Scholarly article on topic 'A potential role for sex hormone receptor antagonists in treatment of malignant salivary gland tumours, as compared to breast cancer: A review of literature'

A potential role for sex hormone receptor antagonists in treatment of malignant salivary gland tumours, as compared to breast cancer: A review of literature Academic research paper on "Clinical medicine"

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{"Malignant salivary gland tumours" / "Mucoepidermoid carcinoma" / "Adenoid cystic carcinoma" / "Salivary duct carcinoma" / "Sex hormone receptor" / "Estrogen receptor" / "Progesterone receptor" / "Androgen receptor"}

Abstract of research paper on Clinical medicine, author of scientific article — T.A. Omar, F. ElDidi, W.M. Nawar

Abstract Malignant salivary gland tumours (MSGTs) account for less than 5% of all cancers of the head and neck. However, their treatment represents a challenge to oral and maxillofacial specialists. Surgical resection followed by radiation therapy represents the primary treatment of localized MSGTs. Since breast and salivary glands share similar morphologic features; similarities in the pathological processes are also expected. Adjuvant hormonal therapy is recommended for breast tumours containing hormone receptor protein. The expression of sex hormones in MSGTs, and their potential use in treatment is still controversial. This review article discusses three types of tumours arising in the breast and salivary glands; namely mucoepidermoid carcinoma, adenoid cystic carcinoma and salivary duct carcinoma. The expression of sex hormone receptor proteins and the potential use of hormone receptor antagonists in treatment are also being addressed.

Academic research paper on topic "A potential role for sex hormone receptor antagonists in treatment of malignant salivary gland tumours, as compared to breast cancer: A review of literature"

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Tanta Dental Journal 10 (2013) 75-85

www.elsevier.com/locate/tdj

A potential role for sex hormone receptor antagonists in treatment of malignant salivary gland tumours, as compared to breast cancer:

A review of literature

T.A. Omar, F. ElDidi, W.M. Nawar*

Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Alexandria University, Egypt

Abstract

Malignant salivary gland tumours (MSGTs) account for less than 5% of all cancers of the head and neck. However, their treatment represents a challenge to oral and maxillofacial specialists. Surgical resection followed by radiation therapy represents the primary treatment of localized MSGTs. Since breast and salivary glands share similar morphologic features; similarities in the pathological processes are also expected. Adjuvant hormonal therapy is recommended for breast tumours containing hormone receptor protein. The expression of sex hormones in MSGTs, and their potential use in treatment is still controversial. This review article discusses three types of tumours arising in the breast and salivary glands; namely mucoepidermoid carcinoma, adenoid cystic carcinoma and salivary duct carcinoma. The expression of sex hormone receptor proteins and the potential use of hormone receptor antagonists in treatment are also being addressed.

© 2013, Production and Hosting by Elsevier B.V. on behalf of the Faculty of Dentistry, Tanta University.

Keywords: Malignant salivary gland tumours; Mucoepidermoid carcinoma; Adenoid cystic carcinoma; Salivary duct carcinoma; Sex hormone receptor; Estrogen receptor; Progesterone receptor; Androgen receptor

Introduction

Tumours of the salivary glands; although uncommon, constitute an important area in the field of oral

* Corresponding author. E-mail address: wedad.nawar@yahoo.com (W.M. Nawar). Peer Review under the responsibility of the Faculty of Dentistry, Tanta University

and maxillofacial pathology. Soft tissue neoplasms, lymphoma and metastatic tumours can also occur within the salivary glands [1].

Malignant salivary gland tumours (MSGTs) account for less than 5% of all cancers of the head and neck [2]. The annual incidence rates in the world vary between slightly less than 2 and greater than 0.05 per 100,000 inhabitants [3].

