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
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
Case 7 - Slide 1
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 . In the 1950's descriptions
included "spindle and giant cell metaplasia" and then in the late 1960's "spindle and giant cell
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
What was uniformly recognized throughout the decades was the aggressive behavior of these
tumors . Survival from anaplastic carcinoma is usually measured in months, with mean survival in
larger series ranging from 3 to 6 months
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 . 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 . 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 .
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
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 .
One very unusual type of anaplastic tumor has also been reported that harbors rhabdoid type cells
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 . 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 . One tumor has been assessed for molecular markers of thyroid
carcinoma and was positive for a RET-PTC translocation . 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 . More than 50% will
harbor point mutations in the p53 gene, and many will have loss of heterozygosity of the p53 gene as well
Several studies have demonstrated a molecular connection between well differentiated tumors
and their anaplastic counterparts, when they arise in the same patient specimen . In general, the
well differentiated tumors have some mutations and these are conserved and amplified in the anaplastic
component . A common mutation in papillary carcinomas, the V600E BRAF point mutation, has also been
seen in high frequency in anaplastic thyroid carcinoma
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
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
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
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)
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 .
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|
|Spindle cell nodules, post-FNA ||Plump spindle cells in intersecting bundles with admixed inflammation and vessels ||(+) SMA |
(+) Factor VIII and CD31
|Riedel's thyroiditis ||Dense collagen with lymphocytes ||None ||Unknown|
|Angiosarcoma ||Highly atypical vascular endothelial cells with slit like spaces ||(+) Factor VIII |
|CASTLE ||Lymphoepithelioma or squamous cell like tumor. ||(+) CD5 |
(+) CD 20
|SETTLE ||Compact spindle cells with glandular component ||(+) Cytokeratins|
|KRAS mutation (codon 12 and 15 in one case)|
|Squamous cell carcinoma ||Squamous differentiation ||(+) Cytokeratins |
(+/-) TTF and thyroglobulin (30-60%)
|Anaplastic thyroid carcinoma ||Spindle cell, giant cell, squamoid, paucicellular, rhabdoid ||(+) Cytokeratin (30-50%)|
(+) p53 (50-60%)
|BRAF positive (40-60%)|
p53 mutations (40%)
- Smith, L.W., Certain so-called sarcomas of the thyroid. Archives of Pathology, 1930. 10: p. 524-530.
- Hutter, R.V., et al., Spindle and giant cell metaplasia in papillary carcinoma of the thyroid. Am J Surg, 1965. 110(4): p. 660-8.
- Maddox, W.A., H.W. Knott, and E.A. Dowling, Carcinoma of the thyroid: review of fifteen years' experience. 1. Origin of spindle and giant cell carcinoma. 2. Occurrence of thyroid cancer in ectopic thyroid tissue. Am Surg, 1971. 37(11): p. 653-60.
- Wolf, B.C., et al., Immunohistochemical analysis of small cell tumors of the thyroid gland: an Eastern Cooperative Oncology Group study. Hum Pathol, 1992. 23(11): p. 1252-61.
- Mendelsohn, G., et al., Anaplastic variants of medullary thyroid carcinoma: a light-microscopic and immunohistochemical study. Am J Surg Pathol, 1980. 4(4): p. 333-41.
- O'Neill, J.P., et al., Anaplastic (undifferentiated) thyroid cancer: improved insight and therapeutic strategy into a highly aggressive disease. J Laryngol Otol, 2005. 119(8): p. 585-91.
- Besic, N., et al., Prognostic factors in anaplastic carcinoma of the thyroid-a multivariate survival analysis of 188 patients. Langenbecks Arch Surg, 2005. 390(3): p. 203-8.
- Goutsouliak, V. and J.H. Hay, Anaplastic thyroid cancer in British Columbia 1985-1999: a population-based study. Clin Oncol (R Coll Radiol), 2005. 17(2): p. 75-8.
- Jiang, J.Y. and F.Y. Tseng, Prognostic factors of anaplastic thyroid carcinoma. J Endocrinol Invest, 2006. 29(1): p. 11-7.
- Aratake, Y., et al., Coexistent Anaplastic and Differentiated Thyroid Carcinoma. Am J Clin Pathol, 2006. 125(3): p. 399-406.
- Hunt, J.L., Unusual thyroid tumors: a review of pathologic and molecular diagnosis. Expert Review of Molecular Diagnostics, 2005. 5(5): p. 725-34.
- Wan, S.K., J.K. Chan, and S.K. Tang, Paucicellular variant of anaplastic thyroid carcinoma. A mimic of Reidel's thyroiditis. Am J Clin Pathol, 1996. 105(4): p. 388-93.
- Canos, J.C., A. Serrano, and X. Matias-Guiu, Paucicellular variant of anaplastic thyroid carcinoma: report of two cases. Endocr Pathol, 2001. 12(2): p. 157-61.
