Expression of oestrogen progestrone and androgen receptors in salivary gland tumours. A review of literature

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Expression Of Oestrogen Progestrone And Androgen Receptors In Salivary Gland Tumours: A Review

Of LiteratureB. Tarakji and o. Kujan

Department of oral Medicine and Diagnostic Sciences, Faculty of Dentistry, Al-Farabi Col-leges, Riyadh, Saudi Arabia

Correspondence: Professor Bassel Tarakji, Head of Department of Oral Medicine and Diagnostic Sciences, Faculty of Dentistry, Al-Farabi Colleges, Riyadh, Kingdom of Saudi Arabia, Email: [email protected]

AbstractHormone therapy is highly recommended

on patients with breast cancer who show positive nuclear staining of the cancer cells. It is not known however whether salivary gland tumours can respond to hormone therapy. Twenty eight studies undertaken between 1980 to 2009 involving different types of salivary gland cancers were evaluated and taken into consideration the type of used antibody and the criteria to assess the intensity staining.

This review has shown that estrogen progesterone and androgen receptors were detected in few cases of salivary gland tumours. Different types of used antibodies were identified, and the criteria of assessment of the staining intensity were different as well.

IntroductionSalivary gland carcinomas accounts for 0.4

% of all cancers and 5% of all head and neck cancers. These tumours occur in major and minor salivary glands, and are comprised of a variety of histological types(1,2). These tumours recur despite combined modality therapy(2) and those recurrences can rarely be avoided with success with the use of chemotherapy treatment (3,4). Therefore, there is a need to develop other treatment options for those recurrent cancers. Salivary gland cancers are histologically similar to certain types of breast cancer (5). The use of hormonal therapy in prostate and breast cancers has been well-known, and the discovery of hormone receptors has given the opportunity to identify other patients who may benefit

The outcome of this review indicated that the growth of those tumours was not dependent on hormone function.

It is recommended that sensitive and specific biochemical methods can be used to determine if estrogen and progesterone receptors can be detected in salivary gland cancers. It is necessary to use one criterion such as positive or negative nuclear staining to determine the existence of estrogen and progesterone receptors and to avoid any bias. The discrepancy in the results reflects a clear need for consensus on a protocol for scoring of immunohistochemical staining.

Keywords oestrogen, progesterone, androgen receptors,

salivary gland tumours.

from such therapy. Steroid hormone receptors are intracellular DNA binding proteins that are found in both the cytosolic and nuclear fractions of a tissue homogenate. They function as growth regulators. Hormone binding causes a conformational change in the receptor followed by transport of the receptor hormone complex to the cell nucleus. In the nucleus the receptor hormone complex binds to specific nucleotide sequences, resulting in transcriptional regulation of the targeted gene. The same hormone may activate different genes in different cells. The sex steroid hormone oestrogen is important in both men and women for a variety of physiological processes. Oestrogen affects growth, differentiation, and function of tissues of the reproductive system, including the uterus, vagina, mammary glands, and ovaries in females, and the testis, epididymis, and prostate in males. It has roles in preventing osteoporosis, and maintaining bone density. In the brain, oestrogen regulates reproductive

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behavior, gonadotropin production and its release from the pituitary gland, in addition to mood and behavior (6,7,8). Immunocytochemical techniques have shown nuclear distribution of oestrogen and progesterone receptors in carcinoma of breast cells and benign lobular or ductal epithelial cells, with no specific staining seen in the surrounding connective tissue. Specific oestrogen, progesterone, and androgen immunostaining were found to be very heterogeneous (7). Progesterone and oestrogen positive tumours showed variations in intensity and distribution of staining among cells and this heterogeneity was attributed either to receptor content variations, which were cell cycle dependent, or to variations in the presence of both progesterone and oestrogen response and non-response cells. Immunocytochemistry of oestrogen has been shown to predict response of breast cancer to endocrine therapy (9,10). Studies have shown that sixty-percent of patients having an oestrogen positive tumour will respond to hormonal treatment. Previous studies 6-12) also reported that some tumours other than breast cancer have hormone receptors e.g. melanoma; carcinoid tumours, pancreatic, and renal cancers. It is unknown whether salivary gland cancers are hormone dependent or independent.

