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  Volume 96
Numero 3
maggio-giugno 2010 		I documenti sono in formato PDF, consultabili utilizzando Acrobat Reader
 
EGFR polysomy in squamous cell carcinoma of the thyroid. Report of two cases and review of the literature

Luca Reggiani Bonetti, Massimo Lupi, Margherita Trani, Nicoletta Trani, Giuliana Sartori, Laura Schirosi, Stefania Bettelli, Giuliana Zanelli, Livia Maccio, Antonio Maiorana
1Dipartimento Integrato Servizi Diagnostici e di Laboratorio e di Medicina Legale, Sezione di Anatomia Patologica, Università degli Studi di Modena e Reggio Emilia;
2Clinica Otorinolaringoiatrica, Policlinico di Modena, Università degli studi di Modena e Reggio Emilia; 3Dipartimento Integrato Servizi Diagnostici e di Laboratorio e di Medicina Legale, Sezione di Medicina Legale, Università degli Studi di Modena e Reggio Emilia, Italy

Key words: squamous cell carcinoma, thyroid, EGFR, polysomy.

abstract

Aims and background. Primary squamous cell carcinoma of the thyroid gland (PSCCT) is an uncommon malignancy characterized by a poor prognosis. A radical surgical approach combined with radiotherapy or chemotherapy is the generally accepted treatment for this tumor. The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor modulating the cell proliferation and biological progression of many human epithelial tumors. The EGFR overexpression in PSCCT suggests an additional therapeutic option for the treatment of this tumor.
Methods and study design. The clinicopathological features and immunohistochemical profiles of two cases of primary squamous cell carcinoma of the thyroid in a 66-year-old and an 83-year-old woman are presented. EGFR status was valued in both cases.
Results. Overexpression of EGFR protein was detected in 50% and 75% of the tumor cell membranes. EGRF gene polysomy was detected in both tumors.
Conclusions. Pharmaceuticals targeting EGFR may help to provide the rationale for an additional, novel therapeutic option for this rare tumor, especially when other therapeutic options have been exhausted. Free full text available at www.tumorionline.it

Introduction
Primary squamous cell carcinoma of the thyroid gland (PSCCT) is an uncommon malignancy characterized by a poor prognosis1. Its pathogenesis is uncertain and heterogeneous immunohistochemical profiles have been described2. A radical surgical approach combined with radiotherapy or chemotherapy is the generally accepted treatment for this tumor2. Long et al. recently described EGFR protein overexpression in PSCCT, suggesting an additional therapeutic option3. Further to this report, we investigated the epidermal growth factor receptor (EGFR) status in 2 cases of PSCCT using immunohistochemical analysis (IHC) and fluorescence in situ hybridization (FISH).

Case reports
Patient selection
Among 1024 cases of thyroid cancer diagnosed at the Pathology Department of the University of Modena and Reggio Emilia during the period 1991-2008, 2 cases of PSCCT were identified (Table 1). In accordance with the WHO definition4, “only tumors composed entirely of squamous cells and showing so-called intercellular bridges and/or forming keratin” were included in this study. Hematoxylin and eosin-stained slides representative of all tumors were available and were reviewed by two pathologists. The mode of presentation, clinical course and follow-up information were obtained by review of the patients’ charts.




Case history

Case 1
A 66-year-old woman complained of progressive enlargement on the right side of the neck, hoarseness, and difficulty swallowing. Physical examination revealed a semi-mobile painless and hard mass located in the right lobe of the thyroid. Palpable lymph nodes were present bilaterally. Ultrasound showed a solid nodule of approximately 4 cm in diameter, lobulated in shape and protruding through the thyroid. Radiological examinations including X-ray and CT of the neck and chest, endoscopic and otorhinolaryngological examinations were meticulously carried out to exclude the possibility of secondary thyroid involvement from other primary cancers in the aerodigestive tract. Plasma levels of thyroid hormone and calcitonin were in the normal range. No family history of thyroid cancer or previous neck irradiation was documented. Clinical malignancy was suspected and a total thyroidectomy was carried out. Grossly, the mass measured 40 × 32 cm and had ill-defined margins. Histologically the neoplasm was composed of infiltrating nests of irregular squamous cells with marked nuclear pleomorphism and focal keratin formation (Figure 1A). Entrapped remnant thyroid follicles were observed within the tumor while scant regular thyroid parenchyma was present at the periphery of the lesions. There was no evidence of associated papillary or follicular thyroid carcinoma. The patient underwent adjuvant chemotherapy after thyroidectomy. Dissection of the regional lymph nodes revealed the presence of multiple metastases. The patient developed liver and lung metastases within 8 months and died 1 year after presentation




