Papillary microcarcinoma in three generations of the first degree relatives

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Introduction

The incidence of thyroid cancer worldwide is steadily increasing due to the increase in tumors from follicular epithelial cells [1; 2]; more than 90 % of cases are sporadic, and 3–10 % of patients have a familial form with a predominance of papillary carcinoma [2–4]. Family cancer from thyroid follicular epithelial cells is cancer in two or more family members of the first-degree of kinship in the absence of other familial syndromes [5]. In families with three to five relatives diagnosed with thyroid cancer, the risk of getting it is 96 % [6]. Family cancer from follicular epithelial cells has an autosomal dominant type of inheritance [5; 7] and is described as a polygenic disease associated with multiple genes of predisposition to low or moderate penetrance and variable expression [4]. There are polar opinions in the literature about the features of the course and treatment tactics for family papillary carcinoma. Some scientists claim that the family form of papillary cancer, compared with the sporadic one, develops at a young age, more often has multifocal growth, bilateral thyroid gland damage, a higher frequency of metastasis to the lymph nodes of the neck and the likelihood of relapse [2; 7–10]. Other works found similar course, outcome and comparable prognosis in a comparative analysis of treatment results in patients with family and sporadic forms of papillary carcinoma, including families with three or more affected family members [11–13]. In this regard, it is relevant to study the clinical characteristics and outcomes of treatment for family papillary thyroid cancer.

The aim of the study is to examine the clinical characteristics and treatment outcomes of family papillary microcarcinoma of the thyroid gland in three generations of one family.

Clinical case

Three patients from one family of the first degree of kinship were operated on at the Voronezh Regional Clinical Hospital No. 1 for family papillary microcarcinoma of the thyroid gland. They all live in the same village M. in the Voronezh region. Cancer was diagnosed in a woman, her son and granddaughter, the son's daughter. No other endocrinological or oncological diseases were detected in them.

Patient 1, born in 1956 (50 years old), was admitted to the Voronezh Regional Clinical Hospital No. 1 in November 2006 with a diagnosis of multinodular nontoxic goiter. She complained of severe deformation of the neck on the right and a feeling of compression in the neck area. TSH (Thyroid Stimulating Hormone) was 1.45 mIU/L (0.3–4.0), free T₄ – 11.45 pmol/l (10.3–24.5), free T₃ – 5.14 pmol/L (4–8.6), anti-TPO (anti-thyroid peroxidase) – 61.5 IU/ml
(0–30). Ultrasound showed a thyroid volume of 22.5 cm³. In the upper third on the right along the capsule of the posterior contour there was a hypoechoic formation of 6´7´10 mm. In the middle third there was an poorly defined hypoechoic formation without clear borders of 9´10´11 mm with calcifications up to 2´3 mm. In the lower third with transition to the isthmus there was an echogenic formation with halo of 25´28´39 mm. In the left lobe in the middle third, there was an echogenic formation with halo of 15´18´19 mm. Along the vessels of the neck, lymph nodes were not changed. The cytological findings from the puncture biopsy of the right lobe were as follows: a follicular tumor from the 25´28´39 mm formation and suspicion of papillary carcinoma from the 9´10´11 mm formation. In the left lobe, the biopsy of the 15´18´19 mm formation suggested a follicular tumor. A thyroidectomy was subsequently performed. Histopathological examination of the surgical specimen revealed papillary carcinoma of the right lobe (1 cm in diameter) with hyalinosis and calcification, a microfollicular-trabecular adenoma of the right lobe, and a microfollicular adenoma of the left lobe, all against the background of chronic autoimmune thyroiditis. Radioiodine therapy was not administered.

In the postoperative period, the patient received thyroxine therapy at a dose of 125 mcg, targeting a TSH level of 0.5–1.0 mIU/L. During the 18 years of follow-up after surgery, there has been no evidence of lymph node metastasis or disease recurrence.

