Romanian Journal of Morphology and Embryology 2010, 51(2):359–363
C CA AS SE E R RE EP PO OR RT T
Thyroid regional metastasis from a giant cell
malignant fibrous histiocytoma of the larynx
in a patient with history of trichinellosis
CORINA LICHIARDOPOL1), I. OSMAN2), S. D. ENACHE3), CAMELIA FOARFĂ4),
VIOLETA COMĂNESCU3), MIRELA GHILUŞI3), M. POPESCU5)
1)Department of Endocrinology,
University of Medicine and Pharmacy of Craiova
3)Department of Pathology
Emergency County Hospital, Craiova
4)Department of Pathology
5)Department of Radiology and Medical Imagistic
University of Medicine and Pharmacy of Craiova
Sarcomas represent less than 1% of malignant laryngeal tumors and giant cell malignant fibrous histiocytoma is exceptionally rare.
Diagnosis is histologically based and immunohistochemistry allows differentiation from other fibro-histiocytic neoplasms. We present the
case of a 53-year-old male patient with positive medical history for trichinellosis and tuberculosis, and a laryngeal tumor invading the
thyroid and causing respiratory distress by airway obstruction. Total laryngectomy and thyroidectomy were performed followed by thyroxine
replacement therapy and radiotherapy. Histologically, the tumor consisted of spindle shaped cells with prominent mitoses, and abundant,
osteoclast-like, multinucleated giant cells. Similar lesions were identified in the thyroid, adipose and muscular tissues. Parasitic elements
were present in muscles. Tumoral cells showed positive immunostaining for Ki67 (40–50%) and vimentin and negative for AE1/AE3, CD31,
S100 and myoglobin; the giant multinucleated cells were CD68-positive. Chronic infection might have had a pathogenic significance.
Keywords: giant cell malignant fibrous histiocytoma, larynx, thyroid, vimentin, CD68, trichinellosis, tuberculosis.
Most of laryngeal malignancies originate from the
laryngeal epithelium and affect the glottis. Glottic squa-
mous cell carcinoma displays thyroid invasion in 23%
of cases. Laryngeal tumors invading the thyroid gland
also invade the cricothyroid membrane, anterior comi-
ssure, laryngeal ventricle and the thyroid cartilage, with
an important impact on the patient’s management .
Also, thyroid cancer may spread posteriorly, enhan-
cing morbidity and mortality: it is estimated that overall,
15% of thyroid cancers exhibit extrathyroid spread ,
which warrants adjuvant radiotherapy and complicates
airway management, especially in cases with anaplastic
thyroid carcinoma, in which more than 70% of patients
experience tumoral infiltration of the surrounding struc-
Age adjusted incidence rate of laryngeal cancer is
3.5 per 100 000 men and women per year, with an age
adjusted death rate of 1.3 per 100 000 men and women
per year (U.S. National Cancer Institute, http://seer.
Sarcomas represent less than 1% of malignant
laryngeal tumors, are much more frequent in males,
especially elderly, are most often situated in the vocal
cords, more definitely localized, and less likely to ulce-
rate and to infiltrate than squamous epithelial carci-
noma. Accurate diagnosis depends on careful biopsy.
Treatment consists of surgical excision followed by
radiotherapy in cases with high grade lesions, positive
surgical margins, tumor size greater than 5 cm or recu-
rrent lesions; the effects of chemotherapy on laryngeal
sarcomas has not been documented .
Survival at 5 years ranges from 50 to 77% [4, 5].
Malignant fibrous histiocytoma (MFH) is the most
common soft tissue sarcoma in adults and consists of
spindle shaped cells, histiocyte-like cells, polymorphic
giant cells and inflammatory cells. There are several
variants of MPH: myxoid, angiomatoid, giant cell,
inflammatory, common type (storiform pleomorphic)
and skin atypical fibroxanthoma . Approximately
15–20% of sarcomas occur within the neck and head
; most often MFH occurs in soft tissues of extremi-
ties and abdomen. Less than 50 cases with MFH of the
larynx were reported [4, 7–9], two of them with giant
cell variant [4, 9]. Less than 20 cases with primary
thyroid MFH and several cases with metastatic thyroid
MFH were also reported [10–13]. Here we report a case
of giant cell MFH of the larynx with regional thyroid
Corina Lichiardopol et al.
? Patient, Methods and Results
We present the case of a 53-year-old male patient,
referred to the Department of Endocrinology for goiter,
weight loss (affirmatively 20 kg in the previous six
months), fatigue, dyspnea lasting for one month,
hoarseness and selective dysphagia, raising the clinical
suspicion of compressive or infiltrative thyroid cancer.
The patient was a smoker and an alcohol consumer and
had a positive history for trichinellosis (20 years ago)
and lung tuberculosis (10 years ago). Chest X-ray
excluded active tuberculosis prior hospitalization.