Surgical resection followed by radiation therapy represents the primary treatment of localized MSGTs [4]. However, in some cases, the disease is rapidly progressive and even metastatic [5]; therefore systemic adjuvant therapies are necessary. They are designed to

1687-8574/$ - see front matter © 2013, Production and Hosting by Elsevier B.V. on behalf of the Faculty of Dentistry, Tanta University. http://dx.doi.org/10.1016/j.tdj .2013.08.006

eradicate microscopic deposits of cancer cells that may have spread or metastasized from the primary tumour [4].

Breast and salivary glands share similar morphologic features; consequently it is reasonable to expect similarities in the pathological processes [6]. Adjuvant hormonal therapy is recommended for breast tumours that contain hormone receptor protein [7]. However the expression of sex hormones in MSGTs and their potential use in treatment is still controversial [4].

This review article addresses the following key points

1. Classification of MSGTs

2. Similarities between MSGTs and Breast Cancers

a. Mucoepidermoid Carcinoma

b. Adenoid Cystic Carcinoma

c. Salivary/Mammary Duct Carcinoma

3. Role of hormones in treatment of breast cancers

4. Expression of sex steroid hormones in MSGTs

5. The potential role of hormones in treatment of MSGTs

1. Classification of MSGTs

The World Health Organization (WHO) in 2005 classified malignant epithelial tumours as follows [8]:

In this review, three types of tumours are discussed; MEC, AdCC and SDC. These tumours are not only similar to breast cancers in terms of morphologic and biologic characteristics, but also at the molecular level [4]. They have also been evaluated for their expression of sex hormone receptor proteins in several studies [12-24].

2.1. Mucoepidermoid carcinoma

Mucoepidermoid Carcinoma of the salivary gland is one of the most common types of MSGTs, accounting for 29-34% of all MSGTs. They occur over a wide age range, from the 2nd to the 7th decades, with slight female predilection. They are the most common MSGTs to occur in children, most commonly affecting the parotid gland [1].

i. Histologically

It is composed of a mixture of mucous, epidermoid and intermediate cells. Some tumours also show variable numbers of clear cells. Mucous cells vary in shape but contain abundant foamy cytoplasm. Epidermoid cells are polygonal in shape and have intercellular bridges. The intermediate cells are the progenitor cells of both types. They vary from small basaloid cells to large ovoid cells with pale eosinophilic cytoplasm [1].

1. Acinic cell carcinoma

2. Mucoepidermoid carcinoma

3. Adenoid cystic carcinoma

4. Polymorphous low-grade adenocarcinoma

5. Epithelial-myoepithelial carcinoma

6. Clear cell carcinoma, not otherwise specified

7. Basal cell adenocarcinoma

8. Malignant sebaceous tumours

9. Cystadenocarcinoma

10. Low-grade cribriform cystadenocarcinoma

11. Mucinous adenocarcinoma

12. Oncocytic carcinoma

13. Salivary duct carcinoma

14. Adenocarcinoma, not otherwise specified

15. Myoepithelial carcinoma

16. Carcinoma ex pleomorphic adenoma

17. Carcinosarcoma

18. Metastasizing pleomorphic adenoma

19. Squamous cell carcinoma

20. Small cell carcinoma

21. Large cell carcinoma

22. Lymphoepithelial carcinoma

23. Sialoblastoma

2. How are MSGTs similar to breast cancers?

Breast and salivary glands are both tubulo-acinar exocrine glands with similar morphologic features. The same types of neoplasms can arise in both sites; such as pleomorphic adenoma, myoepithelioma, acinic cell carcinoma, oncocytic carcinoma [6], mucoepidermoid carcinoma (MEC) [9], adenoid cystic carcinoma (AdCC) [10], and salivary duct carcinoma (SDC) [11].

There are three histopathologic grades; low, intermediate and high grades, according to relative number of mucous and epidermoid cells, amount of cyst formation and cytologic atypia [1].

