Case 6 -

Thyroid Papillary Carcinoma Bruce M. Wenig, M.D. Mary S. Richardson, D.D.S., M.D.

History : A 26 year old woman presented with an enlarging mass in the right lobe of the thyroid gland. Fine needle aspiration biopsy was diagnosed as a "cellular follicular neoplasm with cytologic atypia"; surgical resection was recommended and was subsequently performed. Gross Findings: At the time of surgery the right lobe and isthmus were resected and were sent for frozen section evaluation. The specimen received included an intact subtotal thyroidectomy including a lobe and isthmus portion of the thyroid gland. Externally, the specimen was noteworthy for an enlarged thyroid lobe. The entire external aspect of the specimen was inked and serial sectioning revealed the presence of a well-delineated nodular mass in the thyroid lobe measuring 3 cm in greatest dimension. The mass was solid, tan-brown in appearance and rubbery to firm in consistency. No obvious invasion was seen and there were no additional mass lesions seen in the resected thyroid gland. A representative portion of the specimen was taken for frozen section analysis and simultaneous touch preparations were also performed. Microscopic Findings: At low magnification an encapsulated follicular epithelial cell proliferation was present. The tumor showed a purely follicular growth pattern with readily identifiable colloid-filled follicles. In areas the follicles were irregularly shaped, including twisted to elongated appearing follicles. Focally, intratumoral irregular-appearing fibrosis was identified. There was no evidence of invasive growth into or through the capsule, lymph-vascular space nivasion or invasion of the surrounding non-neoplastic thyroid parenchyma. At higher magnification, the neoplastic cells showed enlarged hyperchromatic appearing nuclei with irregularities in size and shape, haphazard arrangement of the nuclei, a tendency to nuclear crowding and overlapping, nuclear grooves and identifiable intranuclear (pseudo)inclusions. The touch preparations similar cytomorphologic findings, including nuclear irregularities in size and shape, dispersed (fine-appearing) nuclear chromatic and intranuclear inclusions. Intraoperative Diagnosis : Thyroid papillary carcinoma. Result : Completion thyroidectomy was performed. Diagnosis on Permanent Section: Thyroid papillary carcinoma, encapsulated, measuring 3.1 cm in greatest dimension and entirely confined to within the thyroid gland without evidence of extrathyroidal invasion. The remainder of the resected thyroid gland showed separate small adenomatoid nodules and single left-sided normocellular parathyroid gland with intraparenchymal fat. There was no evidence of any other foci of carcinoma. Discussion The use of fine needle aspiration biopsy (FNAB) has had significant impact on intraoperative consultation of thyroid lesions. FNAB is the most direct, accurate and cost-effective diagnostic modality in the evaluation of thyroid nodules. The greatest value of FNAB is the selection for early operation of patients who most likely have a thyroid neoplasm. Some investigators consider frozen section to be useful only when the FNAB findings are atypical or inconclusive, and are of very limited use for follicular lesions due to the high deferral rates. Other investigators show a high accuracy and cost effectiveness of intraoperative consultations for thyroid lesions. While FNAB is more sensitive than frozen section in evaluating thyroid nodules, frozen section is more specific. The combination of both FNAB and intraoperative consultation offers greater accuracy in the diagnosis of a thyroid nodule. Those patients with a definitive diagnosis of malignancy by FNAB undergo total or near total thyroidectomy; those patients with a diagnosis of follicular neoplasm or those with a diagnosis suspicious for malignancy by FNAB undergo a lobectomy and may be subjected to a completion thyroidectomy (as a second surgical procedure) if on completion of the histopathology review a diagnosis of malignancy is rendered. Indications for Intraoperative Consultation The indications for intraoperative consultation of thyroid lesions includes: 1) examination of a lobectomy specimen for the identification of malignancy that may necessitate additional surgery (i.e., completion thyroidectomy); 2) determination whether a given lesion is benign (e.g., adenomatoid nodules, lymphocytic thyroiditis, and less often diffuse hyperplasia) confirming the clinical impression and precluding additional surgery; 3) identification of nodal metastasis that may necessitate additional surgical removal of selective enlarged lymph nodes (thyroid papillary