| Abstract|| |
Background: Thyroid cancer is one of the increasing cancer diagnoses in the United States. Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. There are a few researches done determining the role of human epidermal growth factor receptor 2 HER2 (erbB-2) in PTC prognosis. They also have been controversial. This study is designed to determine the correlation of HER2 expression with tumor size, lymph node involvement, and capsular invasion as prognostic factors. Materials and Methods: This research was a cross-sectional descriptive-analytic study. Information about age, sex, tumor size, and lymph node involvement of 85 patients undergone thyroidectomy and diagnosed PTC in Mostafa Khomeini Hospital during 2010–2012, have been derived from their medical records. Four-micron sections made from paraffin embedded blocks and HER2 expression was assessed by immunohistochemistry. Other sections were stained with H and E Method and capsular invasion was evaluated by microscope. Results: In this study, 88.2% of patients were female and 11.8% of patients were male. About 37.6% of samples were HER2 positive. There was no significant correlation between HER2 and lymph node involvement (P = 0.649), (P > 0.05). A significant correlation found between HER2 and capsular invasion (P = 0.000), (P < 0.05). This study found a significant correlation between HER2 and tumor size (P = 0.000), (P < 0.05). Conclusion: HER2 oncoprotein expression is correlated with increased tumor size and capsular invasion. Hence, HER2 can be used to assess PTC prognosis.
Keywords: Capsules, erbB-2, lymphatic metastasis, papillary, prognosis, thyroid neoplasm, tumor size
|How to cite this article:|
Rabiee S, Nadoushan MJ, Rayeni NM, Ansari I. Correlation between human epidermal growth factor receptor 2 oncoprotein expression and some prognostic factors in papillary thyroid carcinoma. Indian J Pathol Microbiol 2017;60:324-7
|How to cite this URL:|
Rabiee S, Nadoushan MJ, Rayeni NM, Ansari I. Correlation between human epidermal growth factor receptor 2 oncoprotein expression and some prognostic factors in papillary thyroid carcinoma. Indian J Pathol Microbiol [serial online] 2017 [cited 2020 Jul 6];60:324-7. Available from: http://www.ijpmonline.org/text.asp?2017/60/3/324/215372
| Introduction|| |
Thyroid cancer is one of the increasing cancer diagnoses in the United States with a doubling incidence in the past 30 years. There is an estimated number of 62,450 new cases of thyroid cancer in 2015 and based on cases during 2008–2012 the number of new cases per 100,000/year was 13.5. Thyroid cancer is the most common endocrine malignancy, and papillary thyroid carcinoma (PTC) is the most common thyroid carcinoma which accounts for 70%–90% of well-differentiated thyroid carcinomas (DTC). PTC has some specific features such as psammoma bodies, cleaved nuclei, and orphan - Annie appearance caused by large nucleoli. These features allow it to be diagnosed based on fine needle aspiration biopsy samples. PTC tends to invade within the thyroid, through the thyroid capsule and adjacent structures in the neck. PTC also metastasizes to lymph nodes and hematogenously to lung, bone, liver, and brain.,,, Several factors contribute determining the prognosis of PTC including tumor size, capsule invasion, lymph node involvement, age, sex, history of radiation exposure, multicentricity, and distant metastasis., Surgery has the main role in the treatment of PTC. mitogen-activating protein kinase (MAPK), an intracellular signaling pathway, plays a major role in PTC pathogenesis. Mutations in BRAF, RET/PTC, and TRK activate MAPK pathway in PTC.,,, Epidermal growth factor receptor family includes four members (human epidermal growth factor receptor [HER], HER2, HER3, HER4) with tyrosine kinase activity. As a member, HER2 is a 1255-aminoacid glycoprotein which weights 185 kilodaltons, and its gene is placed on 17q21 locus. Although HER2 is very similar to the other growth factor receptors, there is no high-affinity ligand found for it yet, and role of HER2 is mostly assumed as a signal amplifier of other receptors ligands. HER2 overexpression is detected in cancers such as breast carcinoma, adenocarcinoma of the lung, ovarian cancer, salivary gland, and so. In most adenocarcinomas, HER2 overexpression is accompanied with aggressive behavior., There are evidence confirming that HER2 may participate in angiogenesis of tumors. enzyme-linked immunosorbent assay, immunohistochemistry and Western blot are used to measure HER2 protein overexpression., In 2004, Kato et al. evaluated thyroid samples and showed increased HER2 mRNA expression in PTC. There are a few researches done about the role of HER2 in determining thyroid cancer prognosis. These researches are controversial. In 2007, Balta et al. deduced HER2 expression increased in PTC, but it has no striking relation with prognostic factors such as tumor size, lymph node involvement extrathyroidal expansion, vascular invasion, and recurrence. On the other side, Kremser et al. found that HER2 overexpression could be considered as a prognostic factor for PTC  Therefore, this research tried to determine HER2 relation with tumor size, lymph node involvement, and capsular invasion as prognostic factors.