The purpose of this study is to review the literature concerning oestrogen progesterone, and androgen receptors in salivary gland cancers and to determine if salivary gland cancers are dependent or independent on endocrine function.

Materials and methodsA literature search using MEDLINE,

accessed via the National Library of Medicine PubMed interface (http://www.ncbi.nlm.nih.gov/pubmed), searching for articles relating to the existence of oestrogen, progesterone and androgen receptors in different types of salivary gland cancers written in English. We used the following search string: (oestrogen receptors, progesterone receptors, androgen receptors) and salivary gland tumours from 1980-2009. We also used the “Related Articles” feature of PubMed to identify further references of interest within the primary search. These references were obtained, and from their bibliographies, pertinent secondary

references were also identified and acquired. The process was repeated until no further new articles could be identified. The abstracted literature was reviewed.

Studies describing case series and miscellaneous clinical reports were retrieved. Twenty-eight studies have been evaluated taking into consideration the specific criteria enumerated below:

1. All the evaluated studies should involve the existence of oestrogen or progesterone, or androgen receptors in the salivary gland tumours. Other sex steroid hormones were excluded;

2. The used scoring criteria to assess the intensity of immunostaining to demonstrate the existence of estrogen progesterone and androgen receptors in the nucleus tumour cells

3. The type of used antibody4. Comparison tissue processing

ResultNo statistical analysis is presented because

the collected data were different and the results cannot be compared. No randomized controlled trials to assess the possibility of using the hormone therapy in the treatment of salivary gland cancers were located in the literature. Our search has identified only twenty-eight studies available in written literature. These were evaluated by two pathologists to determine their agreement with the suggested criteria.

Molteni et al.(13) assessed various head and neck cancers, and an elevated level of estradiol receptor binding protein was detected in normal and neoplastic salivary gland tissues. Therefore, they suggested that some head and neck cancers may be hormone dependent. Dimery et al.(14) have mentioned that 33 cases of salivary gland tissues from a variety of sites including both minor and major glands. 19 samples consisted of normal salivary gland tissue and 14 tissue samples contained tumour. Oestrogen was considered to be present if the receptor protein value exceeded or was equal to 1 femtomoles per milligram of cytosol protein. In the male patients 10 of the 13 (77%) histologically

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Hormone Receptors In Salivary Gland Tumours, B. Tarakji, et. al.

normal samples and four of the five (80%) tumour samples contained more than 1 fmol/mg of cytosol protein oestrogen. In the female patients, five of the six (83%) normal samples and eight of the nine (88%) tumour samples had observed oestrogen. They established that oestrogen values that exceeded 10 fmol/mg of cytosol protein were considered as positive and therefore hormonally dependent and responsive to hormonal therapy. Values between 3 and 10 fmol/mg of cytosol protein were considered to be intermediate in their response to hormonal therapy. According to their criteria none of the four oestrogen containing tumour samples from male patients were positive, however, of the eight oestrogen containing tumour samples from female patients, four (50%) would be considered positive because the oestrogen values exceeded 10 fmol/mg in these samples. Adenocarcinoma was the predominant histology in the oestrogen containing samples from female patients.

They concluded that oestrogen was identified in the majority of normal and tumour samples from both male and female patients, with the highest levels present in tumour samples obtained from females. These results suggested a possible role for sex steroid hormones in the development of the salivary glands and in promotion of neoplastic growth. Shick et al.(15) have studied oestrogen and progesterone receptors in salivary gland adenoid cystic carcinoma. Their samples consisted of 12 cases of salivary gland adenoid cystic carcinoma and normal salivary glands. The results showed no estrogen staining in either normal or neoplastic groups. Progesterone positive staining was observed in 3 cases out of 12 in normal salivary glands but 6 cases out of 12 showed positive staining in the adenoid cystic carcinomas. These findings were in agreement with Miller et al.(16) who identified progesterone positive and oestrogen negative cells in their study. All the cases in Shick et al.(15) study had aggressive behavior, which was associated with positive progesterone receptor status.

