PROGNOSTIC FACTORS OF CLINICAL INTEREST IN POORLY DIFFERENTIATED
CARCINOMAS OF THE THYROID.
Mauro Papotti, Marco Volante – University of Turin
Background. 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 (1), trabecular (2), insular (3,4), poorly differentiated (1,5-6), intermediate
type (7), primordial cell (8), less well differentiated (9) carcinoma, or follicular carcinoma with
insular component (10). 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 (11-14), thus including in some
instances high grade variants (i.e. tall cell or columnar) of papillary carcinomas in the PD tumors
group (11,14). 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 (6,8,15), following the original observation of Carcangiu and
coworkers (3), which incorporated in the PD carcinoma group both follicular-derived and papillaryderived tumors, whereas others (14,16,17) considered solid papillary carcinoma as a tumor separate
from PD carcinoma, unless necrosis is present within the tumor (17). 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 (18). Moreover, very recently activating BRAF mutations, specific of
papillary carcinomas, have been detected in a series of PD carcinomas having residual papillary
carcinoma foci (19). 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 (20-22) have shown that oxyphilic tumors by no means differ
from conventional follicular or even solid/trabecular carcinomas, except for their mitochondrion1
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 (6), while not confirmed by other Authors (10).
On the search of prognostic factors. As 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 (23,24) 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 (25), 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 outcome.
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 (102
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):
Age > 45 years:
Mitotic count > 3/10HPF:
SCORE 3
SCORE 1
SCORE 1
Prognostic groups:
Group 1: score 0-1
Group 2: score 2-3
Group 3: score 4-5
Cumulative proportion surviving
Histological diagnosis
1
FC
Group 1
PTC
0,8
0,6
Group 2
0,4
Group 3
p < 0.0001
0,2
AC
Scoring system:
Group 1: score 0-1
Group 2: score 2-3
Group 3: score 4-5
0
0
60
120
180
240
Time (months)
300
360
3
Concluding remarks. 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 literature data (3,26-28) and with
our previously reported findings (8). 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 clinicopathological parameters as age of patient, presence of necrosis and mitotic count. In more general
terms, in agreement with LiVolsi and coworkers (24,29), 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.
Well diff.
FTC
Minimally
invasive
PTC
Classical
Follicular
Undiff.
DIFFERENTIATION
FTC
Widely
invasive
PTC
Aggressive
variants
TISC
Necrosis absent
Mitoses < 3
Age < 45
TISC
Necrosis present
Mitoses >3
Age > 45
AC
Good
PROGNOSIS
Poor
4
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