carcinoma) or formal nodal dissection (thyroid medullary carcinoma); 4) a much less frequent occurrence is incisional biopsy with intraoperative consultation in the setting of unresectable disease in order to assure adequacy of material for a diagnosis. Handling of the Specimen Lobectomy Specimen: This represents the most common specimen type and is usually resected for a solitary nodule. The recommendation is to ink the lobectomy specimen routinely in order to evaluate the surgical margins if the lesion proves to be malignant. Cut section through the center of the lesion is made and, and the lesion is measured along its greatest dimension; if there is no obvious evidence of invasion by gross inspection then a single section to include the capsular region is adequate for frozen section evaluation. There is no need to weigh the resected lobe. Subtotal or Total Thyroidectomy: may be the procedure of choice in the face of a FNAB diagnosis of carcinoma rather than a lobectomy with intraoperative consultation, although in most institutes an intraoperative consultation is not requested or gross examination suffices (unless there are unusual findings); if removed for malignancy then the specimen needs to be inked. In the face of an encapsulated follicular neoplasm where the differential diagnosis is between follicular adenoma and follicular carcinoma, at least four blocks from the capsule-to-thyroid interface is recommended for frozen section examination (Luna). Diagnostic categories on frozen section (adopted from Chan JKC): Lesion Diagnotic Considerations Follicular lesion with low cellularity and predominantly large follicles Adenomatoid (colloid) nodule(s) Adenoma Encapsulated cellular follicular lesion with no invasion on frozen section Follicular neoplasm, defer to permanent section for diagnosis (adenoma v. carcinoma); TPC, follicular variant confirmed by touch preparations; Follicular neoplasm suspicious for carcinoma Follicular lesion with invasion (capsular/LVI) Follicular carcinoma, widely invasive Invasive papillary lesion Thyroid papillary carcinoma and variants Other Medullary carcinoma, lymphoma, anaplastic carcinoma, other Intraoperative Cytologic Preparations Cytologic preparations (touch preps, scrap preps, needle aspiration) are extremely valuable and often superior to frozen sections in diagnosing TPC. There is a substantial amount of literature showing that The use of intraoperative cytologic preparations and frozen sections are complementary and increase the diagnostic accuracy of thyroid nodules. Therefore, in any case where a diagnosis of TPC is considered (and perhaps arguable in all thyroid gland cases) intraoperative cytologic preparations should be performed at the time of frozen section. Thyroid Papillary Carcinoma Thyroid papillary carcinoma (TPC) may be difficult to diagnose in frozen sections. The diagnosis of TPC is based on a constellation of features, including architectural and cytomorphologic findings. However, the constellation of diagnostic criteria for TPC may be absent in frozen sections creating difficulties in the diagnosis. Architecturally, the presence of papillary architecture may be absent in the tissue sample used for frozen section and/or a papillary architecture may be entirely absent in TPC (so-called follicular variant of TPC). Further, the classic cytomorphologic (i.e., nuclear) findings including clear nuclear chromatin (so-called orphan Annie nuclei) is an artifact of tissue fixation and not present in frozen sections. Among the helpful diagnostic features that may suggest the diagnosis or are diagnostic for TPC in frozen section include the combination of architectural and nuclear findings: Architecture: papillary architecture; elongated and twisted appearing follicles; intratumoral irregular fibrosis; psammoma bodies. Nuclear: enlarged nuclei; irregularities in size and shape of the nuclear outlines; numerous nuclear grooves; intranuclear pseudoinclusions Thyroid Papillary Carcinoma Most Important Criteria ( see Lloyd et al) Cytoplasmic invaginations into nucleus (25%) Abundant nuclear grooves (100%) Ground glass nuclei (98%) Psammoma bodies (16%) Enlarged overlapping nuclei (99%) Irregularly shaped nuclei (100%) Thyroid Papillary Carcinoma Less Important Criteria ( see Lloyd et al) Dark staining colloid (86%) Irregular contours of follicles (64%) Scalloping of colloid (59%) Elongated follicles (80%) Multinucleated macrophages in lumen of follicles (14%) It cannot overly emphasized that the diagnosis of TPC is based on a constellation of diagnostic criteria and should not be based on any single features. Microscopic thyroid papillary carcinoma is usually an