—  SPECIALTY CONFERENCE  —

Cytopathology

Case 2 - Insular Carcinoma

William C. Faquin
Massachusetts General Hospital
Boston, Massachusetts


Click on each slide thumbnail image for an enlarged view
Clinical History: A 27 year-old woman presents with a palpable 3.0 cm mass in the right thyroid gland that had been slowly enlarging over the past six months. An FNAB was performed. (Images 2A-2C)

Cytologic Findings:
Direct smears stained with Papanicolaou and Diff-Quik stains were hypercellular and contained large, loosely cohesive clusters of crowded follicular cells in a background of blood, scattered single follicular cells, and absent colloid. Some groups of follicular cells were surrounded by bands of dense stroma and suggested a nested or insular architecture. Individual follicular cells had scant cytoplasm and were uniform in size, but at higher magnification, the round to oval nuclei were moderately pleomorphic, chromatin was slightly clumped, and occasional mitotic figures were seen. Immunocytochemical stains performed on this specimen showed that the tumor cells were strongly positive for thyroglobulin and negative for calcitonin, thus excluding medullary carcinoma from the differential diagnosis. The FNA was diagnosed as "suspicious for a follicular neoplasm, with features suggestive of insular carcinoma" and surgical excision was recommended.


Figure 2A - Hypercellular smears containing large loosely cohesive clusters of crowded follicular cells with a "nested" appearance. (Papanicolaou stain, low power)
Figure 2B - The individual follicular cells had scant cytoplasm and were uniform in size with round to oval nuclei. (Papanicolaou stain, medium power)
Figure 2C - At higher magnification the individual follicular cell nuclei were moderately pleomorphic with slightly clumped chromatin. (Papanicolaou stain, high power)

Histology and Clinical Follow-Up:
A total thyroidectomy was performed and revealed a circumscribed, tan-white nodule measuring 3.0 cm within the right thyroid lobe. Histologic examination showed an encapsulated microfollicular neoplasm that was partially replaced by discrete solid clusters of crowded, small, hyperchromatic follicular cells in a nested or insular architectural arrangement. Groups of follicular cells were surrounded by bands of sclerotic stroma; mitotic activity was brisk and focal individual cell necrosis was present. A diagnosis of an encapsulated insular carcinoma (poorly differentiated thyroid carcinoma) was made.

Clinical follow-up was uneventful until at two years post-surgery, when a routine CT scan revealed the presence of multiple liver nodules. A liver FNA performed under CT guidance demonstrated metastatic insular carcinoma.

Discussion: Insular carcinoma
This case raises two important issues in the evaluation of thyroid nodules by FNA: 1) The limits of FNA as a screening test for follicular carcinoma, and 2) the clinicopathologic significance of insular carcinoma .

The extremely large number of benign thyroid lesions (up to 7% of the population have palpable thyroid nodules) relative to the small number of admixed malignant ones creates a clinical dilemma - how to manage patients with a detectable thyroid nodule that statistically is more likely to be benign. Over the past two decades,FNA has become the single most important first step in the evaluation of a thyroid nodule. Thyroid FNA is widely accepted as a highly cost-effective, safe, and accurate technique, and it is also considered by many to be the most sensitive and most specific non-surgical thyroid cancer test available:

  • Thyroid FNA is >95% accurate for satisfactory specimens
  • Reduced the number of patients requiring thyroid surgery by approximately 50%
  • Increased the yield of thyroid malignancy at thyroidectomy by 2-3x
  • Decreased the cost of managing thyroid nodules by over 25%.

While the above facts about thyroid FNA sound very good, the truth is that thyroid FNA has severe limitations when applied as a screening test for follicular carcinoma.

In general, thyroid lesions to be evaluated by FNA can be divided into two groups: 1) those lesions for which FNA is primarily a screening procedure (follicular and oncocytic neoplasms) and 2) those lesions for which FNA is a diagnostic test (thyroiditis, papillary thyroid carcinoma, anaplastic carcinoma, medullary carcinoma, malignant lymphoma, and metastatic disease). The first group, where FNA is a screening procedure, consists of follicular and oncocytic lesions of the thyroid including multinodular goiter, follicular adenoma, follicular carcinoma, and oncocytic (Hurthle cell) neoplasms. As a screening test, FNA is able to identify a majority of thyroid nodules which can be diagnosed as "benign" and which in many instances can be managed without direct surgical intervention. The remainder of the cases fall into a category of follicular neoplasm where histologic evaluation is necessary to distinguish a benign follicular lesion from a malignant one. These cases are diagnosed as "suspicious for a follicular neoplasm."

