Where to Set the Threshold Between
Well Differentiated and Poorly Differentiated Follicular Carcinomas of the Thyroid
LSU Health Science Center
In order to answer the question posed in the title of my presentation, I would like first
to briefly review the concept of poorly differentiated thyroid carcinoma with a follicular phenotype.
The concept of poorly differentiated thyroid carcinoma began to emerge in 1983 when
Sakamoto et al  analyzed 258 malignant thyroid neoplasms and on the basis of solid, trabecular and
scirrhous patterns, were able to segregate a group of carcinomas that they interpreted as poorly
differentiated. Surprisingly, the cytologic features of these poorly differentiated carcinomas were not
described. However, the tall cell variant of papillary carcinoma and papillary thyroid carcinomas with
stromal sclerosis were illustrated and included in the poorly differentiated group. The authors
emphasized that the prognosis of these poorly differentiated thyroid carcinomas was worse than that of
well differentiated thyroid carcinomas, and therefore, their separation was fully justified.
Hawk and Hazard  first described the tall cell variant of papillary thyroid carcinoma
as having an aggressive clinical course and as being microscopically characterized by tall cells (cell
height at least twice the width) with abundant oxyphilic cytoplasm that formed papillae. Because of its
aggressive clinical behavior and the fact that this variant often has a prominent trabecular pattern,
some pathologists have included it in the poorly differentiated category. However, the nuclear features
and thyroglobulin immunoreactivity of the tall cell variant are similar to those of conventional
papillary thyroid carcinoma.  In fact, the only difference between the tall cell variant and
conventional papillary carcinoma is cell height. Moreover, the clinical course appears to best correlate
with stage of disease, especially extrathyroidal extension rather than histology alone.
In 1984 Carcangiu et al  recognized a distinctive form of thyroid carcinoma associated with a poor
prognosis and with a characteristic insular pattern that was regarded as poorly differentiated.
According to the authors, this unusual form of thyroid carcinoma was originally described by Langhans in
1907. In addition to the insular pattern, the tumor often showed follicles, and trabecular and
sheet-like growth patterns. Many of the neoplastic cells had nuclear features that were similar to those
of papillary carcinoma while others exhibited nuclear features that were similar to those of follicular
carcinoma. All tumors showed variable thyroglobulin reactivity. The biologic behavior of these insular
tumors was thought to occupy an intermediate position between the well differentiated papillary and
follicular carcinomas and undifferentiated or anaplastic carcinomas. Eight of the 25 patients reported
by Carcangiu, et al had either lymph node or skeletal metastases at presentation. The overall death rate
for patients 50 years of age or older was 55.5%.
Soon after the columnar cell variant of papillary thyroid carcinoma was described by Evans
 in 1986 as an aggressive neoplasm, Sobrinho-Simoes et al  expressed the opinion that this tumor
fell into the category of poorly differentiated thyroid carcinoma. Microscopically, the columnar cell
variant shares the follicular, papillary, trabecular, solid and cribriform patterns described in other
forms of poorly differentiated carcinomas. Moreover, the columnar cells, which show prominent
pseudostratification, infrequently exhibit the large clear nuclei with grooves and pseudoinclusions that
are characteristic of conventional papillary carcinoma. The thyroglobulin immunoreactivity varies
considerably from tumor to tumor and even in different areas of the same tumor. A few tumors are, in
fact, thyroblobulin negative. Originally thought to be an aggressive form of papillary carcinoma, its
prognosis correlates best with clinical stage and the presence of extrathyroidal extension appears to be
the single most important prognostic parameter.  Columnar cell variants of papillary carcinoma that
are encapsulated or confined to the thyroid behave as conventional papillary carcinomas.
Papotti et al  in 1993 collected 63 examples of thyroid carcinomas considered to be
poorly differentiated and characterized by insular, trabecular, solid and/or follicular patterns.
Because they demonstrated paranuclear thyroglobulin deposits in the neoplastic cells these were compared
to the primordial cells of the developing fetal thyroid. In our experience, however, paranuclear
thyroglobulin deposits or "inclusions" can also be seen in both adenomas and well differentiated
follicular carcinomas .
