THYROID

Volume 8, Number 8, 1998

Mary Ann Liebert, Inc.

Anaplastic Thyroid Carcinoma:

Behavior, Biology, and Therapeutic Approaches
KENNETH B. AIN

ABSTRACT

Anaplastic thyroid carcinoma (ATC), although exceedingly rare, is the most aggressive solid tumor known. Early
studies on the effects of different therapies may be biased by the inclusion of responsive "small cell" ATC pa¬
tients, which are now known to be mostly lymphoma patients. Local control of disease with surgery and/or ex¬
ternal beam radiotherapy (XRT) is of fundamental importance to enhance survival. Ultimately, nearly all ATC
patients die from their disease, which is widely metastatic. Development of effective systemic chemotherapy agents
would provide the best chance for long-term survival of patients. Early preliminary data suggest that paclitaxel
may be helpful, although no agent has yet been identified to result in dramatic improvements in survival. Select
patients may benefit from aggressive multimodal therapy, although it is important to provide appropriate pallia¬
tive care when desired.

INTRODUCTION There are regional differences as well as changes over

time. In recent reports, ATC cases constituted 7.5% of thy¬
certainly the
is roid cancer cases in Tel Aviv (4), 4.7% in Bombay (5), 5%
Anaplastic
mans.
aggressive and lethal solid
most
It is
fortunate that
(ATC)
thyroid carcinoma

ATC is
the least
tumor afflicting hu¬
common of thy¬
roid neoplasms; however, this has also made it difficult to
study and test therapeutic strategies. Spindle and giant cell
ATC remains the neoplasm most recalcitrant to known
therapeutic modalities and present the greatest challenge
for clinical management. The rarity of this cancer, its fail¬
ure to respond to treatment, and the relative lack of active
research regarding its management, justifies its classifica¬
tion as a true "orphan disease."
EPIDEMIOLOGY
The incidence of thyroid carcinomas in the United States
is approximately 17,200 cases per year (1). Although some
older studies described up to 20% of thyroid cancers as
ATC or "undifferentiated" (2), the most recent results from
the Surveillance, Epidemiology and End Results (SEER)
Program show 251 ATC cases of 15,698 thyroid cancers
(1973-1991), indicating that ATC constitutes 1.6% of thy¬
roid cancers in the United States (3) for an estimated an¬
nual incidence of less than 300 cases.
in a national Italian survey, and 1% in Arsizio, Italy (6).
There is a distinct temporal trend of reduction in the pro¬
portion of thyroid carcinomas found to be ATC. In Bom¬
bay, the relative proportion of ATC declined from 7.7%
in 1969-1973 to 4.2% in 1989-1993, at the same time
that the total number of thyroid carcinomas increased by
3.5-fold (5). Likewise, between f979 and 1989, the pro¬
portion of ATC declined from 11% to 5% in Italy as a
whole and from 10% to 1% in Arsizio, Italy (6). Similar
decreases in the frequency of ATC have been ascribed to
improvements in socioeconomic status (7). Potential addi¬
tional explanations for this decline include enhanced
pathologic discrimination with reclassification of some tu¬
mors as medullary cancers or lymphomas and earlier treat¬
ment of differentiated carcinomas to prevent anaplastic
transformation.
Female patients typically outnumber male patients by a
ratio of from 3.1 to 1.2 to 1 in various series (3-5,8-10).
The mean age at diagnosis is from 57 to 67 years with a
range of ages from 15 to 91 years (3,5,9-11). This is def¬
initely a disease of older adults with 90% over the age of
50 years in one series (4) and only 4 patients under the age
of 40 years in another series of 121 ATC patients (10).

