and a thyroid scintigraphy demonstrating a diffuse goiter with increased radiotracer uptake. Ultrasound-guided fine needle aspiration (FNA) suggested MTC, Bethesda category VI. Immunohistochemistry was positive for synaptophysin and negative for thyroglobulin. The serum calcitonin level was elevated at 78 pg/mL.

History of past illness

There was no history of past illness.

Personal and family history

There was no personal history of thyroid disease. The family history was notable for PTC in her mother. She had no prior history of radiation exposure.

Physical examination

Physical examination revealed a grade 1 goiter.

Laboratory examinations

An evaluation for multiple endocrine neoplasia (MEN) was performed. Chromogranin A was initially markedly elevated at 1870 ng/mL, while plasma fractionated metanephrines were within normal limits (20 pg/mL). Serum calcium (8.8 mg/dL) and parathyroid hormone (PTH) levels (54 pg/mL) were also normal. On follow-up, the chromogranin A level decreased to 770 ng/mL. Genetic testing for MEN, including sequencing of the RET oncogene, revealed no pathogenic variants. MEN was therefore ruled out.

Imaging examinations

Imaging studies were performed to evaluate for metastatic disease and neuroendocrine tumors. Computed tomography of the thorax and abdomen was unremarkable, and gallium-68 positron emission tomography showed no abnormal uptake. Thyroid scintigraphy demonstrated a diffuse goiter with increased radiotracer uptake, consistent with GD. Thyroid ultrasound-guided FNA of the right thyroid nodule suggested a MTC, Bethesda category VI. Immunohistochemistry was positive for synaptophysin and negative for thyroglobulin, and the serum calcitonin level was elevated at 78 pg/mL.

MULTIDISCIPLINARY EXPERT CONSULTATION

The patient received comprehensive care through a specialized multidisciplinary approach. She was evaluated, managed, and monitored by a collaborative team including specialists in endocrine oncology, radiology, and head and neck surgery.

FINAL DIAGNOSIS

GD, medullary carcinoma in the right thyroid lobe and papillary microcarcinoma in the left lobe.

TREATMENT

Total thyroidectomy with central lymph node dissection was performed. Histopathological examination revealed a 1.2 cm × 1.0 cm × 0.7 cm medullary carcinoma in the right thyroid lobe (Figure 1A and B), without capsular invasion or extrathyroidal extension, along with areas of C-cell (parafollicular) hyperplasia. Additionally, a 3 mm papillary microcarcinoma was identified in the left lobe (Figure 1C). The resected lymph nodes demonstrated reactive hyperplasia without evidence of metastatic disease. These findings were consistent with a thyroid collision tumor composed of medullary thyroid carcinoma and papillary thyroid microcarcinoma, staged as T1N0M0. Following surgery, levothyroxine supplementation was initiated, resulting in symptom resolution. Postoperative laboratory evaluation demonstrated a normal thyroid profile, TSH: 2.3 µU/mL (0.3-4.5 µU/mL) and FT4: 1.03 ng/dL (0.92-1.7 ng/dL). Tumor markers were within normal limits, including carcinoembryonic antigen (CEA), 0.2 ng/mL (0.1-3 ng/mL), and calcitonin: 2 pg/mL (5-20 pg/mL). Thyroglobulin was below the lower limit of detection at 0.6 ng/mL , with negative thyroglobulin antibodies: 12 IU/mL (0-135 IU/mL).

Figure 1 Pathology. A: Medullary carcinoma of the thyroid hematoxylin and eosin 10 ×; B: Calcitonin immunohistochemical stain 10 ×; C: Micropapillary carcinoma of the thyroid hematoxylin and eosin 10 ×.

OUTCOME AND FOLLOW-UP

The patient has been followed by the endocrinology service for 5 years and remains in stable clinical remission. Serial follow-up evaluations, including measurements of tumor markers (CEA, calcitonin, thyroglobulin, and anti-thyroglobulin antibodies) and neck ultrasonography, have demonstrated no evidence of disease recurrence. She continues levothyroxine replacement therapy, with TSH levels maintained within the target range.

DISCUSSION

Thyroid collision tumors

MTC is a rare type of cancer, accounting for 1%-2% of all thyroid cancers[8]. About 25% of MTC cases are hereditary, while the remaining 75% are sporadic. The RET proto-oncogene plays a central role in its pathophysiology and is the primary driver of most cases[9]. RET mutations may occur as somatic events in up to 50% of sporadic MTC cases or as autosomal dominant germline mutations associated with multiple endocrine neoplasia type 2 (MEN2), including MEN2A, MEN2B, and familial MTC (FMTC) syndromes[1,8]. Sporadic MTC occurs more frequently in women, with a typical age of presentation between 40-60 years. Approximately 75% of cases present as a solitary nodule located in the upper part of the thyroid gland. At diagnosis, cervical lymph node involvement is observed in up to 70% of patients, and distant metastases are present in approximately 5%-10% of cases[1].

The coexistence of an MTC and PTC is very rare, initially reported by Lamberg et al[10] in 1981. It has been described in two scenarios; a synchronous occurrence of both tumors separated by normal thyroid tissue[11-13], or tumor collision or a mixed carcinoma showing dual differentiation[3,14]. In this case, we present a patient with concurrent MTC and PTC that has characteristics of a collision tumor. No mutations in the RET gene were detected. Notably, the patient presented with hyperthyroidism, and hyperfunctioning thyroid nodules are rarely associated with malignancy[2]. Previously, hyperthyroidism was considered a protective factor for thyroid cancer[15]. However, the incidence of hyperthyroidism in patients with thyroid cancer has been reported as high as 20.6%[16].