In 1994, our group studied 41 thyroid carcinomas that had an insular component . We
have now examined 11 additional cases and have expanded our original observations related to these
carcinomas. Based on nuclear features and growth patterns, we classified these tumors as follicular
carcinomas or as follicular variants of papillary carcinomas. (figs.1-6). In most tumors, the cells
lining the follicles were similar to those arranged in nests, trabecular and cribriform structures.
Cells with clear nuclei, grooves, and pseudoinclusions were identified in the papillary carcinomas,
whereas, cells with round or oval nuclei having granular chromatin were recognized in the follicular
carcinomas. (figs.2-6). Occasionally, however, papillary carcinomas had cells with nuclei which were
less clear or even hyperchromatic and similar to those of follicular carcinoma. The insular pattern
predominated in most tumors and was focal in others. Achitecturally and cytologically, the tumors were
heterogeneous. A variable proportion of trabecular, solid and, occasionally, cribriform structures were
also indentified. (figs.7-8). A predominance of clear cells was recognized in three tumors and
collections of oncoytic cells were seen in another. (fig. 9). Abundant extracellular alcian blue
positive mucin was seen in two tumors. The majority of carcinomas (57%) with insular, trabecular and
cribriform patterns showed diffuse immunoreactivity for thyroglobulin.(Figs. 10-12). We have now seen a
conventional papillary carcinoma, rich in clear cells, in which, the metastases had predominantly
trabecular, solid and insular growth patterns but the population of clear cells was similar to that of
the primary tumor. We have also seen the opposite situation, that is, a papillary carcinoma with
trabecular, solid and insular growth patterns that metastasized as a conventional papillary carcinoma.
None of the 41 patients we reported had distant metastases at presentation and the overall
mortality rate was 9.4%. In our series, the biologic behavior of these tumors appeared to correlate with
stage of disease rather than with the presence of an insular growth pattern. Other authors, however,
have found that the insular component is an independent risk factor in thyroid carcinomas. 
Likewise, the extent of the insular pattern appears to correlate with prognosis. A focal insular pattern
in an otherwise conventional papillary or follicular carcinoma does not alter prognosis. 
In 1999, Nishida et al  reported 302 thyroid carcinomas of which 102 (33.7%) were interpreted as
poorly differentiated. Included in the poorly differentiated group were carcinomas with solid,
trabecular or scirrhous patterns as well as insular carcinomas, columnar cell carcinomas and tall cell
carcinomas. This heterogeneous group classified as poorly differentiated thyroid carcinomas were
subdivided into focal-poorly differentiated (<10% of poorly differentiated component) and
diffuse-poorly differentiated. (> 10% of poorly differentiated component). The authors concluded
that the diffuse poorly differentiated thyroid carcinoma was associated with a poor prognosis and,
therefore, was an important clinicopathological entity.  It is unjustified to include the focal
tall cell or columnar cell variants of papillary carcinoma in the poorly differentiated carcinoma
category because the definition of those tumors do not fulfill the established morphologic criteria for
the tall cell and the columnar cell variants of papillary carcinomas.
We recently described a rare but distinctive form of thyroid neoplasm that we believe fullfilled the
morphologic criteria for poorly differentiated carcinoma. It was characterized by nodular, trabecular
and sheet-like growth patterns and a small number of follicles (5% of the tumor), (figs.13-14). The
neoplastic cells had large vesicular nuclei with prominent nucleoli. In addition, 10 to 30% of the
neoplastic cells had rhabdoid inclusions  (Fig.15). Focal immunoreactivity for thyroglobulin was
detected in about 20% of cells. We have now seen two additional neoplasms with similar features except
for the rhabdoid inclusions.
Under the category of poorly differentiated thyroid carcinoma a variety of malignant thyroid
neoplasms have been described. The morphologic criteria employed to define poorly differentiated thyroid
carcinoma in most publications have been trabecular, solid, insular, cribriform and scirrhous growth
patterns. These growth patterns, however, lack specificity and can be seen in hyperplastic lesions and
benign thyroid tumors. For example, insular, trabecular, nodular and solid patterns have long been
recognized in dyshormonogenetic goiters as, well as in sporadic and endemic adenomatous goiters. 