Thyroid Nodule and Oncology Clinical Service, Division of Endocrinology and Molecular Medicine, Department of Internal Medicine,
University of Kentucky Medical Center, Thyroid Clinic, Veterans Affairs Medical Center Lexington, Kentucky.
The author is the recipient of NCI Grant CA58935 and support from the Ephraim McDowell Cancer Research Foundation (Lexington,
KY).
715
716
PRESENTATION
The majority of ATC patients present with a rapidly
growing thyroid mass (4,10,11). Nearly half of the patients
have symptoms of hoarseness and dyspnea, with some not¬
ing dysphagia or cervical pain (4,9,11). Clinicians should
also be alert to unusual presentations such as ball-valve
type respiratory obstruction (12,13), gastrointestinal symp¬
toms from métastases (14,15), or superior vena cava syn¬
drome (16,17). From 28% to 71% of patients have a his¬
tory of previous or concurrent differentiated thyroid
carcinomas, either follicular or papillary (and its variants)
(9,10,18). It appears likely that more extensive histopatho-
logic analysis reveals higher rates of associated differenti¬
ated thyroid carcinoma.
Physical examination typically demonstrates palpable
thyroid masses that are usually multiple and bilateral.
Nearly 80% of patients have tumors greater than 5 cm in
diameter at presentation (11). Cervical adenopathy is pres¬
ent in more than 40% of patients and vocal cord paraly¬
sis in around 30% (4,11,17). At least 50% of patients have
distinct métastases at presentation, of whom around 80%
have métastases in the lung, 15% in bone, and 13% in
the brain (4,10). This probably underestimates the predilec¬
tion for aggressive distant spread since an autopsy study
of 15 ATC patients revealed all to have pulmonary metas-
tases, 80% with bone métastases, 60% to soft tissue of the
neck, 27% to trachea, and 53% with other soft tissue
métastases (2).
CLINICAL COURSE AND MORTALITY
ATC has a relentless and deadly clinical course with
rapid progression and dissemination. Clinicians may ob¬
serve tumors double in volume over a period of several
days to a week. With rare exception, nearly all patients die
from their tumor within several months. This outcome is
essentially unaltered by any known therapies, although (as
will be discussed below) mortality may be delayed. It is
difficult to rely on some published literature for valid mor¬
tality information because of the failure to discriminate
"small cell" ATC (representing lymphomas, medullary can¬
cers, or insular carcinomas with slower growth rates or
better responses to treatment) from spindle and giant cell
ATC. For example, Rossi et al. (19) compiled survival data
on 96 cases of "ATC" (most treated with external radio¬
therapy), comprised of 51 giant cell ATC patients with
long-term (5-year) survival of 4 patients (8%), and 45 pa¬
tients with "small cell" ATC whose long-term survival ex¬
ceeded 28%. Likewise, the 1969 report by Rafia (20)
claims a 24% long-term (approximately 5-year) survival of
ATC patients, in contrast to a contemporary report of 53
ATC patients with 92% mortality before 1 year (21), which
could be explained by a 25% subset of "small cell" ATC
cases. In another study at the Mayo Clinic, only 3 of 82
(3.6%) ATC patients were reported to have a reported 5-
year survival (11). A re-analysis of the histology of these
3 patients by Rosai et al. (22) revealed them to consist of
2 cases of lymphoma and 1 case of medullary carcinoma,
leaving the Mayo Clinic series with no long-term ATC sur¬
vivors. This nosological problem may also affect our abil¬
AIN
ity to interpret the effectiveness of different therapeutic in¬
terventions.
Mean reported survival times of ATC patients range
from 2.5 to 7.4 months (6,8,10,23), while median survival
is reported as 4 to 12 months (9,11,18). In a representa¬
tive series, 21% of patients died within the immediate post¬
operative period (8). From 82% to 90% of patients expire
by 6 months (8,23). In the largest American series of ATC
patients, those presenting with clinical evidence of only lo¬
cal disease had an 8.1-month median survival compared
to a 3.3-month median survival of patients presenting with
distant métastases (p < 0.001) (10). Likewise, evidence of
distant disease at presentation results in a mortality risk
ratio of 3.2 (95% confidence limits at 2.0-5.1) compared
with patients with only localized disease (3). The rare ATC
patients with apparent long-term survival are typically
younger, have small primary foci of localized ATC, and
have been aggressively treated with surgical resection, ex¬
ternal radiation therapy, and usually systemic chemother-
apy (9,10,23).
PATHOLOGY AND IMMUNOHISTOCHEMISTRY
In its gross appearance, ATC is frequently seen as a tan-
white, fleshy, large thyroid tumor that infiltrates extrathy-
roidal tissues and has regions of necrosis and hemorrhage
(24). Three predominant histological patterns are com¬
monly seen, often coexisting: spindle cell in 53%, giant cell
in 50%, and squamoid in f 9% (8,22). Common features
to all of these patterns are large foci of necrosis, marked
invasiveness, and predilection for growth into the muscu¬
lar walls of medium-sized veins and arteries (angiotropism)
(22). Cytological assessment reveals anaplasia with bizarre
tumor cells and a high mitotic rate (24). Up to 10% of
ATC tumors have osteoclast-like giant cells, which exhibit
immunohistochemical staining for vimentin and KP-1 an¬
tibody (thought to be specific for histiocytic cells), sug¬
gesting that these cells may be nonneoplastic in origin and
may have resulted from a coalescence of histiocytic
mononuclear cells (22,25,26). As would be expected for
this aggressive tumor, the rate of proliferation exceeds that
of any other type of primary thyroid malignancy, while the
rate of apoptosis is the lowest (27), accounting for its ex¬
ceedingly rapid rate of growth.
As introduced earlier, current pathological opinion sug¬
gests that the former classification of small cell ATC is a
misnomer and does not represent any true subset of ATC.
In a rigorous analysis, Wolf et al. (28) studied 68 cases of
putative small cell ATC with a variety of immunohisto¬
chemical markers for B-cells and T-cells, as well as leuko¬
cyte common antigen, vimentin, thyroglobulin, calcitonin,
cytokeratins, carcinoembryonic antigen, and chromo-
granin. Sixty-seven cases were found to be lymphomas (63
cell, 2 of indeterminate phenotype, and 2 large cell) and
the remaining case was morphologically similar to small
cell lung carcinoma. In another series of 31 unselected ATC
cases, similar immunohistochemical reclassification
demonstrated 7 cases to be lymphomas, which included all
3 of the "small-cell" type and 4 of 16 putative giant cell
ATC cases (29). Corrected nosology of the "small cell"
ATC designation reveals lymphomas, insular carcinomas,
ANAPLASTIC THYROID CARCINOMA 717

and medullary carcinomas, all of which have better prog¬ duction of thyroid hormone with clinical thyrotoxicosis
noses than ATC. In general, a series of ATC patients with due to an activating mutation of the thyrotropin receptor
long-term survivors should be suspected of having lym¬ (47).
phomas, medullary carcinomas, or insular carcinomas mis-
classified as ATC (8,22,24,30).

Immunohistochemistry of ATC shows varied results in GENESIS OF ANAPLASTIC CARCINOMA