Düe et al.(17) analyzed oestrogen and progesterone receptors in samples of adenoid cystic carcinoma in both breast cancer and salivary gland tissues. No positive staining

was detected for oestrogen or progesterone in any of these cases, though sensitivity with antibodies was uncertain. Dori et al.(18) assessed oestrogen and progesterone receptors in adenoid cystic carcinomas of salivary gland origin. Progesterone receptors were identified in only 2 out of 27 cases but oestrogen was not detected in any of these cases. Their results suggested that the application of hormone therapy to salivary gland was not supported by their study. Dodd & Slevin(19) have studied one hundred and fourteen publications to determine the role of oestrogen and progesterone in salivary gland adenoid cystic carcinoma. They found the role of those receptors to be limited.

Nasser et al.(20) have studied the expression of oestrogen and progesterone in salivary gland tumours where oestrogen and progesterone expressed in only a few cases of salivary gland tumors. Glas et al.(21) have studied the prognostic significance of progesterone receptor and oestrogen receptor in patients with recurrent pleomorphic adenomas, comparing the results in a group of patients with primary adenomas without recurrences during 10 years of follow-up. Oestrogen receptor expression was low in both groups (19% and 17% respectively). Progesterone receptor expression in the recurrent group (96%) was higher compared with progesterone receptor expression in the control group (61%; P < 0.001). Teymoortash et al.(22) have evaluated the steroid hormone receptors in Warthin’s tumour of the parotid gland. Progesterone-positive cells were founded in the epithelial components of Warthin’s tumour. Oestrogen receptor showed negative expression in the epithelial components of Warthin’s tumour.

Jeannon et al.(23) have detected nine oestrogen receptor and six progesterone receptor positive tumours from a sample of 36 salivary tumours. Kolár et al.(24) have indicated that oestrogen receptors, progesterone receptors and some other estrogen-induced proteins were found in the cells of salivary gland carcinomas. Ozono et al.(25) have confirmed the existence of the receptor for progesterone in salivary adenoid cystic carcinomas. Furthermore, Lamey et al.(26) have studied the presence of hormone receptors for

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oestrogen and progesterone in the major salivary gland tumours. Eight salivary gland tumours exhibiting varied histology, none showed high affinity receptors for oestrogen or progesterone.

Ito et al.(27) have reported that all cases of

pleomorphic adenomas, Warthin’s tumors, mucoepidermoid carcinomas and adenoid cystic carcinomas of salivary glands were negative for oestrogen and progesterone receptors. Androgen receptor was positive in two cases

Table 1 : shows the outcome of the expression of oestrogen, progesterone and androgen receptors in salivary gland tumours (1980-2009).

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each of pleomorphic adenoma, mucoepidermoid carcinoma and adenoid cystic carcinoma. Tarakji et al.(28) observed that all cases of carcinoma ex pleomorphic adenoma were negative for oestrogen and progesterone receptors.

It is very clear from the presented literature that the expression of oestrogen and progesterone receptors in salivary gland tumors have reported conflicting results. Interestingly, Larbcharoensub et al.(29) have reported that three

Table 1 (cont’d) : shows the outcome of the expression of oestrogen, progesterone and androgen receptors in salivary gland tumours (1980-2009).

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cases of metastasizing pleomorphic adenoma shows positive reactivity to progesterone receptor but negative reactivity to oestrogen receptor.

Fan et al.(30) have mentioned that androgen receptor was noticed in 11 of 12 cases of salivary duct carcinoma. Moreover, Kapadia et al.(31) observed that androgen shows positive reactivity in 11 out of 12 of salivary duct carcinoma but oestrogen and progesterone receptors were negative. Likewise, Wick et al.(32) have indicated that oestrogen receptor was negative in salivary duct carcinoma.

