Although the cause of thyroid angiosarcoma is considered to be multifactorial, its incidence is higher in countries where there is a dietary iodine deficiency—particularly the Alpine countries of central Europe.²,³ Interestingly, iodized salt prophylaxis in the mountain areas of Austria where there was previously iodine deficiency resulted in a decrease in the prevalence of angiosarcoma from 3% of all thyroid gland cancers⁴ in 1957-1975 to 0.7% in 1986-1995. Even so, these tumors are also reported in many countries where the intake of dietary iodine is adequate.¹,⁵,⁶,⁷,⁸ Significant occupational exposure to industrial vinyl chloride and other polymeric materials may also be contributory.³

An endothelial origin seems to have been confirmed, although the possibility of an undifferentiated stem cell with both epithelial and endothelial differentiation has not been entirely ruled out.²,⁹

Thyroid angiosarcomas account for <2% of all thyroid gland malignancies, although there is geographic variability, as discussed above. Women are affected much more frequently than men (4:1). Most cases arise in the seventh decade of life. Patients present with a painless mass that has often developed in the setting of long-standing goiter; other symptoms include dyspnea, asthenia, and weight loss.²,⁵,⁷,⁸,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷ Occasionally, a rapidly growing mass is noted with pressure symptoms.¹,⁶,¹¹,¹² Hyperthyroidism is rare, with some authors suggesting that the angiosarcoma has a trophic effect on the follicular epithelium.¹⁸ Scintigraphic studies usually show a “cold” nodule,² although ultrasound and CT studies can also be used to evaluate the nodule, showing a vascular tumor with irregular Doppler flow.¹²

An angiomatous pattern can be seen in undifferentiated carcinoma,²,⁹,¹⁵,²¹,²³,²⁶ but there is often a greater degree of pleomorphism and significantly more giant tumor cells. Immunostains for endothelial markers confirm the diagnosis. Adenomatoid nodules with degenerative or retrogressive changes may contain areas of vascular proliferation. Organization of clot within a nodule can yield a mass lesion.¹⁵ In the post-fine-needle aspiration (FNA) setting, a Masson papillary endothelial hyperplasia type of reaction may be seen; sometimes, it is quite florid. However, a well-defined area of involvement, a finding of involvement within a vessel or nodule, a lack of cytologic atypia, and a lack of freely anastomosing vessels help make the distinction.¹⁵,²⁷ Metastatic tumors (renal cell carcinoma and angiosarcoma²⁵) and direct invasion into the thyroid gland from a soft-tissue primary should be separable based on clinical, radiographic, and histologic findings and immunophenotypic studies.²⁸

Combination adjuvant therapy (particularly rapid radiation) and surgical eradication may not alter the prognosis, as most patients

die of their tumors in <6 months, frequently from massive hemorrhage.²,³,⁵,⁷,¹¹,¹²,¹⁴,¹⁸,²⁰ Razoxane may benefit patients as a radiation sensitizer.³,⁸,¹⁶ In rare cases, a patient will survive beyond 5 years. Tumors confined to the thyroid gland seem to behave less aggressively than do tumors that spread extrathyroidally.³,⁷,⁸,¹⁶ Distant metastases (lung, gastrointestinal tract [Fig. 16.6], and bone) may cause fatal bleeding.¹,²,³,²⁰,²⁴,²⁸,²⁹ Fibrinogen, factor VIII, and FVIII-RA in the serum may be used as surrogate markers during follow-up.¹⁶

Teratomas include tissues from all three primordial layers (ectoderm, mesoderm, and endoderm). They are believed to arise from misplaced embryonic germ cells (rests) in the thyroid gland that continue to develop in the new location.³⁰

Teratomas represent <0.1% of all primary thyroid gland neoplasms. The age range of affected patients at the initial presentation extends from newborns to 85 years, but the average age is <10 years. This average is skewed by the number of older patients
with malignant teratomas; the median age at presentation is <1 month.³⁰,³¹,³³,³⁴,³⁵,³⁶,³⁷ When neonates and infants are considered apart from children and adults, two distinct biologic groups appear: >90% of the tumors in the neonatal group are benign and >50% of tumors in the older group are malignant. There is no predilection for either sex.³⁰ All patients present with a neck mass that often reaches a significant size. In addition, patients experience dyspnea, difficulty breathing, and/or stridor. Other congenital anomalies may be present in neonatal patients. Ultrasonographic images (in utero, at the time of birth, or later) provide the best information and are easiest to obtain. The most common finding is a multicystic mass lesion of the thyroid gland. CT demonstrates an inhomogeneous mass arising in the thyroid gland and compressing the upper airway for both benign and malignant teratomas (Fig. 16.7).³⁰,³⁸,³⁹,⁴⁰,⁴¹,⁴²

The clinical differential diagnosis, especially in neonates, includes lymphangioma, thyroglossal duct cyst, and branchial cleft cyst.