different series (8,10,26,31,32). Generally, positive stain¬
ing for thyroglobulin is seen in from none to 55% of cases. It appears likely that ATC represents a terminal dedif¬
Vimentin is positive in 23% to 94%, keratins or cytoker- ferentiation of pre-existing differentiated carcinoma of the
atin positive in 12% to 80%, epithelial membrane antigen thyroid follicular cell in most, if not all, cases. This is based
positive in 8% to 55%, ai-antichymotrypsin positive in on indirect, although convincing, evidence. A large portion
48%, coexpression of vimentin and keratin in 39-75%, of ATC cases develop in longstanding goiters or in the con¬
desmin negative in all cases, and 30% of cases may be neg¬ text of pre-existing, incompletely treated papillary or fol¬
ative for all of the above markers. Squamoid variants of licular thyroid cancers. Likewise, careful examination of
ATC typically stain for carcinoembryonic antigen (8). primary ATC tumors reveals coexisting areas of differen¬
Cases staining positive for calcitonin are medullary can¬ tiated thyroid carcinoma in 80% to 90% of cases (17,21).
cers, those positive for factor VHI-associated antigen are Such differentiated tumors include papillary and follicular
angiosarcomas or hemangioendotheliomas (32,33), and varieties, as well as Hiirthle-cell variants (48). Some pathol-
those positive for smooth muscle actin or muscle-specific ogists describe areas of histological transition from differ¬
actin are usually leiomyosarcomas (34,35). Immunohisto¬ entiated carcinoma to ATC and occasional tiny foci of ATC
chemistry has proven a powerful tool to discriminate tu¬ may be found within well-differentiated carcinomas (4,24).
mors with distinct clinical behaviors and to suggest differ¬ Two studies evaluated metaplastic transition into ATC
ent therapeutic approaches. in fatal thyroid cancers. Harada et al. (49) autopsied 27
There are a few variants of ATC with distinctive fea¬ consecutive cases of fatal thyroid carcinomas and found
tures. A recent report suggests that just under 6% of ATC 10 cases of uniform ATC, 4 cases of uniform well-differ¬
cases constitute the paucicellular variant of ATC, charac¬ entiated carcinoma, and 9 cases with both tumor types co¬
terized by rapid growth of an infiltrating fibrotic thyroid existing, suggesting a natural progression of well-differen¬
mass presenting with compressive symptoms and rapid tiated carcinomas to ATC. Furthermore, 26% of 86
death. Histopathology reveals large areas of fibrosis, foci patients who died of papillary carcinoma demonstrated
of calcification, regions of infarction, atypical spindle cells spindle and giant cell metaplasia in their tumors, but only
obliterating large blood vessels and immunohistochemical 2% of 241 papillary carcinoma survivors had such meta¬
staining for carcinoembryonic antigen, actin, and cytoker- plasia in their primary malignancies, usually as minute foci,
atin (36). These cases could have easily been confused for if present. Once large amounts of metaplasia became evi¬
Riedel's struma. Other unusual ATC cases have apprecia¬ dent, the average survival shortened to 5 months (50).
ble areas of osteosarcomatous differentiation (carcinosar- A contrary view of Wallin et al. (51) derived from their
coma). These areas stain for vimentin, but not keratin, and analysis of 11 of 17 ATC tumors with coexistent differ¬
have prominent osteoid formation and focal calcification, entiated carcinoma. Utilizing cytophotometric DNA analy¬
suggesting a mixed epithelial-mesenchymal differentiation sis, they found that in only 36% of the cases the differen¬
(37). In two reports of this type of ATC, recurrent and tiated carcinoma foci shared DNA aneuploidy with the
metastatic tumor foci were purely osteosarcomatous and ATC component, suggesting that the majority of ATC cases
were both fatal at 26 months, although similar cases in the arise de novo rather than through clonai transformation
literature generally died within 5 months (38,39). of differentiated carcinomas. However, Galera-Davidson
Pure squamous cell carcinoma of the thyroid is extremely et al. (52) evaluated 8 similar cases and found DNA ane¬
rare, although metaplastic squamoid elements are not un¬ uploidy in both the differentiated and ATC components.
common components of ATC (40). The tumor is highly in¬ Their conclusion was that differentiated thyroid carcino¬
vasive and usually far advanced at time of presentation. mas with aneuploidy represented cases with a higher risk
Most patients expire within 6 months, although Simpson of ATC transformation. In fact, most ATC cases are found
and Carruthers (41) noted two patients alive after 4 years. to be aneuploid (53) and analysis of ATC DNA content
Insular carcinoma has previously been considered a va¬ has little, if any, prognostic significance (54-56). It is likely
riety of ATC and has also been called a solid variant of that aneuploidy, as a feature of the anaplastic phenotype,
follicular carcinoma or a poorly differentiated type of pap¬ may be a later metaplastic development, rather than a pre¬
illary carcinoma (22). This cancer is composed of nests of requisite for anaplastic transformation.
uniform cells and small follicles in an "insular" architec¬ An early observation of primary cultures of ATC re¬
tural pattern. The cells range from uniformly round to pleo- vealed that rounded epithelial cells spontaneously trans¬
morphic with nuclear features typical of papillary cancer formed into spindle and giant cell forms, recapitulating the
(intranuclear inclusion, grooves, and folds), rare mitoses, morphology of the original tumor (57). This is likely to be
and scant fine cytoplasm (42). Insular carcinomas have a an epiphenomenon of culture conditions because I see such

