| disease | Stony Goiter (Thyroid Carcinoma) |
Stony goiter (thyroid carcinoma) accounts for approximately 1% of all cancers. In regions endemic for nodular goiter, the incidence of stony goiter (thyroid carcinoma), especially poorly differentiated stony goiter (thyroid carcinoma), is notably high. Age-adjusted incidence rates show fewer than 3 cases per 100,000 males annually, while the rate is 2–3 times higher in females. The age distribution varies among different types of stony goiter (thyroid carcinoma). Papillary adenocarcinoma has the broadest distribution, occurring in individuals from children under 10 years old to centenarians. Follicular carcinoma is most common between 20 and 100 years of age, medullary carcinoma predominantly occurs between 40 and 80 years, and undifferentiated carcinoma is most frequently seen between 40 and 90 years.
bubble_chart Epidemiology
Among malignant thyroid tumors, adenocarcinomas account for the vast majority, while malignancies originating from the thyroid stroma make up only 1%. Stony goiter (thyroid carcinoma) constitutes approximately 1.5% of all systemic cancers and 2.7% to 17.0% of all thyroid tumors. According to statistics from the International Cancer Society, the incidence of stony goiter (thyroid carcinoma) has been increasing year by year in various countries. In Shanghai, China, the incidence rate was 1.02 per 100,000 in 1960, 2.39 per 100,000 in 1972, and had risen to 3.80 per 100,000 by 1978. Data from Zhongshan and Huashan Hospitals affiliated with Shanghai Medical University show that between 1975 and 1985, the two hospitals treated a total of 6,432 cases of thyroid diseases, including 4,363 cases of thyroid tumors, with stony goiter (thyroid carcinoma) accounting for 435 cases, or 10.1% of all thyroid tumors.
Stony goiter (thyroid carcinoma) occurs more frequently in women, with a male-to-female ratio of 1:2.58. In terms of age, it can occur from childhood to old age, but unlike most cancers that predominantly affect the elderly, stony goiter (thyroid carcinoma) is more common in young and middle-aged adults, with an average onset age of around 40 years.The exact and specific cause of the disease is still difficult to confirm, but epidemiological surveys, experimental tumor research, and clinical observations suggest that the occurrence of stony goiter (thyroid carcinoma) may be related to the following factors.
(1) Radioactive injury: Irradiating the thyroid glands of experimental mice with X-rays can induce stony goiter (thyroid carcinoma) in the animals. Experiments have shown that 131I can alter the metabolism of thyroid cells, deform the cell nuclei, and significantly reduce the synthesis of thyroxine. It is evident that radiation, on one hand, causes abnormal division of thyroid cells, leading to carcinogenesis; on the other hand, it damages the thyroid, preventing it from producing endocrine hormones. The resulting massive secretion of thyroid-stimulating hormone (TSH) can also promote the carcinogenesis of thyroid cells.
Clinically, many facts indicate that the occurrence of thyroid carcinoma is related to the effects of radiation. Particularly noteworthy is that children who received radiation therapy to the upper mediastinum or neck during infancy or early childhood due to thymic enlargement or lymphoid hyperplasia are especially prone to developing stony goiter (thyroid carcinoma). This is because the cells of children and adolescents proliferate vigorously, and radiation acts as an additional stimulus, easily promoting tumor formation. In contrast, adults who receive neck radiation therapy rarely develop stony goiter (thyroid carcinoma).
(3) Other thyroid pathologies: There are clinical reports of thyroid adenocarcinomas, chronic thyroiditis, nodular goiter, or certain toxic goiters undergoing malignant transformation. However, the relationship between these thyroid pathologies and stony goiter (thyroid carcinoma) remains difficult to confirm. Taking thyroid adenoma as an example, the vast majority of thyroid adenomas are follicular, with only 2–5% being papillary. If stony goiter (thyroid carcinoma) were derived from adenomas, the majority should be follicular. In reality, however, over half of stony goiter (thyroid carcinoma) cases are papillary carcinoma, suggesting that the incidence of malignant transformation in thyroid adenomas is very low.