Remarkably, Barnes et al.(33) observed that one (8%) of 12 salivary duct carcinomas was positive for oestrogen receptors and none was positive for progesterone receptors. Onitsuka(34)

have observed that estradiol was positive in pleomorphic adenoma. Recently, Sygut et al.(35)

have reported that nuclear immunoreactivity for androgen was demonstrated in 3 of 4 salivary duct carcinomas, 2 of 7 adenocarcinomas and 1 of 2 carcinoma ex pleomorphic adenoma. Expression of androgen was evaluated semi-quantitatively according to DAKO oestrogen/


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al.(39) have indicated that androgen receptor was negative in all cases of salivary duct carcinomas while progesterone receptor was positive in one case. Gaffney et al.(40) observed that androgen receptor was negative in 72 patients with benign salivary tumors and 26 patients with malignant tumors. All related published literature was systematically reviewed in Table 1.

DiscussionImmunohistochemistry has become an

important tool in surgical pathology, especially in the diagnosis of tumours. The demonstration of antigens more or less specific for different types of tumours has dramatically improved diagnostic accuracy. As well as being diagnostically important, the expression of several antigens as demonstrated by immunohistochemistry correlates with the prognosis of some cancers. There are discrepancies of the results found in

progesterone pharmDx scoring guidelines whereas all positive cases came from male patients. There was no immunoreactivity seen in 13 adenoid cystic carcinomas, 7 mucoepidermoid carcinomas and 4 acinic cell carcinomas. Locati et al.(35) observed that oestrogen and progesterone receptors were negative in 139 samples of salivary gland carcinomas, androgen receptor was found in 13% of samples. Luo et al.(36) have mentioned that 75% of cases of adenoid cystic carcinoma were positive for oestrogen receptor-alpha, only 17 percent of cases of adenoid cystic carcinoma were positive for oestrogen receptor-beta. Williams et al.(37) observed that oestrogen receptor-beta was detected in 67% (56/84) of salivary duct carcinoma. In addition, androgen receptor was expressed in 45% (34/75). Pires et al.(38) observed that oestrogen receptors were negative in 136 mucoepidermoid carcinomas and 72 adenoid cystic carcinomas. Lewis et


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the literature as mentioned because of different methodological problems. First, there may have been selection of patients and differences in treatment of different types of salivary gland tumours. Second, there are often differences in tissue processing from study to study, especially with regard to the type of antibody and the application of antigen retrieval. Also there are several steps in tissue processing that may influence staining patterns and intensity. These include type and duration of fixation, section thickness, antigen retrieval procedures, type and concentrations of primary, second and third step antibodies.

Third, and possibly most important, interpretation of staining and presentation of the results are not standardized resulting in low intra-observer and inter-observer reproducibility. Many authors used different criteria, so the results cannot be compared. This study has shown that different criteria such as (0=negative staining, 1=low, 2= moderate, 3= strong or 0-3= negative and 4= positive or 0-2= negative and 3-4=positive or negative and positive staining) have been used in the literature to assess the existence of oestrogen, progesterone and androgen receptors. Therefore, the use of one criterion such as negative or positive staining only for the assessment of staining will avoid any confusion in the interpretation of the results.

In the presented studies, there was a lack of definition in which part of the tumour the staining had been assessed.

ConclusionThe above mentioned shortcomings are

a very important obstructions for possible clinical applications. There is therefore a clear need for consensus on a protocol for scoring of immunohistochemical staining. The number of studied cases in literature is limited. A small number of salivary gland cancers have shown positive reactivity to the oestrogen, progesterone, and androgen receptors. Also it is recommended that further work involves large series of salivary gland cancers (randomized control trial) to determine if oestrogen, progesterone, and androgen receptors using sensitive and specific biochemical methods can be detected in these tumours. It is necessary to use one criterion such as positive or negative nuclear staining to determine the existence of oestrogen progesterone, and androgen receptors. Interestingly, studies showed that oestrogen, progesterone, and androgen receptors were detected in few cases of salivary gland tumours. This may indicate that the tumourgenesis of salivary gland is not dependent on hormone function.

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Expression of oestrogen progestrone and androgen receptors in salivary gland tumours. A review of literature