Low grade tumours show prominent cyst formation, and a high proportion of mucous cells. High grade tumours consist of solid islands of squamous and intermediate cells. Intermediate tumours have a relatively equal number of mucous and squamous cells [1].Fig. 1

Fig. 1. Ref. [25] A: Intermediate-grade MEC showing limited cyst formation and nearly absent mucocytes. B: A high-grade tumour with mitoses and profound pleomorphism.

ii. Prognosis and treatment

Prognosis depends on the grade and stage of the tumour. Generally 90—98% of the patients are cured. Submandibular gland tumours have worse prognosis than parotid tumours.

Surgical resection of the involved gland and postoperative radiation therapy is the main line of treatment [1].

On the other hand, Mucoepidermoid Carcinoma of the Breast is very rare entity with an estimated incidence of 0.2% [6].

i. Histologically

Mucoepidermoid carcinoma of the breast can also be categorized as low, intermediate and high grades. Low grade MEC discloses well circumscribed, sometimes cystic lesions, filled with mucins. Neoplastic nests and cysts are lined at the periphery by basaloid cells and intermediate cells. Epidermoid or mucous secreting cells are usually found in the central aspects [6].

High grade breast MEC encompasses different entities of high histological grade, which are composed

Fig. 2. Ref. [6] E: Low grade mammary mucoepidermoid carcinoma (MEC) composed of neoplastic nests outlined by basaloid cells and centrally containing epidermoid and mucous secreting cells; F: high power magnification of high grade mammary MEC showing a complex admixture of basaloid and epidermoid elements and mucous secreting cells.

of a complex admixture of glandular structures with mucin production, foci of squamous differentiation, and so called intermediate cells, with a pronounced predominance of the squamous and intermediate cell components [26].Fig. 2

ii. Prognosis and treatment

Because of the rarity, the prognosis of MEC of the breast is still controversial [9].

iii. On the molecular level

A reciprocal translocation t(11; 19) (q21; p13) (MAML2:MECT) was shown in breast MEC, which is known as the most frequent genetic alteration of salivary MEC [27].

2.2. Adenoid cystic carcinoma

Adenoid cystic carcinoma (AdCC), formerly known as cylinderoma, is a form of adenocarcinoma that affects minor and major salivary glands, lacrimal glands, excretory glands of the female genital tract [28] and the breast [6].

Adenoid cystic carcinoma of the salivary gland is one of the most common minor salivary gland tumours, accounting for 22% of all head and neck tumours [29], with the palate being the primary site affected. AdCC represents 8-15% of all palatal salivary neoplasms. It is common between the 5th and 7th decades with slight female predilection [1].

Adenoid cystic carcinoma is a slowly growing mass, firm on palpation and it is characterized by pain due to perineural sheath invasion [1].

i. Histologically

Adenoid cystic carcinoma is composed of two main types of cells; myoepithelial and ductal cells. Three histologic patterns can be recognized: the cribriform, the tubular-trabecular and the solid patterns [30].

In the cribriform pattern, islands of basaloid epithelial cells contain cyst-like spaces resembling Swiss cheese. These spaces often contain a mildly basophilic mucoid material and a hyalinised eosinophilic product. Tumour cells are small and cuboidal, exhibiting deeply basophilic nuclei and little cytoplasm [28].

In the tubular pattern, there are duct-like spaces. These spaces are lined by one to several layers of the tumour cells [1].

The solid variant consists of large islands or sheets of tumour cells. Unlike the cribriform and tubular patterns, cellular pleomorphism, mitotic activity and focal necrosis in the centre of the tumour islands may be observed [1].Fig. 3

ii. Immunohistochemically

Positive immunostaining reactions to CD43 and c-kit (CD117) have proven useful in diagnosing AdCC [32].

Some other markers have been suggested to be diagnostically relevant; such as vimentin, collagen IV, laminin, integrins, ki-67, smooth muscle actin, and various cytokeratins [1].

iii. Prognosis and treatment

Adenoid cystic carcinoma is prone to local recurrence. Eventual distant metastases occur in 35% of the patients. Metastatic spread most commonly occurs to the lungs

and bones. It does not usually metastasize to regional lymph nodes. Prognosis is poorer for the solid type. With respect to the site, it is poorest for tumours affecting the maxillary sinus and submandibular glands [1].