prognosis falling between ATC and differentiated carcino¬
mas. They may represent as much as 4% to 7% of thyroid
cancers (43). Unlike ATC, insular carcinomas frequently
retain iodide uptake and respond to radioiodine therapy
(44^16). A unique case demonstrated autonomous pro¬
reversible phenotypic changes in most thyroid carcinoma
cell lines, of all varieties of tumor histology, consequent to
nutritional status or degree of confluency. In contrast, a
fascinating report focuses attention on a more likely fac¬
tor involved in transformation of thyroid carcinomas to
718
ATC. A case of well-differentiated follicular carcinoma
contained multiple tiny foci of ATC, which uniquely im-
munostained for p53 protein overexpression consequent to
mutation of this gene. When microdissected, these specific
foci were shown to share the identical mutation in exon 6
exhibited by the lung and brain métastases of ATC that
killed this patient 8 years later (58). Other investigators
have found a high incidence of p53 mutations in ATC, but
rare, if any such mutations in coexisting differentiated can¬
cer foci, suggesting that inactivating mutations of this tu¬
mor-suppressor gene are important in triggering progres¬
sion from differentiated to anaplastic carcinomas (59-62).
This issue is not completely clear because some researchers
have found similar p53 mutations or immunohistochem¬
istry in well-differentiated thyroid carcinomas (63,64).
Other oncogenes that appear to be highly expressed in ATC
include c-myc (65) and Nm23 (65,66). Activation of ras
oncogenes is implicated in the development of ATC from
the study of Stringer et al. (67) in which DNA, extracted
from four ATC tumors, was transfected into murine 3T3
cells, resulting in malignant transformation and the ex¬
pression of human -ras. In another experiment, an ATC
cell line, TTA-1, was the recipient of normal human chro¬
mosome 11 using microcell-fusion-mediated chromosome
transfer (68). This caused suppression of tumorigenicity
and growth in soft-agar, suggesting that ATC cells were
deficient in activity of another putative tumor suppressor
gene located on chromosome 11.
Considering the fatal consequences of ATC, demonstra¬
tion of its genesis from differentiated thyroid carcinomas
places a particular burden on the clinician to aggressively
eliminate differentiated cancers in their earliest stages, be¬
fore anaplastic transformation can take place. At the very
least, reductions in tumor cell numbers may lessen the
chance for oncogene mutations that could result in ATC.
DIAGNOSTIC APPROACH
Fine-needle aspiration (FNA) biopsy has supplanted
most other methods of diagnosing thyroid malignancies,
both to avoid unnecessary resection of benign lesions and
to optimize the therapeutic approach by discriminating the
type of malignancy. This can be accomplished without
morbidity as an office procedure. FNA is an appropriate
diagnostic modality for the evaluation of ATC presenting
as a thyroid or cervical mass. In a series of 113 cases of
ATC evaluated by a FNA biopsy (69), 89.7% were cor¬
rectly identified with ATC, whereas 5% were thought to
be another type of thyroid malignancy. Just under 3% of
the FNA biopsies were inadequate for diagnosis and an
equal number were rated suboptimal. Reasons for inade¬
quate FNA results included: tumor regressive changes
(necrosis, hemorrhage, and leukocytic infiltration), exten¬
sive fibrosis, and sampling errors in regions of differenti¬
ated carcinoma. Others have also found that coexistent ar¬
eas of differentiated thyroid carcinoma contributed to FNA
sampling error (70). FNA biopsies may reveal the presence
of osteoclast-like giant cells and provide sufficient cellular
material for immunocytochemical analysis (71,72). Unfor¬
tunately, although early detection of ATC by FNA biopsy
allows diagnosis while the primary tumor size is small and
AIN
permits complete thyroid resection, this did not alter out¬
come in a small series of these patients (73). In some cases,
FNA produces insufficient diagnostic material, necessitat¬
ing open biopsy.
In most cases, features of rapid tumor enlargement and
invasive growth are reliable clues to the presence of ATC.
In other cases, a single tiny focus of ATC in an otherwise
well-differentiated thyroid carcinoma primary tumor or
metastasis is revealed after resection of the differentiated
tumor. Because the latter cases may have improved sur¬
vival (17) and be amenable to therapy, it is important to
carefully review the pathological findings of all thyroid tu¬
mors.
Nuclear and radiographie imaging procedures have lit¬
tle role in the diagnosis of ATC, but may be helpful in stag¬
ing disease. Astute clinicians refrain from using intravenous
contrast containing iodine for radiographie studies of thy¬
roid tumors because this would compromise radioiodine
treatment of differentiated carcinomas. Once the diagno¬
sis of ATC is established, however, there is no reason to
avoid such studies. Nuclear scans using radioiodine trac¬
ers are usually not appropriate because ATC does not con¬
centrate iodine and optimal scanning preparation requires
induction of hypothyroidism, which further weakens de¬
bilitated patients. Sometimes radioiodine scanning may
demonstrate the extent of coexistent differentiated thyroid
cancer; however, differentiated cancers do not contribute
much to the mortality of ATC patients. Thallium-201 nu¬
clear scans may assist in discerning ATC métastases that
evade detection by computerized tomographic radio-
graphic scanning or magnetic resonance imaging. Consid¬
ering the rapid growth of this tumor type, métastases rarely
remain undetected for long.
SURGICAL MANAGEMENT
Primary surgical management of ATC is an uncertain
and controversial topic. In view of the dismal prognosis,
there is a distinct tendency to severely limit tumor and thy¬
roid resection so as to merely provide confirmatory histo¬
logical samples and protect the airway. Frequently, this is
not a matter of choice because grossly invasive disease of¬
ten precludes significant resection. It appears that a total
thyroidectomy is justifiable if cervical and mediastinal dis¬
ease can be resected with reasonable morbidity, particu¬
larly to avoid upper airway obstruction (74). Patients with
more complete thyroid resections seem to have longer sur¬
vival (75). Junor et al. (76) evaluated 91 ATC patients
treated between 1961 and 1986. The 5% of patients with
total thyroidectomies, along with the 31% of patients with
partial thyroidectomies, had significantly prolonged sur¬
vival compared with patients who were merely biopsied.
Kobayashi et al. (77) found that more complete tumor re¬
section prolonged the mean survival from 2 months to 6
months. Although a study of 82 ATC patients by Nel et
al. (11) was compromised by the inclusion of 19 patients
