Insular thyroid carcinoma in adolescents

A potentially lethal endocrine malignancy

Authors


Abstract

Insular thyroid carcinoma, which is intermediate in aggressiveness and morphology between well differentiated and anaplastic thyroid carcinomas, is exceptionally rare in children. The authors describe two children with this carcinoma who had different outcomes.

Thyroid carcinoma is relatively uncommon in children. The most common type of thyroid malignancy in iodine-sufficient areas in both children and adults is papillary carcinoma. Thyroid carcinoma generally has a better prognosis in children than in adults despite the greater extent of disease at diagnosis in children.1 Insular thyroid carcinoma, which arises from the follicular epithelium, was initially described in 1984 by Carcangiu et al,2 who defined its histologic diagnostic criteria. This type of thyroid carcinoma is intermediate in clinical behavior and morphology between well differentiated and undifferentiated (anaplastic) carcinomas. The latest World Health Organization classification includes insular carcinoma among variants of follicular thyroid carcinoma.3 Recently, it was classified as a separate entity among other thyroid tumors.4 A few articles have described insular carcinoma in adults,2, 5-7 but to the authors' knowledge there has been only one report of this tumor in a child.6

In this article, the authors describe two cases of insular thyroid carcinomas in children who were recently seen at the study institution and compare them with adult cases described in the literature.

Report of Cases Case 1

A white girl from South Dakota aged 15 years, 2 months presented in July 1993 for the evaluation of abdominal pain and frontal headaches that had been present for 6 months. There was no history of radiation therapy or exposure. No family members were known to have thyroid carcinoma. Physical examination was remarkable for a 7.2 cm × 4 cm pulsating mass in the region of the right thyroid lobe, associated with a thrill and a bruit. There were multiple enlarged lymph nodes on the right side of the neck and in the right supraclavicular fossa. The total thyroxine value was 79.8 nmol/L, and the thyroid-stimulating hormone (TSH) value was 4.1 mIU/L (normal, 0.3-5 mIU/L). Because pulsations raised the possibility of a vascular tumor, fine-needle aspiration was not attempted. Ultrasonography of the thyroid demonstrated a 6-cm solid nodule replacing the right lobe and markedly increased blood flow, as well as multiple enlarged lymph nodes on the right side. Total thyroidectomy was performed. Pathologic examination (Fig. 1) demonstrated insular carcinoma involving the right lobe (6 cm × 4 cm × 3.5 cm) with metastasis to several lymph nodes in the right neck. Immunostaining was positive for thyroglobulin and negative for chromogranin and calcitonin.

Figure 1.

Figure 1.

Case 1. (a) Gross appearance of large right thyroid lobe nodule. The tumor is well demarcated peripherally, and vascularity is prominent. (b) Microscopic appearance of nodule, showing insular pattern of tumor cells surrounded by delicate fibrovascular stroma (H & E, original magnification ×100).

Figure 1.

Figure 1.

Case 1. (a) Gross appearance of large right thyroid lobe nodule. The tumor is well demarcated peripherally, and vascularity is prominent. (b) Microscopic appearance of nodule, showing insular pattern of tumor cells surrounded by delicate fibrovascular stroma (H & E, original magnification ×100).

Six weeks postoperatively, a small mass was palpable in the right supraclavicular region. The total thyroxine value was 2.6 nmol/L and the TSH level was 54.4 mIU/L. The serum thyroglobulin value was significantly increased to 1735 ng/mL. A 131I whole body scan showed 3.7% uptake in a prominent thyroid remnant with additional uptake in the right lower neck. Fine-needle aspiration of the supraclavicular lymph node revealed insular thyroid carcinoma. The patient underwent right modified neck dissection. Pathologic examination confirmed the presence of insular carcinoma in 8 of 24 lymph nodes from the right side of the neck. Lymph nodes from the left side of the neck were negative for metastasis. Flow cytometry demonstrated a DNA diploid pattern in representative nuclei.