Likewise, trabecular, solid and insular patterns are characteristic features of some thyroid adenomas.
On the other hand, oncocytic (Hürthle cell} carcinoma, which is regarded as a form of
follicular carcinoma, often shows trabecular, solid, nodular and nesting patterns, and yet, the term
poorly differentiated carcinoma is not employed for this tumor probably because their characteristic
cytologic features are the same in both the follicular and non-follicular areas.  Thyroid
carcinomas that occur in patients with familial adenomatous polyposis coli characteristically show focal
papillary architecture, cribriform features, solid, trabecular and spindle cell areas as well as squamoid
morules. Moreover, these tumors express only focal thyroglobulin reactivity yet they are not included in
the poorly differentiated category. They are considered to be variants of papillary carcinoma with
In one study poorly differentiated thyroid carcinomas were identified on
the bases of cytologic atypia, mitotic activity and necrosis ; features which do not reflect cell
differentiation, especially in endocrine tumors.
With minimal variations, the cytologic features of the vast majority of "poorly differentiated
carcinomas" are similar to or overlap with those of the conventional varieties of papillary or
follicular thyroid carcinomas including the expression of thyroglobulin and TTF-1. As a result of the
inconsistencies in the definition of poorly differentiated thyroid carcinoma and the inclusion of several
different types of carcinoma in the poorly differentiated category, the term poorly differentiated
carcinoma has led to considerable confusion and remains controversial.
An important clinical feature that has justified the attempts to characterize poorly differentiated
thyroid carcinoma as a distinct entity is its aggressive clinical course. It is unclear however, whether
the aggressive clinical course of these tumors correlates with their morphologic features or with other
well established prognostic factors such as gender, age, size of the tumor, extrathyroidal extension and
. A large series from the AFIP has shown that minimally invasive follicular
carcinomas, regardless of their growth patterns (with or without trabecular, insular or solid patterns),
are very low grade malignant tumors that rarely recur and seldom metastasize . The death rate in
this series was less than 1%. We have now seen four minimally invasive follicular carcinomas with
predominant insular growth patterns that have not metastasized despite long term follow-up (mean
follow-up 9 years).
There have been numerous immunohistochemical and molecular pathology studies on poorly differentiated
thyroid carcinoma that have had conflicting results. The use of different morphologic criteria and the
inclusion of different types of carcinomas such as the columnar and the tall cell variants in the poorly
differentiated group makes it difficult to compare results and to reach valid and definitive
conclusions. It is unlikely that a single, or a panel of immunohistochemical or molecular markers will
allow a distinction between well and poorly differentiated thyroid carcinomas since the latter tumors
have not been well defined
. Immunohistochemical markers such as high molecular weight
cytokeratins, HBME-1, galectin-3, CD44v6, p53,PAX8-PPAR ﻻ1 and Bcl-2 do not reliably distinguish
well differentiated from poorly differentiated follicular and papillary carcinomas. Likewise, the
molecular abnormalities described in anaplastic or poorly differentiated follicular and papillary
carcinomas can also be detected in well differentiated thyroid carcinomas with follicular phenotype.
However, with the use of DNA microarray technologies, the discovery of new markers might help
surgical pathologists clarify the controversial issue of poorly differentiated thyroid carcinoma. 
We would like to emphasize that an aggressive clinical course does not justify the inclusion of a
carcinoma in a poorly differentiated category. Clinical behavior is not necessarily related to cell
differentiation. In fact, cell differentiation is a complex biological phenomenon related to gene
expression and other factors. The actin cytoskeleton which participates in locomotion also maintains
cell morphology. Several cell to cell adhesion molecules are involved in cell differentiation and
molecules involved in cell interaction with the extracellular matrix also play a role in cell
differentiation.` (31} The demonstration that conventional papillary carcinoma can develop metastases
that grow predominantly in trabecular and insular patterns and, viceversa, that a primary papillary
carcinoma that shows predominantly insular and trabecular patterns can develop metastases that grow as
conventional papillary carcinoma, suggests that the microenviroment may play a role in the development of
these growth patterns.