Patient 2, born in 1974 (46 years old), was examined by an endocrinologist in May 2020 while being treated by a cardiologist for hypertension. The examination was carried out to rule out thyroid pathology. As a result, the patient was diagnosed with multinodular nontoxic goiter and referred for surgery at the Voronezh Regional Clinical Hospital No. 1. TSH was 2.33 mIU/L (0.3–4.0), free T₄ – 10.78 pmol/l (10.3–24.5), free T₃ – 6.26 pmol/L (4–8.6), anti-TPO – 80.4 IU/ml (0–30), calcitonin – 1.2 pg/mL. Ultrasound showed a thyroid volume of 24.1 cm³. In the right lobe, in the upper third along the capsule of the posterior contour there was an poorly defined hypoechoic formation without clear borders of 12´10´11 mm with several calcifications up to 5´3 mm. The formation was avascular and assigned TIRADS 5. In the lower pole of the right lobe there were hypoechoic formations of 4 and 4.5 mm with peripheral blood flow (TIRADS 3). In the left lobe, in the middle third there was an echogenic formation with halo of 13´15´10 mm. It was vertically oriented and had peripheral blood flow, TIRADS 4. In the lower third along the posterior capsule there was a hypoechoic formation of 5´3´6 mm with peripheral flow, TIRADS 3. Along the vessels of the neck, lymph nodes weren’t changed. The cytological findings from the puncture biopsy of the right lobe were as follows The cytological findings from the puncture biopsy of the thyroid were as follows: from the 7´9´10 mm formation in the right lobe (TIRADS 5) – probable papillary carcinoma (Bethesda V); from the 13´15´10 mm formation in the left lobe (TIRADS 4) – follicular tumor (Bethesda IV). A thyroidectomy was performed. Histopathological examination of the surgical specimen revealed a follicular adenoma in the left lobe and papillary carcinoma in the right lobe (0.9 cm in diameter) with secondary degenerative changes, including fibrosis and hyalinosis of the tumor nodule. The tumor was confined within the thyroid tissue with no evidence of extrathyroidal extension. No lymphovascular invasion or tumor emboli in the vascular lumens were identified. Surgical margins were clear of tumor involvement.

 Outside the tumor, there was tissue with a morphological picture of micro- and macrofollicular colloid goiter and moderately severe autoimmune thyroiditis. Radioiodine therapy wasn’t carried out. In the postoperative period, he received therapy with thyroxine at a dose of 150 mcg with a target TSH level of 0.5–1.0 mIU/L. There has been no data on metastasis to the lymph nodes or disease recurrence during the 5 years of observation after surgery.

Patient 3, born in 2001 (19 years old), learned in May 2020 that her father was diagnosed with thyroid cancer with no complaints from the neck. She decided to be examined and was diagnosed with multinodular nontoxic goiter. A week after her father's discharge, she was hospitalized at the Voronezh Regional Clinical Hospital No. 1 for surgical treatment. TSH was 1.42 mIU/L (0.3–4.0), free T₄ – 15.61 pmol/l (10.3–24.5), free T₃ – 7.11 pmol/L (4–8.6), anti-TPO – 42.4 IU/ml (0–30), calcitonin – 2.3 pg/mL. Ultrasound of the thyroid gland showed a volume of 27.2 cm³. In the right lobe, in the upper pole there was a hypoechoic formation of 4.5 mm in diameter with an irregular shape and an indistinct contour with hyperechoic inclusions up to 1 mm. The formation had peripheral blood flow (TIRADS 5). Along the posterior contour in the middle third there was a multi-nodular isoechoic formation with halo. It had a heterogeneous structure due to areas of rarefaction and mixed blood flow (TIRADS 3). In the lower third of the left lobe there was a hypoechoic formation with scalloped irregular shape of 5´7´8 mm and heterogeneous structure. It also had mixed blood flow (TIRADS 4). Along the vessels of the neck, lymph nodes weren’t changed. The cytological findings from the puncture biopsy were as follows: from a 4.5 mm formation in the right lobe (TIRADS 5) – suspicion of papillary cancer (Bethesda VI), from a 5´7´8 mm formation in the left lobe (TIRADS 4) – follicular tumor (Bethesda IV). Thyroidectomy was performed. In the study of postoperative material: microfollicular adenoma of the left lobe, papillary microcarcinoma with multicentric growth in the right lobe against the background of autoimmune thyroiditis (tumor foci from 0.1 to 0.7 cm), growing within the thyroid tissue, without invasion into the adjacent tissue. Lymphovascular invasion and tumor emboli in the vascular lumens weren’t found. Surgical excision lines showed no signs of tumor growth. Radioiodine therapy wasn’t carried out. In the postoperative period, she received therapy with thyroxine at a dose of 150 mcg with a target TSH level of 0.5–1.0 mIU/L. There has been no data on metastasis to the lymph nodes or disease recurrence during the 5 years of observation after surgery.