Histologically, teratomas should be separated from dermoids (which only contain skin elements), extraskeletal Ewing sarcoma, rhabdomyosarcoma, small-cell carcinoma, lymphoma, and melanoma.⁵¹ The diagnosis of teratoma under these circumstances is largely dependent on the identification of other tissue elements and a confirmatory immunohistochemical panel.³⁰,³¹,⁴¹,⁴⁵,⁵¹

The outcome for patients with thyroid teratomas depends on the patient’s age, the size of the tumor at the time of presentation, and the presence and proportion of immaturity. The age at presentation and tumor histology are strongly correlated. In neonates and infants, there is a preponderance of immature teratomas (grade 1 or 2 immaturity) and a near-absence of malignant tumors. Conversely, among children and adults, there is a preponderance of malignant teratomas (grade 3 immaturity). No patient with a grade 0, 1, or 2 tumor (benign mature or benign immature) dies of disease, although some die with disease; when death does occur in such cases, it is generally a direct result of significant morbidity secondary to tracheal compression or a lack of development of vital structures in the neck during
fetal growth. Therefore, surgery for benign thyroid teratomas should be instituted without delay because preoperative morbidity (mass effect) and mortality are significant.³⁰,⁴⁸ Malignant teratomas exhibit a clinically malignant behavior, thus emphasizing the importance of identifying their morphology and distinguishing them from the benign mature and benign immature types of teratoma.³⁰,⁵² Malignant teratomas may invade by direct extension into the esophagus, trachea, salivary glands, and/or the soft tissues of the neck. Recurrence and dissemination (usually in the lungs) are known to occur in about one-third of these patients; most of these cases are fatal. These patients are managed with radiation and chemotherapy, although treatment is palliative.³⁰,³¹,³⁵,³⁸,³⁹,⁴⁰,⁴¹,⁴³,⁴⁴,⁴⁵,⁴⁶ Staging does not apply to malignant teratomas.

There is no known etiology for smooth muscle tumors of the thyroid gland, specifically including radiation exposure.⁵⁴ A single case of an EBV-associated thyroid smooth muscle tumor has been reported in a child with a congenital immunodeficiency disease.⁵⁵ No specific thyroid topographic location is seen in smooth muscle tumors, although association with smooth muscle-walled vessels at the periphery of the gland (thyroid gland capsule) has been shown (Fig. 16.15).⁵⁴

Although not experimentally proven, the histogenesis of thyroid smooth muscle tumors occurs in the thyroid vessels—that is, the smooth muscle in the vascular walls (Fig. 16.15). Smooth muscle tumors are classified into cutaneous and subcutaneous, deep soft tissue, and vascular origins; the latter is the favored histogenesis for thyroid gland primaries.⁵³,⁵⁴,⁵⁶

Primary smooth muscle tumors of the thyroid gland are exceedingly rare, representing <0.02% of all thyroid gland tumors.⁵⁴,⁵⁵,⁵⁶,⁵⁷,⁵⁸,⁵⁹,⁶⁰,⁶¹,⁶²,⁶³,⁶⁴,⁶⁵,⁶⁶ According to reports, no patient with a leiomyoma has died of disease, but almost all patients with a leiomyosarcoma in whom follow-up was available did die from their disease.⁵⁶,⁶⁰,⁶¹,⁶³,⁶⁴,⁶⁵,⁶⁶,⁶⁷,⁶⁸
Unlike their benign counterparts, primary thyroid leiomyosarcomas tend to occur in older patients. In view of the limited number of cases, no predilection for either sex has been established.

Patients present with nonspecific signs and symptoms. A thyroid mass, usually increasing in size (leiomyosarcoma cases), is associated with dyspnea, difficulty breathing, and/or stridor. The duration of symptoms ranges from days to years, depending on the extent of the tumor. Thyroid scans with radioactive isotopes demonstrate a cold nodule. CT reveals an inhomogeneous low-density mass in the thyroid gland; the signal intensity is similar to that of the surrounding soft tissue. Compression of the upper airway, infiltration into the soft tissues or destruction of the thyroid gland, and necrosis suggest a malignant process, but these signs are not specific for a leiomyosarcoma. In general, lymphadenopathy is absent. Ultrasonographic examination does not yield a specific diagnosis, although an ill-defined hypoechoic mass without halo has been reported.⁵⁴,⁶⁵