incidental finding in thyroid glands resected for other lesions. These foci are considered to be of little to no clinical importance and frozen section is unnecessary since there are no therapeutic issues predicated on this diagnosis. Follicular Adenoma, Follicular Carcinoma and Oxyphilic ("Hürthle") Thyroid Lesions The differentiation of a follicular adenoma from a minimally invasive (low-grade) follicular carcinoma is virtually impossible by frozen section analysis. This differentiation is potentially problematic in permanent sections often requiring multiple sections along the tumor-to-capsule-to-nonneoplastic thyroid parenchymal interface in order to identify the definitive diagnostic criteria for a carcinoma (i.e., capsular and/or lymph-vascular space invasion). Intraoperatively, it is not practical to take multiple sections of the capsular region in order to determine if the diagnostic criteria for carcinoma is present. Further, numerous sections taken intraoperatively may disrupt and distort the capsular region precluding a diagnosis in permanent sections. The diagnosis of a widely invasive follicular carcinoma is relatively straightforward and is made in the presence of capsular and lymph-vascular space invasion. Often the growth characteristics of the invasive tumor is that of a large bulbous protrusion of tumor through the entire capsule with or without invasion of the djacent thyroid parenchyma. The lymph-vascular space invasion is usually of larger caliber sized endothelial lined spaces. Hürthle cells, arguably better referred to as oncocytic or oxyphilic cells, are characterized by the presence of a prominent brightly eosinophilic cytoplasm due to an absolute increase in the mitochondrial content of the cells. It should be noted that a Hürthle cell lesion of the thyroid gland is not by definition an aggressive thyroid neoplasm and for that matter is not necessarily even a neoplasm. Numerous lesions of the thyroid gland, including nonneoplastic lesions and benign neoplasms are composed of Hürthle cells. A diagnosis of carcinoma in an encapsulated oxyphilic (Hürthle cell) tumor is based on invasive growth. As detailed above, for those encapsulated follicular lesions the differentiation of a follicular adenoma with oxyphilic cells from a minimally invasive (low-grade) follicular carcinoma with oxyphilic cells is virtually impossible by frozen section analysis and it is not practical to take multiple sections of the capsular region in order to determine if the diagnostic criteria for carcinoma is present intraoperatively. It should be noted that only about 20% of follicular or oxyphilic (Hürthle cell) neoplasms will be diagnosed as malignant after complete histopathologic examination of the tumor. Therefore, in the majority of patients with a follicular or oxyphilic (Hürthle cell) neoplasm, lobectomy represents adequate treatment. The presence of cytoplasmic oxyphilia may cause nuclear enlargement that may in turn suggest a thyroid papillary carcinoma. However, despite nuclear enlargement and in contrast to TPC the nuclei remain round and regular with coarse nuclear chromatin and lacking the constellation of features seen in TPC. Mitochondria are extremely sensitive to changes in oxygen and as a result of a variety of insults, including but not limited to fine needle aspiration biopsy may undergo degenerative and other secondary changes that may complicate the histologic evaluation of these lesions. Among these alterations may be papillary architecture and in conjunction with nuclear enlargement may result in an erroneous diagnosis of TPC. Strict attention to the nuclear details will allow for differentiation from TPC. An oxyphilic variant of TPC exists but it is extremely rare and is characterized by cells with prominent oxyphilia, as well as the presence of classic nuclei seen in TPC. In this variant of TPC the nuclei tend to be situated along the apical aspect of the cells. Adenomatoid Nodules Clinically, thyroidectomy for adenomatoid nodules (multinodular goiter) is indicated to relieve pressure symptoms, for cosmesis or to rule out a carcinoma. The diagnosis of adenomatoid nodules is rather straightforward. Multiple similar appearing nodules may be present. Secondary (degenerative) changes, including cyst formation, papillae, fibrosis, calcifications, hemorrhage (recent and remote) and cholesterol granulomas may be present. Adenomatoid nodules lack complete encapsulation and, therefore, concern for a neoplastic proliferation and the possible differential diagnosis of a follicular adenoma from follicular carcinoma is minimized. The absence of architectural and cytomorphologic features of thyroid