Undifferentiated (anaplastic) thyroid carcinoma arising in association with largely papillary thyroid carcinoma, hobnail (micropapillary) variant with tall cell features (4.5 cm) with focal extrathyroidal extension into skeletal muscle. Papillary thyroid carcinoma, follicular variant (1.8 cm), contralateral lobe (not shown). Metastatic papillary thyroid carcinoma (1.1 cm focus) to a paratracheal lymph node with no visible extranodal extension. Peter M. Sadow, Massachusetts General Hospital, Boston, MA

Clinical History From the surgeon's note (abridged): 65 year old tax accountant with a history of recent hypothyroidism. Exam in December 2009 for a right neck tenderness revealed a hard right thyroid nodule. Ultrasound showed a 3 cm right upper pole nodule. FNA came back positive for papillary carcinoma. She notes no further recent enlargement and denies related symptoms. ?On review of systems, the patient has no neck pain, dysphagia, choking sensation, change in voice or energy. No intolerance of heat or cold, palpitations, skin changes, or shortness of breath. Complete review is otherwise negative in detail. No family history of thyroid cancer or other endocrine tumors, but a brother with Graves disease. No history of head/neck irradiation. Her past medical history includes uncomplicated ovarian cystectomy. ?Her medications are levothyroxine 75 mcg daily and MVI. ? On examination, she is a well-appearing woman, in no distress, 5'3", 153#, 148/90, HR70, RR14. She has a normal affect and judgment and ability to communicate. Her eyes are anicteric. She has no lid lag or stare. Her oropharynx is clear. Her neck is supple. Her trachea is midline. Her carotid upstrokes are normal bilaterally. Her thyroid has a rock hard, 3cm right thyroid mass which is mobile, nontender. There is no cervical lymphadenopathy. Her chest is clear to auscultation and percussion. Her heart is regular rate and rhythm with no murmurs. Her extremities are without clubbing, cyanosis, edema or tremor. Her skin is warm and dry. The patient has a 3 cm papillary thyroid cancer which has a generally excellent prognosis. I detect no signs of metastasis or local invasion. I therefore recommended total thyroidectomy which would then be followed by radioiodine ablation for her best chance of cure. I reviewed the technique of surgery as well as the risks which are low but include life-threatening bleeding, infection, parathyroid damage, and voice damage. I reviewed my strategies for minimizing these and she would like to proceed this week. We will plan the surgery accordingly. I will also obtain a neck ultrasound to assess her lymph nodes prior to surgery. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 100X image showing a striking micropapillary pattern with fibrovascular cores and no colloid. Figure 2 400X image where the prominent apical snouts are seen as well as classical papillary carcnoma- type nuclear features. Figure 3 1000X image reveals similar features as the 400X image, including apically placed oval nuclei. Figure 4 Immunohistochemistry displaying strong positivity for keratin 7 and keratin 19, as well as epithelial membrane antigen. TTF shows nuclear positivity. Figure 5 Cells are positive, in a membranous staining pattern, for beta catenin and E-cadherin. Nuclei are multifocally positive for p53 with a ki-67 proliferative index of 8%. Figure 6 40X image of a spindle cell proliferation adjacent to the papillary carcinoma. Figure 7 This 400X image is a zoom in .on the spindle cell component of the tumor showing tapered nuclei that are somewhat pleomorphic, focally hyperchromatic, and atypical. Figure 8 Immunohistochemistry performed on the spindle cell component shows the cells to have striking positivity for keratin 7 and keratin cocktail (AE1/AE3/CAM5.2), as well as scattered p53 nuclear staining with a marked elevation in the ki-67 proliferation index up to 30%, supporting the diagnosis of an undifferentiated carcinoma. Introduction: The patient is a 65 year old tax accountant who presents a tender right neck. She has a large (3 cm at ultrasound), right upper pole thyroid tumor with no pre-operative indication of high grade features, firm to palpation. FNA diagnosis is a papillary thyroid carcinoma. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: On excision, the thyroid is 65 grams. Occupying the majority of the right lobe is a 4.5 cm mass. There is a 1.8 cm circumscribed mass in the lower left lobe, distinct from the larger tumor. Microscopically, the larger tumor has two areas, a micropapillary component and spindle cell component. The micropapillary component is the majority of the tumor, >95%. The cells are cuboidal, largely, with apical snouts and centrally to apically placed nuclei. There is focal tall cell morphology. The spindle cell component shows some nuclear atypia but no areas of extensive necrosis and no wild pleomorphism or prominent atypical mitoses. Immunohistochemistry reveals the papillary component to be positive for TTF1 and thyroglobulin, whereas the spindle cell component is negative. The spindle cell component, as well as the papillary component, is positive for keratin 7 and cytokeratin cocktail (AE1/AE3/CAM5.2). The spindle cell component also shows an elevated mitotic index (up to 30%) over the papillary component (up to 8%). p53 and beta catenin are expressed in both areas. Differential Diagnoses: Morphologically, the tumor is a papillary thyroid carcinoma with an adjacent spindle cell component. The differential diagnosis for the papillary component is the newly described hobnail variant vs classical type or tall cell variant. The spindle cell component represents an undifferentiated carcinoma versus a myofibroblastic proliferation vs an associated Riedel thyroiditis. Final Diagnosis: Undifferentiated (anaplastic) thyroid carcinoma arising in association with largely papillary thyroid carcinoma, hobnail (micropapillary) variant with tall cell features (4.5 cm) with focal extrathyroidal extension into skeletal muscle. Papillary thyroid carcinoma, follicular variant (1.8 cm), contralateral lobe (not shown). Metastatic papillary thyroid carcinoma (1.1 cm focus) to a paratracheal lymph node with no visible extranodal extension. Case Discussion: When performing a gross examination of any excised organ, especially endocrine organs, it is important to note the number of grossly appearing lesions and their proximity to the surgical margins. Also, if there is a pre-operative FNA diagnosis, it is important to make sure that you are grossly able to discern (via the cytology report), which lesion corresponds to that/those biopsied. Preoperative diagnosis of papillary carcinoma is very different from preoperative diagnosis of a follicular neoplasm, as an individual follicular neoplasm will require histologic review of the entire lesional capsule. However, if there is a presurgical diagnosis of papillary carcinoma, which does not require sampling of the entire tumor capsule, the lesion should be finely dissected to look for any heterogenous areas. All areas of tissue heterogeneity should be well-represented for histologic review. Areas of fibrosis or necrosis should be sampled. Areas at the periphery of the lesion should also be well- sampled to assess for lymphovascular invasion. If the lesion is relatively small (subjective), entirely submit it. If there are multifocal lesions, be sure that you are able, if you are going to identify them in some way, to note where the lesion comes from, so that if there were to turn out to be an unexpected finding on the slide, you would be able to go back and either more extensively sample the area or at least be able to name the size of the lesion. In our case, where there was a focus of anaplastic carcinoma measuring 0.9 cm on a slide, and this focus is somewhat cut through. Although no additional anaplastic carcinoma was seen with more thorough review, this area would have likely been grossly fibrotic, and, if so, a notation may have been made about this gross finding, were the area needed for further sampling. It is unclear what the significance of this 0.9 cm focus of anaplastic carcinoma arising in association with a 4.5 cm papillary thyroid carcinoma. And, though volume-wise, it accounted for <5% of examined tissue, it's presence in association with hobnail variant of PTC, as well as extrathyroidal extension and lymphovascular invasion (of the PTC), are worrisome. The concept of an undifferentiated (anaplastic) thyroid microcarcinoma is really not well-discussed. According to the AJCC, any diagnosis of undifferentiated thyroid carcinoma is given a pathologic T stage of pT4, with pT4a being surgically resectable and pT4b being surgically unresectable/extensive. Technically, an undifferentiated (anaplastic) thyroid microcarcinoma would be a pT4a lesion. As more of these microscopic undifferentiated carcinomas are identified, presumably in association with a more well-differentiated counterpart, the reason for surgery, we will be better able to assess their prognostic significance, especially when the undifferentiated areas are those which metastasize and recur, rather than the more well-differentiated