Physical examination revealed underweight (body
mass index 17 kg/m2), tachycardia, resting inspiratory
dyspnea with stridor and a large, diffuse, painless goiter,
with impalpable lower poles, firm texture, preserved
movement during swallowing and absent regional
Thyroid ultrasound revealed a 65 mL goiter with
diffuse hypoechoic pattern and hyperchoic septae,
resembling chronic thyroiditis, and an ill-defined
hyperechoic region in the posterior part of the right
lobe. No abnormalities were detected on abdominal
TSH was normal (2.26 mUI/mL) and also the
routine laboratory screening except elevated ESR
(35/63 mm), low blood glucose (75 mg/dL) and total
cholesterol (138 mg/dL).
Laryngoscopy identified a violaceous, nonulcerated
glottic tumor, extended subglottically and in the
laryngeal vestibulum, with irregular-shaped surface;
histologic examination of a tumoral fragment obtained
by biopsy showed a proliferation of spindle shaped
malignant cells invading the squamous epithelium.
The patients’ condition aggravated, obstructive respi-
ratory failure ensued, imposing emergency tracheotomy.
CT-scan was then
1.25/1.55/3.51 cm laryngeal mass infiltrating the right
vocal cord and adjacent muscular and adipose tissues,
with marked laryngeal narrowing (Figure 1), a large
goiter extending to the cervicomediastinal junction,
sequelar lung tuberculosis, absence of distant lung, liver
and spleen metastases and no regional lymph nodes
greater than 1 cm.
performed, showing a
Given the infiltrative features of the tumor, total
laryngectomy and total thyroidectomy with lymph node
dissection were performed under general anesthesia with
endotracheal intubation, with pharyngeal suture, reposi-
tion of prelaryngeal muscular planes and skin sutures.
Figure 1 – CT-scan of the laryngeal MFH.
Specimens were fixed in 10% formalin, embedded
in paraffin, sectioned, Hematoxylin–Eosin stained or
processed by LSAB (HRP) (LSAB – Labeled Strep-
tavidin Biotin; HRP – Horseradish Peroxidase) .
Monoclonal mouse antihuman antibodies (except for
myoglobin-polyclonal) were used (DAKO Carpinteria
CA) anti: cytokeratin (AE1/AE3 clone; citrate 5c; 1:50),
vimentin (V9 clone; citrate 3c; 1:30), CD31 (JC 70A
clone; Tris EDTA 5c; 1:20), CD68 (PG-M1; citrate 7c;
1:100), Ki67 (MIB-1 clone; citrate 7c; 1:20) and also,
without unmasking, S100 protein (1:500) and myo-
Histopathological examination revealed a malignant
proliferation, consisting of spindle shaped cells, with
prominent mitoses, abundant osteoclast-like multi-
nucleated giant cells (Figure 2) and vascular tumoral
emboli (Figure 3).
Figure 2 – Malignant
spindle-shaped and multinucleated giant cells (HE
proliferation consisting of
Figure 3 – Vascular emboli in tumoral vessels (HE
Thyroid regional metastasis from a giant cell malignant fibrous histiocytoma of the larynx in a patient with history…
Lesions with similar histologic pattern and inflamma-
tory infiltrates were identified in the thyroid (Figure 4),
adipose and skeletal muscular tissues (Figure 5). Para-
sitic elements (Trichinella) were identified in muscles
(Figure 6). By immunohistochemistry, 40–50% of tumor
cells were positive for Ki67 (Figure 7). Tumor cells were
also vimentin-positive (Figure 8) and negative for
AE1/AE3 (Figure 9), CD31, S100 and myoglobin. CD68
staining was present in the giant multinucleated cells and
histiocytes (Figure 10). Squamous epithelial cells were
positive for AE1/AE3 (Figure 9), tumor vessels for
CD31 (Figure 11), mesenchymal cells and nerve fibers
Histologic and immunohistochemical
established the diagnosis of giant cell variant of
malignant fibrous histiocytoma. After surgery, the
patient was given L-Thyroxine replacement therapy and
Figure 4 – Thyroid regional metastasis of laryngeal
MPH (HE stain, 100×).
Figure 5 – Tumoral invasion in skeletal muscle (HE
Figure 6 – Trichinella spiralis in muscular tissue (HE
Figure 7 – Ki67-positivity in tumoral cells nuclei (IHC,
Figure 8 – Vimentin-positivity in tumoral cells (IHC,
Figure 9 – AE1/AE3-negativity
positive intern control in squamous epithelium (IHC,
in tumoral cells;
Corina Lichiardopol et al.
Figure 10 – CD68-positivity in histiocytes and multi-
nucleated giant cells (IHC, 200×).
Figure 11 – CD31-positivity in tumoral vessels (IHC,
Sarcomas are tumors of connective tissue comprising
more than 100 distinct mesenchymal neoplasms with
marked heterogeneity in structure and biological beha-
vior. Mainly, sarcomas can be classified in soft tissue
sarcomas and bone sarcomas. The most important
prognostic variables are grade, size and location of the
tumor. Surgical treatment alone is indicated in small,
low-grade tumors with wide pathologically negative
margins. Larger or higher-grade lesions must associate
radiotherapy, which reduces the incidence of local
recurrence but has no effect on overall survival.
Chemotherapy may be used before or after surgery
(doxorubicin, ifosfamide and gemcitabine alone or in
combination with docetaxel) .
