Pseudoangiosarcomatous Features in

Medullary Carcinoma of the Thyroid

.
Report of Two Cases
Mauro Papotti, M.D.,*Anna Sapino, M.D.,* Giancarlo Abbona, M.D.,*
Nicola Palestini, M.D.,† and Gianni Bussolati, M.D., FRCPath*

Two casesof medullary carcinoma of the thyroid showing an angiosarcomatous pat-

tern of growth are reported. Extensive hemorrhagic areas, strongly suggestive of a
vascular tumor, characterized the gross appearance of case 1. Microscopically, pseu-
dovascular spaces lined by elongated cells or containing nests of clear polygonal cells
intermingled with red blood cells were a prominent feature in both cases. Calcitonin
immunostaining was present in all neoplastic cells, both those in clear cell nests and
the flat ones lining the pseudovascular spaces. A similar pattern was observed in cell
block material obtained by fine-needle aspiration biopsy of case 2. Angiosarcoma-
like medullary carcinoma of the thyroid patterns add to the long series of masquer-
ades featuring medullary carcinoma of the thyroid and have to be considered in the
differential diagnosis with hemangioendothelioma of the thyroid. Int J Surg Pathol
3(1):29-34, 1995
Key words: medullary carcinoma, thyroid, angiosarcoma, differential diagnosis,
pathology.

In the original report on medullary carcinoma of
the thyroid (MCT), Hazard and co-workersl
described the classic features of this entity, but they
also stressed its marked heterogeneity in terms of
histologic patterns of growth. These authors men-
tioned spindle cell, giant cell, pseudopapillary, and
carcinoid-like variants as rare occurrences in the
setting of MCT. Later, several papers appeared on
different variants of MCT (for review see LiVolsF
and Schrbder and co-ivorkers’). No mention has
terns in MCT, although a prominent vascular com-
ponent wasdescribed in a case of MCT presented
by Ljungberga in his recent textbook (in Fig. 9.54).
We report the clinicopathologic features of two
cases of MCT with pseudoangiosarcomatous fea-
tures and discuss the problems encountered in the
differential diagnosis with vascular tumors of the
thyroid.
’

been made so far to pseudoangiosarcomatous pat-

Case Reports
Case 1
From the Departments of *Biomedical Sciences and Oncol-
ogy, and †Surgery, University of Turin, Italy. A 77-year-old man was admitted to the hospital
Supported by grants from the Italian Association for Cancer in November 1992 because of a progressively
Research (AIRC, Milan) and the Italian Ministry of University
(MURST, Rome). enlarging thyroid gland. Goiter had been present
Received for publication July 26, 1994; accepted in revised for many years, but recently dysphagia and dys-
form Jan. 30, 1995.
Reprint requests: Professor M. Papotti, Department of
phonia appeared. On examination, the whole thy-
Biomedical Sciences and Oncology, University of Turin, Via San- roid gland was enlarged and multinodular. Presur-
tena 7, 10126 Torino, Italy. gical tests as well as laboratory tests proved