Six weeks after the second surgery, the total thyroxine level was 2.6 nmol/L, the TSH level was 98.4 mIU/L, and the serum thyroglobulin value was 9.6 ng/mL. 131I whole body scanning showed an area of 0.35% uptake in the thyroid bed, and ultrasonography of the neck demonstrated a 9-mm suspicious-appearing right supraclavicular lymph node. Biopsy of the lymph node was performed with fine-needle aspiration under ultrasound guidance. Cytologic results were negative for malignancy. The patient received 300 millicuries (mCi) of 131I. Therapy with L-thyroxine, 0.112 mg daily, was started. In June 1994, 131I whole body scanning showed only 0.2% uptake, and there was no evidence of distant metastases. In December 1994, while the patient was receiving thyroxine therapy, the serum thyroglobulin level was 2.3 ng/mL, and the TSH level was 6.9 mIU/L. Ultrasonography of the neck showed no evidence of recurrence. Because the TSH level was inadequately suppressed, the L-thyroxine dose was increased to 0.175 mg daily. At the time of last follow-up, in October 1995, ultrasonography of the neck showed no recurrent mass in the thyroid bed, nor were there any suspicious lymph nodes. The serum TSH level was adequately suppressed with 0.175 mg of L-thyroxine daily. At 22 months after initial diagnosis, no evidence of distant metastasis was found.

Case 2

A white girl from Iowa aged 16 years, 3 months noticed swelling in the right side of her neck in January 1992. Cytologic findings from a thyroid fine-needle aspiration biopsy were suspicious for follicular malignancy. She underwent total thyroidectomy. Pathologic examination of the 54-g thyroid revealed 4 tumor masses in the larger right lobe measuring up to 2.5 cm in greatest dimension and 3 smaller masses in the left lobe. Microscopy of the fixed section led to a final diagnosis of insular thyroid carcinoma (Fig. 2). Immunostaining was positive for thyroglobulin and negative for calcitonin.

Figure 2.

Case 2. Microscopic appearance of thyroid tumor showing an insular pattern surrounded by delicate fibrosis and vessels. A mitotic figure is present (H & E, original magnification ×400).

The patient presented to the study institution in February 1992. Flow cytometry studies of tumor tissue demonstrated a DNA diploid pattern. The serum thyroglobulin level was < 1.6 ng/mL and the TSH value was 41 mIU/L. 131I whole body scanning performed in March 1992 showed 2 foci of uptake in the thyroid bed with 0.8% uptake after 16 hours. She was treated with 29.9 mCi of 131I for the purpose of ablation of the thyroid remnant.

At follow-up in June 1992, biopsy of a right submandibular lymph node under ultrasound guidance confirmed recurrent insular carcinoma. Computed tomography of the neck and chest demonstrated right submandibular lymph node enlargement with a suspicious enlarged left submental lymph node and a tiny lung nodule. The patient was treated with a therapeutic dose (200 mCi) of 131I.

The patient returned in August 1992 with an enlarging, painless right neck mass. She underwent right modified neck dissection; pathologic examination demonstrated recurrent insular carcinoma involving a single high jugular lymph node measuring 5 cm in greatest dimension. She was later given external irradiation (5040 centigray [cGy] in fractionated doses) to the neck and mediastinum, followed by a boost to the right neck of 1000 cGy via electron beam.

In November 1993, some fullness developed in the left lower neck. The serum thyroglobulin level was increased to 63.7 ng/mL. Computed tomography of the neck and chest demonstrated enlarged lymph nodes involving the left neck, left upper mediastinum, and left hilar and subcarinal regions. 131I whole body scanning showed persistent neck foci with uptake of 0.46% at 24 hours. There was also a focus in the posterior region of the left lower chest with uptake of 0.14%. Ultrasound-guided fine-needle aspiration demonstrated metastasis in the enlarged left supraclavicular lymph node. Because of disease progression and evidence of radioiodine uptake at distant sites, the patient was treated with 300 mCi of 131I, for a cumulative dose of 530 mCi.

In January 1994, the patient presented elsewhere with a dense left hemiparesis and underwent emergency craniotomy for a right parietal hemorrhage. Microscopy of the parietal lobe hematoma revealed the presence of metastatic insular thyroid carcinoma, which stained positively for thyroglobulin. She was treated with radiation to the central nervous system (total doses to the brain and spinal cord were 3000 and 4460 cGy, respectively) and, after developing respiratory distress in March 1994, was given an additional dose of 200 mCi (total dose, 730 mCi) of 131I for her lung and mediastinal metastasis. She died in August 1994, 31 months after the initial diagnosis.

DISCUSSION

Insular thyroid carcinoma has been found more frequently in Italy and Paraguay and continues to be rare in the U. S.8 All cases thus far described in the literature were in adults, except for one described by Sironi et al.6 In that report, a 16-year-old girl had "papillary" thyroid carcinoma, but it was retrospectively thought to be insular carcinoma with a papillary (rather than follicular) pattern.

