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
The concept of poorly differentiated thyroid carcinoma began to emerge in 1983
when Sakamoto et al (1) 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 (2) 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. (3) 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
In 1984 Carcangiu et al (4) 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 (5) in 1986 as an aggressive neoplasm, Sobrinho-Simoes et al (6) 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. (7) Columnar cell variants of papillary carcinoma that are encapsulated or
confined to the thyroid behave as conventional papillary carcinomas.
Papotti et al (8) 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 (9).
In 1994, our group studied 41 thyroid carcinomas that had an insular component
(10). 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. (11) 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. (12)
In 1999, Nishida et al (13) 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. (13) 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
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 (14) (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. (15)
Likewise, trabecular, solid and insular patterns are characteristic features of some thyroid
adenomas. (16, 17) 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. (17) 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 atypical histology. (18, 19) In one study poorly
differentiated thyroid carcinomas were identified on the bases of cytologic atypia, mitotic
activity and necrosis (20); features which do not reflect cell differentiation, especially in
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 distant metastases (21-24). 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 (23). 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 (21,25). Immunohistochemical markers such as high
molecular weight cytokeratins, HBME-1, galectin-3, CD44v6, p53,PAX8-PPAR 1 ﻻand
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. (26-29) 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. (17) 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
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 (32) parathyroid glands
(33) adrenal glands (34) and endocrine pancreas (35). Perhaps cytologic features and
growth patterns are insufficient criteria to recognize the degree of cell differentiation in
malignant neoplasms in these endocrine organs.
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