Anaplastic/Undifferentiated Carcinoma of the Thyroid gland
– Pleomorphic spindle and giant cells invade the normal thyroid gland, capsule, and extrathyroidal extension into adjacent adipose tissue (brown arrow). The parathyroid gland appears free from the tumor.
– A mixture of various cell types – pleomorphic spindle cells, epithelioid/rhabdoid-like cells (yellow square), and pleomorphic tumor giant cells are seen.
– Pleomorphic tumor giant cells show large, hyperchromatic, and bizarre nuclei with abundant amphophilic or eosinophilic cytoplasm
– Spindle cell areas show the fascicular arrangement of cells with dense sclerotic and colalgenised stroma (black arrow), in which the entrapment of markedly pleomorphic malignant cells mimics spindle cell sarcoma or sarcomatoid squamous carcinoma.
– Epithelioid/rhabdoid-like areas (yellow square) show large polygonal cells with vesicular nuclei, prominent nucleoli, and abundant cytoplasm.
– Few thyroid follicles of residual differentiated carcinoma are seen (red arrow).
– Frequent and abnormal mitoses (black circle), areas of necrosis (blue arrow) and hemorrhage are seen.
– Chronic inflammatory cells (green arrow) are seen at the interface of undifferentiated carcinoma and differentiated thyroid structures.-
– One blood vessel shows thrombosis and obliteration (orange arrow) without tumor cell invasion.
– A few stag-horn pattern of hemangiopericytomatous blood vessels is also seen (purple arrow). Occasional area shows extravasated red blood cells (white arrow).
– Osteoclastic-like giant cells are not seen in this example.
Practical points of Pathoclinics:
- Anaplastic carcinoma (undifferentiated or dedifferentiated) of thyroid is an uncommon (approximately 2% of all primary malignant thyroid tumors) and highly aggressive thyroid malignancy.
- It is commonly seen in the old age group with a slight female predominance.
- Clinically presents with a rapidly growing firm to hard mass with compression symptoms due to extensive local invasion.
- It is commonly associated with a long history of goiter, iodine deficiency, and a history of radiation exposure. It is also associated with other differentiated thyroid carcinomas, especially papillary thyroid carcinoma.
- On histology, the most common morphologic appearance of anaplastic carcinomas is biphasic spindle and giant cell-rich areas. Anaplastic carcinomas commonly replace the entire thyroid tissue and infiltrate into adjacent adipose tissue, skeletal muscle, larynx, trachea, esophagus, lymph nodes, and vascular and neural tissue. Frequent blood vessel invasion and thrombosis are seen. Numerous atypical mitotic figures, necrosis with inflammatory infiltrates are common. Anaplastic carcinomas can show undifferentiated large malignant cells that mimic large cell carcinoma. Osteoclast-like giant cells-rich areas can be seen. It is uncommon to have neoplastic bone and cartilage (carcinosarcoma) areas. Anaplastic carcinoma can show squamous morphology with desmoplastic stroma and dense eosinophilic cytoplasm. Anastomosing blood vessels and hemangiopericytomatous vascular pattern are seen in the angiomatous pattern of anaplastic carcinoma. In paucicellular type, dense fibrosis and sclerosis with entrapment of highly atypical spindle cells are seen. In rare cases, large neoplastic cells show eccentrically placed vesicular nuclei with prominent nucleoli and abundant eosinophilic cytoplasm containing inclusions. The prominence of these cell type should be considered as rhabdoid form of anaplastic carcinoma.
- Even a small area of undifferentiated foci in an otherwise well-differentiated thyroid carcinoma should be mentioned in the report, as this finding is a marker of aggressive behavior.
- The most critical point in diagnosing anaplastic carcinoma is to prove the thyroid follicular origin of tumor cells. Adequate gross sectioning is necessary to catch the residual thyroid gland and areas of well differentiated thyroid carcinoma. Immunohistochemistry has a limited role in the diagnosis but is helpful in the distinction from its close differentials. TTF-1, thyroglobulin, and Pax-8 should be tried in required cases, as these markers do not stain all anaplastic thyroid carcinomas. Patchy reactivity of these markers should be evaluated carefully as these stains may highlight entrapped normal thyroid. Cytokeratin (CK7, CK8, and CK18) stain is helpful in ruling out sarcoma and lymphomas. Squamoid areas of anaplastic carcinoma may exhibit reactivity for high molecular weight keratins and/or EMA. Solid, insular, and trabecular patterns of the non-pleomorphic cells population should raise the concern for poorly differentiated carcinoma of the thyroid. Any doubt of medullary thyroid carcinoma should be ruled out with the use of calcitonin and CEA, as it also show pleomorphic, spindle, giant cells, and small cell morphology. CD5 and C-kit can be used to make a distinction from thymic carcinomas.
- Detailed clinical history (like the absence of laryngeal or esophageal or any other primary malignancy, long-standing thyroid enlargement or radiation exposure) and radiology findings (predominant thyroid-located tumor) are very helpful to achieve a diagnosis of anaplastic carcinoma of thyroid, as above-described morphology is not specific.
- Most anaplastic thyroid carcinomas have BRAF or RAS mutations in the differentiated and undifferentiated areas. Undifferentiated areas show TP53, TERT promoter and CTNNB1 mutation. Other molecular alterations are also seen in PTEN, EIF1AX and PIK3CA mutations. Alterations SWI/SNF complex and histone methyltransferases are also seen. P53 immunohistochemistry is diffusely positive in anaplastic carcinoma of the thyroid.
- The aim of surgery is the resection of the tumor, if possible, and to obtain the tissue for a diagnosis. Surgical debulking is challenging to achieve due to extensive infiltration into surrounding structures. Targeted therapy (BRAF, ALK, RET, NTRK inhibitors, MEK inhibitors and EGFR inhibitors) and immune checkpoint inhibitors (anti PDL-1) can achieve good results. Radiation therapy can be given along with chemotherapy for specific management and palliation purposes. For further treatment information, please refer to the references.
- Metastasis in lymph nodes, lung, bones and brain are very common. Median survival is only few months after the diagnosis. The outcome is little better in young age and thyroid-confined encapsulated tumor.
– Jannin A, Escande A, Al Ghuzlan A, Blanchard P, Hartl D, Chevalier B, Deschamps F, Lamartina L, Lacroix L, Dupuy C, Baudin E, Do Cao C, Hadoux J. Anaplastic Thyroid Carcinoma: An Update. Cancers (Basel). 2022 Feb 19;14(4):1061. doi: 10.3390/cancers14041061. PMID: 35205809; PMCID: PMC8869821.
– Bible KC, Kebebew E, Brierley J, Brito JP, Cabanillas ME, Clark TJ Jr, Di Cristofano A, Foote R, Giordano T, Kasperbauer J, Newbold K, Nikiforov YE, Randolph G, Rosenthal MS, Sawka AM, Shah M, Shaha A, Smallridge R, Wong-Clark CK. 2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer. Thyroid. 2021 Mar;31(3):337-386. doi: 10.1089/thy.2020.0944. Erratum in: Thyroid. 2021 Oct;31(10):1606-1607. PMID: 33728999; PMCID: PMC8349723.