Malignant teratoid tumor of the thyroid gland: an aggressive primitive multiphenotypic malignancy showing organotypical elements and frequent DICER1 alterations-is the term "thyroblastoma" more appropriate?

Abstract

Primary thyroid teratomas are exceedingly rare. Mature and immature variants recapitulate their gonadal counterparts (predilection for infants/children, triphasic germ layer differentiation, and favorable outcome). On the other hand, the so-called malignant teratomas affect predominantly adults and elderly, are highly aggressive, and, according to a few published cases, harbor DICER1 mutations. We describe three highly aggressive sporadic malignant teratoid thyroid tumors in 2 females (17 and 45 years) and one male (17 years). Histology showed triphasic neoplasms composed of solid nests of small primitive monomorphic cells embedded in a cellular stroma with primitive immature rhabdomyosarcoma-like (2) or pleomorphic sarcoma-like (1) phenotype. The third component was represented by TTF1+/PAX8+ primitive teratoid epithelial tubules reminiscent of primitive thyroid follicles and/or Wilms tumor, admixed with scattered respiratory- or enteric-type tubules, neuroepithelial rosettes, and fetal-type squamoid nests. Foci of cartilage were seen in two cases, but none contained mature organoid adult-type tissue or skin adnexa. SALL4 was expressed in the small cell (2) and stromal (1) component. Other germ cell markers were negative. Molecular testing revealed a known "hotspot" pathogenic DICER1 mutation in two cases. In addition, case 1 had a missense TP53 variant. This type of thyroid malignancy is distinct from genuine teratomas. The immunoprofile suggests primitive thyroid- or branchial cleft-like differentiation. Given that "blastoma" is a well-accepted terminology in the spectrum of DICER1-associated malignancies, the term "thyroblastoma" might be more convenient for these malignant teratoid tumors of the thyroid gland. Relationship of thyroblastoma to the DICER1 syndrome remains to be addressed.

Keywords: DICER1; Germ cell tumor; Head and neck; Malignant teratoma; Rhabdomyosarcoma; Teratocarcinosarcoma; Thyroblastoma; Thyroid.

Fig. 1

Representative images of case 1. a Highly infiltrative growth amid thyroid tissue. Most areas show biphasic growth with cohesive basophilic large columnar cells surrounded by cellular mesenchymal-type stroma (b; higher magnification of spindled stroma in c). d _Primitive intestinal-type and respiratory-type tubules are seen, focally encased by primitive small cell stroma. e Tubules and clear cell squamoid nests are surrounded by neuroepithelial-type matrix. The stromal component strongly expressed desmin (f) and myogenin (g). SALL4 was limited to the cohesive epithelial-like component (h)

Fig. 2

Representative images of case 2. a Macroscopic aspect of the tumor. b HE, nested pattern with necrosis and rich stromal component. c HE, small cell component with apoptotic and mitotic figures. d HE, chondroid matrix and cellular stroma. e HE, small cell (top) and epitelial tubular component (bottom). f SALL4 in the small cell component. g Desmin in the stromal component. h p63 in the epitelial component

Fig. 3

Representative images of case 3. a Biphasic (right) and epithelial/tubule-predominant areas were seen juxtaposed in this area, note centrally located cartilage island. b The epithelial component was composed of primitive tubules lined by basophilic columnar cells admixed with glomeruloid papillary structures. c Highly cellular sarcomatoid stroma with scattered intestinal-type tubule and glomeruloid structures are seen. d In some areas, fetal-type tubules lined by clear cells are evident. Expression of PAX8 (e) and TTF1 (f) is predominantly mutually exclusive. Primitive small cell stroma shows variable expression of TTF1 as well (g). Otherwise, the stroma was focally desmin-positive (h) and diffusely SALL4 positive (i), note that tubules inconsistently expressed SALL4 in i