Results and discussion

Currently, the gene for family papillary thyroid cancer has not been identified, so clinicians rely on family history when diagnosing it [1; 3]. In our study, papillary cancer was found in the woman, her son and her granddaughter. Given that cancer was detected in three family members of first-degree kinship, the likelihood of sporadic mutations is extremely low [5; 6]. The first patient had a tumor measuring 1 cm, her son had one measuring 0.9 cm, and the granddaughter had foci from 0.1 to 0.7 cm in diameter. In all cases, cancer was localized in the right lobe combined with damage to the left lobe by follicular adenoma, which may indicate similar genetic mutations in the pathogenesis of family papillary thyroid cancer [4]. Only the first patient complained of neck deformity. In the next two generations, the disease was asymptomatic. Metastasis to the lymph nodes of the neck and bilateral tumor localization in family papillary carcinoma [2; 7; 10], including tumors up to 1 cm, noted in the work by M. Capezzone et al. [8], weren’t found in our patients. We believe that family papillary cancer may have a less aggressive course when the tumor size is up to 1 cm. T.-Y. Sung et al. describe that in patients with family papillary carcinoma up to 1 cm in size, aggressiveness regarding multifocality, extrathyroidal invasion, metastasis to central lymph nodes, and the likelihood of recurrence are lower than in patients with a tumor larger than 1 cm [14]. According to A. Rios et al., the probability of relapse increases by 1.403 times with each 1 mm increase in tumor size [13]. In our study, multifocal tumor growth appeared in the granddaughter of the first patient. Z. Li et al. report a higher frequency of multifocality in the familial form compared to the sporadic one [2]. In the third generation, cancer was diagnosed at 19 years old, which is 2.4 and 2.6 times earlier compared to the second and first generations, respectively. M. Lakis et al. also point out younger age in cases of family papillary carcinoma [10]. Given the contradictory information about the aggressiveness of family papillary carcinoma compared to sporadic ones, the question of the need for aggressive treatment tactics remains open [4; 13]. Some researchers perform thyroidectomy with central lymph node dissection and radioiodine therapy [2; 4; 7; 9]. Other scientists recommend treating patients with a family form according to the stage of the disease, similar to sporadic ones [11–13]. In our study, all patients underwent thyroidectomy, since no metastases to the lymph nodes of the central zone were detected based on the examination data. The first patient had 18 years of relapse-free follow-up after surgery, while the second and third patients had 5 years.

Conclusions

The presence of papillary thyroid cancer in first-degree relatives who have undergone surgery for this condition increases the likelihood of a malignant thyroid tumor in descendants. In the case of family papillary carcinoma of the thyroid gland, we consider active screening of relatives justified, since the disease in the new generation may develop at a younger age and with the risk of multifocal damage to the thyroid gland even in cases of microcarcinomas.

About the authors

A. A. Tsurkan

Voronezh State Medical University named after N. N. Burdenko

Email: alexandertsu@yandex.ru
ORCID iD: 0000-0003-1814-9260

Student

Russian Federation, Voronezh

A. V. Karpova

Voronezh State Medical University named after N. N. Burdenko

Email: alexandertsu@yandex.ru
ORCID iD: 0000-0001-9551-6381

Vice-Rector for International Affairs, PhD (Medicine). Associate Professor

Russian Federation, Voronezh

A. Yu. Tsurkan

Voronezh Regional Clinical Hospital No. 1

Author for correspondence.
Email: alexandertsu@yandex.ru
ORCID iD: 0000-0001-9319-717X

PhD (Medicine), Associate Professor

Russian Federation, Voronezh

References

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