Surgical excision is usually the treatment of choice, followed by adjunct radiation therapy. The 5, 10 and 20-year survival rates are 70%, 50% and 25% respectively [33].

On the other hand, adenoid cystic carcinoma of the breast is rare; representing 0.1-1% of all breast neoplasms [9]. It usually affects adult female patients [33] ranging from 38 to 81 years. It presents as a nodule 0.7-12 cm in diameter, frequently located in the per-iareolar region [6].

i. Histologically

Adenoid cystic carcinoma of the breast is composed of large sheets, nests or small aggregates of round to oval cells, sometimes with hyperchromatic nuclei. It might show areas of squamous differentiation; also sebaceous features can be found [34].

Three histologic patterns-similar to those of AdCC of the salivary gland-can be recognized: the cribriform, the tubular-trabecular and the solid patterns [6].

Also two types of spaces characterize AdCC of the breast. The first space contains myxoid stroma or collagen fibres. The second space is composed of glands that contain a granular secretion of Periodic Acid Schiff positive mucosubstances [6].

These spaces are lined by two types of cells; basa-loid cells, with central oval nuclei surrounded by a thin cytoplasmic rim, and the second type characterized by round nuclei and eosinophilic cytoplasm [6].Fig. 4

ii. Immunohistochemically

Immunostaining reactions of basaloid cells are positive for vimentin and CK14 and focally for myoepithelial markers, such as smooth muscle actin, calponin, p63 and maspin [6].

iii. Prognosis and treatment

Adenoid cystic carcinoma of the breast is not aggressive. The prognosis is usually good. Local recurrences and axillary lymph node metastasis are rare. Distant metastasis is uncommon and usually affects the lungs. Simple mastectomy with no axillary dissection is the treatment of choice [6].

iv. On the molecular level

AdCC of the breast share similar chromosomal abnormalities with AdCC of the salivary glands; including alterations in the 6q arm [35]. The genetic translocation t(6; 9) (q22-23; p23-24) is characteristic for salivary AdCC [36], and is also detected in breast AdCC [37].

2.3. Salivary/mammary duct carcinoma

Salivary duct carcinoma is a rare highly aggressive neoplasm [4].

i. Histologically

The epithelium tends to form cribriform, papillary and solid growth patterns along with duct-like structures. The morphology of SDC is characterized by

Fig. 4. Ref. [6] C: Adenoid cystic carcinoma of the breast showing solid and cribriform architecture; inset, breast ACC is composed of basaloid cells that outline spaces containing basal-like material and of eosinophilic cells lining true glandular lumina; D: staining for smooth muscle actin (SMA) demonstrates myoepithelial cells.

cuboidal and polygonal cells forming ducts and nests; often with central necrosis [4].Fig. 5

ii. Immunohistochemically

Her2 expression is demonstrated in SDC and since Her2 can enhance androgen receptor (AR) function, antiandrogen therapy may be more effective against MSGTs when Her2 is overexpressed [39].

iii. Prognosis and treatment

Generally SDC shows less survival rates than other MSGTs [4].

On the other hand, mammary duct carcinoma comprises a heterogeneous group of lesions with diverse malignant potential. Most patients present with lumps that are not palpable and are clinically occult [40].

i. Histologically

are comedo, cribriform, solid, micropapillary and papillary [41].Fig. 6

ii. Prognosis and treatment

The rates for mortality and the risk of invasive recurrence at eight years are 1.4% and 7% respectively. Current treatments for ductal carcinoma in situ range from simple tumour excision, to various forms of wider excision to mastectomy. All treatments less than mastectomy may be followed by radiotherapy [41].

iii. On the molecular level

There are similar alterations on chromosomal arms 6q, 16q, 17p and 17q in both salivary and mammary duct carcinomas [11].

