Historic Background

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 (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

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best correlate with stage of disease, especially extrathyroidal extension rather than

histology alone.

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

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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.

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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-

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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

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 (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.

Discussion

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

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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

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.

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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 1ال 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

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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.

(30)

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

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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 (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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