Collision tumors have been described in several organs, but it is extremely rare in the thyroid, with a prevalence of less than 1% of all thyroid tumors[17]. The most frequently reported thyroid collision tumor is the coexistence of differentiated thyroid cancer with medullary cancer presenting in females between the fifth, sixth and seventh decades[14].

The concomitant presence of PTC and MTC is a rare event, as described in the literature in case series and reports[18,19]. There are case series in the literature where MTC components are separated from PTC by normal thyroid tissue. In 2004, Biscolla et al[20] reported one of the largest case series, with 27 patients with MTC and PTC, of which 77% were micropapillary.

Although the mechanisms by which this clinical situation occurs are not entirely clear, several hypotheses have been proposed: The theory that one tumor predisposes to another tumor; the stem cell theory and the theory of the random collision effect[17,21,22]. Among those, the theory of a coincident co-occurrence stands out, given that both neoplasms are separated by healthy thyroid tissue and have distinct embryological origins and pathogenesis mechanisms. While PTC is primarily associated with mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1), MTC is associated with mutations in RET[23,24].

Because it is a rare pathology, there are currently no standard treatment guidelines. Some authors suggest treating both neoplasms separately as if they were two primary tumors[25], while other authors suggest that treatment is based on the more aggressive neoplasm[26]. Total thyroidectomy is the treatment of choice for primary disease because of the aggressive nature of the medullary thyroid carcinoma component. The extent of lymph node dissection should be guided by preoperative calcitonin levels and the stage of disease[1]. In PTC, postoperative management should be guided by risk stratification, with radioactive iodine therapy considered according to the assigned risk category. Follow-up surveillance should include serial thyroglobulin measurements to assess for disease recurrence[2]. In cases of concomitant MTC and PTC, both calcitonin and thyroglobulin should be monitored to detect disease recurrence, while the degree of TSH suppression should be determined according to the risk stratification of the PTC component. The present case represents sporadic MTC with a coexisting papillary thyroid microcarcinoma, treated with total thyroidectomy and followed clinically with serial measurements of thyroglobulin, anti-thyroglobulin antibodies, calcitonin and CEA, with no evidence of disease recurrence.

GD and thyroid cancer

GD is an organ-specific autoimmune disorder due to the presence of thyrotropin receptor-stimulating autoantibodies, with increased synthesis and release of thyroid hormones[27]. GD is the primary cause of hyperthyroidism in patients under 40 years of age with an incidence of 20 to 40 cases per 100000 population per year[28].

Thyroid carcinoma in GD was initially considered a rare phenomenon, and GD was even proposed to have a protective effect through autoimmune-mediated antitumor activity[29]. However, subsequent studies have reported a higher prevalence of thyroid cancer compared to the general population, with an even greater incidence observed among patients with GD, particularly those managed surgically[7,30,31]. The routine use of thyroid ultrasound in this population has possibly led to overdiagnosis of cancer, and it has been suggested that thyrotropin receptor-stimulating autoantibodies stimulates tumor formation and angiogenesis, with upregulation of several growth factors[32,33].

In 2016, Staniforth et al[34] published a meta-analysis of surgically resected specimens and found that the rate of GD-associated thyroid carcinoma was 0.07 (95%CI: 0.04-0.12), with a thyroid cancer rate 2.5 times higher in patients with GD than in the general population. In contrast, the American Thyroid Association states that thyroid cancer occurs in GD with a frequency of 2% or less[35]. In this meta-analysis, 88% were papillary carcinoma, 10% follicular, 0.6% mixed (papillary-follicular), 0.6% medullary, and 0.3% anaplastic. Of the papillary carcinomas, 29% were micropapillary, consistent with the literature[34].

In 2019, a meta-analysis by Mekraksakit et al[36] evaluated the association between GD and prognosis in patients with differentiated thyroid cancer. They found an increased risk of multifocality/multicentricity (odds ratio = 1.45, 95%CI: 1.04-2.02, I² = 6.5%, P = 0.381) and distant metastasis at the time of cancer diagnosis (odds ratio = 2.19, 95%CI: 1.08-4.47, I² = 0.0%, P = 0.497) in differentiated thyroid cancer patients with GD than those without GD.

The reported case describes a patient with GD and a collision tumor of the thyroid gland with PTC and MTC. MTC is rarely associated with GD or other forms of hyperthyroidism[37,38]. One of the earliest reported cases was described by McFarland et al[39] in 1980, involving a 30-year-old female with hyperthyroidism and an associated goiter who underwent thyroidectomy, with histopathology revealing MTC. Up to 2019, Sapalidis et al[40] conducted a systematic review identifying 21 reported cases of hyperthyroidism and MTC. Of these, only 15 cases occurred in the setting of GD, and just seven represented incidentally discovered MTC in patients with GD[41-43].

To our knowledge, only one prior case of a thyroid collision tumor involving MTC and GD has been reported. Mazziotti et al[44] described in 2001 a Caucasian woman with MTC, a concomitant papillary thyroid microcarcinoma, and GD, with no detectable mutations in the RET proto-oncogene. At present, no established pathophysiological mechanism explains the association between MTC and GD, and their coexistence has been suggested to be incidental.

CONCLUSION

Collision tumors are rare entities characterized by the coexistence of two distinct neoplastic histologies within the same organ, separated by normal tissue and without histological admixture. Thyroid collision tumors in the setting of GD are even more uncommon, despite the known association between GD and differentiated thyroid cancer. The mechanisms underlying this clinical entity remain unclear, and due to its rarity, no specific management guidelines currently exist. Consequently, treatment should be individualized and guided by the more aggressive neoplasm or addressed separately for each tumor.