—  SLIDE SEMINAR #10  —

Head and Neck Pathology
Moderators: Dr. Christina MacMillan and Dr. Nina Gale

Case 7 - Anaplastic Thyroid Carcinoma, Rhabdoid Type, Arising in a Pre-existing Papillary Carcinoma

Dr. Jennifer Hunt


Case History:
A 69 year old man presented with a large thyroid mass and difficulty swallowing and a weak voice. Fine needle aspiration was suspicious for papillary carcinoma. The patient underwent resection of the tumor.


Case 7 - Slide 1
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Diagnosis: Anaplastic thyroid carcinoma, rhabdoid type, arising in a pre-existing papillary carcinoma.

Case Seven Discussion
In the 1930's anaplastic carcinomas were thought to be a sarcomas [1]. In the 1950's descriptions included "spindle and giant cell metaplasia" and then in the late 1960's "spindle and giant cell carcinomas" [2, 3]. When immunohistochemistry became more widely available the epithelial nature was proven in many of these tumors. However, it was also discovered that many tumors that had been designated as "small cell anaplastic thyroid carcinoma were actually medullary carcinomas and lymphomas [4, 5]. What was uniformly recognized throughout the decades was the aggressive behavior of these tumors [6]. Survival from anaplastic carcinoma is usually measured in months, with mean survival in larger series ranging from 3 to 6 months [7, 8]

Undifferentiated or anaplastic thyroid carcinomas represent the extreme end of the differentiation spectrum. These tumors are highly aggressive and usually present in the elderly. Patients usually present at between 60 and 70 years of age [9]. Clinically, these patients present with a rapidly enlarging neck mass and often come to medical attention because of respiratory distress; this may even necessitate an emergent tracheotomy. Sometimes, the diagnostic biopsy will be obtained during the tracheotomy procedure, which may limit the available material of frozen sections once requested, it is important to preserve some non-frozen fixed material for immunohistochemistry. The major differential from the clinical perspective will be lymphoma, which can have a similar clinical presentation.

Undifferentiated carcinomas may develop in patients who have a history of thyroid disease, either a goiter, or possibly even a history of a well differentiated carcinoma [10]. In the latter situation, anaplastic dedifferentiation may occur after multiple recurrences or metastases. An additional group of patients will have a component of a well differentiated thyroid carcinoma in their tumor specimens. The well differentiated component may be minor (in volume), because the fast growing undifferentiated component may overgrow the well differentiated areas by the time of presentation. The well differentiated tumors most commonly reported in combination with anaplastic carcinoma are papillary carcinoma and Hurthle cell carcinoma. This can be present in up to 50% of well sampled tumors [11].

Anaplastic thyroid carcinomas can exhibit various morphologies from the very bland to the highly pleomorphic. They can be imposed in spindle cells, giant cells, or squamoid cells. There is also a variant, which has been described as "paucicellular", that has dense fibrous tissue deposition with only scattered highly atypical neoplastic cells [12, 13]. These variant morphologies do not have significant differences in prognosis. In fact, nearly all undifferentiated tumors are lethal, with less than 10% of patients surviving beyond 2 years in most studies. An unusual morphologic feature of anaplastic carcinoma is its propensity to invade into vessels. The invasion has a unique appearance that is more like colonization or replacement of the vessel wall by anaplastic tumor cells [14].

One very unusual type of anaplastic tumor has also been reported that harbors rhabdoid type cells [15, 16, 17]. Eight cases of this have been reported in the literature, all in association with a primary well differentiated follicular or papillary carcinoma. In this type of lesion, the tumor cells have eccentric vesicular nuclei that may show nucleoli. There are is abundant eosinophilic cytoplasm that may contain spherical or whorled hyaline intracytoplasmic inclusions were described in one study [17]. The immunohistochemical staining pattern usually shows the tumor cells to be positive for sarcomeric actin and myoglobin, along with low molecular weight cytokeratins and vimentin. Tumor cells negative for desmin, smooth muscle actin and S100. TTF-1 and thyroglobulin are likely to be negative, but origin from the follicular epithelium is supported by the fact that these tumors show anaplastic de-differentiation from a well differentiated component [18]. One tumor has been assessed for molecular markers of thyroid carcinoma and was positive for a RET-PTC translocation [15]. The tumors that have been reported have all had an aggressive time course with extensive local invasion. Most reported cases describe death from disease between months to 3 years after presentation. This provides supportive evidence that rhabdoid phenotype should be considered to be a form of anaplastic carcinoma.

