CASE REPORT

A case of rapidly progressing primary thyroid angiosarcomain a Japanese man

Nana Rokutanda • Jun Horiguchi • Yukio Koibuchi • Daisuke Takata •

Rin Nagaoka • Ayako Sato • Hideaki Tokiniwa • Sayaka Uchida •

Mio Furuya • Tetsunari Oyama • Izumi Takeyoshi

Received: 28 October 2013 / Accepted: 26 May 2014

� The Japan Society of Clinical Oncology 2014

Abstract Primary thyroid angiosarcoma is a very rare

and aggressive disease, originally reported in patients from

the Swiss Alpine region, but is rare in other parts of the

world. We describe a Japanese case of primary angiosar-

coma of the thyroid in a 64-year-old man, who presented

with a rapidly enlarging painful neck mass. Fine-needle

aspiration biopsy was performed, and the results were

interpreted as malignant. FDG-PET-CT demonstrated a

necrotic lesion on the right side of the neck with high FDG

uptake. The patient underwent a total thyroidectomy.

Pathological findings revealed a proliferation of atypical

cells lined vascular spaces. Immunohistochemistry staining

(IHCS) was positive for factor VIII, and CD31, but not

CD34, and negative for CK 5, CK 7, and CK 20. From

these findings, it was diagnosed as an epithelioid angio-

sarcoma. Two weeks after the operation, bilateral bloody

pleural effusion was observed, and he died 3 months after

the surgery.

Keywords Primary � Angiosarcoma � Thyroid

Introduction

Primary thyroid angiosarcoma is a very rare and aggressive

disease. The incidence of primary thyroid angiosarcoma is

highest in European alpine regions, and it constitutes

2–10 % of all malignant thyroid tumors in Switzerland,

Austria, and northern Italy [1, 2]. In other parts of the

world, it is extremely rare [1–9].

Local recurrence and metastasis are frequent, and

patients usually die within a short period of time after

diagnosis. Early tumor metastasis to regional lymph nodes

and the lungs is frequent. Currently, no optimal treatment

strategy is available for this malignancy [7]. Here, we

present a Japanese case of angiosarcoma of the thyroid

gland that underwent a markedly progressive course as an

undifferentiated thyroid carcinoma.

Case report

A 64-year-old Japanese man with a painful neck mass was

referred to our hospital for evaluation. The patient had

noticed the neck mass 2 months prior. At the first visit, the

patient had no hoarseness. There was no prior history of

neck trauma or irradiation, or a family history of thyroid

disorders. Physical examination revealed a hard, irregular,

and tender painful nodular lesion measuring 5 9 3 cm in

the right thyroid lobe. A few hard, painful lymph nodes

were also palpable in the right neck. Ultrasonography of

the neck revealed a well-circumscribed mass that measured

4.9 9 3.9 cm arising from the right thyroid lobe, as well as

a few swollen lymph nodes. Fine-needle aspiration biopsy

was performed for the thyroid tumor and lymph nodes, and

the results were interpreted as malignant. These cells dis-

played nuclear atypia and prominent nucleoli, absent

N. Rokutanda (&) � J. Horiguchi � Y. Koibuchi � D. Takata �R. Nagaoka � A. Sato � H. Tokiniwa � S. Uchida � I. Takeyoshi

Department of Thoracic and Visceral Organ Surgery, Gunma

University Graduate School of Medicine, 3-39-22 Showa-Machi,

Maebashi, Gunma 371-8511, Japan

e-mail: nana.rokutanda@gmail.com

M. Furuya � T. Oyama

Department of Diagnostic Pathology, and Clinical Department of

Pathology, Gunma University Graduate School of Medicine,

Maebashi, Gunma, Japan

123

Int Canc Conf J

DOI 10.1007/s13691-014-0170-x

colloid, and poor cellularity (Fig. 1). Immunohistochem-

istry staining of the atypical cells in the aspirate of lymph

node was slightly positive for thyroglobulin, which was

probably of thyroidal origin. Laboratory investigation

showed slight increases in leukocytes (9700/ll), C-reactive

protein (3.8 mg/dl), and liver function (GOT 70 g/dl, GPT

81 mg/dl). Serum thyroid hormone levels were normal, but

thyroglobulin was markedly elevated to 2960 ng/ml (nor-

mal range, 0–35 ng/ml).