Case 2
A 83-year-old woman with a 2-month history of swallowing difficulty and dysphagia presented to us. Her past medical history was significant only for goiter diagnosed 2 years before. No family history of thyroid cancer or previous neck irradiation was documented. Plasma levels of thyroid hormone and calcitonin were in the normal range. Radiological examinations including x-ray and CT of the neck and chest, and endoscopic and otorhinolaryngological findings were unremarkable. The patient underwent radical thyroidectomy followed by chemotherapy. Grossly, the mass measured 42 × 36 mm and had ill-defined margins. Histologically, the neoplasm was composed of infiltrating nests of squamous cells with marked nuclear pleomorphism and focal keratin formation. Regional lymph node dissection revealed the presence of metastatic lymph nodes. The patient died of cardiovascular disease about 4 months after surgery. Autopsy revealed no visceral metastases.

Pathological and immunohistochemical features
The panel of antibodies used for the immunohistochemical analyses is listed in Table 2. Appropriate negative and positive controls were run concurrently for all tests. Positive staining for thyroglobulin and TTF-1 was limited to normal follicles entrapped within the tumor and in the intrafollicular colloid (Figure 1B).
The aim of this study was to test the EGFR status in 2 cases of PSCCT. Expression of EGFR protein was determined by means of IHC using mouse antihuman EGFR monoclonal antibody (clone H11, Dako, Carpinteria, CA, USA). Assessment was based on the proportion of reactive cells within the tumors. IHC positivity was defined as more than 10% of tumor cells showing membranous staining of any intensity. Both our cases were uniformly and markedly immunoreactive for this EGFR antibody (Figure 2A).








EGFR fluorescence in situ hybridization
All samples provided enough diagnostic material for molecular determinations. FISH studies were performed on selected sections of paraffin-embedded tissue areas containing representative malignant cells, using the LSI EGFR SpectrumOrange/CEP7 Spectrum Green probe (Vysis, Abbott Laboratories, Abbott Park, IL, USA). Two observers analyzed 100 intact non-overlapping tumor cell nuclei for the observed number of red (EGFR gene) and green (chromosome - CEP7) signals. We determined the number of gene copies of the EGFR gene and classified them according to the FISH categories defined by Cappuzzo et al.5 EGFR amplification was considered present when the ratio of the EGFR gene to the chromosome (EGFR/CEP7) was ≥2. Polysomy of the EGFR gene was defined as an increase in red EGFR signals in a large proportion of tumor cells. In particular, we defined low polysomy as the presence of >4 gene copies in 10-40% of scored cells and high polysomy as the presence of >4 gene copies in >40% of scored cells. No EGFR gene amplification was found in our patients. Low polysomy was detected in case 1 (>4 gene copies in 38% of tumor cells) and high polysomy (>4 gene copies in 51.4% of tumor cells) in case 2. Details are summarized in Table 2 and shown in Figure 2B, 2C, and 2D.

Discussion
To date, fewer than 200 cases of PSCCT have been described in the English medical literature1. Its reported incidence ranges from 0.7% to 3.4% and it is more common in women, with a male:female ratio of approximately 1:22. Although the neoplasm tends to occur more often in elderly patients, sporadic young patients affected by PSCCT have been reported1-3. Aggressive clinical behavior and an unfavorable prognosis characterize PSCCT. Most patients die with metastatic disease within a year of the diagnosis and only rare cases of a long disease history have been reported4,5. The clinical manifestation of obstructive symptoms attests to the tendency of this tumor to invade adjacent aerodigestive structures such as the trachea and esophagus1-3,6. The origin of PSCCT is unknown and different theories concerning its pathogenesis have been put forward, including development from embryonic remnants1,7 and malignant transformation of squamous metaplastic changes associated with chronic diseases such as goiter or Hashimoto thyroiditis8. The main differential diagnosis includes squamous cell carcinoma extending into or metastasizing to the thyroid gland from the lungs, thymus, or – most frequently – upper aerodigestive tract. Radiological examinations may be useful to rule out secondary involvement of the thyroid1-2,5,9. Different cytokeratins can be tested to characterize the tumor1,5,9. CD5 is practical for distinguishing CASTLE (thyroid gland carcinoma showing thymus-like differentiation), which is positive for this marker, from PSCCT, which is CD5-negative. Overexpression of the oncoprotein p53 and a high MIB-1 index (≥20%) are reported to be associated with the degree of differentiation and with a poor prognosis9.
Long et al.3 documented a case of PSCCT that was strongly immunoreactive for EGFR. EGFR is a transmembrane tyrosine kinase receptor modulating the cell proliferation and biological progression of many human epithelial tumors. Upregulation of EGFR with a significantly increased binding capacity for EGF compared to normal thyroid tissue was demonstrated in a case of SCC involving the thyroid10. Further to these reports, we tested the functional status of EGFR. Both our cases were uniformly and markedly immunoreactive for the EGFR antibody. Expression of EGFR protein was demonstrated in 50% and 75% of the tumor cell membranes. Two studies analyzing EGFR expression in benign and malignant thyroid tumors demonstrated protein overexpression in thyroid tumors and suggested its prognostic and diagnostic significance11-13. Lee et al.12 using FISH in a series of anaplastic thyroid carcinomas reported high EGFR gene polysomy in a large proportion of tumor cells (≥4 copies in ≥40% of cells). Four of these cases showed squamoid differentiation. In the present study, we found low EGFR polysomy (>4 copies in 38% of scored tumor cells) and high polysomy (>4 copies in 51.4% scored cells) in case 1 and case 2, respectively.
Although the main treatment for PSCCT is surgery followed by radiotherapy or chemotherapy, most reported cases were found to be unresponsive1,2. This report documents EGFR protein overexpression and EGFR gene polysomy in a high rate of PSCCT cells. These preliminary results prompt consideration of EGFR as a therapeutic target for this rare tumor. It may help to provide the rationale for the use of new targeted therapies for refractory PSCCT when other options have been exhausted. Additional information will be needed to clarify these findings.