29
30
inconclusive (except for elevated carcinoembryonic
antigen [CEA] -48.3 ng/mL). Calcitonin was not
tested. No familiar history of thyroid tumors was
reported. A near-total thyroidectomy was per-
formed. Grossly the left lobe of the thyroid mea-
sured 7 x 1 ~ cm and the right one 7 x 7 cm. Multi-
ple colloid nodules admixed with whitish areas
were found on cut section of the left lobe, while a
single cystic mass occupied the entire right lobe.
The central cavity of this mass was partially filled by
blood clots and librinous material. A thick fibrous
capsule surrounded the mass (Fig. 1). Four months
after the operation serum calcitonin and CEA levels
were just above upper normal limits, but no sec-
ondary deposits were found by scintiscan with 9&dquo;Tc
dimercaptosuccinic acid. The patient is presently
alive and well, 11/2 years after diagnosis.
Case 2
A 60-year-old woman underwent thyroid ultra-
sonography in November 1992 and was found to
bear a 13-mnl nodule in the midportion of the right
lobe. The nodule was apparently capsulated and
hyporeflecting. Six months later, another ultrasono-
gram showed an increase oi’ nodule size up to 17 mm
and a line-needle aspiration biopsy was performed.
A neoplastic growth with prominent spindle cell
pattern and a highly vascular stroma was observed
(see discussion later). Preoperative laboratory tests
were within normal range. Calcitonin was not
tested. A thyroid scan with nil disclosed multi-
odular goiter with a hypoactive nodule in the mid-
Fig. huge cystic tumor with extensive hem-
1. Case 1. A
orrhagic and
areas a thick fibrous capsule was observed
(arrow indicates the site of sampling ot Pig. 2a).
portion of right lobe. No familiar history of thyroid
tumors was reported. A total right thyroidectomy
and a near-total left lobe resection were performed.
Grossly, the right thyroid lobe contained a soft red-
dish nodule in the midportion, 1.5 cm in its largest
diameter, apparently encapsulated. The patient is
currently free o~ disease 1 year after operation.
Materials and Methods
Both surgical specimens were fixed in formalde-
and embedded in paraffin; fine-needle aspira-
hyde
tion cell block material was fixed in etl-~anol. Sec-
tions serial to the one conventionally stained with
hematoxylin and eosin (of both surgical and cyto-
iogic specimens) were submitted to Congo red stain
and to a battery of immunocytochemical reactions.
The imnlunoperoxidase procedure with avidin-
biotin-complex and diaminobenzidine as a sub-
strate was employed.
The following primary antibodies were used:
polyclonal to calcitonin (Ortho Diagnostic, Raritan,
NJ), kit diluted 1/1; monoclonal to chromogranin A
(Ortho), kit diluted 1/1; monoclonal to cytokeratin,
clone KLI (Immunotech, Marseille Cedex, France),
diluted 1/200; monoclonal tovimentin clone V9
(Dako, Glosstrup, Denmark), diluted 1/30; poly-
clonal to factor VIII-related antigen (Dako), diluted
1/1000.
Pathologic Findings
Surgical Specimens
Case 1 presented with a cystic tumor filled with
extensive blood clots as a result of hemorrhage (Fig.
1 ~. Neoplastic islands were identified exclusively in
the context of a thick fibrous capsule tfig. 2a); only
1 of the 12 samples taken from capsular areas did
contain groups of polygonal cells arranged in solid
cell nests as typically observed in classic MCT,
though lacking amyloid stroma. In case 2, a solid
tumor was present associated with a prominent
vascular stroma and an irregular fibrous capsule.
In both cases, elongated, occasionally ps~lristrati-
fied ~~eoplastic cells lined pseudovascular spaces.
An empty space, occasionally containing red blood
cells, was usually present between the neoplastic
nests bordering the wall of the pseudovascular
space: this picture strongly recalled the architec-
ture of some well- or moderately differentiated
angiosarcomas. &dquo;Tufting&dquo; of elongated neopiastic
cells made this similarity even more striking (Fig.
2a,b; Fig. 3).
 31

~’~g. 2. Case 1. At low magni-

fication,, the capsuie shows
fibrous bundles with residual
thyroid follicles and tumor
eclls arranged in solid nests
or lining pseudovascular
spaces (a). These have an
irregular profile, are lined by
elongated cells, and occasion-
ally contain red blood cells
and fibrin (b) (a: H&E x 1 iO,
b: H&E x 300).

Thick collagen bands separated the pseudovascu-

lar spaces (Fig. 3~. Amyloid was virtually absent in
both cases. No necrosis ivas present. The cells had a
clear or finely granular cytoplasm. The nuclei had
an irregular border and marked hyperchromasia.

Pieomorphic nuclei were occasionally seen as well

as few miiotic figures.

Fine-needle Aspiration Cytologic Findings

In the smears by fine-needle aspiration
obtained
biopsy of case 2 the
majority of ~eoplastic cells
were spindle- shaped and showed a poorly defined

cytoplasm. Moreover, in the cell block prepared

from aspirated tissue fragments, a prominent pseu-
dovascular component lined by tumor cells was
recognized.

lmmunocytochemistry
The cells lining the pseudovascular spaces were
invariably positive for calcitonin and chromogranin
(F Ig. 4), while immunostainings for endothelial and
r~esencl~yr~~ai markers (factor Vill-related antigen
and vimentin) were negative. CEA and cytokerann
were intensely positive.