| Materials and Methods|| |
This research was a cross-sectional descriptive-analytic study. Medical records of 85 patients undergone thyroidectomy during 2010–2012 and diagnosed with PTC were gathered. Samples were selected through accidental sampling. Inclusion criteria for medical records were to be complete and reachable during past 3 years. Information about age, sex, lymph node involvement, and tumor size derived from medical records. Four-micron sections were made from paraffin blocks and stained by immunohistochemistry (based on Novocastra ®, UK laboratory kit staining protocol) then HER2 expression evaluated by Zeiss ® microscope, ×40 magnification. Other sections were stained by H and E staining and capsule invasion evaluated by microscope. All sections were analyzed by unique pathologist. Collected data were analyzed by SPSS version 18.0 (SPSS Inc., Chicago, IL, USA) application and Chi-square, Fischer's exact test, and t-test.
| Results|| |
There were 85 patients evaluated in the study including 75 (88.2%) women and 10 (11.8%) men. The patients ranged in age from 13 to 80 and mean age was 40.8 ± 16.4 years. Immunohistochemistry studies showed 32 samples (37.6%) were HER2 positive and 53 (62.4%) were HER2 negative. Based on measurements samples ranged in size from 0.5 to 14 cm and mean size was 3.7 ± 2.2 cm [Figure 1]. Microscopic studies on H and E stained samples showed that capsule invasion was positive in 11 (12.9%) of samples and negative in 74 (87.1%). The study found 19 (22.4%) samples having lymph node involvement and the resting 66 (77.6%) without lymph node involvement. No statistically significant correlation found between HER2 and Lymph node involvement (P > 0.05) using Chi-square test. A significant correlation found between HER2 and capsule invasion (P < 0.05) using Fisher's exact test. Negative HER2 expression was related to negative capsule invasion. HER2-lymph node involvement and HER2-capsule invasion cross tabulation are mentioned in [Table 1].
|Figure 1: Microscopic view of the papillary thyroid carcinoma with HER2 positive cells (a) Original Magnification, ×400, (b) Original Magnification, ×40|
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|Table 1: Human epidermal growth factor receptor 2 - lymph node involvement and human epidermal growth factor receptor 2 - capsule invasion cross tabulation|
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Mean tumor size was 5.3 ± 2.2 among HER2 positive samples and 2.7 ± 1.6 among HER2 negative samples. T-test showed HER2 is correlated with tumor size (P < 0.05). Tumor size increased in HER2 positive samples.
| Discussion|| |
The study found HER2 is correlated to capsule invasion and tumor size but found no relation between HER2 and lymph node involvement.