Soft tissue sarcomas may be benign, intermediate
malignant or malignant and are classified according to
their similarity to normal tissue; the current WHO
classification include adipocytic, fibroblastic/myofibro-
blastic, smooth and skeletal muscle, pericytic and vas-
cular, chondro-osseous tumors and tumors of uncertain
differentiation (i.e. synovial sarcoma). Diagnosis is
based on the study of Hematoxylin–Eosin sections,
which represents the gold standard and immunohisto-
chemical tests aimed to identify cell line differentiation
or a typical antigen pattern .
MFH is now termed high-grade undifferentiated
pleomorphic sarcoma . No specific immunohisto-
chemical marker exists for MFH, but immunohisto-
chemistry can be used to differentiate MFH from other
malignancies . In the presented case, histological
study confirmed giant cell MFH and immunohisto-
chemistry confirmed the mesenchymal origin of the
tumor (vimentin and CD68-positivity), allowed differ-
rentiation from a sarco-matoid carcinoma (AE1/AE3-
negativity), malignant schwannoma and melanoma
(S100-negativity), angiosarcoma (CD31-negativity),
rhabdomyosarcoma (myoglobin-negativity); Ki67-posi-
tivity in 40–50% of tumor cells confirms malignancy
and proves aggressiveness of the tumor.
It is considered that the development of sarcomas
is unrelated to smoking and alcohol use (nevertheless,
our patient was a smoker and an alcohol consumer)
and certain sarcomas are related to genetic syndromes
(Li Fraumeni, neurofibromatosis) and irradiation .
Recently, major progresses were made concerning
MFH pathogeny; it was showed that MFH is the only
soft tissue sarcoma with a pattern of gene expression
significantly associated to that of undifferentiated
mesenchymal stem cells. This proves that human
mesenchymal stem cells (hMSC) are the progenitors of
MFH. Moreover, MFH cells overexpress DKK1, a
secreted inhibitor of the Wnt developmental program,
which stimulates proliferation of hMSC. WNT-
β-catenin signaling mediates commitment of hMSC to
differentiation and inhibition of WNT-β-catenin signa-
ling results in MFH-transformation and morphology
. By the contrary, carcinogenesis (colorectal, breast,
ovarian carcinomas and melanoma) is triggered by
activating mutations in the WNT-β-catenin pathway.
WNT-signaling mediates epithelial – mesenchymal
transition, while WNT-pathway down-regulation media-
tes mesenchymal – epithelial transition . In this
context, the medical history of the patient (tuberculosis
and trichinellosis) could be relevant for the occurrence
of the tumor.
Several reports of trichinellosis and laryngeal cancer
suggest that the chronic irritation of the larynx may
have resulted in cancer [21–23]. Chronic trichinellosis
elicits connective tissue mast cell hyperplasia with
production of cytokines and chemokines required for
pathogen clearance . A reduced cell mediated
immune response is induced by chronic tuberculosis;
suppression of cell mediated immunity along with
proangiogenic cytokines (IL-6) and reduced apoptosis
by release of macrophage inflammatory protein (MIP-1)
that suppresses p53-activity provide the ideal environ-
ment for occurrence of serial mutation required for the
development of malignant disease .
Proliferation and differentiation of tissue progenitor
cells or adult stem cells is the main prerequisite for
tissue homeostasis maintenance, and tissue injury or
repair stimulates stem cell recruitment. Persistent states
of chronic inflammation, infection and injury promote
genomic instability leading to DNA-damage, oncogene
activation or impaired function of a tumor suppressor
gene and further malignancy. After establishment of
Thyroid regional metastasis from a giant cell malignant fibrous histiocytoma of the larynx in a patient with history… Download full-text
cancer, the development of an inflammatory micro-
environment promotes tumor cell proliferation, tumoral
angiogenesis, invasion and metastasis . Under-
standing the complex pathways involved in cancer-
related inflammation will provide new therapeutic
perspectives. It is estimated that head and neck MFH
develop local recurrence in 20–42% of cases (more
common seen in MFH with 19p+ cytogenetic alteration),
regional lymph involvement in up to 15% of cases and
distant metastases in 25–35% of cases, especially in the
case of a high-grade tumor or larger than 5 cm. Distant
metastases (lung, liver, bone) are rare in the absence of
regional metastases. In the presented case, lymph node
involvement was absent, and even if regional thyroid
metastasis was documented, no distant metastases were
detected. After surgical treatment (total laryngectomy
and thyroidectomy) radiotherapy was indicated because
of the high grade of the tumor and positive surgical
margins detected on histologic examination.
Giant cell malignant fibrous histiocytoma of the
larynx is a very rare tumor originating from mesen-
chymal stem cells. Diagnosis is based on the histologic
appearance and immunohistochemistry allows different-
iation from other tumors with similar features. No current
guidelines for laryngeal MPH exists because of lack of
evidence-based data. Treatment of this aggressive tumor
consists of surgical removal and adjuvant radiotherapy
but farther understanding of malignancy related infla-
mmation will reveal the molecular basis and will provide
new-targeted therapeutic options.
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Received: January 15th, 2010 Accepted: March 30th, 2010