The cytologic criteria used to distinguish "benign" from "suspicious" thyroid lesions include the follicular group architecture, smear cellularity, and amount of colloid; cytologic atypia is generally not a useful feature. Among the most important of these criteria is follicular architecture, specifically whether the lesion is composed predominantly of macrofollicles, or microfollicles, trabeculae, and crowded groups. This approach works because follicular carcinomas are virtually never composed of predominantly normal-sized or macrofollicles. In smears of thyroid aspirates, macrofollicles are recognized as colloid-filled spheres usually with numerous follicular cells, or as flat sheets of evenly spaced follicular cells. The flat sheets result from fragmentation of macrofollicles with extrusion of colloid during the smear preparation. Smears with a predominance of macrofollicles and flat orderly honyecomb sheets of follicular cells are diagnosed as "benign" thyroid nodules by FNA. In contrast, thyroid aspirates composed of microfollicles (small follicular groups of 6-12 follicular cells in a ring with or without a small amount of central colloid) or crowded trabeculae and groups of overlapping follicular cells are a feature of follicular carcinomas as well as some follicular adenomas. These aspirates are diagnosed as "suspicious for a follicular neoplasm," and it is this group of patients for whom surgical removal of the lesion is generally considered warranted.

FNA As A Screening Test For Follicular Carcinoma:
CYTOLOGIC FEATURE FNA Diagnosis HISTOLOGIC Diagnosis
PREDOMINANTLY MACROFOLLICULAR BENIGN MULTINODULAR GOITER & SOME FOLLICULAR ADENOMAS
PREDOMINANTLY MICROFOLLICULAR, TRABECULAR, OR CROWDED SUSPICIOUS FOR A FOLLICULAR NEOPLASM FOLLICULAR CARCINOMAS & SOME FOLLICULAR ADENOMAS

While thyroid FNA is associated with an overall very low false negative (approx. 0.7%) and false positive rate (approx. <6%), the severe limitation of thyroid FNA as a screening test is in the fact that 75-85% of thyroid aspirates diagnosed as "suspicious for a follicular neoplasm" are actually benign nodules when surgically resected. Since cytologic features can only take us so far in the evaluation of this group of thyroid FNAs, clearly what is needed is a biologic marker that could distinguish the many resected follicular adenomas from the few follicular carcinomas. Unfortunately, no ancillary markers (immunohistochemical or molecular) have been identified to date that can do this with high sensitivity and specificity. Some candidate biologic markers being studied in both histologic and cytologic specimens include: HBME-1, galectin-3, CD44v6, PPAR-gamma rearrangements, as well as various proliferation markers (Ki-67, p27, topoII-alpha). Until a single marker or panel of markers is demonstrated to be effective at differentiating follicular carcinomas from adenomas, FNA as a screening test will continue to have severe limitations.

With regard to the specific diagnosis of insular carcinoma in this case, insular carcinoma is considered the classic form of "poorly differentiated" thyroid carcinoma. It is a rare neoplasm, representing approximately 4% of all thyroid cancers. Patients are typically older, presenting at a mean age of 55 years. A majority of insular carcinomas exhibit a high stage at presentation due to extrathyroidal extension or distant metastases, especially to lung and bone. The long-term mortality for patients with insular carcinoma is thought to be as high as 50%, considerably greater than for most well-differentiated papillary and follicular carcinomas. Importantly, the presence of an insular histologic pattern, even if only a small component of an otherwise well-differentiated carcinoma, is considered a strong independent aggressive prognostic factor.

As in the case presented here, FNA of insular carcinoma is characterized by cellular smears comprised of monomorphic-appearing small follicular cells singly and in crowded clusters, as well as in intact insulae. Nuclei are round and variably hyperchromatic with mild to moderate nuclear irregularities. Mitotic activity and individual cell necrosis distinguish this neoplasm from most other microfollicular and benign macrofollicular lesions but these two features may be sparse. In addition, colloid is typically scant to absent. In most cases, an FNA diagnosis of "suspicious for a follicular neoplasm" is appropriate since it may be cytologically difficult if not impossible to accurately distinguish insular carcinoma from other benign follicular neoplasms. Again, no ancillary marker is available to help us.

The cytologic differential diagnosis of insular carcinoma includes medullary carcinoma, the solid variant of papillary carcinoma, and anaplastic thyroid carcinoma. Insular carcinoma can be distinguished from medullary carcinoma by the absence of stippled neuroendocrine-type chromatin as well as the lack of immunohistochemical staining for calcitonin. Although occasional nuclear grooves or rare intranuclear pseudoinclusions may be found, insular carcinoma lacks the classic nuclear features of papillary carcinoma such pale chromatin, papillary architecture, and extensive nuclear grooving, and the nuclear atypia of insular carcinoma is much less pronounced than is seen in anaplastic carcinomas. Imunohistochemically, insular carcinomas are positive for keratin, thyroglobulin and TTF-1, and negative for calcitonin.

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