HER2 expression is detected in 37.6% of samples. This finding is different from Aasland's that showed all the thyroid samples were HER and HER2 RNA positive. This could be the result of the different method because in the current study HER2 protein expression evaluated by Immunohistochemistry method. Furthermore in Asland's, only five cases were assessed and findings cannot be generalized. Wiseman et al.'s study showed HER2 protein expression in only 2% of differentiated thyroid tumor samples; this incompatibility may be due to that Wiseman et al. assessed HER2 expression in DTC, but in this study, PTC was evaluated as the most common type of DTC., The amount of HER2 expression found in the study was less than such found in Akslen et al.'s in 1995 (85%), Akslen et al.'s in 1993 (46%), Qin et al.'s (52%), and was more than HER2 expression found in Balta et al.'s (14.9%).,,, HER2 expression found in the study was similar to Freudenberg et al.'s, 34%. In the current study, no significant correlation found between HER2 and lymph node involvement. In Akslen et al.'s study in 1995, membranous staining of HER2 was significantly more frequent in patients without lymph node spread. The current finding (no correlation between HER2 and lymph node) is compatible with Balta et al.'s, Kremser et al.'s, and Wiseman et al.'s studies.,, Based on the findings, there was a correlation between HER2 and capsule invasion which is not compatible with Balta et al.'s. Balta et al. showed HER2 is not associated with extrathyroidal expansion, in Turkey in 2012. This finding is also incompatible with Kremser et al.'s in Austria in 2003 and Wiseman et al.'s in Canada in 2008 in which HER2 had no relation to T stage of tumor (based on tumor node metastasis [TNM] staging system)., Here, it can be mentioned that Akslen's study, in Norway in 1993, showed strong cytoplasmic HER staining was relevant to extrathyroidal growth; which was compatible with ours. This compatibility can also be seen in Ensinger et al. study., The mentioned study was done in Austria in 2003 and showed that HER2 expression in poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma is associated with increased aggressive behavior.
The study found a significant association between HER2 and tumor size so that tumor size increased with the HER2 expressed. The finding was not compatible with Balta et al.'s in which no correlation found between HER2 and tumor size. This incompatibility can also be seen in Kremser et al.'s and Wiseman et al.'s in which HER2 overexpression was not associated with T stage of tumors (based on TNM staging system)., There are a few researches done about HER2 and tumor size association.
Totally in this research, it is found that HER2 is associated with poor prognosis of the PTC patients. However, in Balta et al.'s and Wiseman et al.'s studies, it is mentioned that HER2 is not associated with prognosis factors of PTC., Qin et al. measured HER2 overexpression in two groups of cured and noncured groups after treatment of 131 I. They found no difference in expression of HER2 between two groups of patients. In this study, prognostic factors of PTC in thyroidectomy derived samples were assessed and this can rationalize the difference between our findings and Qin's.
In an attempt to review compatible findings, it can be said that Freudenberg et al. showed progression, recurrence, and death were significantly more among HER2 positive patients than HER2 negatives, so they assumed HER2 correlated with prognosis. Akslen et al. found that HER2 was associated with extrathyroidal growth and recurrence-free survival and so correlated with prognosis. Kremser et al. found a correlation between HER2 and distant metastasis and mentioned that it can be regarded as a prognostic factor in DTC. Kremser's study is important due to it was done based on TNM staging system. There is also a correlation between HER2 and prognosis in Sugg's research but it is associated with good prognosis.
| Conclusion|| |
Based on the current study and previous studies, HER2 as an oncoprotein can be used to determine the prognosis of PTC patients; although studies do not have equal opinions and more comprehensive researches is required to gather more evidence.
Financial support and sponsorship
This study was the result of MD thesis of Dr. Shervin Rabiee at Shahed University, Tehran, Iran.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Morris LG, Sikora AG, Tosteson TD, Davies L. The increasing incidence of thyroid cancer: The influence of access to care. Thyroid 2013;23:885-91.
Jameson J, Weetman A. Disorders of thyroid gland. In: Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J, editors. Harrison's Principles of Internal Medicine. 18th
ed. New York: McGraw Hill; 2012. p. 2911-40.
Kumar V, Abul Abbas K, Fausto N, Richard M. Robbins Basic Pathology. 8th
ed. Philadelphia: Saunders/Elsevier; 2007. p. 751-801.
Lal G, Clark O. Thyroid, parathyroid and adrenal. In: Brunicardi F, Anderson D, Billiar T, Dunn D, Hunter J, Matthews J, editors. Schwartz's Principles of Surgery. 9th
ed. New York: McGraw-Hill; 2010. p. 2587-717.
Rosai J, Tallini G. Thyroid gland. In: Rosai J, editor. Rosai and Ackerman's Surgical Pathology. 10th
ed. New York: Elsevier; 2011. p. 488-565.
Leboulleux S, Rubino C, Baudin E, Caillou B, Hartl DM, Bidart JM, et al.