An 18F-fluorodeoxyglucose positron emission tomog-

raphy computed tomographic (FDG-PET-CT) scan dem-

onstrated an irregular shaped mass on the right side of the

neck and right cervical lymphadenopathy. Max SUV was

higher than 10 MBq/ml with central loss of FDG uptake

(Fig. 2). CT showed bilateral multiple small lung nodules

resembling metastatic lesions, which had no FDG uptake.

Bronchoscopy was performed, but there was no abnor-

mality in the pharynx or larynx on the first visit.

The patient was scheduled for total thyroidectomy. During

the month in which the patient was waiting for an operation,

he complained of increasing pain in the neck with concomi-

tant hoarseness and coughed up bloody phlegm. Bronchos-

copy revealed right vocal cord central fixation, which had not

been present at the first visit. The day before the operation, re-

examination by ultrasonography revealed an enlarged right

thyroid mass that measured 7 9 5 cm and massive lymph

nodes. From the evidence of rapid glowing tumor and his

progressive symptoms, we suspected the disease as anaplastic

carcinoma, but there was no definite cytological or histolog-

ical diagnosis of anaplastic carcinoma. So we decided the

operation to get histological diagnoses and to keep airways or

to improve the prognosis by any chance, under informed

consent to the patient and his family.

The patient underwent a total thyroidectomy and central

neck lymph node dissection (Level I–IV). At surgery, the

anterior surface of the right lobe of the thyroid had a firm,

fairly noncircumscribed 8 9 7 9 5 cm solid mass strongly

adherent to the right laryngeal recurrent nerve; however,

there was no evidence of invasion to any other extra thy-

roidal invasion of the trachea/larynx or the esophagus/

pharynx. The thyroid was totally removed including the

right laryngeal recurrent nerve.

Three hours after surgery, the patient presented with

acute airway obstruction caused by paralysis of recurrent

nerve and laryngeal edema, and then an emergency tra-

cheostomy was performed.

Pathological findings of gross features showed that the

right lobe of the thyroid measured 7.5 9 6.7 9 3.5 cm.

The cut surfaces showed a well-capsulated nodule that

appeared cystic and hemorrhagic in the central sur-

rounded by solid tumor lesion colored gray-white-brown

(Fig. 3).

Fig. 1 Fine-needle aspiration specimen of the thyroid mass (Papa-

nicolaou stain; a 940, b 9200). Atypical cells were evident singly, as

well as in loose clusters. These cells had a high nucleocytoplasmic

ratio, round to irregular nuclei, a coarse chromatin pattern, and

prominent nucleoli

Fig. 2 An 18F-fluorodeoxyglucose positron emission tomography

computed tomographic (FDG-PET-CT) scan demonstrated a necrotic

lesion on the right side of the neck (a); max SUV was higher than

10 MBq/ml with central loss of FDG uptake (b)

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Microscopic features revealed a proliferation of atypical

cells with enlarged hyperchromatic nuclei with prominent

nucleolus disposed in sheets and nests. In some lesions,

spindle-shaped cells were seen (Fig. 4a, b). These neo-

plastic cells lined vascular spaces that included erythro-

cytes, and intracytoplasmic lumina were observed.

Papillary, follicular, squamous, or any other recognizable

epithelial differentiation was not seen. Mitotic figures were

frequently observed and a rim of residual thyroid tissue

was noted in some areas. All of dissected lymph nodes

were involved tumor cells and vascular invasion.