component. In this case, the patient was greatly reassured when given the percentage and exact size of the anaplastic component of the tumor relative to the papillary carcinoma component. This is what prompted her to pursue treatment for her tumor, as she was prepared to originally refuse any additional treatment following surgery having been self-informed about the clinical course of anaplastic carcinoma. Review of the Literature/Treatment Options (if applicable): Papillary Thyroid Carcinoma, Hobnail Variant About one year ago, Ricardo Lloyd's group published a series of 8 cases of PTC with hobnail features. This cohort demonstrates an aggressive clinical course, although larger series will be needed to determine whether this clinical association will be held up. Of this group, the cases were predominantly female (3:1) with a wide age range (mean 57.6 years). Mean tumor size was 2.5 cm. Distant metastases presented in 5 of 8 patients to various organs, bone and brain. Of this small group, half (4) died of disease in 3.5 years, with 2 alive with disease and 2 alive with no evidence of disease. Among 8 patients, three morphologic patterns were described. A papillary pattern (6 of 8 cases) with variably sized papillae with micropapillary structures and prominent vascular cores was most common. Epithelial cells showed cuboidal to oval epithelium with increased nuclear:cytoplasmic (N:C) ratio. Traditional features of PTC were present in these cases but only focally. Nuclei were located in the middle or apex of cytoplasm, giving a "hobnail" appearance. Two cases showed a follicular pattern with variably sized follicles with nuclear features as described above. One case had clustered pattern with numerous tiny clusters of cancer cells with hobnail features and a papillary structure, primarily seen in lymphovascular spaces with no single primary lesion. Immunohistochemically, all cases were positive for TTF1, thyroglobulin, cytokeratin 7, cytokeratin 19, HBME1, and p53. Beta catenin and e-cadherin showed a membranous staining pattern, and the proliferative index was up to 20% with a mean of 10% in tumor cells. BRAF was mutated in 4 of 7 cases available for review (57%), all with lymphovascular invasion, 3 of 4 with lymph node metastases, 2 of 4 with extrathyroidal extension. Two of 4 died of disease. No RET/PTC rearrangements were identified in these cases. Undifferentiated (Anaplastic) Thyroid Microcarcinoma No body of literature exists on the findings of microcarcinomas that are of an undifferentiated (anaplastic) type. However, there are scattered references to these cases, which are generally excluded from larger studies due to better outcomes. Conclusion(s): The hobnail variant of papillary carcinoma is a newly described entity most striking for its micropapillary pattern and apical snouts which give the cells a somewhat hobnail appearance. Although the original series published by Dr. Lloyd's group does show an aggressive biological activity in these patients, the cohort is small and will require additional validation and potentially distinct biological markers. The presence of a microscopic focus of anaplastic (undifferentiated) thyroid carcinoma associated with papillary thyroid carcinoma is a rare occurrence. The biologic significance of this finding is unclear. What is also unclear is the exact incidence of these tumor types, confounded, likely, by sampling bias as well as an under recognition of these small areas within a larger tumor. If this is truly the case, it is important to document these tumors and prove that they 1) truly do have biologic and molecular features of undifferentiated (anaplastic) thyroid carcinomas, 2) have the capacity to arise de novo or by progression from better differentiated carcinomas, and 3) bear prognostic significance for a patient with an otherwise straightforward, curable papillary thyroid carcinoma. References: Asioli S, Erickson LA, Sebo TJ, et al. Papillary thyroid carcinoma with prominent hobnail features: a new aggressive variant of moderately differentiated papillary carcinoma. A clinicopathologic, immunohistochemical, and molecular study of eight cases. Am J Surg Pathol. Jan 2010;34(1):44-52. Sugitani I, Kasai N, Fujimoto Y, and Yanagisawa A. Prognostic factors and therapeutic strategy for anaplastic carcinoma of the thyroid. World J Surg. May 2001; 25 (5):617-622. Ordonez N, Baloch Z, Matias-Guiu X, et al. Undifferentiated (anaplastic) carcinoma. In: DeLellis RA, Lloyd RV, Heitz PU, and Eng C, Eds. WHO classification of Tumours: Tumours of Endocrine Organs. Lyon: IARC Press, 2004.