with probably lymphoma (ie, "small cell" ATC), there was
a distinct trend toward prolonged survival with more com¬
plete resections. The increased likelihood of small primary
tumors to receive the most aggressive resections, introduces
obvious selection bias to account for this finding. Hermann
ANAPLASTIC THYROID CARCINOMA
et al. (78) found that reoperation of patients after tumor
recurrence to provide only palliative tracheostomy
a was
associated with a mean survival of 64 days compared with
a mean survival of 4f 2 days in those patients successfully
treated with a complete resection of the recurrent tumor
after a primary surgery that involved radical tumor resec¬
tion.
Prophylactic tracheostomies may not provide much help
to patients with unresected local disease. In 32 ATC pa¬
tients treated with tracheostomies (of which 45% were pro¬
phylactic against later respiratory complications), survival
was significantly lower (2 months compared with 5
months) than for 45 patients who did not receive tra¬
cheostomies. Many of the patients with tracheostomies had
local wound healing complications that were considered to
prevent postoperative radiation therapy (79).
RADIOTHERAPY
Local control of disease is an important component of
clinical management. External beam radiotherapy (XRT)
can provide substantial benefits in this regard, although
ATC should be considered as radioresistant relative to
other solid malignancies. In one series, analysis of survival
in ATC patients demonstrated a prolonged mean survival
of 6 months in patients receiving local XRT of more than
30 Gy as compared with 2 months in patients receiving
lower XRT doses (77). Similarly, a retrospective assess¬
ment of 51 ATC patients treated between 1970 and 1986,
with 22 patients having distant métastases at the time of
diagnosis and an additional 21 patients developing distant
métastases after diagnosis, noted that only 1 such patient
had a successful total thyroidectomy without gross resid¬
ual local tumor (80). Among those patients, cumulative
XRT doses less than 30 Gy were associated with a median
survival of 0.6 months with no patients alive at 1 year,
while cumulative XRT doses greater than or equal to 30
Gy were associated with a median survival of 3.3 months
with a 10% survival at 1 year. The subgroup of patients
who completed their course of XRT without evidence of
residual local disease, despite distant métastases, had a 7.5-
month median survival compared with a 1.6 month me¬
dian survival for patients with residual local ATC tumor.
Ultimately, all of the patients in this series died of ATC.
Both of these studies demonstrate the importance of local
disease control in prolonging survival and the utility of
XRT to provide this control, particularly when complete
surgical resection is not possible. On the other hand, Junor
et al. (76) noted that, despite an 80% total response rate
to local XRT and 39% with complete responses, there was
no apparent enhancement of survival by XRT in their large
patient cohort.
In 1983, Kim and Leeper (81) reported the use of hy¬
perfractionated XRT, augmented with low-dose doxoru¬
bicin (10 mg/m2) as a radiosensitizer, for local control of
ATC. Their final report in 1987 (82) revealed the results
of this treatment in f 9 patients with ATC. Patients received
5760 cGy XRT over 6 weeks administered in 160 cGy
doses twice daily (4 hours apart) for 3 consecutive days of
each week with doxorubicin administered once weekly, 1.5
hours before XRT. There was 84% complete local tumor
719
response after completion of the full 6-week course and
68% retained local disease control until their death. Al¬
though all patients died of distant métastases and all de¬
veloped moderate pharyngoesophagitis and tracheitis from
the XRT, the median survival of 12 months was quite long.
This method appears to provide the best opportunity for
local disease control in the absence of complete surgical re¬
section; however, there was no control group to test the
value of the chemoradiosensitization and local morbidity
was significant. A later review of 32 patients treated with
a different schema of hyperfractionated local XRT (initial
dose of 5 Gy followed by 1 Gy given 4 times daily, with
3 hours between doses, for 5 days each week to a total
dose of 30-45 Gy) resulted in a median survival of less
than 6 months and showed no benefit from concomitant
doxorubicin administered to half of the patients at 40
mg/m2 every 3 weeks (83). Skin and esophageal toxicities
appeared more severe than conventional XRT and 2 pa¬
tients developed radiation myelopathy despite the use of
posterior spinal cord shielding at 30 to 40 Gy, no expo¬
sure to doxorubicin, and low total spinal doses of 39.9 and
48.3 Gy, respectively. Because the latency of myelopathy
is around 20 months, far longer than these patients sur¬
vived, it is possible that the risk for this complication could
be greater than observed. In an earlier report from the same
institution, Simpson (84) emphasized that toxkity with this
variety of hyperfractionated XRT was quite severe.
Tennvall et al. (85,86) treated 33 ATC patients with
chemosensitized XRT before and after attempted surgical
resection of local disease. They used two regimens of hy¬
perfractionated XRT, 1 Gy or 1.5 Gy fractions (given twice
daily for 5 days each week to totals of 30 Gy before surgery
and 16 Gy after surgery), each given with concomitant
doxorubicin at 20 mg administered 1 to 2 hours prior to
each week's first XRT fraction. Median survival was sim¬
ilar with each regimen (3.5 and 4.5 months, respectively);
however, 4 of the 33 patients were alive without evidence
of disease at the time of publication, for periods ranging
from 30 to 84 months, and 48% of the patients achieved
local disease control. With that approach, the preoperative
hyperfractionated XRT may have improved the resectabil-
ity of the primary tumors. Hyperfractionation generally
permits the administration of higher total radiation doses
with less toxicity; however, the addition of chemosensiti-
zation is still unsettled in reference to types of agents, doses,
and acceptable toxicity. Nonetheless, for patients with
residual local postoperative disease, there is sufficient evi¬
dence to support the use of XRT (in some form, provid¬
ing at least 30 Gy) to provide a degree of local disease con¬
trol and prolongation of survival, even in the presence of
lethal distant métastases.
SYSTEMIC CHEMOTHERAPY
With one-half of ATC patients presenting with distant
disease, the rest developing distant métastases at some time
after presentation, and even patients with local control of
disease dying of distant spread of tumor, successful sys¬
temic therapy is the fundamental key to survival. Unfor¬
tunately, there has not yet been any chemotherapeutic
agent or combination of agents with sufficient antineo-
720 AIN

