Pathology of the Thyroid Gland
Case 4 -
Follicular Variant of Papillary Carcinoma
Zubair W. Baloch and Virginia A. LiVolsi
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.
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)
Well Developed, Diffuse Well-Diff Ca Follicular Ca
Well-Diff Ca, NOS
Pap Ca, Follicular Variant
Well Developed, Diffuse 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
|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|
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
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
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.
Follicular Variant of Papillary Thyroid Carcinoma - Histology
Follicular Variant of Papillary Thyroid Carcinoma-Cytology
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