(4) Genetic factors: Approximately 5–10% of medullary thyroid carcinomas have a clear family history and are often associated with pheochromocytoma and other conditions. It is speculated that the occurrence of such cancers may be related to chromosomal genetic factors.
(1) Papillary adenocarcinoma is the most common type of stony goiter (thyroid carcinoma), accounting for about 70%. It varies in size and is generally well-differentiated with low malignancy. The cancerous tissue is brittle, soft, and easily fragmented, appearing dark red; however, in elderly patients, papillary carcinoma is usually firmer and paler. The center of papillary carcinoma often undergoes cystic changes, filled with bloody fluid. Sometimes, the cancerous tissue may calcify, presenting a gritty texture on cross-section. These cystic changes and calcifications are unrelated to the malignancy and prognosis of the tumor. Microscopically, the carcinoma consists of columnar epithelial papillary projections, sometimes mixed with follicular-like structures, and even transitions from papillary to follicular patterns may be observed.
Papillary adenocarcinoma has a complete capsule, but in the late stage [third stage], it can also penetrate the capsule and invade surrounding tissues. The primary route of spread is lymphatic, with cervical lymph node metastasis being the most common. Approximately 80% of children and 2% of adult patients may present with palpable lymph nodes. Hematogenous spread to the lungs or bones is less frequent.
(2) Follicular adenocarcinoma is less common than papillary adenocarcinoma, accounting for about 20% of stony goiter (thyroid carcinoma), ranking second. The average age of patients with this type is higher than that of papillary carcinoma. The tumor is soft, elastic, or rubbery, appearing round, oval, or lobulated. The cross-section shows a reddish-brown color with areas of fibrosis, calcification, hemorrhage, and necrosis. Well-differentiated follicular adenocarcinoma microscopically resembles normal thyroid tissue but exhibits invasion of the capsule, blood vessels, and lymphatic vessels. Poorly differentiated follicular adenocarcinoma displays irregular structures, with densely packed cells forming clusters or cords, rarely forming follicles. Although lymphatic metastasis can occur, the primary route of spread is hematogenous, typically to the lungs, bones, and liver. Some follicular adenocarcinomas may recur long after surgical resection, but their prognosis is worse than that of papillary adenocarcinoma.
(3) Medullary thyroid carcinoma accounts for 2–5% of stony goiter (thyroid carcinoma). This disease was first described by Hazard in 1959 and is characterized by the secretion of thyroid calcitonin and association with pheochromocytoma and thyroid hyperplasia (multiple endocrine neoplasia type II, MEN II). Medullary carcinoma originates from the ultimobranchial body of the thyroid embryo, derived from parafollicular clear cells (C cells). Parafollicular cells are endocrine cells derived from the neural crest, which share the common function of uptaking precursors such as serotonin and dopamine and decarboxylating them via decarboxylase enzymes, hence also called amine precursor uptake and decarboxylation (APUD) cells. The tumor is usually a single nodule, occasionally multiple, firm and fixed, with amyloid deposits, and rarely takes up radioactive iodine. The cancer cells are primarily composed of polygonal and spindle-shaped cells, arranged in diverse patterns.
(4) Undifferentiated thyroid carcinoma accounts for 5% of stony goiter (thyroid carcinoma), primarily occurring in middle-aged and older patients, more commonly in males. The mass is hard, irregular, fixed, and grows rapidly, quickly diffusely involving the thyroid. It often infiltrates the trachea, muscles, nerves, and blood vessels within a short period, causing difficulty in swallowing and breathing. Local tenderness may be present. Microscopically, the cancerous tissue mainly consists of poorly differentiated epithelial cells with pleomorphic features and frequent mitotic figures. Cervical lymph node enlargement and lung metastases may occur. The prognosis is poor, with no response to radioactive iodine therapy, and external radiation only controls local symptoms.
bubble_chart Clinical Manifestations
Due to the various pathological types and biological characteristics of stony goiter (thyroid carcinoma), its clinical manifestations also differ. It can coexist with multiple thyroid nodules, often asymptomatic, and occasionally a nodule or mass is discovered in the anterior neck region. Some masses may have existed for years before rapidly enlarging or metastasizing recently. Some patients experience no discomfort for a long time, and only in the late stage [third stage] do symptoms such as cervical lymph node metastasis, pathological fracture, hoarseness, respiratory obstruction, dysphagia, or even Horner syndrome draw attention. Local signs also vary, presenting as asymmetric thyroid nodules or masses, which may be within the gland and move up and down with swallowing. When surrounding tissues or the trachea are invaded, the mass becomes fixed.