plastic activity against ATC to alter its fatal outcome. How¬ tients was reported using a combination of bleomycin, cy¬
ever, in rare patients with partial or complete responses, clophosphamide, and 5-fluorouracil (100).
delay in the progression of disease may significantly pro¬ Consideration of the relative ineffectiveness of antineo¬
long lives. As in many studies of ATC, because lymphomas plastic agents in ATC suggests an active role for one or
constitute a majority of the "small cell" ATC subtype, usu¬ more cellular mechanisms associated with chemotherapy
ally with greater response to chemotherapy than giant and resistance. Satake et al. (101) summarized their results, in¬
spindle cell ATC, some positive responses may be spurious. cluding two previous studies, investigating the expression
For ATC, doxorubicin (Adriamycin®, Pharmacia, of P-glycoprotein (MDR1 gene product), MRP (multidrug
Dublin, OH) has been used most commonly, but mono¬ resistance-associated protein, MRP1 gene product), LRP
therapy with this drug has been quite disappointing. A re¬ (major vault protein), and mutations of DNA topoiso-
view of chemotherapy for advanced thyroid carcinoma by merase Il-alpha (TOPII) in 10 ATC cell lines and 3 pri¬
Poster et al. (87) found most studies to have patients with mary tumors. Using immunohistochemistry for these pro¬
only a few partial responses (PR) to this agent, and little teins, reverse-transcriptase polymerase chain reaction
evidence of any complete responses (CR). Likewise, in 16 (RT-PCR) analysis for respective mRNAs, as well as DNA
ATC patients treated with multiple chemotherapy drugs, sequence analysis to assess for TOPII mutations, they
as single agents or in different combinations, Gottlieb and found all cell lines to express MRP (protein and mRNA),
Hill (88) found that doxorubicin provided only one PR, 7 positive for LRP proteins (8 positive by RT-PCR), and
with the same investigators later reporting only 2 PRs in 6 expressing MDR1 (protein and mRNA). All cell lines and
9 ATC patients treated with doxorubicin monotherapy tissues expressed TOPII and there were no mutations in
(89). One decade later, Shimaoka et al. (90) verified the this gene. All 3 of the tumors were positive for MRP and
failure of doxorubicin monotherapy, documenting only LRP, but MDR1 was seen in only 1 tumor. Most or all of
one PR in 2f patients receiving this modality, despite hav¬ the cell lines were resistant to doxorubicin, vincristine, cis¬
ing previously reported a summary of the literature in 1980 platin, and etoposide, with 2 resistant to bleomycin. P-gly¬
showing 23% PR to this agent alone (91). Reviewing many coprotein and MRP are membrane proteins that pump
of these same studies in 1987, Ahuja and Ernst (92) re¬ chemotherapy agents out of cells, resulting in resistance to
ported a similar 22.1% total response rate for 77 ATC pa¬ those agents. MRP has a similar spectrum of drug trans¬
tients. Other chemotherapy agents have been even less ef¬ port activity as p-glycoprotein, except that it is less able to
fective as monotherapy, although minimal activity has been transport paclitaxel (Taxol®, Bristol-Myers Squibb Oncol¬
claimed for bleomycin (87), etoposide (VP-16) (93), cis¬ ogy, Princeton, NJ) or colchicine (102). LRP has similar
platin (93), and methotrexate (23). drug transport properties in the membrane of intracellular
Chemotherapy combinations for ATC have typically in¬ vesicles, resulting in sequestration and ultimate exocytosis
cluded doxorubicin. Two studies evaluated doxorubicin in of chemotherapy agents, while mutations in TOPII may al¬
combination with cisplatin. The best results were reported ter this potential drug target (103). Our laboratory has re¬
by Shimaoka et al. (90) who noted 3 CRs and 3 PRs in 19 ported roughly similar results as above, except that all of
ATC patients for a 33% response rate. However, Williams our 6 ATC cell lines expressed MRP1 mRNA by RT-PCR
et al. (94) terminated their trial after finding only 1 PR in and none expressed MDR1 mRNA (104). Besides serving
a small number of patients, claiming the treatment to be as an explanation for the failure of systemic antineoplas¬
toxic and ineffective. These results are similar to the dis¬ tic therapies, these results suggest that MRP and LRP may
mal findings reported in a recent series of 14 ATC patients provide appropriate targets for inactivation, in order to re¬
(95). Addition of bleomycin to this regimen (ie, doxoru¬ store clinical response to standard chemotherapies.
bicin, cisplatin, and bleomycin) seemed to increase the re¬
sponse rate in a subset of 5 ATC patients out of a larger
series, resulting in 2 CRs and 1 PR, as well as a long mean COMBINED MODALITY TREATMENT
survival of 16 months (range 3-58 months) (96). Sokal and
Harmer (97) substituted vincristine for cisplatin (ie, doxo¬ Given the rapid, locally invasive growth of the ATC pri¬
rubicin, vincristine, and bleomycin) and found 4 PRs in a mary tumor, as well as its propensity for widespread dis¬
subset of 5 ATC patients from a larger group of advanced tant metastasis, with distant disease already evident at the
thyroid cancer, noting that the mean survival was only 7.6 time of diagnosis, it is logical to combine XRT with sys¬
months despite this response rate. Melphalan was added temic chemotherapy. Clearly, clinical studies have demon¬
to this regimen (ie, doxorubicin, vincristine, bleomycin, strated that local tumor control gained with XRT can pro¬
and melphalan) by Bukowski et al. (98) resulting in 2 PRs long survival in the face of unresected local disease, while
out of 5 giant cell ATC patients, with no noticeable dif¬ concomitant chemotherapy can interact to radiosensitize
ference in survival between responders and nonresponders. the primary tumor and may also enhance the ability of the
There are two promising studies of chemotherapy com¬ surgeon to clear otherwise unresectable gross disease. The
binations that do not contain doxorubicin. Kober et al. weak link in this therapeutic schema is the lack of a dis¬
(99) used a combination of cisplatin, vincristine, and mi- tinctively effective systemic antineoplastic regimen.
toxantrone in f 5 ATC patients, and reported 4 CRs and Nonetheless, several clinical studies have suggested the pos¬
6 PRs resulting in prolonged mean survival of 15.5 months sibility of enhanced survival and are discussed below.
and median survival of 20.8 months, compared with 3.8 One of the largest cohorts of ATC patients managed with
months and 4.5 months, respectively, in nonresponders. multimodality therapy consisted of 71 patients seen at one