The vast majority of thyroid carcinomas considered to be poorly differentiated have not been well
defined and are, in fact, differentiated follicular or papillary carcinomas with unusual growth
patterns. Currently, there is agreement that the tall and the columnar cell thyroid carcinomas are
variants of papillary carcinoma rather than forms of poorly differentiated carcinomas.  When
insular and trabecular patterns are present in follicular or papillary carcinomas, we recommend the
inclusion of the patterns in the surgical pathology report because, in some series, they have been
associated with an aggressive clinical course. The terms follicular or papillary carcinoma with
predominantly or focal insular growth patterns can be employed for these tumors.
In our opinion, the ideal definition of poorly differentiated thyroid carcinoma must include cell
morphology, cell function measured by thyroblobulin reactivity and growth patterns. The neoplastic
cells should be morphologically different from those of differentiated papillary or follicular carcinomas
as well as anaplastic carcinomas. Few follicles should be present (<20% of the tumor) and only focal
thyroglobulin immunoreactivity should be demonstrated in the tumor (<20% of the tumor). Defined as
such, poorly differentiated thyroid carcinoma becomes an exceedingly rare neoplasm. We believe, however,
that more data are needed to reach a concensus and to clearly define this controversial tumor. Once the
tumor is defined it might be possible to set the threshold between well differentiated and poorly
differentiated follicular carcinoma of the thyroid.
Poorly differentiated carcinomas are difficult to define and characterize not only in the thyroid but
in all endocrine organs. For example, the term poorly differentiated has not been adopted for
carcinomas that arise in the pituitary gland  parathyroid glands  adrenal glands  and
endocrine pancreas . Perhaps cytologic features and growth patterns are insufficient criteria to
recognize the degree of cell differentiation in malignant neoplasms in these endocrine organs.
- Sakamoto A, Kasai N, Sugano H. Poorly differentiated carcinoma of the thyroid. A clinicopathologic entity for a high-risk group of papillary and follicular carcinomas. Cancer 52:1849-55, 1983.
- Hawk WA, Harzard JB. The many appearances of papillary carcinoma of the thyroid. Cleve Clin Q 43:207-16, 1976.
- Ostrowski ML, Merino MJ. Tall cell variant of papillary thyroid carcinoma: A reassessment and immunohistochemical study with comparison to the usual type of papillary carcinoma of the thyroid. Am J Surg Pathol 20:964-74, 1996
- Carcangiu ML, Zampi G, Rosai J. Poorly differentiated ("insular") thyroid carcinoma. A reinterpretation of Langhans' "wuchernde struma". Am J Surg Pathol 8:655-68, 1984.
- Evans HL. Columnar-cell carcinoma of the thyroid. A report of two cases of an aggressive variant of thyroid carcinoma. Am J Surg Pathol 85:77-80, 1986.
- Sobrinho-Simoes M, Nesland J, Johannessen J. Columnar-cell carcinoma. Another variant of poorly differentiated carcinoma of the thyroid. Am J Clin Pathol 89:264-7, 1988.
- Wening BM, Thompson LD, Adair CF, et al. Thyroid papillary carcinoma of columnar cell type: clinicopathologic study of 16 cases. Cancer 82:740-53, 1998.
- Papotti M, Micca B, Favero A, et at . Poorly differentiated thyroid carcinomas with primordial cell component. A group of aggressive lesions sharing insular, trabecular, and solid patterns. Am J Surg Pathol 17:291-301, 1993.
- Vardaman JC, Albores-Saavedra J. Cytoplasmic inclusions in thyroid neoplasms of follicular cell origin (abstract). Am J Clin Pathol 96:410, 1991.
- Ashfaq R, Vuitch F, Delgado R, Albores-Saavedra J. Papillary and follicular thyroid carcinomas with an insular component. Cancer 73:416-23, 1994.
- Sasaki A, Daa T, Kashima T, et al. Insular components as a risk factor of thyroid carcinoma. Pathol Int 46:939-46, 1996.
- Nishida T, Katayama S, Tsujimoto M, et al. Clinicopathologic significance of poorly differentiated thyroid carcinoma. Am J Surg Pathol 23:205-11, 1999.