IHCS was done with antibodies against the following

antigens: factor VIII (F8/86, Dako, 1:100 dilution, prote-

ase, 8 min retrieval), CD31 (JC70A, Roche, 1:20 dilution,

EDTA(pH 8.5), heat, 60 min retrieval), CD34 (NU-4A1,

Nichirei, ready to use for dilution, EDTA(pH 8.5), heat,

60 min, retrieval), CK5 (XM26, Novocastra, 1:200 dilu-

tion, EDTA (pH 8.5), heat, 60 min retrieval), CK 7 (SP52,

Roche, ready to use for dilution, EDTA (pH 8.5), heat,

60 min retrieval), CK 20 (SP33, Roche, ready to use for

dilution, protease, 4-min retrieval), pan-cytokeratin

(PCK26, AE1/AE3, Roche, ready to use for dilution, pro-

Fig. 3 The macroscopic photograph shows the cut surfaces of

resected thyroid tumor. It showed a well-capsulated nodule that

appeared cystic and hemorrhagic in the central surrounded by solid

tumor lesion colored gray-white-brown

Fig. 4 Microscopic findings revealed a proliferation of atypical cells

with enlarged pleomorphic nuclei and prominent nucleoli disposed in

sheets and nests. In some lesions, spindle-shaped cells were seen (a, b,

HE, 9200)

Fig. 5 Immunohistochemically, tumor cells were positive for vascu-

lar endothelial markers, factor VIII (a), and CD31 (b)

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tease, 4 min retrieval), SMA (1A4, Dako, 1:100 dilution),

S-100 protein (polyclonal, Roche, ready to use for dilu-

tion), c-kit (polyclonal, Dako, 1:50, EDTA (pH 8.5), heat,

60 min retrieval), TTF-1 (SPT24, Nichirei, ready to use for

dilution, EDTA (pH 8.5), heat, 60 min retrieval), Thyro-

globulin (DAK-Tg6, Dako, 1:100 dilution). All of them

were examined using I-VIEW DAB kit. The result of IHCS

of this tissue was intensely positive for vascular endothelial

markers, factor VIII (Fig. 5a), and CD31 (Fig. 5b), but not

CD34. IHCS was negative for CK 5, CK 7, and CK 20, but

partially positive for pan-cytokeratin. IHCS for SMA,

S-100 protein, c-kit, TTF-1, and thyroglobulin was nega-

tive. Based on the microscopic and immunohistochemical

findings, the patient’s neck tumor was diagnosed as an

epithelioid angiosarcoma.

The patient was scheduled for local radiation therapy,

but it was not performed because of an eventful postop-

erative course. Two weeks after the operation, bilateral

bloody pleural effusion was observed, and during the next

2 weeks, the patient required mechanical ventilation. Two

months after the surgery, the patient developed local

recurrence and rapid progress, and then died 3 months after

the surgery.

Discussion

Primary angiosarcoma is a rare tumor of the thyroid gland.

The highest prevalence of primary angiosarcoma is in

Switzerland and the alpine regions; it is rare in other parts

of the world. A search of acknowledged primary epitheli-

oid thyroid angiosarcomas from Asia in the English liter-

ature yielded only seven cases: two from Singapore and

one case each from Malaysia, China, Korea, Iran, and

Turkey [1, 7–12]. This is the first case reported in English

from Japan according to a PubMed search.

Kaur et al. [13] reviewed 47 cases of angiosarcoma of

the thyroid gland, described that the mean age of this

disease is 66.1 years old, and 79.2 % were 60 years or

more years of age. The most common presenting symptom

was rapid increase in a neck mass either with a long-

standing goiter or a new mass. Other common symptoms

are dyspnea, dysphagia, neck pain, weight loss [13]. This

patient complained of a rapid glowing mass and increasing

neck pain and finally hoarseness and severe cough with

bloody phlegm. We imagined that this case would be an

anaplastic carcinoma, but we had never expected a diag-

nosis of angiosarcoma because of its extremely rare

incidence.

