Discussion
Laryngeal cancer is most frequently seen between the 5. and 7. decades of life in the world.1 Laryngeal cancers include 1.1% of all malignancies worldwide and this rate is 1.9% in males, and 0.3% in.4 The age average and gender ratio in our study was in consistency with the literature.
Heat shock proteins are chaperon proteins that have a protective function for the cell by normally creating an adaptation mechanism and increasing against environmental and pathophysiological stressors, and they make up an important step in the defense system. HSP70t and HSP70-2 (HSPA-2), unlike other HSP70 chaperon proteins, are expressed in the testicular tissues and are not seen in other tissues or are rarely seen in them.16 In a study conducted on rats, Zhu et. al. stated that when they caused HSPA-2 defects, the primer spermatocytes got stuck at meiosis I, and other HSPA proteins cannot compensate for it. According to these results, they have argued that HSPA-2 is a molecular chaperone for CDC2/cyclin B1 complex formation, and that their interaction is necessary to ensure the G2/M-phase transition during mitosis and meiotic cell cycles.17 In a different study, it has been noted that the G1/S phase arrest occurred, and malign cell proliferation decreased after the HSPA-2 gene was suppressed in the lung adenocarcinomas. It was shown that after the HSPA-2 decreased; the ERK1/2 cascade having functions such as cell survival rate, proliferation stimulation, cell differentiation, cell aging and apoptosis was affected.18
It has been reported that HSPA-2 is effective in many malignancy carcinogenesis. While it is not expressed in normal tissues, it is excessively expressed in malign cells.12 In our study, HSPA-2 expression was only observed in the basal layer of adjacent squamous epithelium not containing dysplasia in all of the cases. In well-differentiated tumors expression was observed predominantly in the periphery of tumor solid islands, and a more intense expression was observed in a more diffused way in areas where differentiation loss was distinct in tumors cells. A diffused and strong expression being observed in moderately and poorly differentiated tumors while weak staining seen in the adjacent epithelial basal and the periphery of well-differentiated tumor islands have suggested that HSPA-2 might have a role in tumor cell migration, invasion and carcinogenesis. Zhang et. al. reported that while they did not observe staining with HSPA-2 in the normal esophagus epithelial, they observed poor staining in areas adjacent the tumor and squamous epithelium basal layer, and stronger staining in infiltrative areas.13 In their study, Scıeglnska et. al. reported observing positive HSPA-2 in keratinocytes in the adjacent epidermis basal layer and in the infiltrative areas of all the skin tumors. On the other hand, they reported observing positive HSPA-2 in the infiltrative areas of half of their cases, while they did not find positivity in the normal epithelium in areas adjacent the tumor in the head and neck areas of SCC cases.12
A different point that we have observed in our study is to see important differences regarding straining intensity and frequency in the low-grade epithelial dysplasia and high-grade epithelial dysplasia areas of the adjacent epithelium. In all of our cases in low-grade epithelial dysplasia areas, positivity was found in only 1/3 of the basal part of the epithelium, while a full coat staining was seen in high-grade epithelial dysplasia areas. We think that while differentiating epithelial dysplasia in laryngeal biopsies with this different staining pattern, the HSPA-2 expression type can also be immensely helpful in differential diagnosis immunohistochemically. No study has been conducted in the literature on this subject, and we think that new studies should be conducted with a larger number of cases.
In addition to HSPA-2 being excessively expressed in many types of cancer, there are many studies showing that it has an effect on tumor progression. It is indicated that tumor cells gain resistance against apoptosis related to hypoxia with an increase of HSPA-2, and that is how they stay alive.19 In our study, a significant relationship was observed between the excessive expression of HSPA-2 and important prognostic parameters such as the primary tumor, lymphovascular invasion, lymph nodule metastasis, the TNM stage and survival rate. Fu et. al. reported that histological grade, tumor radius, clinical stage in hepatocellular carcinomas were directly proportionate to HSPA-2, thus HSPA-2 can have a role in carcinogenesis, tumor development, progression and metastasis. They indicated that they found a significant negative correlation especially between survival rate and HSPA-2 expression.15 In their study emphasizing on esophagus SCC cases, Zhang et. al. stated that the excessive expression of HSPA-2 was associated with the primary tumor, clinical stage, lymph nodule metastasis and recurrence.13 Garg et. al. have argued that HSPA-2 expression is related to cellular motility and growth, so HSPA-2 has a role in cancer spread during the early stages. In their study on bladder cancer, they stated that they observed a significant relationship between the clinical stage, histological grade and HSPA-2 expression.11 In a different study conducted by Garg et. al. on cervix cancer, they obtained similar results and indicated that HSPA-2 had an effect on the progression of cervix cancer.10 In their study, Zhai et. al. have noted that HSPA-2 is related to a poor prognosis in tumor angiogenesis and pancreatic adenocarcinoma, and has an important place in its progression.9 Similar to our study, various studies have shown that in cases where excessive expression of HSPA-2 is seen, there are higher lymph nodule metastasis and therefore a worse prognosis.11,20 In their study, Scıeglınska et. al. found a significant relationship between HSPA-2 expression and the TNM stage, histological grade and prognosis in Non-Small Cell Lung Carcinomas. They have highlighted that especially in stage I and II cases, high HSPA-2 expression is related to lower survival rates.12 In their in vivo study using a mouse model, Garg et. al. considered the matter from a different point of view and stated that they decreased tumor growth rates by 75% with HSPA-2 inhibition in rats.10 When the results of our study and the available data in the literature were evaluated, finding a significant relationship between important prognostic parameters such as the primary tumor, lymphovascular invasion, lymph nodule metastasis, the TNM stage, survival rate suggested that this marker can be used in prognosis in LSCC immunohistochemically.