Prognostic Factor of Clinical Interest in Poorly Differentiated Carcinomas of the Thyroid
University of Turin
The term "poorly differentiated
(PD) carcinoma" has been proposed twenty years ago to define non-follicular, non-papillary thyroid
carcinomas, which produced thyroglobulin and were unrelated to anaplastic carcinoma, showing an
intermediate behavior between follicular/papillary and anaplastic carcinomas. Different terms were
selected to refer to these tumors, including solid , trabecular
, poorly differentiated
, intermediate type , primordial cell
, less well differentiated  carcinoma, or follicular
carcinoma with insular component . On the one hand these tumors have been
defined according to their growth pattern, being among the variable histological patterns recognized in
such tumors, trabecular/insular/solid (TIS) areas usually predominant. Conversely, some authors pointed
out that PD carcinomas are characterized by unequivocal high grade histology, with atypias, high mitotic
count and necrosis, rather than by a specific growth pattern
including in some instances high grade variants (i.e. tall cell or columnar) of papillary carcinomas in
the PD tumors group
. As a consequence, there are several different
criteria that define PD carcinoma and most published series are not easily comparable. Additional source
of controversies on PD carcinomas comes from some studies
the original observation of Carcangiu and coworkers , which incorporated in
the PD carcinoma group both follicular-derived and papillary-derived tumors, whereas others
considered solid papillary carcinoma as a tumor separate from PD
carcinoma, unless necrosis is present within the tumor . Recent molecular
evidence have shown that a link of PD carcinoma and papillary carcinoma exists also from a genetic point
of view, since the RET/PTC1 rearrangement (typical of papillary carcinoma) was also found in a fraction
of PD carcinomas having the nuclear features of papillary carcinoma and/or some (residual) foci of
papillary carcinoma . Moreover, very recently activating BRAF mutations,
specific of papillary carcinomas, have been detected in a series of PD carcinomas having residual
papillary carcinoma foci . This indicates that PD carcinoma may
de-differentiate from either well differentiated conventional follicular or even papillary carcinoma.
Another source of debate concerning the histogenetic relationship between PD carcinomas and other thyroid
tumors refer to the presence of an oxyphilic phenotype in PD carcinomas. Oxyphilic carcinomas have long
been considered a separate entity based on their apparently higher malignant potential, and therefore
excluded from several studies. Others
have shown that oxyphilic
tumors by no means differ from conventional follicular or even solid/trabecular carcinomas, except for
their mitochondrion-rich cytoplasm. Concerning the extent of TIS growth patterns which have to be
recognized to make a diagnosis of PD carcinoma, it is generally accepted that a PD carcinoma is defined
by the presence of 75% or more of such areas. However, if even a minor TIS component could affect the
prognosis of an otherwise folicular/papillary carcinoma is still a matter of discussion. In fact, the
observation that even a minor insular component was associated with a prognosis worse than that of the
control well differentiated follicular carcinoma had already been reported by Nishida and coworkers
, while not confirmed by other Authors .
On the search of prognostic factors
already mentioned above, it is well known that the group of PD carcinomas behave intermediately between
well differentiated and anaplastic carcinomas. However, in this tumor group no data were available on
large case series concerning prognostic factors. Recently, some authors
analyzed the influence of histological parameters such as atypias, mitoses
and necrosis on the prognosis of well differentiated papillary carcinoma. It was shown that a malignant
behavior was significantly associated with the presence of such high grade features rather than related
to the pattern of growth. Since some PD carcinomas have a fatal outcome and others follow an indolent
course, we decided to apply the same approach. The influence of clinical and histological parameters on
prognosis was analyzed in a large series of 183 PD carcinomas of the thyroid, in which TIS patterns of
growth were more or less extensively represented (165 cases) or were only focally recognized (18
remaining cases). Clinico-pathological features such as sex, age, tumor diameter, stage, therapy
administered, extent of TIS patterns, presence of oxyphilic features, presence of necrosis, mitotic
count, cell size, extent of vascular invasion, and type of associated component (follicular vs papillary)
were studied by univariate and multivariate overall survival analysis and compared with the clinical
outcome. Subgroups included tumors having predominant oxyphilic features (n=66) and (residual) papillary
carcinoma features (n=24). Control groups of papillary (n=68), follicular (n=71) and anaplastic (n=35)
carcinomas were also included for overall survival analysis. Our data ,
showed that PD carcinomas had an intermediate behavior between papillary/follicular and anaplastic
carcinomas (p<0.0001). Univariate and multivariate statistical analysis
demonstrated that age >45 years (p=0.007), presence of necrosis (p<0.0001) irrespective of its
extent (focal versus extensive), and mitotic count >3x10HPF (p=0.01) were associated with poor
No statistically significant differences were observed comparing the patient's sex, tumor size (cutoff
4 cm) and radioiodine therapy administered and the overall survival. No significant differences in
behavior were observed between minimally and widely invasive TIS carcinomas. Relating the extent of the
TIS component with clinical behavior, we did not find any statistically significant difference in the
overall survival of carcinomas having only minor TIS component (10-50%) versus those with a well
represented (50-75%) component versus virtually "pure" TIS carcinomas (> 75%), although a better
prognosis was observed in cases with minor TIS component compared to the latter two groups considered
together (p=0.08). From a practical point of view, we suggest that the
presence of a TIS component must appear in the final pathological report of a thyroid carcinoma. If the
tumor also shows aggressive features (large tumor size, necrosis, mitoses), then the diagnosis of "poorly
differentiated" carcinoma with TIS patterns is appropriate.
Prognostic scoring system
Overall, these findings indicate that combining the statistically significant
parameters into a scoring system, PD carcinomas can be grouped into three prognostic categories
(p<0.0001). Group 1 (score 0-1) had a survival overlapping to that of well differentiated papillary
and follicular carcinomas. Group 3 (score 4-5) showed a clinical course closer to that of anaplastic
carcinoma, while group 2 (score 2-3) had a survival curve intermediate between the former two. From a
practical point of view, since PD carcinomas all together represent a clinically heterogeneous group of
tumors, we suggest that this scoring system may be useful to identify those tumors which have a higher
risk of an unfavourable clinical outcome.
| Proposed scoring system:|| |
|Presence of necrosis|
(either focal or diffuse):
| SCORE 3|
|Age > 45 years: || SCORE 1|
|Mitotic count > 3/10HPF: || SCORE 1|
|Group 1: ||score 0-1|
|Group 2: ||score 2-3|
|Group 3: ||score 4-5|
In this study, we have
confirmed that poorly differentiated TIS carcinomas of the thyroid have a clinical behavior intermediate
between follicular/papillary carcinoma and anaplastic carcinoma. This is in agreement with the
and with our previously reported findings . We
here show that in PD carcinomas, age >45 years, presence of necrosis and mitotic index > 3 were
significantly affecting prognosis. The classification of PD carcinomas into a separate group (also
encompassing solid/trabecular oxyphilic carcinomas) appears justified, irrespective of the label which
these tumors are to be referred to. Moreover, three different prognostic categories can be specifically
identified by a scoring system applied to clinico-pathological parameters as age of patient, presence of
necrosis and mitotic count. In more general terms, in agreement with LiVolsi and coworkers
, our data suggest that the grading of thyroid carcinoma is of high prognostic
and clinical value.
A scheme defining the proposed spectrum of follicular-derived thyroid carcinomas as compared to their
differentiation and clinical behaviour is shown below.
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