References
 1. Makay O, Kaya T, Ertan Y, Icoz G, Akyildiz M, Yilmaz M, Tuncyurek M, Yetkin E: Primary squamous cell carcinoma of the thyroid: report of three cases. Endocr J, 55: 359-364, 2008.
 2. Fassan M, Pennelli G, Pelizzo MR, Rugge M: Primary squamous cell carcinoma of the thyroid: imunohistochemical profile and literature review. Tumori, 93: 518-521, 2007.
 3. Long JL, Strocker AM, Wang MB, Blackwell KE: EGFR expression in primary squamous cell carcinoma of the thyroid. Laryngoscope, 119: 89-90, 2008.
 4. Lam KY, Sakamoto A: Squamous cell carcinoma. In: World Health Organization classification of tumours. Pathology and genetics of tumours of endocrine organs. DeLellis RA, Lloyd RV, Heitz PU, Eng C. (Eds). IARC Press, Lyon 2004.
 5. Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, Haney J, Witta S, Danenberg K, Domenichini I, Ludovini V, Magrini E, Gregorc V, Doglioni C, Sidoni A, Tonato M, Franklin WA, Crino L, Bunn PA, Jr, Varella-Garcia M: Epidermal growth factor receptor gene copy number, gene mutations and protein level predict outcome to gefitinib therapy in advanced non-small cell lung cancer. J Natl Cancer Inst, 97: 643-655, 2005.
 6. Müssig K, Dahm J, Koitschev A, Horger M, Müller M, Bares R, Wehrmann M: Primary squamous cell carcinoma of the thyroid. Intern Med J, 38: 69-70, 2008.
 7. Riddle PE, Dincsoy HP: Primary squamous cell carcinoma of the thyroid associated with leukocytosis and hypercalcemia. Arch Pathol Lab Med, 111: 373-374, 1987.
 8. Sahoo M, Bal CS, Bhatnagar D: Primary squamous-cell carcinoma of the thyroid gland: new evidence in support of follicular epithelial cell origin. Diagn Cytopathol, 27: 227-231, 2002.
 9. Sanchez-Sosa S, Rios-Luna NP, Tamayo Bdel R, Simpson K, Albores-Saavedra J: Primary squamous cell carcinoma of the thyroid arising in Hashimoto’s thyroiditis in an adolescent. Pediatr Dev Pathol, 9: 496-500, 2006.
10. Lam KY, Lo CY, Liu MC: Primary squamous cell carcinoma of the thyroid gland: an entity with aggressive clinical behaviour and distinctive cytokeratin expression profiles. Histopathology, 39: 279-286, 2001.
11. Kanamori A, Abe Y, Yajima Y, Manabe Y, Ito K: Epidermal growth factor receptors in plasma membranes of normal and diseased thyroid glands. J Clin Endocrinol Metab, 68: 899-903, 1989.
12. Lee DH, Lee GK, Kong SY, Kook MC, Yang SK, Park SY, Park SH, Keam B, Park do J, Cho BY, Kim SW, Chung KW, Lee ES, Kim SW: Epidermal growth factor receptor status in anaplastic thyroid carcinoma. J Clin Pathol, 60: 881-884, 2007.
13. Elliott DD, Sherman SI, Busaidy NL, Williams MD, Santarpia L, Clayman GL, El-Naggar AK: Growth factor receptors expression in anaplastic thyroid carcinoma: potential markers for therapeutic stratification. Hum Pathol, 39: 15-20, 2008.
 
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