(1) Papillary carcinoma: This is a well-differentiated stony goiter (thyroid carcinoma) and the most common type, accounting for about 3/4 of all cases. The lesion is usually solitary and varies in size, with the smallest diameter below 0.5 cm, referred to as microcarcinoma; those under 1 cm are called occult carcinomas, while larger lesions can exceed 10 cm in diameter. Small tumors are often solid sexually transmitted disease foci, whereas larger tumors are frequently accompanied by cystic changes. In cystic cases, grape-like nodules may protrude into the cyst cavity, which contains old bloody fluid. This type of carcinoma generally lacks a membrane, with only 5% having an incomplete one. Microscopically, some tumor cells are arranged in papillary structures of varying sizes and lengths, often with three or more levels of branching. The center of the papillae consists of fibrovascular sacs, with uniformly sized cells; nuclei are small, and mitoses are rare. Papillary carcinoma often contains follicular carcinoma components, but the tumor is still named papillary carcinoma rather than follicular or mixed type. If papillary carcinoma includes undifferentiated carcinoma components, it should be classified as undifferentiated carcinoma, indicating that the undifferentiated carcinoma may represent further progression of papillary carcinoma. Sometimes the mass is very small, and cervical lymph node metastasis is often the first sign. This carcinoma has a low malignancy, with a 10-year survival rate of up to 88%. Clinically, papillary carcinoma often presents as a solitary nodule in the thyroid region, usually over 1 cm in diameter. Occult carcinomas are often discovered during autopsies or when cervical lymph node metastasis has already occurred.
(2) Follicular carcinoma: Accounts for 10–15% of all stony goiter (thyroid carcinoma) cases. Gross examination reveals follicular carcinoma as a solid tumor with a membrane, often densely covered with a rich vascular network. Smaller carcinomas resemble thyroid adenomas. The cut surface is reddish-brown, often showing fibrosis, calcification, hemorrhage, and necrosis. Histologically, it consists of follicles with varying degrees of differentiation. Well-differentiated cases have more typical follicular structures and less cellular atypia, making them difficult to distinguish from adenomas; pathological diagnosis relies on membrane or vascular invasion. Poorly differentiated cases have fewer follicular structures, greater cellular atypia, and more mitotic figures, sometimes forming cord-like or solid nest arrangements. Occasionally, cancer cells penetrate the membrane into multiple veins, forming tumor thrombi, which often become the starting point for distant metastasis. Thus, follicular carcinoma is more commonly associated with hematogenous metastasis, reported in 19–25% of cases. Follicular carcinoma is more common in middle-aged and elderly women aged 40–60. Its clinical presentation is similar to papillary carcinoma, but the tumor is generally larger, with fewer local lymph node metastases and more distant metastases. A few cases of follicular carcinoma infiltrate and destroy adjacent tissues, leading to symptoms such as respiratory obstruction.
(3) Medullary Thyroid Carcinoma First described by Horn in 1951 and further elucidated by Hazard et al. in 1959, this special type of cancer was named medullary carcinoma. It accounts for 3–10% of stony goiter (thyroid carcinoma) cases. The tumor is generally round or oval in shape, with clear boundaries, firm or irregular, often accompanied by infiltration of the surrounding thyroid parenchyma. The cut surface appears gray-white or pale red and may exhibit hemorrhage, necrosis, and calcification. The average tumor diameter is approximately 2–3 cm. Microscopically, the cancer cells are oval, polygonal, or spindle-shaped, with few to moderate mitotic figures. The cells are arranged in nests, bands, or glandular patterns. The stroma contains varying amounts of amyloid; when cancer cells are abundant, amyloid is relatively sparse, and vice versa—a pattern also observed in metastatic lesions. Medullary thyroid carcinoma is a grade II malignant tumor that can occur at any age, with no significant difference in incidence between males and females. Most cases are sporadic, while about 10% are familial. Clinically, in addition to the common symptoms of stony goiter (thyroid carcinoma), such as thyroid masses and cervical lymph node metastasis, it presents unique manifestations. Approximately 30% of patients have a history of chronic diarrhea accompanied by facial flushing resembling carcinoid syndrome or Cushing’s metabolic syndrome, which are related to tumor cell products.