3. Role of sex hormones in treatment of breast cancer

Ductal carcinoma in situ is a proliferation of malignant epithelial cells within the ductolobular system of the breast that show no light microscopic evidence of invasion through the basement membrane into the surrounding stroma. Several forms of histological architecture are recognised, the most common of which

Estrogen promotes the growth of about 2 out of 3 of breast cancers; estrogen receptor (ER) positive cancers

[43]. Because of this, several approaches to blocking the effect of estrogen or lowering estrogen levels are used to treat hormone receptor-positive breast cancers

Fig. 5. Ref. [38] A number of different patterns of growth can be seen. A: A micropapillary architecture infiltrating into the surrounding parenchyma. B: Papillary pattern. C: A more solid pattern of growth is noted, composed of large, polygonal tumour cells. D: This area shows a sarcomatoid pattern to the cells that are infiltrating into the adjacent fat and parenchyma.

Fig. 6. Ref. [41] A: Comedo-type ductal carcinoma in situ, HE stains. B: Cribriform-type ductal carcinoma in situ. C: Solid-type ductal carcinoma in situ. D: Papillary-type ductal carcinoma in situ.

Among women with ER-positive disease, the reduction in the recurrence rate and in the breast cancer death rate are highly significant, both in the trials of 1—2 years of tamoxifen, an ER-antago-nist, and in those of 5 years of tamoxifen, but are significantly greater in the latter. However, there seems to be no significant benefit in ER-negative women [45].

There are several strategies for treatment of ERpositive breast cancer [46]:

i. Blocking ovarian function

Ovarian ablation can be done surgically through an operation to remove the ovaries or by treatment with radiation. This has a permanent effect.

Alternatively, ovarian function can be suppressed temporarily by treatment with drugs called gonadotropin-releasing hormone (GnRH) agonists, which are also known as luteinizing hormone-releasing hormone (LH-RH) agonists. These medicines interfere with signals from the pituitary gland that stimulate the ovaries to produce estrogen.

Examples of ovarian suppression drugs that have been approved by the U.S. Food and Drug Administration (FDA) are goserelin (Zoladex®) and leuprolide (Lupron®).

ii. Blocking estrogen production

Aromatase inhibitors are used to block the activity of aromatase, which is used by the body to make estrogen in the ovaries and in other tissues. Aromatase inhibitors are used primarily in postmenopausal women because the ovaries in premenopausal women produce too much aromatase for the inhibitors to block effectively. However, these drugs can be used in premenopausal women if they are given together with a drug that suppresses ovarian function.

iii. Blocking estrogen's effects

Several types of drugs interfere with estrogen's ability to stimulate the growth of breast cancer cells. Selective estrogen receptor modulators (SERMs) bind to estrogen receptors, preventing estrogen from binding.

An example of SERMs approved by the FDA is tamoxifen (Nolvadex®). Tamoxifen has been used for more than 30 years to treat hormone receptor-positive breast cancer.

Hormone therapy can be used as:

1. Adjuvant therapy for early-stage breast cancer to increase the likelihood of a cure [47].

2. Treatment of metastatic breast cancer: Several types of hormone therapy are approved to treat metastatic hormone-sensitive breast cancer [48].

3. Neoadjuvant treatment of breast cancer: The use of hormone therapy to treat breast cancer before surgery (neoadjuvant therapy) has been studied in clinical trials. The goal of neoadjuvant therapy is to reduce the size of a breast tumour to allow breast-conserving surgery [49].

4. Prevention of the development of breast cancer in high risk women; since most early breast cancers are ER-positive [50].

4. Expression of sex steroid hormones in MSGTs

Human breast cancer [51] and human colorectal cancer [52] have shown the presence of steroid receptors to estrogen and progesterone. Evidence is accumulating concerning other hormone dependant malignancies including lymphoblastic leukaemia [53], cancer of the prostate [54], endometrial cancer [55] and other solid tumours [56].