- Carcangiu, M.L., et al., Anaplastic thyroid carcinoma. A study of 70 cases. American Journal of Clinical Pathology, 1985. 83(2): p. 135-58.
- Lai, M.L., et al., Rhabdoid tumor of the thyroid gland: a variant of anaplastic carcinoma. Arch Pathol Lab Med, 2005. 129(3): p. e55-7.
- Carda, C., et al., Anaplastic carcinoma of the thyroid with rhabdomyosarcomatous differentiation: a report of two cases. Virchows Arch, 2005. 446(1): p. 46-51.
- Sato, K., et al., Papillary thyroid carcinoma with anaplastic transformation showing a rhabdoid phenotype solely in the cervical lymph node metastasis. Pathol Res Pract, 2006. 202(1): p. 55-9.
- Albores-Saavedra, J. and S. Sharma, Poorly differentiated follicular thyroid carcinoma with rhabdoid phenotype: a clinicopathologic, immunohistochemical and electron microscopic study of two cases. Modern Pathology, 2001. 14(2): p. 98-104.
- Hunt, J.L., et al., Co-Existing Anaplastic and Well-Differentiated Thyroid Carcinoma: Genotpying to Assess Transformation. Modern Pathology, 2003. 16(1): p. 105A.
- Nikiforov, Y.E., Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroid carcinomas. Endocr Pathol, 2004. 15(4): p. 319-27.
- Lam, K.Y., et al., Insular and anaplastic carcinoma of the thyroid: a 45-year comparative study at a single institution and a review of the significance of p53 and p21. Annals of Surgery, 2000. 231(3): p. 329-38.
- Hunt, J.L., et al., Molecular evidence of anaplastic transformation in coexisting well-differentiated and anaplastic carcinomas of the thyroid. American Journal of Surgical Pathology, 2003. 27(12): p. 1559-64.
- Salvatore, G., et al., BRAF is a therapeutic target in aggressive thyroid carcinoma. Clin Cancer Res, 2006. 12(5): p. 1623-9.
- Quiros, R.M., et al., Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer, 2005. 103(11): p. 2261-8.
- Nikiforova, M.N., et al., BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. Journal of Clinical Endocrinology & Metabolism, 2003. 88(11): p. 5399-404.
- Shikama, Y., et al., Spindle cell metaplasia arising in thyroid adenoma: characterization of its pathology and differential diagnosis. J Endocrinol Invest, 2006. 29(2): p. 168-71.
- Aker, F.V., et al., Spindle cell metaplasia in follicular adenoma of the thyroid gland: case report and review of the literature. Endocr J, 2004. 51(5): p. 457-61.
- Vergilio, J., Z.W. Baloch, and V.A. LiVolsi, Spindle cell metaplasia of the thyroid arising in association with papillary carcinoma and follicular adenoma. Am J Clin Pathol, 2002. 117(2): p. 199-204.
- Baloch, Z.W., H. Wu, and V.A. LiVolsi, Post-fine-needle aspiration spindle cell nodules of the thyroid (PSCNT). Am J Clin Pathol, 1999. 111(1): p. 70-4.
- Chan, J.K., M.L. Carcangiu, and J. Rosai, Papillary carcinoma of thyroid with exuberant nodular fasciitis-like stroma. Report of three cases. American Journal of Clinical Pathology, 1991. 95(3): p. 309-14.
- Naganuma, H., et al., Papillary carcinoma of the thyroid gland forming a myofibroblastic nodular tumor: report of two cases and review of the literature. Pathol Int, 2002. 52(1): p. 54-8.
- Roka, S., et al., Carcinoma showing thymic-like elements--a rare malignancy of the thyroid gland. British Journal of Surgery, 2004. 91(2): p. 142-5.
- Dorfman, D.M., A. Shahsafaei, and A. Miyauchi, Intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE) exhibits CD5 immunoreactivity: new evidence for thymic differentiation. Histopathology, 1998. 32(2): p. 104-9.
- Berezowski, K., et al., CD5 immunoreactivity of epithelial cells in thymic carcinoma and CASTLE using paraffin-embedded tissue. American Journal of Clinical Pathology, 1996. 106(4): p. 483-6.
- Chan, J.K. and J. Rosai, Tumors of the neck showing thymic or related branchial pouch differentiation: a unifying concept. Human Pathology, 1991. 22(4): p. 349-67.
- Erickson, M.L., et al., Early metastasizing spindle epithelial tumor with thymus-like differentiation (SETTLE) of the thyroid. Pediatr Dev Pathol, 2005. 8(5): p. 599-606.
- Booya, F., et al., Primary squamous cell carcinoma of the thyroid: report of ten cases. Thyroid, 2006. 16(1): p. 89-93.
- Miettinen, M. and K.O. Franssila, Variable expression of keratins and nearly uniform lack of thyroid transcription factor 1 in thyroid anaplastic carcinoma. Human Pathology, 2000. 31(9): p. 1139-45.
- Begum, S., et al., BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment. Modern Pathology, 2004. 17(11): p. 1359-63.