—  SHORT COURSE #41  —

Pathology of the Thyroid Gland

Case 4 - Follicular Variant of Papillary Carcinoma

Zubair W. Baloch and Virginia A. LiVolsi


Clinical History
A 24-year-old woman was noted to have a 2 cm thyroid nodule during a prenatal physical examination. She was euthyroid clinically and by laboratory evaluation. FNA was performed and a diagnosis of "follicular neoplasm" was rendered. During the third trimester of her pregnancy, thyroid lobectomy was performed. Grossly the nodule was 2cm appeared circumscribed and was partially encapsulated. Upon serial sectioning the nodule showed a small cystic area lined by a smooth wall and filled with brown serous fluid.


Case 4 - Figure 1 - Follicular Variant of Papillary Thyroid Carcinoma
Case 4 - Figure 2 - Follicular Variant of Papillary Thyroid Carcinoma


Case 4 - Figure 3 - Follicular Variant of Papillary Thyroid Carcinoma
Case 4 - Figure 4 - Follicular Variant of Papillary Thyroid Carcinoma

Diagnosis: Follicular Variant of Papillary Carcinoma

Follicular variant of papillary carcinoma is the most commonly encountered form of papillary cancer after excluding usual papillary cancer. Lindsay first described it in 1960. Rosai and Chen later described its biologic similarities to the usual papillary carcinoma. Before the recognition of this variant of papillary carcinoma, a majority of such cases were classified among true follicular carcinoma. Grossly, the tumors may appear partially or totally encapsulated. On microscopic examination, these tumors show follicle formation with intermixed areas of fibrosis. The follicles are usually of different sizes and shapes, ranging from micro to macro-follicles. Usually these lesions show a mixture of both types of follicles in varying proportions; however, sometimes the entire lesion is composed of macro-follicles resembling closely a hyperplastic nodule. Albores-Saavedra et al first described such lesions as macro-follicular variant of papillary carcinoma.

The lining cells of neoplastic follicles demonstrate features of papillary carcinoma; nuclear enlargement, elongation, nuclear chromatin clearing, grooves and inclusions. The colloid within the lumen of these follicles is usually of a thick eosinophilic variety and shows peripheral scalloping. In a good number of these cases the nuclear features of papillary carcinoma are diffusely present throughout the lesion, nevertheless some of these tumors show multi-focal distribution of nuclear features of papillary carcinoma with intermixed follicles lined by cells with rather bland nuclear morphology. Such cases may lead to diagnostic difficulties and may be under-diagnosed as hyperplastic nodules or follicular adenomas. Rosai et al proposed a scheme for diagnosing such lesions and stated that if a follicular patterned lesion displays multifocally well developed features of papillary carcinoma then it should be classified as follicular variant of papillary carcinoma.

Table 1. Diagnostic Scheme for Encapsulated Follicular lesions.
Rosai et al AFIP Facicle 5 (3rd series)

Cap and/or Vasc Inv Nuclear Features of Pap Ca Diagnosis
Present Absent Well-Diff Follicular Ca
  Imperfectly Developed Well-Diff Ca, NOS
  Well Developed, Diffuse Pap Ca, Follicular Variant
Absent Absent Follicular Adenoma
  Imperfectly Developed Follicular Adenoma
  Well Developed, Diffuse Pap Ca, Follicular Variant
   
 Well Developed, Focal 
 1. Rest of the nodule similar nuclear features. Pap Ca, Follicular Variant
 2. Rest of the nodule benign Follicular adenoma with with Pap-Micro Ca
Present Absent Imperfectly Developed Well Developed, Diffuse Well-Diff Ca Follicular Ca Well-Diff Ca, NOS Pap Ca, Follicular Variant Absent Absent Imperfectly Developed Well Developed, Diffuse Follicular Adenoma Follicular Adenoma Pap Ca, Follicular Variant Well Developed, Focal 1. Rest of the nodule, similar Features. 2. Rest of the nodule benign Pap Ca, Follicular Variant Follicular adenoma with focal Pap Ca

Albores-Saavedra et al in their study of macro-follicular variant of papillary carcinoma found similar multi-focal distribution of diagnostic nuclear features and stated that such lesions can be mistaken for a benign hyperplastic/adenomatous nodule.

We believe, that if one encounters a follicular patterned proliferation (encapsulated or non-encapsulated), which focally shows nuclear features of papillary carcinoma, a careful search should be made throughout the lesion in multiple sections to prove the multi-focality of such features. Such lesions should be classified as follicular variant of papillary carcinoma, and for staging purposes; the entire nodule should be diagnosed as cancer.

Recently some authors have suggested that encapsulated follicular patterned lesions, which only show minor nuclear changes of papillary thyroid carcinoma, should be classified as "well-differentiated tumor of uncertain malignant potential (WDT-UMP)". These authors also indicate that this may be an easy diagnosis and will sound like a lack of diagnostic commitment on the part of pathologist. We agree that encapsulated tumor with lack of diffuse distribution of nuclear features of papillary thyroid carcinoma and obvious capsular and/or vascular invasion are low-grade/slow growing tumor and most likely will not metastasize and can be cured by excision alone. However, before we introduce an "indeterminate" category into the field of thyroid pathology, there is a need for a study in adult thyroid tumors (to be diagnosed as WDT-UMP) with clinical follow-up to prove the value of this diagnostic term to the treating clinician.