In salivary gland tumours, expression of estrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) have been studied [12-24]. There is substantial disparity in the reported results. This could be attributed to variations in the technique employed; such as tissue fixation, sensitivity and specificity of antibodies used and antigen retrieval. In addition, some

Table 1

Summary of the reports of estrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) in adenoid cystic carcinoma.

Author Year No. of cases ER+ PR+ AR+

Shick et al. [12] 1995 12 0 6 0

Jeannon et al. [13] 1999 6 3 0 np

Dori et al. [14] 2000 27 0 2 np

Moriki et al. [15] 2001 6 np np 0

Nasser et al. [16] 2003 10 0 0 2

Pires et al. [17] 2004 72 0 np np

Miller et al. [18] 2004 5 0 np np

Ito et al. [19] 2009 30 0 0 2

Riad S. [20] 2009 11 0 1 8

TOTAL 3/173 9/96 12/69

1.73% 9.4% 17.4%

np: not performed.

Table 2

Summary of the reports of estrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) in mucoepidermoid carcinoma.

Author Year No. of cases ER+ PR+ AR+

Lamey et al. [21] 1987 1 0 0 np

Jeannon et al. [13] 1999 10 3 0 np

Moriki et al. [15] 2001 8 np np 0

Nasser et al. [16] 2003 10 1 1 2

Pires et al. [17] 2004 136 0 np np

Ito et al. [19] 2009 30 0 0 2

TOTAL 4/187 1/51 4/48

2.1% 2% 8.3%

np: not performed.

differences may be related to the criteria adopted for judging a tumour positive for the marker [16,19].

Tables 1—3 summarize the reports of ER, PR and AR in Adenoid Cystic Carcinoma (ACC), Mucoepidermoid Carcinoma (MEC) and Salivary Duct Carcinoma (SDC) respectively.

Most of these studies [12—24] do not support a role for ER and PR in AdCC, MEC and SDC. However, SDC expresses AR in the majority of patients [16,22—24]. Thus immunostaining for AR on cytologic smears is useful for the diagnosis of these patients [15]. It was also suggested that the high expression of AR in SDC may play a role in tumour progression [11]. This may assist in triaging patients with SDCs for novel therapies1 [15].

5. What is the potential role of hormones in treatment of MSGTs

To date, no phase II trials have been performed, so it is difficult to define the role of hormone therapy in MSGTs [5].

Elkin and Jacobs [57] in 2008 reported partial remission of two cases of AdCC in which tamoxifen, an ER antagonist, was used. Both patients obtained long-term stability of disease with no associated toxicity.

Table 3

Summary of the reports of estrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) in salivary duct carcinoma.

Author Year No. of cases ER+ PR+ AR+

Fan CY [22] 2000 13 np np 9

Fan CY [23] 2001 12 np np 11

Nasser [16] 2003 10 0 0 6

Williams [24] 2007 84 np np 56

TOTAL 0/10 0/10 82/119

0 % 0% 68.9%

np: not performed.

Fig. 7. Ref. [58]: A: Local recurrence before treatment, B: After 2 months with androgen-deprivation therapy.

Since there are no successful treatment modalities available for AdCC, and because of the low toxicity of ER antagonists; therefore, such treatment is recommended for its potential disease-stabilizing effects [24].

In 2003, Locati et al. [58] reported complete remission of a recurrent case of AR-expressing adenocarcinoma in the parotid gland. The 73-year old patient received a complete anti-androgen blockade with monthly triptorelin and bicalutamide. Skin lesions reduced rapidly, until disappearance 2 months later.

Complete remission was confirmed by a CT scan (Fig. 7) [58].

In conclusion, MSGTs refractory to conventional therapy would possibly benefit from hormonal therapy [17].

6. Recommendations

1. Further studies concerning the expression of sex hormone receptors in MSGTs need to be evaluated with greater numbers of samples.

2. Standard protocols for such studies should be clarified by an approved organization to allow for meta-analysis.

3. Clinical trials may be conducted —after patients' consents- in advanced cases, when the disease is refractory to conventional treatment modalities.

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