- Albores-Saavedra J, Housini I, Vuitch F, et al. Macrofollicular variant of papillary thyroid carcinoma with minor insular component. Cancer 80:1110- 1116, 1997.
- Albores-Saavedra J, Sharma S. Poorly differentiated follicular thyroid carcinoma with rhabdoid phenotype: a clinicopathologic, immunohistochemical and electron microscopic study of two cases Mod Pathol 14:98-104, 2001.
- Ghossein RA, Rosai J, Heffess C, Dyshormonogenetic goiter: a clinico- pathologic study of 56 cases. Clin Res 8:238-292, 1997.
- Carney JA, Ryan J, Gollmen RR. Hyalinizing trabecular adenoma of the thyroid gland. Am J Surg Pathol. 11:583-591, 1987.
- Rosai J, Carcangiu ML, DeLellis RA. Tumors of the thyroid gland. Atlas of tumor pathology. Series 3. Fascicle 5. Washington, DC: AFIP; 1992.
- Harach HR, Williams GT, Williams ED. Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm. Histo- pathol 25:549-556, 1994.
- Perrier ND, Van Heerden JA, Goellner JR et al. Thyroid cancer in patients with familial adenomatous polyposis World J Surg 22:738-743, 1998.
- Wreesmann VB, Ghossein RA, Patel S G, et al. Genome wide appraisal of thyroid cancer progression Am. J. Pathol. 161: 1549-1556, 2002.
- Akslen LA, Li Volsi VA. Poorly differentiated thyroid carcinoma-it is important (letter). Am J Surg Pathol 24:310-3, 2000.
- Jorda M, Gonzalez-Campora, Mora J, et at. Prognostic factors in follicular carcinoma of the thyroid. Arch Pathol Lab Med 117:631-5, 1993.
- Thompson LDR, Wieneke JA, Paal E, et al. A clinicopathologic study of minimally invasive follicular carcinoma of the thyroid gland with a review of the English literature. Cancer 91:505-524, 2001.
- Schmid KW, Tötsch M, Öfner D. et al. Minimally invasive follicular thyroid carcinoma: a clinicopathologic study. Curr Topics Pathol 91:37-43, 1997.
- Raphael SJ, The meanings of markers: Ancillary techniques in diagnosis of thyroid neoplasia. Endocrine Pathol. 13:301-311, 2002.
- Wiseman SM, Loree TR, Hicks WL, et al Anaplastic thyroid cancer evolved from papillary carcinoma Arch. Otolaryngol Head Neck Surg. 129:96-100, 2003.
- Takeuchi Y, Daa T, Kashima K, et al, Mutation of p53 in thyroid carcinoma with an insular component. Thyroid 9:377-381, 1999.
- Park KY, Koh JM, Kim Yl et al. Prevalences of G, a ras, p53 mutations and ret/PTC rearrangements in differentiated thyroid tumors in Korean population. Clin. Endocrinol. 49:317-323, 1998.
- Fogelfeld L, Bauer TK, Schneider AB, et al. p53 gene mutations in radiation-induced thyroid cancer. J. Clin. Endocrinol. Metab. 81:3039-3044, 1996.
- Owens LV, Xu L, Yang X, et al. Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer. Ann Surg Oncol 3:100-105, 1996.
- Gubiner BM. Cell adhesion; the molecular basis of tissue architecture and mor- phogensis. Cell 84;345-357, 1996.
- Pernicone PJ, Scheithauer BW, Sebo TJ, et al. Pituitary carcinoma: a clini- copathologic study of 15 cases. Cancer 79;804-812, 1997.
- Hundahl SA, Fleming ID, Gremgen AM, et al. Two hundred eighty-six cases of parathyroid carcinoma treated in the US between 1985-1995. Cancer 86:538- 544, 1999.
- Weiss LM, Madeiros LJ, Vickery AL, Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13:202-06, 1989.
- Solcia E, Capella C, Klöppel G. Tumors of the pancreas. Atlas of tumor pathology. Fascicle 20. Third series. Washington D.C. AFIP, 1997.