Prognostic factors for persistent or recurrent disease of papillary thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the thyroid capsule at initial diagnosis. J Clin Endocrinol Metab 2005;90:5723-9.
Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, et al.
Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 2005;115:94-101.
Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: Genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003;63:1454-7.
Bazley LA, Gullick WJ. The epidermal growth factor receptor family. Endocr Relat Cancer 2005;12 Suppl 1:S17-27.
Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, et al.
Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985;230:1132-9.
Klapper LN, Glathe S, Vaisman N, Hynes NE, Andrews GC, Sela M, et al.
The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci U S A 1999;96:4995-5000.
Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, et al.
ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: Implications for breast cancer. EMBO J 1996;15:254-64.
Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, et al.
Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro
and in vivo
: Angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 1997;151:1523-30.
Park K, Han S, Kim HJ, Kim J, Shin E. HER2 status in pure ductal carcinoma in situ
and in the intraductal and invasive components of invasive ductal carcinoma determined by fluorescence in situ
hybridization and immunohistochemistry. Histopathology 2006;48:702-7.
Shi Y, Huang W, Tan Y, Jin X, Dua R, Penuel E, et al.
A novel proximity assay for the detection of proteins and protein complexes: Quantitation of HER1 and HER2 total protein expression and homodimerization in formalin-fixed, paraffin-embedded cell lines and breast cancer tissue. Diagn Mol Pathol 2009;18:11-21.
Kato S, Kobayashi T, Yamada K, Nishii K, Sawada H, Ishiguro H, et al.
Expression of erbB receptors mRNA in thyroid tissues. Biochim Biophys Acta 2004;1673:194-200.
Balta AZ, Filiz AI, Kurt Y, Sucullu I, Yucel E, Akin ML. Prognostic value of oncoprotein expressions in thyroid papillary carcinoma. Med Oncol 2012;29:734-41.
Kremser R, Obrist P, Spizzo G, Erler H, Kendler D, Kemmler G, et al.
Her2/neu overexpression in differentiated thyroid carcinomas predicts metastatic disease. Virchows Arch 2003;442:322-8.
Aasland R, Lillehaug JR, Male R, Jøsendal O, Varhaug JE, Kleppe K. Expression of oncogenes in thyroid tumours: Coexpression of c-erbB2/neu and c-erbB. Br J Cancer 1988;57:358-63.
Wiseman SM, Griffith OL, Melck A, Masoudi H, Gown A, Nabi IR, et al.
Evaluation of type 1 growth factor receptor family expression in benign and malignant thyroid lesions. Am J Surg 2008;195:667-73.
Akslen LA, Myking AO, Salvesen H, Varhaug JE. Prognostic impact of EGF-receptor in papillary thyroid carcinoma. Br J Cancer 1993;68:808-12.
Akslen LA, Varhaug JE. Oncoproteins and tumor progression in papillary thyroid carcinoma: Presence of epidermal growth factor receptor, c-erbB-2 protein, estrogen receptor related protein, p21-ras protein, and proliferation indicators in relation to tumor recurrences and patient survival. Cancer 1995;76:1643-54.
Qin C, Cau W, Zhang Y, Mghanga FP, Lan X, Gao Z, et al.
Correlation of clinicopathological features and expression of molecular markers with prognosis after 131
I treatment of differentiated thyroid carcinoma. Clin Nucl Med 2012;37:e40-6.
Freudenberg LS, Sheu S, Görges R, Mann K, Bokler S, Frilling A, et al.
Prognostic value of c-erbB-2 expression in papillary thyroid carcinoma. Nuklearmedizin 2005;44:179-82, 184.
Ensinger C, Prommegger R, Kendler D, Gabriel M, Spizzo G, Mikuz G, et al.
Her2/neu expression in poorly-differentiated and anaplastic thyroid carcinomas. Anticancer Res 2003;23:2349-53.
Sugg SL, Ezzat S, Zheng L, Rosen IB, Freeman JL, Asa SL. Cytoplasmic staining of erbB-2 but not mRNA levels correlates with differentiation in human thyroid neoplasia. Clin Endocrinol (Oxf) 1998;49:629-37.
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