Discussion

Angiosarcoma-like features are described in two

cases of medullary carcinoma of the thyroid. One
Fig. 3. Case 2. Pseudovascular spaces separated by thick
collagenous bands are lined by one to few layers of cells. case had both gross and microscopic features
’Tufiing- of neuplastic cells is highly suggestive of a vas- resembling angiosarcoma, while in the other, areas
cular tumor (H&E x 200). showing cyiohistologic patterns recalling vascular
32
Fig. 4. Case 1. (a) Immuno-
peroxidase staining for calci-
tonin. Positivity is limited to
neoplastic cells lining pseu-
dovascular spaces of the
tumor (center lower field)
while surrounding thyroid is
negative, (b~ At higher mag-
nification, the granular cyto-
plasmic staining is shown.
Notice the &dquo;tufting&dquo; of elon-
gated tumor cells (a: H&E x
40, b: H&E x 300).
tumors merged with areas of classic (alveolar) MCT.
Gross appearance was remarkable. In case ~, a huge
cyst with hemorrhagic and necrotic content sur-
rounded by a fibrous capsule was
ture strongly suggesting hemangioendothelioma
(see Fig. I in E~asebi et al.5j. At first glance, the dif-
ferentiil diagnosis was between an hemorrhagic
cyst and a vascular tumor: Both lesions
tively common occurrences in our
and areassociated with multinodular goiter.&dquo;
Iv1icroscopically, the rmajor distinctive feature in
both cases was the presence of pseudovascular
spaces lined by elongated cells and containing clus-
ters of polygonal neoplastic cells. This cell arrange-
ment is similar to the case reported by Ljungberg’¡ in
Fig. 9.54 of his textbook. Even in his case, pseu-
dovascular spaces lacking endothelial lining were
found (personal communication). Such spaces also
contained fibrin and red blood cells, and stromal
hemorrhage was a common feature. In some areas,
the spaces had a roundish profile and recalled pseu-
doglandular structures with intraluminal artifactual
clefts. In the glandular variant of MCT/ ~owever,
neoplastic cells are arranged in small or large
islands containing tubular structures filled with col-
loid, a pattern that was never recognized in the
present cases.
Morphology alone could not allow a differential
diagnosis with a vascular tumor in case 1, where
areas of classic MCT and amyloid deposits were vir-
tually absent. Only immunocytochemistry allowed
a correct classification of this tumor, since mes-
enchymal and endothetial markers proved negative
and epithelial differentiation was detected by ker-
atin i~rn~.mostair~. Rare cases of angiosarcoma can
express c~tokeratir~,5 and this event can lead to
erroneous diagnoses of epithelial versus vascular
tumors. In the present cases, the concurrent
expression of cytokeratin and r;euroer~docrir~e
markers permitted us to identify the C cell origin of
observed, a fea- the tumor.
The nature of the pseudovascular spaces is not
clear. An analogy can be traced with the pseu-
dopapillary variant of MCT since in the latter
are rela- empty-appearing spaces do occur, artiiactuai sepa-
alpine region ration of groups of tumor cells attached to rigid
stromal bundles being the most probable explana-
tion.1 A similar mechanism may lead to the creation
of clefts lined by tumor cells in our cases.
Features similar to those described here, sig-
nateiiy hemorrhage, necrosis, and occasionally
papillary endothelial hyperplasia, have been
described as artifactual effects of fine-needle aspira-
tior~.9 Fir~e-neeciie aspiration however, had not
been performed in case i, and pseudoangiosarco-
matous features could already be traced in fine-
needle aspiration material in case 2. The prominent
vascular component observed in the ceil block and
the spindle-shaped cells with poorly defined cyto-
plasm are uncommon cytologic features of MCT,
and a differential diagnosis with malignant heman-
gioendothelioma was considered.
The distinction of MCT from angiosarcoma has
important prognostic implications because MCT,
including cases with angiosarcoma-like features
like those described here, can follow an indolent
course, while malignant vascular tumors are highly
aggressive neoplasms.&dquo;
Acknowledgment
The skillful photographic assistance of Mr. A. Fer-
raro is gratefully acknowledged.

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