The characteristics of familial medullary carcinoma are as follows:
① The age of onset is relatively young, with an average age of 33 at diagnosis, while the average age at diagnosis for sporadic medullary carcinoma is over 55.
② It is invariably bilateral and multicentric, with asymmetric tumor distribution and morphology. One side may have a large mass while the other shows only histological signs, but bilateral involvement is always present. Sporadic cases are mostly unilateral.
③ Familial medullary carcinoma tumors are smaller, and some are discovered incidentally through screening. Sporadic tumors often exceed 4 cm in diameter.
④ Lymph node metastasis is less common in familial cases, and distant metastasis is even rarer, likely due to earlier detection.
⑤ Familial medullary carcinoma is often located where parafollicular cells are concentrated, at the junction of the upper and middle thirds of the thyroid lobe.
⑥ Familial medullary carcinoma is frequently associated with pheochromocytoma or hyperparathyroidism.
(4) Anaplastic thyroid carcinoma: This is a highly malignant and relatively rare tumor, accounting for about 5–10% of all thyroid carcinomas. It predominantly occurs in the elderly. Anaplastic carcinoma grows rapidly and often invades surrounding tissues early. Grossly, the tumor lacks a capsule, and the cut surface appears fleshy, pale, with areas of hemorrhage and necrosis. Histologically, anaplastic carcinoma can be divided into spindle cell and small cell types. The main clinical manifestation is a hard, fixed, poorly defined mass in the anterior neck region, often accompanied by dysphagia, respiratory distress, hoarseness, and neck pain. Enlarged lymph nodes in the neck are common, and hematogenous metastasis is also frequently observed.
The diagnosis of stony goiter (thyroid carcinoma) is most valuable when made early. Any solitary thyroid nodule found clinically should be evaluated to rule out the possibility of stony goiter (thyroid carcinoma). If the nodule is hard and irregular, accompanied by cervical lymphadenopathy, recurrent laryngeal nerve paralysis, or a history of neck irradiation, the likelihood of malignancy is high. Similarly, if one nodule stands out as particularly prominent and hard among multiple thyroid nodules, stony goiter (thyroid carcinoma) should also be suspected. Additionally, if the thyroid itself shows asymmetric enlargement or hard nodules, with rapid growth or fixation, the possibility of stony goiter (thyroid carcinoma) should be considered.
During diagnosis, over-reliance on surface irregularity and hardness as characteristic features of stony goiter (thyroid carcinoma) should be avoided. Some stony goiter (thyroid carcinoma) masses can be quite soft, smooth, and mobile, which is not uncommon in papillary adenocarcinoma. Antagonism, heavily calcified stony goiter (thyroid carcinoma) tumors, nodular goiter, and sclerosing thyroiditis may also feel hard and granular, leading to misdiagnosis as stony goiter (thyroid carcinoma). Assuming that all cystic changes in thyroid nodules are benign is clearly incomplete. Reports indicate a malignant transformation rate of 1.4% in cystic lesions, and the cystic degeneration rate of stony goiter (thyroid carcinoma) also increases with nodule growth.
131I or 99mTc thyroid scans can only reflect the morphology and isotope uptake function of nodules but cannot determine their nature. However, clinical data suggest that in scan images of hot, warm, cool, and cold nodules, the likelihood of stony goiter (thyroid carcinoma) increases progressively. Scans can detect nodules larger than 0.5 cm. If a nodule loses its isotope uptake function, stony goiter (thyroid carcinoma) should be considered (after excluding the presence of cysts via ultrasound). However, not all stony goiter (thyroid carcinoma) cases present as cold nodules. Additionally, defects in isotope distribution are related to tumor size, and sometimes images of functionally impaired tumors may be obscured by normal thyroid tissue. A few stony goiter (thyroid carcinoma) cases may appear as hot nodules.