At the molecular level, anaplastic carcinomas have a high burden of somatic mutations. These aggressive tumors will show mutations in many common tumor suppressor genes [19]. More than 50% will harbor point mutations in the p53 gene, and many will have loss of heterozygosity of the p53 gene as well [20, 21]. Several studies have demonstrated a molecular connection between well differentiated tumors and their anaplastic counterparts, when they arise in the same patient specimen [22]. In general, the well differentiated tumors have some mutations and these are conserved and amplified in the anaplastic component [20]. A common mutation in papillary carcinomas, the V600E BRAF point mutation, has also been seen in high frequency in anaplastic thyroid carcinoma [23, 24, 25]. This probably reflects that fact that many of these high-grade tumors derive from papillary carcinoma, even when the well differentiated component is no longer histologically apparent [24, 25].

The major differential diagnoses for anaplastic thyroid carcinomas will include other lesions that can mimic the morphology (Table 1). This can include benign conditions as well as malignant tumors. The benign lesions that are in the differential diagnosis are rare spindle cell lesions, such as spindle cell metaplasia in an otherwise well differentiated neoplasm, post-FNA spindle cell nodules, nodular fasciitis like areas, and Riedel's thyroiditis [12, 26, 27, 28, 29, 30, 31]. All of these entities can have spindle cell areas of varying cellularity. The features most useful for differentiating these lesions from features with anaplastic thyroid carcinoma are a general lack of cellular pleomorphism, atypia, and mitotic activity. The assessment of these features can be further enhanced by the use of proliferative markers (Ki67 or MIB1) and a stain for the p53 protein, which should be negative in these benign entities. Additional stains, such as strong positivity for TTF-1 and thyroglobulin would also suggest a benign spindle cell lesion.

The malignant tumors in the differential diagnosis for anaplastic thyroid carcinoma include other sarcomas (especially angiosarcoma), carcinoma with thymus like differentiation (CASTLE) and spindle epithelial tumor of thymus origin (SETTLE), and squamous cell carcinoma of the head and neck, either primary to the thyroid or secondarily involving the thyroid [32, 33, 34, 35, 36, 37]. Immunohistochemical stains may not be as useful in this differential diagnosis, since the staining of anaplastic carcinoma is not uniform or consistent. Up to 30% of anaplastic thyroid carcinomas will not stain for any epithelial markers or markers of thyroid origin (TTF-1 or thyroglobulin) [14, 38]. The morphology and the clinical history may be necessary to resolve these difficult differential diagnoses. Molecular testing can also be helpful, given the fact that BRAF mutations are not found in any of the other lesions in this differential and are frequent in anaplastic thyroid carcinomas [39].

Table 1: Differential diagnosis for anaplastic thyroid carcinoma with morphologic, immunohistochemical and molecular profiles.

Tumor type Morphology Immunohistochemistry Molecular
Spindle cell metaplasia Bland spindle cells arranged in fascicles (+) TTF-1
(+) Thyroglobulin 		Unknown
Spindle cell nodules, post-FNA Plump spindle cells in intersecting bundles with admixed inflammation and vessels (+) SMA
(+) Factor VIII and CD31 		Unknown
Riedel's thyroiditis Dense collagen with lymphocytes None Unknown
Angiosarcoma Highly atypical vascular endothelial cells with slit like spaces (+) Factor VIII
(+) CD31
(+/-) Cytokeratins 		Unknown
CASTLE Lymphoepithelioma or squamous cell like tumor. (+) CD5
(+) CD 20
(-) Thyroglobulin 		Unknown
SETTLE Compact spindle cells with glandular component (+) Cytokeratins
(-) Thyroglobulin
(-) CD5
(-) CD20 		KRAS mutation (codon 12 and 15 in one case)
Squamous cell carcinoma Squamous differentiation (+) Cytokeratins
(+) p63
(+/-) TTF and thyroglobulin (30-60%) 		BRAF negative
Anaplastic thyroid carcinoma Spindle cell, giant cell, squamoid, paucicellular, rhabdoid (+) Cytokeratin (30-50%)
(-) TTF-1
(+/-) Thyroglobulin
(+) Vimentin
(-) p63
(+) p53 (50-60%) 		BRAF positive (40-60%)

p53 mutations (40%)

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