Cytomorphology of Follicular Variant of Papillary Carcinoma
Reflecting the variable histologic features, the cytologic findings in follicular variant of papillary carcinoma can be variable. Some cases can be easily diagnosed as papillary cancer due to presence of easily discernible nuclear features and presence of follicles, whereas, some cases may lack nuclear features and may resemble hyperplastic foci within nodular goiter or follicular neoplasm. This variable presentation we believe is a reflection of multi-focal distribution of nuclear features of papillary carcinoma and intermixed areas resembling hyperplastic goiter in some cases of follicular variant of papillary carcinoma.

In our experience, the FNA smears from cases of follicular variant of papillary carcinoma usually show a background of moderate to abundant thin watery colloid appearing as a bluish-pink film with a delicate chicken-wire appearance on Romanowsky-stained smears. Thick ropy colloid, which is most talked about by some authors as diagnostic for papillary carcinoma can also be seen varying proportions. Most commonly it is seen in association with cellular groups with follicle formations or placed freely in the background. The cellularity of the smears is usually high with follicular cells arranged in monolayer sheets, micro-follicles and as single cells. The follicular cells usually show abundant eosinophilic cytoplasm with ill-defined cytoplasmic borders. The nuclei are usually enlarged and show finely dispersed chromatin, small faint nucleoli and nuclear grooves. In a study performed at our own institution, easily discernible nuclear inclusions were only observed in 30% cases of follicular variant of papillary carcinoma. Due to paucity of these nuclear features one may hold back and classify these lesions as follicular neoplasm or even as hyperplastic goiter. We believe, that if one sees some nuclear features (enlargement, elongation, chromatin clearing) which are suspicious for papillary carcinoma, this should be conveyed in the body of cytology report which may foster appropriate use of intraoperative pathology assessment (frozen section and touch preparations) in an attempt to give a definite diagnosis to avoid the need for a second surgical intervention for completion thyroidectomy.

The use of frozen section in determining the extent of resection in the surgical management of thyroid nodules is controversial. Several authors have published their findings in both pathology and surgical journals either in favor or against the use of intra-operative consultation in the surgical management of thyroid nodules. The arguments against the use of frozen sections in thyroid nodules include: 1) frozen section is not indicated and cost effective in cases diagnosed as definite for papillary thyroid carcinoma on FNA due to high sensitivity and specificity of FNA for diagnosing this tumor 2) Freezing can lead to artifactual nuclear changes that can be mistaken for papillary thyroid carcinoma leading to false positive diagnosis 3) diagnosis of follicular and Hürthle cell carcinoma requires detailed histologic examination of the lesion's capsule to assess capsular and/or vascular invasion. Therefore, many lesions diagnosed as follicular neoplasm on FNA will be diagnosed as follicular lesion on frozen section and definite diagnosis will be deferred to final histologic examination.

Among the reports in favor of frozen section evaluation of thyroid nodules the one that stands out is the publication by Paphavasit et al from Mayo Clinic. These authors studied 1023 patients undergoing thyroid surgery following the diagnosis of follicular and Hürthle cell thyroid neoplasms; the diagnosis of malignant neoplasm was achieved in 78% of patients on frozen section, thus permitting definite surgical management instead of a two step procedure (lobectomy followed by completion thyroidectomy). Despite all arguments in favor and against the use of frozen section in surgical management of thyroid nodules, some authors have shown that intra-operative evaluation can be useful in cases diagnosed as suspicious for papillary thyroid carcinoma on FNA. Recently few retrospective analyses have indicated that intra-operative cytology can be a useful adjunct to frozen section analysis of thyroid nodules especially in cases diagnosed as suspicious for papillary thyroid carcinoma on FNA. Basolo et al retrospectively reviewed Ultrafast Papanicolaou stained scrape preparations from various thyroid lesions and found a 98% correlation between the scrape and final histologic diagnosis as compared to 71% correlation between frozen section alone and final diagnosis.

We believe that intra-operative cytology is a rapid and sensitive method that can be used in combination with frozen sections to diagnose cases of papillary thyroid carcinoma, which are diagnosed as suspicious for papillary thyroid carcinoma on FNA, thus, preventing a two stage procedure for completion thyroidectomy.

Thus, cases diagnosed as definite for papillary carcinoma on FNA should not be submitted for intra-operative evaluation due to a negligible false positive rate on aspiration biopsies of such lesions. The diagnosis of follicular and/or Hürthle cell carcinoma cannot be rendered on frozen section, because the diagnosis of these lesions requires analysis of tumor capsule for capsular and/or vascular invasion. A majority of lesions will be diagnosed as follicular neoplasm on both scrape preparation and frozen section and will be deferred for final histologic examination.

References

Follicular Variant of Papillary Thyroid Carcinoma - Histology

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Follicular Variant of Papillary Thyroid Carcinoma-Cytology
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Thyroid Frozen Sections
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