If the above examinations are inconclusive, fine-needle aspiration cytology can be performed, preferably one day before surgery, as it has a high diagnostic accuracy rate. In 10% of cases, further cytological classification cannot be made, and surgical exploration with histological examination is still required.
For medullary thyroid carcinoma, serum calcitonin measurement and calcium or pentagastrin stimulation tests can aid in diagnosis.
In some cases, stony goiter (thyroid carcinoma) may be highly malignant, first manifesting as metastatic cancer in enlarged cervical lymph nodes, while the primary stony goiter (thyroid carcinoma) remains unnoticed by the patient. Generally, a solitary thyroid nodule is more likely to be malignant than multiple nodules or nodular goiter. Patients with the following manifestations should be alert to the possibility of cancerous nodules:
① In non-endemic goiter regions, a solitary thyroid nodule in children under 14 years old has a 10–50% chance of being malignant, though these are usually well-differentiated stony goiter (thyroid carcinoma).
② A solitary thyroid nodule in adult males.
③ A long-standing thyroid nodule that shows significant enlargement in a short period.
④ Patients living in coastal areas have a much higher chance of a solitary nodule being malignant compared to those from endemic goiter regions.
⑤ Patients who underwent head and neck radiation therapy in childhood are more suspicious of having a malignant solitary thyroid nodule.
⑥ Physical examination reveals a hard, fixed, irregular nodule or ipsilateral cervical lymphadenopathy, with vocal cord paralysis.
⑦ Neck X-rays show cloudy or granular calcifications within the thyroid, with irregular borders. Tracheal stenosis caused by stony goiter (thyroid carcinoma) often maintains normal anteroposterior and transverse diameters.
⑧ B-ultrasound shows solid or mixed solid-cystic lesions with heterogeneous internal echoes, unclear and irregular borders.
⑨ Tumor cells are found on aspiration cytology. For cystic lesions, the aspirated fluid may gradually turn dark red, which is a characteristic feature of metastatic papillary thyroid carcinoma.
bubble_chart Treatment Measures
(I) Surgical Treatment Surgical treatment mainly involves two issues: first, how to correctly handle thyroid nodules suspected to be cancerous? Second, what is the optimal treatment plan for confirmed stony goiter (thyroid carcinoma)?
1. Management of nodules suspected to be stony goiter (thyroid carcinoma): A more reasonable approach is to conduct screening, with routine 131Ⅰ scans for all thyroid nodules. Except for nodules identified as functional or inflammatory by 131Ⅰ scans, surgical exploration is generally performed. Early surgical intervention is particularly recommended under the following circumstances:
① Nodules that cannot be ruled out as cancerous.
② Cystic nodules larger than 3–5 cm in diameter, or those with cancerous cells found in puncture examinations, or nodules that persist after 2–3 punctures.
③ Solid masses identified by ultrasound. For the choice of surgical approach for solitary nodules, due to the high incidence of cancer in such nodules (5–35%), and the lack of reliable diagnostic methods—even intraoperative frozen section examinations may occasionally miss fistula disease—and the high postoperative recurrence rate (up to 16.7%) after simple nodule excision, our standard practice is to perform resection of the affected lobe plus isthmusectomy for solitary solid nodules, mixed solid-cystic nodules, or cystic nodules >4 cm. If no lymph node enlargement is detected during surgery, neck dissection is not performed.
2. The treatment protocol for confirmed stony goiter (thyroid carcinoma) depends on the patient's constitution, the pathological type of the cancer, and the clinical stage.
(1) Papillary carcinoma: Clinically characterized by low malignancy, high rates of cervical lymph node metastasis, and prevalence among young and middle-aged women, surgical treatment must consider these factors. If the cancer is confined to one lobe, the affected lobe and isthmus are completely removed, along with partial resection of the contralateral lobe during seasonal epidemics. However, if the cancer has invaded both lobes, total thyroidectomy including the isthmus is required. The 5-year cure rate post-surgery exceeds 80%. Clinical practice has shown that prophylactic neck dissection does not improve cure rates for papillary carcinoma without cervical lymph node metastasis. However, postoperative follow-up is crucial. For patients in remote mountainous or rural areas with limited follow-up options, individualized management is necessary. For patients with enlarged lymph nodes, a combined radical surgery for stony goiter (thyroid carcinoma) including neck dissection is universally recommended.