Insular carcinoma is probably derived from follicular cells and may share features of both follicular and papillary thyroid carcinoma.2, 7, 9 However, it has specific features that set it apart both clinically and microscopically.2, 9 Carcangiu et al.2 first used the term "insular" to describe the characteristic formation of solid clusters or nests of tumor cells separated from surrounding cells by artifactual clefts. These insulae are oval or round and are comprised of a monotonous population of small cells with scant cytoplasm and round nuclei. Microfollicles, with or without colloid, are commonly observed within the solid growth. Variable numbers of mitotic figures are present, and blood vessel invasion is common. Small foci of necrosis are frequently located in the center of insulae. Large areas of necrosis sometimes spare tumor cells surrounding blood vessels, giving a peritheliomatous appearance.2, 8

This tumor is infrequently reported (particularly in the U. S.), but the low frequency may be misleading because the tumor may currently be inappropriately classified as poorly differentiated thyroid carcinoma, moderately differentiated, or less well differentiated follicular or papillary thyroid carcinoma.10 Other pathologists have described it as follicular or papillary carcinoma with solid growth pattern11 or have included insular tumors with anaplastic thyroid tumors.12, 13 Most of the cases were described in adults, although some authors described their patients' ages as between 17 and 70 years14 or 15 and 78 years11; thus, the tumor does occur in teenagers. Insular carcinomas are more frequent in females than males (the ratio is at least 2:1),2, 6, 15 similar to the ratio for thyroid carcinoma in general.

The patients in the current study presented with neck masses and euthyroidism, as have most patients.2, 11, 14, 16 Postoperatively, these two patients had increased serum thyroglobulin levels and their tumors concentrated 131I. These characteristics are found in both insular and well differentiated thyroid carcinoma but are almost never observed in anaplastic thyroid carcinoma.12, 16 Few authors have defined the cytologic characteristics of insular carcinoma.6, 15, 17 Some features, such as high cellularity with loose cells and scanty, poorly defined cytoplasm, were found in the patients in the current study. Other features include mild atypia, microfollicles, nuclear inclusions and grooving, and cytoplasmic thyroglobulin positive vacuoles. Blood vessel invasion and lymph node involvement at presentation (the latter found in both of the study patients) have been frequently described in these tumors.2, 14

The insular pattern appears to reflect a worse prognosis than the relatively good prognosis of most thyroid carcinomas in children. Poorly differentiated variants of papillary or follicular carcinoma, including those with solid, trabecular, or scirrhous patterns, have been associated in Japan with a reduction in survival rate (65% in patients with poorly differentiated carcinoma at 5 years and 95.1% in patients with well differentiated carcinoma at 5 years).10 Most investigators have demonstrated a worse prognosis, or more aggressiveness in regard to recurrence or tumor-related deaths, in insular tumors than in papillary or follicular tumors.2, 5-7, 14-16 It has been suggested that the presence or absence of a well differentiated component has no appreciable effect on clinical behavior and outcome.2 However, Papotti et al.16 showed that a predominant insular pattern in poorly differentiated thyroid carcinoma significantly increased the risk of recurrence compared with the risk when such a pattern was not present, or when the insular pattern was minimal. By contrast, Ashfaq et al.11 found no difference in the rate of regional or distant spread of these tumors between patients with a minor and those with a predominant insular component. However, they found a 15% mortality rate in patients with insular carcinoma during a mean follow-up of < 5 years. This is higher than the 5-year mortality rate associated with well differentiated thyroid carcinoma shown by others.10

Both of the patients in the current report showed early evidence of regional (lymph node) metastasis. In Case 2, distant recurrence also developed, and the patient died as a consequence of metastatic disease in the lung and brain. Tumors from both patients demonstrated a DNA diploid pattern on flow cytometry, as have most of the studied insular carcinomas; this finding reemphasizes that DNA aneuploidy is not necessarily present in aggressive thyroid carcinoma.11

The authors conclude that insular thyroid carcinoma may occur in children. It may cause cancer-related death, as it does in adults, even when it presents with a DNA diploid pattern. Because of the aggressive nature of the tumor, the authors believe that initial management, at any age, should include at least near-total thyroidectomy with appropriate lymph node dissection, followed by remnant ablation and radioiodine therapy for iodophilic metastases.

Ancillary