Another high response rate of 7 responders of 9 ATC pa¬ institution between 1973 and 1989 (105). Despite preop-
ANAPLASTIC THYROID CARCINOMA
erative combinations of chemotherapy agents and XRT,
only 13% of patients were able to undergo successful com¬
plete resection of their primary tumors. Nearly three-quar¬
ters of these patients had distant métastases at presenta¬
tion and only 9% of the cohort survived for more than a
year, suggesting the inadequacy of the systemic component
of this treatment regimen. Likewise, Schlumberger et al.
(106) treated 20 ATC patients with either doxorubicin and
cisplatin (60 mg/m2 and 90 mg/m2 every 4 weeks) or mi-
toxantrone (14 mg/m2 every 4 weeks), both regimens in
combination with XRT (17.5 Gy in 7 fractions between
days 10-20 of the first 4 chemotherapy cycles), and noted
only 1 patient alive with each treatment regimen (at 34
and 40 months, respectively) and all patients suffering se¬
vere pharyngoesophagitis and tracheitis. Although the lo¬
cal response appeared good, the systemic response was
poor, and both long-term survivors were from among the
few patients with successful complete local surgical resec¬
tions.
Tallroth et al. (107) divided 47 patients into 1 of 4 dif¬
ferent combinations of chemotherapy and XRT. The first
group received methotrexate with XRT (30—40 Gy); the
second group received bleomycin, cyclophosphamide, and
5-fluorouracil with XRT; the third group received the same
treatment as the second group, with the addition of surgi¬
cal resection in midcourse and XRT increased in dose to
46 Gy and hyperfractionated; the fourth group was treated
similarly to the third group except that doxorubicin was
the only chemotherapy. The majority of patients in each
treatment group demonstrated some response to treatment
with median and mean survivals (months) of: 9 and 9 for
group 1; 4 and 15 for group 2; 4 and 15 for group 3; and
4 and 5 months for group 4. There was 1 long-term sur¬
vivor of more than f 2 years in group 2; 2 such survivors
(3.5 and fl years) in group 3; and 1 survivor for more
than 10 months in group 4. Although there did not seem
to be a clear advantage to any particular treatment regi¬
men, the long-term survival of over 8% appears more fa¬
vorable than otherwise expected.
In a recent Japanese series of 37 ATC patients
(1971-1993) treated with different chemotherapy agents
in combination with XRT, the median survival was in¬
creased to 8 months as compared with an unspecified group
receiving palliative treatment with 2-month median sur¬
vival. In a similar result as reported in the other series
above, there were 3 unusual long-term survivors for more
than 3 years. This is also similar to the result seen with 19
ATC patients treated with bleomycin, cyclophosphamide,
and 5-fluorouracil in combination with hyperfractionated
XRT to a dose of 30 Gy, followed by thyroidectomy and
an additional XRT to 15 Gy (108). The 9 patients pre¬
senting with distant disease or locally invasive tumor had
a median survival of 7 months, while the 10 patients with
local, noninvasive disease had a median survival of 12
months and included 3 long-term survivors (at 31, 61, and
80 months, respectively). Twelve of the 19 patients were
able to undergo thyroidectomy consequent to the preop¬
erative combined therapy. A similar approach with 5 ATC
patients used preoperative doxorubicin and cisplatin with
postoperative XRT, resulting in an average survival of 11.2
months and 1 long-term survivor at 31 months (109).
721
These studies are remarkable in that, although there was
little effect on general mortality, each regimen was associ¬
ated with a small number of unique patients with long-
term survival.
Two case reports delineate particularly aggressive com¬
bined modality therapies with apparently good results.
Casterline et al. (110) reported one ATC patient treated
with a total thyroidectomy and unilateral radical neck dis¬
section, followed by XRT (60 Gy over 40 days) with acti-
nomycin-D therapy started during the last week of irradi¬
ation (0.5 mg weekly for 10 doses). A later course of
actinomycin-D therapy (total dose of 26.5 mg) was sup¬
plemented with immunotherapy utilizing a methanol-ex-
tractable residue of BCG for 12 monthly courses. This pa¬
tient was reported as free of clinical disease at the final
48-month follow-up. A recent report of Sweeney et al.
(Ill) described a 61-year-old woman presenting with mas¬
sive and unresectable local disease treated with a combi¬
nation of: hydroxyurea (f g twice daily for 11 doses), 5-
fluorouracil (800 mg/m2 per day continuously over 5 days),
paclitaxel (20 mg/m2 continuously over 5 days), and XRT
(2 Gy daily for 5 days). This combination was adminis¬
tered every 2 weeks for 7 cycles (total XRT dose of 70
Gy). Although there was severe mucositis, dysphagia, and
weight loss requiring total parenteral nutrition, the primary
tumor regressed sufficiently to perform a near-total thy¬
roidectomy and unilateral modified neck dissection at 6
months from the initiation of therapy. Pathological evalu¬
ation revealed necrotic tissue with no evidence of viable
tumor. Despite the transient appearance of pulmonary nod¬
ules on computerized axial tomography (CAT) scanning,
the patient has remained free of evidence of ATC for at
least 38 months (E.E. Vokes, personal communication). A
key component of both of these cases is the absence of dis¬
cernible distant disease at the time of initiating aggressive
chemoradiotherapy.
BIOLOGICAL INVESTIGATIONS AND FUTURE
CLINICAL DIRECTIONS
In the face of an aggressive, rare, and usually untreat-
able cancer, further research is essential. Prospective clin¬
ical trials have no reasonable chance of acquiring enough
subjects to evaluate more than a few likely therapeutic ap¬
proaches. In addition, there is no clear evidence that cur¬
rently available therapies are likely to provide sufficient ac¬
tivity against this disease. ATC cell lines furnish the
investigator a versatile model system to study the cellular
and molecular biology particular to this malignancy, as
well as to devise and test novel antineoplastic strategies. In
the past decade, the number of ATC cell lines have in¬
creased dramatically. These cells can be grown in culture
dishes or as xenograft tumors in athymic mice and appear
to appropriately reproduce many of the features of the pri¬
mary tumors, including cytokinetics (112), radioresistance
(113), invasive, and metastatic behavior (114). Cell line
monolayers provide an opportunity for inexpensive and
rapid screening of potential antineoplastic agents; however,
active agents so identified must be tested against xenograft
tumors to verify preclinical effectiveness. For example,
722 AIN