(2) Follicular carcinoma: Although a low-grade malignant stony goiter (thyroid carcinoma), it primarily metastasizes via the bloodstream, with lymph node metastasis accounting for about 20%. Prophylactic neck dissection is generally not performed in the absence of clinically enlarged lymph nodes. However, therapeutic neck dissection is necessary for confirmed lymph node metastasis, as it does not necessarily indicate concurrent bloodstream metastasis.
(3) Medullary carcinoma: Moderately malignant, often metastasizing via lymphatic and bloodstream routes. Once cervical lymph node metastasis occurs, it can rapidly infiltrate beyond the membrane and involve surrounding tissues. Therefore, selective neck dissection is performed regardless of whether enlarged lymph nodes are clinically palpable. For patients with pheochromocytoma, the pheochromocytoma must be addressed before thyroid surgery to avoid intraoperative hypertension and surgical complications.
(4) Anaplastic carcinoma: Due to its short course, rapid progression, and poor prognosis, most cases are ineligible for radical surgery at initial diagnosis. Surgery is generally not recommended, except for biopsy to confirm diagnosis. However, for rare cases with smaller, operable lesions, radical surgery should be actively pursued.
(II) Chemotherapy Differentiated stony goiter (thyroid carcinoma) responds poorly to chemotherapy and is only selectively combined with other treatment methods for some advanced-stage patients with locally unresectable tumors or distant metastases. Doxorubicin is the most effective, with a response rate of 30–45%, which can prolong life and even lead to long-term survival without tumor shrinkage. In contrast, undifferentiated carcinoma is more sensitive to chemotherapy, often treated with combination chemotherapy. Commonly used drugs include doxorubicin (ADM), cyclophosphamide (CTX), mitomycin (MMC), and vincristine (VCR). For example, the COA regimen consists of CTX 0.8 d1, VCR 1.4 mg/m² d1d8, and ADM 30–40 mg/m² d1, administered every 21 days per cycle.
(3) Endocrine Therapy Thyroid hormone can inhibit TSH secretion, thereby suppressing the proliferation of thyroid tissue and well-differentiated cancers. It has a good therapeutic effect on papillary and follicular carcinomas. Therefore, after surgery for these types of stony goiter (thyroid carcinoma), a TSH-suppressive dose of thyroid hormone is routinely administered, which has some effect in preventing cancer recurrence and treating metastatic lesions. However, it is ineffective for undifferentiated carcinoma. In China, dried thyroid tablets are generally used at a daily dose of 80–120 mg to maintain high levels of thyroid hormones.
(4) Radiotherapy The sensitivity of various types of stony goiter (thyroid carcinoma) to radiation varies greatly and is almost directly proportional to the degree of differentiation of the stony goiter (thyroid carcinoma). The better the differentiation, the lower the sensitivity, and the poorer the differentiation, the higher the sensitivity. Therefore, radiotherapy is the primary treatment for undifferentiated carcinoma. Stony goiter (thyroid carcinoma) has a certain ability to take up iodine.
In malignant tumors, the prognosis of stony goiter (thyroid carcinoma) is generally good. Many cases of stony goiter (thyroid carcinoma) with metastasis still allow patients to survive for more than a decade. Numerous factors influence the prognosis, such as age, gender, pathological type, extent of the lesion, metastasis status, and surgical approach, among which pathological type is the most critical. Patients with well-differentiated stony goiter (thyroid carcinoma) have a 95% chance of long-term survival, especially papillary adenocarcinoma, which tends to have favorable biological characteristics and the best prognosis. However, a small number may dedifferentiate into highly malignant undifferentiated carcinoma. Undifferentiated carcinoma has the worst prognosis, often leading to patient death within six months. Larger tumor volumes increase the likelihood of infiltration and worsen the prognosis. According to relevant statistical data, the presence or absence of lymph node metastasis does not significantly affect patient survival rates. Failure to control the primary tumor or local recurrence can increase mortality, and the extent of direct tumor spread or infiltration is more significant than lymph node metastasis.