papillary carcinoma excludes that diagnostic consideration. In any given case a single, dominant nodule may be present with increased cellularity (with or without cytoplasmic oxyphilia) and in conjunction with irregular fibrosis may suggest a follicular neoplasm (e.g., adenoma or carcinoma). The clinical history is helpful in preventing an erroneous diagnosis. If uncertainty exists then deferral to permanent sections is acceptable. Lymphocytic Thyroiditis Usually the frozen section diagnosis of lymphocytic thyroiditis is straightforward. Problems in the interpretation of lymphocytic thyroditis may occasionally occur. Lymphocytic thyroiditis may be associated with cytoplasmic oxyphilia which in turn may result in nuclear enlargement. These changes may suggest the diagnosis of thyroid papillary carcinoma. However, cytologic preparations in conjunction with the frozen section will assist in preventing misdiagnosis; further, the full constellation of features diagnostic for thyroid papillary carcinoma are absent. As noted above, when the surgeon submits tissue indicating that it is separate from the thyroid gland proper the consideration that the structure represents a lymph node may lead to an erroneous diagnosis of nodal metastasis. The latter is even more problematic if this tissue specimen is the initial one submitted for frozen section. The absence of histologic features for thyroid papillary carcinoma, and the absence of a subcapsular sinus (a feature that identifies a structure as a lymph node) should prevent misdiagnosis. Thyroid Medullary Carcinoma A diagnosis of thyroid medullary carcinoma is an indication for total thyroidectomy. Further, a diagnosis of thyroid medullary carcinoma will necessitate nodal dissection. The diagnosis of TMC may be difficult intraoperatively given its varied growth characteristics, including follicular, papillary, and solid growth patterns, and histologic variability, including cells with cytoplasmic oxyphilia and small cell features. When this diagnosis is suspected intraoperatively but there is uncertainty, deferral to permanent sections is advocated since confirmation of the diagnosis and differentiation from a follicular epithelial neoplasm may require immunohistochemical staining. Lateral Aberrant Thyroid Tissue Lateral aberrant thyroid tissue is normal or hyperplastic thyroid tissue (the latter also referred to as a parasitic nodule) located separate from the normally situated thyroid gland connected to the main gland by a thin fibrous strand (which may or may not be appreciated by the surgeon or pathologist) or with no discernible attachment to the thyroid gland proper. Clinically, this tissue may be of concern for a (metastatic) carcinoma. The histologic evaluation of this tissue may be further complicated by the presence of associated lymphocytic thyroiditis suggesting, in conjunction with the surgeons designation of this tissue as unrelated to the thyroid gland, nodal metastasis. In order to minimize the possibility of misdiagnosis, the pathologist should be aware of the existence of lateral aberrant thyroid tissue and/or parasitic nodule, should note the absence of histologic features for thyroid papillary carcinoma, and should note the absence of a subcapsular sinus (a feature that identifies a structure as a lymph node) thereby indicative of lymphocytic thyroiditis. Mechanical implantation of thyroid tissue that is unattached to the thyroid gland may be the result of prior surgery or accidental trauma. In this situation there is usually a prominent fibrotic reaction or suture material in association with the thyroid tissue. Thyroid Tissue in Lymph Nodes and in Other Sites A controversial issue exists in regard to the existence of benign thyroid tissue in lymph nodes. While some authorities advocate for the existence of benign thyroid tissue in lymph nodes, a diagnosis of thyroid papillary carcinoma should be rendered if thyroid tissue is located in any lymph node irrespective of the architectural and cytomorphologic findings. Morphologic alterations secondary to FNAB Histologic changes that may be associated with prior FNAB potentially impacting on the intraoperative consultation evaluation include: hemorrhage; infarction; nuclear atypia; capsular pseudoinvasion; lymph-vascular space pseudoinvasion. Post-FNAB foci of pseudoinvasion appear linear and are surrounded by hemorrhage and granulation tissue. Reparative changes may be exuberant and in conjunction with cytologic atypia may raise concern for a malignant neoplasm such as a carcinoma or a sarcoma (e.g., angiosarcoma). Accuracy of Intraoperative Diagnosis of Thyroid Gland Lesions Frozen section evaluation