suramin appears to be a potent cytotoxic agent in ATC
monolayer cultures, yet this agent accelerates the growth
of the same cell lines grown as xenograft tumors (115).
Analysis of cellular receptors for hormones and growth
factors may predict responses to their ligands. BHT-101
cells display estrogen and progesterone receptors and are
inhibited by tamoxifen (116). The absence of high-affinity
binding sites for thyrotropin on ATC cell membranes, de¬
except for partial sensitivity to doxorubicin and cisplatin
in only 1 cell line. Xenografts of primary ATC tumors in
nude mice showed only slight inhibition by doxorubicin
treatment and no enhancement of this effect with cy¬
clophosphamide coadministration (131). We have investi¬
gated chemosensitivity with a panel of six distinct ATC cell
lines, grown in monolayer cultures as well as in nude mice
as xenografts, in an attempt to define new active agents.

spite an intact adenylate cyclase transduction system, ac¬ Paclitaxel exhibited unique antineoplastic activity against
curately correlates with the absence of clinical ATC tumor all of the cell lines as monolayers and xenograft tumors
responses to endogenous or exogenous thyrotropin (117). were dramatically diminished with complete disappearance

Transforming growth factor-/? (TGF-/3) seems to function of some of them (132). Consideration of MRP as a mech¬
as an endogenous physiological inhibitor of thyroid follic¬ anism for ATC chemotherapy resistance, with its decreased
ular cell growth and differentiation, suggesting that the low activity against intracellular paclitaxel accumulation, sug¬
expression of its receptor, seen in ATC, may contribute to gests a reason for paclitaxel's activity in this disease. Con¬
its rapid growth and undifferentiated status (118). Al¬ sequently, an ongoing phase 2 human trial of paclitaxel
though the expression of platelet-derived growth factor monotherapy for ATC has demonstrated notable clinical
(PDGF) receptor B-type has been thought to be restricted response rates, with 1 complete response and 6 partial re¬
to mesenchymal and glial cells, the ATC cell line, C643, sponses in the first 11 évaluable patients, for a 64% re¬
expresses this receptor in a form that has more complex sponse rate (unpublished results). These preliminary results
glycosylation than in normal human fibroblasts (119). suggest this agent to be one of the most active for
ATC cells have been found to express angiogenesis factors chemotherapy of this disease.
(120), IGF-I-like growth-stimulating factors (121), and Despite the absence of radioiodine uptake in ATC tu¬
highly glycosylated forms of CD97 with unknown func¬ mors and lack of expression of sodium-iodide symporter
tion (122). We have shown that ATC cell lines express so- in ATC cell lines (our unpublished data), there may still be
matostatin receptor subtypes 1, 3, and 5 (123). Because so- a role for nuclear medicine therapy of ATC. Astatine-211
matostatin receptor agonists can inhibit cellular is an -emitting (mean energy 6.8 MeV) halogen isotope
proliferation (124), this provides a rationale for evaluat¬ with a half-life of 7.2 hours. In two separate studies
ing receptor subtype-specific somatostatin analogues for (133,134) human ATC expiants were grown as subcuta¬
antineoplastic activity. neous xenografts in nude mice. They were given a single
ATC can be associated with aseptic purulent effusions, intravenous or intraperitoneal injection of 370 or 740 kBq
leukocytosis, and fever. Iwasa et al. (125) described such of sodium astatine-211. By some unknown mechanism,
a case in which the tumor demonstrated immunohisto¬ ATC was able to concentrate astatine-211 2.6- to 12.5-
chemical staining for granulocyte-macrophage colony- fold over iodine-125 (134), taking 11% to 28% of the ad¬
stimulating factor (GM-CSF). In a similar patient, culture ministered dose per gram of tumor tissue in 6 of 8 ATC
of ATC cells from a malignant pleural effusion yielded the expiants (133). In normal thyroid glands, astatine uptake
KHM-5M cell line, which expressed interleukin 8 (IL-8) is blocked by C104~, TcO-t", and SCN~, much like iodide;
and GM-CSF, producing neutrophil infiltrations in nude however, propylthiouracil and thiouracil treatment in¬
mouse xenografts (126). The K-119 cell line was estab¬ creases astatine uptake, contrary to the effect on iodide up¬
lished from another ATC patient with marked neutrophilia take (133), implying a different route for astatine concen¬
and also spontaneously secreted GM-CSF, with augmented tration in ATC tissue. There are several impediments to
secretion in the presence of tumor necrosis factor (TNF), research with astatine-211, including the need to be in close
IL-la, and IL-1/3 (127). Evaluation of a panel of ATC cell proximity to a sufficiently powerful cyclotron to generate
lines revealed that secretion of GM-CSF spontaneously, or the isotope, the unknown chemical toxicity of astatine, and
after stimulation by IL-la, TNF-a, or phorbol esters, is the difficulty of dealing with radiotoxicity of an -emitter
common (128). The role of such immunoactive factors is to normal tissues. Nonetheless, this is a provocative idea
not well understood; however, Baba et al. (129) reported for potential new therapies.
an interesting case of a woman with ATC (the source of
the ATC cell line, KOA-2) who received intratumoral in¬
jections of -432/fibrinogen solution in a futile attempt CURRENT SUGGESTIONS FOR MANAGEMENT
at immunotherapy. The patient'slymphocytes were fused
with a human lymphoblastoid cell line (HO-323), pro¬ The current therapeutic armamentarium for ATC is very
ducing hybridoma that secreted monoclonal IgM (3C5) limited, but can be life-prolonging, or at least palliative, if
a
and reacted with cell membranes of KOA-2, as well as a appropriately utilized. Rare individuals with tiny foci of
number of other ATC tumors and some normal tissues. anaplastic carcinoma may enjoy long-term survival with
This suggests the possibility of future application of im¬ aggressive therapy. Certainly, any opportunity to enroll
munotherapy for this disease. ATC patients into clinical therapy trials should be taken,
A few investigators have attempted to define activity of because their scarcity impedes the progress of prospective
chemotherapeutic agents using ATC cell lines in monolayer clinical research and delays the development of new treat¬
culture. Asakawa et al. (130) used 3 ATC cell lines to eval¬ ments. These suggestions on management reflect one ap¬
uate the response to doxorubicin, cisplatin, etoposide, and proach to care and cannot be considered definitive in this
carboplatin. These cell lines were resistant to those agents changing field.
ANAPLASTIC THYROID CARCINOMA
Careful management of the local tumor mass can extend
survival. If resectable, this should be the first aspect of treat¬
ment, provided that vital structures are not severely com¬
promised. This is helpful, even in the presence of known
distant métastases, provided that distinct disease is not clin¬
ically more advanced than the local tumor. Complete re¬
section of gross disease is frequently impossible and local
hyperfractionated external beam radiotherapy is distinctly
helpful in this circumstance. It is uncertain whether
chemoradiosensitization provides sufficient therapeutic
benefit to justify increased radiation morbidity, but this may
be considered. Likewise, it is unclear whether prophylactic
tracheostomies enhance patient survival or comfort.
Systemic therapy is usually necessary, if aggressive treat¬
ment is desired, because most patients either present with
distant disease or develop these métastases soon after di¬
agnosis. Although traditionally, most patients have re¬
ceived chemotherapy centered on doxorubicin, initial data
on paclitaxel suggests that this agent has at least as much
activity, if not more, than doxorubicin or other agents.
Certainly, effective systemic therapies are the cornerstone
to radically improving the dismal survival data.
Limited reported experience with combination modali¬
ties suggests that aggressive and appropriate combinations
of surgery, radiation, and chemotherapy may provide some
benefit. Preoperative chemotherapy and radiation may en¬
hance the completion of a surgical resection of the primary
tumor. Enhanced networking of clinical investigators may
identify sufficient subjects to obtain prospective data on
the value of combination modality therapy for ATC.
Finally, because the typical ATC patient is far-advanced
in years, often with other comorbidities, the option of pal¬
liative care with or without local XRT must be considered.
It is essential to provide patients with appropriate comfort
measures and emotional support.
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