There could have been options in treating the cancer had

it been anaplastic carcinoma, like chemotherapy or radia-

tion. However, as there was no definite cytological or

histological diagnosis of anaplastic carcinoma, an

operation was decided on under the informed consent of

the patient and the family, for three reasons: to get histo-

logical diagnoses of this rare case, and to keep the airways

of the patient and to improve the patient’s prognosis even

by a small chance.

Angiosarcoma of the thyroid can rapidly spread to the

lungs, which is the most common site for distant metas-

tasis, lymph nodes, brain, and intestines, and cause severe

bleeding [1, 14–16]. In the present case, non-symptomatic

bilateral small lung metastasis without FDG uptake was

determined preoperatively. After surgery, the lung metas-

tasis immediately worsened and caused bloody pleural

effusion.

Diagnosis of thyroid angiosarcoma can hardly be made

by aspiration cytology, in most cases reported previously

cytology was reported as inconclusive or nonspecific

malignancy or anaplastic/follicular thyroid cancer [13].

Whether thyroid angiosarcomas exist distinctly from

variants of anaplastic thyroid carcinoma with endothelial

differentiation is still controversial [10]. However, the

WHO classification of thyroid tumors, published in 2004,

has added angiosarcoma to the four traditional major tumor

groups [17] and more recent findings support the inde-

pendent existence of thyroid angiosarcomas based on IHCS

criteria, such as expression of endothelial-specific markers

by these tumors [18] and specific electron-microscopic

criteria [19]. In our case, IHCS revealed that the cytoplasm

of a large number of neoplastic cells was strongly positive

for factor VIII and CD31, but negative for several epithe-

lial, lymphocytic, oncofetal, and neuroendocrine markers.

In this case, IHCS of the fine-needle aspiration cytology

was slightly positive for thyroglobulin, but IHCS of the

specimen was negative for thyroglobulin. When non-fol-

licular cells exist near thyroid follicles, false-positive

staining is frequently observed because of antigen perme-

ation. Especially on cytological preparations, the phe-

nomenon more frequently occurs.

The differential diagnosis of this case is anaplastic or

poorly differentiated carcinoma with angiomatoid features.

Pathological findings did not show any evidence of ana-

plastic thyroid carcinoma, or epithelial structure, but the

evidence of a lot of atypical cells lined imitating blood

vessel, and IHCS of CD31 and factor VIII-related antigen,

which were found to be the most consistently vascular

endothelial. And some angiosarcoma showed partially

IHCS positivity for cytokeratin antigen [13]. Taken toge-

ther, these findings support the notion that our patient’s

tumor was indeed an angiosarcoma.

Thyroid angiosarcoma is known to be an aggressive

tumor with poor prognosis. Mortality rate was described up

to 90 % [13]. It is very difficult to assess the true mortality

rate and average survival time from previous reports

because of high variability in follow-up period. Metastatic

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disease is associated with poor prognosis and limits the

mean survival time to a few months after diagnosis and

surgical treatment. Good prognosis seems to be related

mainly to the absence of distant metastasis and complete

dissection of the tumor [5]. In the present case, there was

extraglandular tumor invasion and lung metastasis, and the

patient died 3 months after surgery.

There is lack of data to suggest the best treatment for

angiosarcoma of the thyroid. However, studies have been

done to review the treatment options and outcome in cases

of angiosarcoma of the head and neck. Radical excision of

the tumor with adjunctive radiotherapy has been shown to

improve outcome and survival. Chemotherapy was

described as having undefined role in these studies [20–22].

Nowadays, newer treatments under investigation include

drugs targeting VEGF/VEGFR pathway (bevacizumab)

and tyrosine kinase inhibitors with activity against VEGFR

(sunitinib and pazopanib) [23].

In conclusion, we had experienced a very rare and

aggressive primary angiosarcoma of the thyroid. With the

luck of statistical data and guideline for treatment, unfor-

tunately we could not save his life. To provide a more

useful date for the future patients, collating known cases

and studying them are needed to find an effective treatment

for this kind of rare disease.

Conflict of interest Nana Rokutanda and the other co-authors have

no conflict of interest.

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