has been extensively utilized for thyroid lesions. The lesions that are usually identifiable at frozen section include thyroid papillary carcinoma (conventional types), widely invasive follicular carcinoma, anaplastic carcinoma and medullary carcinoma. Problems arise in the frozen section diagnosis of a single encapsulated thyroid mass that has a follicular growth pattern. The differential diagnosis in this setting usually includes follicular adenoma, follicular carcinoma and the follicular variant of thyroid papillary carcinoma. The differentiation of a follicular adenoma from a follicular carcinoma is predicated on the presence or absence of capsular and/or vascular space invasion. This finding may only be present in a very limited aspect of the tumor. Sampling this area at frozen section would be purely fortuitous as, macroscopically, the invasive foci are not discernable. Thyroid papillary carcinoma in permanent sections often displays characteristic ground-glass appearing nuclei, a feature that is typically not present in frozen sections. Rosen et al point out that the relatively low-sensitivity of frozen section diagnosis of thyroid carcinomas relate to these issues. Kingston et al reported on the role of frozen section in distinguishing benign from malignant thyroid follicular neoplasms. Of 395 cases, 198 had frozen section at the time of surgery. Using the final histologic diagnosis as seen in permanent sections as the gold standard, these authors report that frozen section was accurate in 79 percent of the cases in differentiating follicular adenoma from follicular carcinoma with a sensitivity of 52 percent and a specificity of 100 percent; an incorrect diagnosis of a benign lesion was reported in 21 percent of the patients. Kingston et al compared the accuracy of frozen section diagnosis to the accuracy of using clinical factors alone to predict malignancy, including age greater than 50 years, tumor size greater than 3 cm, and a history of previous neck irradiation. These three clinical features were shown by Davis et al to be strong predictors of malignancy in thyroid follicular neoplasms. Kingston et al found an equally low sensitivity between frozen section and clinical parameters, ranging from 38 to 53 percent, in predicting malignancy but that frozen section resulted in a much higher specificity and positive predictive value than any of the clinical parameters. These authors recommended the continued use of frozen section for thyroid follicular lesions as a guide to the required extent of surgery. Irish et al reported the overall diagnostic accuracy by FNAB, frozen section and paraffin section diagnosis in thyroid lesions to be 81%, 87% and 94%, respectively. These authors state that given the high positive predictive value and specificity of both the FNAB and frozen section, that intraoperative consultation given a preoperative diagnosis by FNAB positive for malignancy, offers little further in the treatment of the patient. Irish et al report an average deferral rate of 11% for thyroid gland lesions, which they indicate is comparable to the world literature. They also indicate that this deferral rate is high in comparison to other body sites where average deferral rates of 3% are reported. In spite of the arguments for and against the use of frozen section in the surgical management of thyroid nodules, intraoperative evaluation is useful in those cases diagnosed by FNAB as suspicious for thyroid papillary carcinoma, and intraoperative consultation especially in conjunction with cytologic preparations is highly sensitive and specific in the diagnosis of thyroid papillary carcinoma. Basolo et al report a 98% correlation between intraoperative consultation including frozen section and cytologic preparation and the final histologic diagnosis as compared to 71% correlation between frozen section alone and the final histologic diagnosis. In summary, intraoperative consultation in thyroid gland pathology: is not indicated in cases diagnosed as definitive for malignancy by FNAB due to high sensitivity and specificity; is of limited or no value in the diagnosis of follicular carcinoma (with or without cytoplasmic oxyphilia) because a determination of malignancy based on invasion, which is often impractical by frozen section analysis; is most effective in those cases where the FNAB diagnosis is suspicious for thyroid papillary carcinoma. Most of the latter on permanent section prove to be the follicular variant of thyroid papillary carcinoma that are encapsulated and without evidence of invasion. References Axiotis CA , Merino MJ, Ain K, Norton JA. 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