A Pitfall of the Androgen Deprivation Therapy for Salivary Duct Carcinoma: Hormonal Therapy-Induced Castrate-Resistant Prostate Cancer

Abstract

Introduction

Salivary duct carcinoma (SDC) is a rare, high-grade salivary gland malignancy. Recently, targeting the androgen receptor (AR) is one of the most promising new therapeutic strategies for AR-positive SDC.

Case Review

In this report, a 70-year-old man who was diagnosed with an AR-positive SDC underwent androgen deprivation therapy (ADT) as a treatment for recurrence after primary therapy. The ADT well contributed to control of SDC; however, the patient was referred to urologists for urinary hesitancy and slow flow and he was diagnosed as having castration-resistant prostate cancer.

Literature Review

Since SDC is a rare disease, it has been difficult to establish the most effective therapy. Nevertheless, several papers have reported the clinical benefit of ADT for AR-positive SDC, and the latest version of the National Comprehensive Cancer Network guidelines also states the importance of assessing for the presence of AR in SDC.

On the other hand, in the field of urology, it is also known that although ADT is initially effective in prostate cancer patients, prostate cancer often develops into castrate-resistant prostate cancer due to the adaptation of prostate cancer cells to ADT for survival and growth.

Conclusion

We reported a case of castrate-resistant prostate cancer diagnosed during the ADT for metastatic SDC. The present case emphasizes the importance of screening for prostate cancer at the initiation of ADT treatment and during treatment.

Introduction

Salivary duct carcinoma (SDC) is a rare, high‐grade salivary gland malignancy: the recurrence rate is high and distant metastases occur early [1].

The presence of androgen receptors (AR) in SDC is common [2]; thus, androgen deprivation therapy (ADT) in patients with recurrent or disseminated SDC may be beneficial.

We report a unique case of castration-resistant prostate cancer diagnosed during the ADT for metastatic SDC, and we review the literature regarding the SDC.

Case Review

A 70-year-old man presented with a progressively growing tumor mass on the left side of his neck.

He underwent tumor resection and the modified radical neck dissection and was pathologically diagnosed with an AR-positive SDC. Pathological examination revealed no lymph node metastasis, and imaging evaluation revealed no distant metastasis. No postoperative adjuvant therapy was given, and the patient received a follow-up examination.

Three years after surgery, follow-up computed tomography (CT) revealed multiple pulmonary nodules, and resection of the left lower lobe and dissection of the inferior mediastinal lymph nodes were performed.

Pathologically, the pulmonary nodules were diagnosed as AR-positive and human epidermal growth factor receptor 2 (HER2) positive adenocarcinoma arising from primary SDC, and no lymph node metastasis was seen. The patient did not wish to receive adjuvant therapy and received a follow-up examination again, but at one year postoperatively, the lung metastasis recurred. Subsequently, the patient received ADT that consisted of goserelin acetate once a month. At the time ADT was initiated, there was no screening for prostate cancer: in other words, his serum level of prostate-specific antigen (PSA) before ADT was not measured and no pelvic positron emission tomography (PET) scan was performed. The lung lesions diminished and ADT was continued.

Five years after starting ADT, the patient was referred to urologists for urinary hesitancy and slow flow.

At the first visit to urologists, his serum prostate-specific antigen was 1.15 ng/ml. CT and magnetic resonance imaging (MRI) revealed prostate cancer which has spread to the bilateral seminal vesicles. Besides, pubic bone metastasis which spread into the pelvic wall was also confirmed (Fig. 1). A trans-perineal prostate biopsy revealed a Gleason grade 5 + 5 prostate adenocarcinoma. Whole-body bone scintigraphy showed multiple foci of increased radiotracer uptake in the pubic bone and ilium. At the time of diagnosis with prostate cancer, his serum neuron-specific enolase (NSE) was 12.8 ng/ml, and levels of total testosterone were suppressed (< 3.0 ng/dL).

Fig. 1.

Magnetic resonance (MR) images of the patient. An axial T2 weighted-MR image and diffusion-weighted MR image (DWI) at b = 2000 s/mm² show the prostate cancer which has spread to the bilateral seminal vesicles (white arrow), pubic bone metastasis which spread into the pelvic wall (arrowhead)

Combined androgen blockade (CAB) with bicalutamide 80 mg once daily was begun as an additional treatment to eliminate any remaining androgens in the body. His PSA level, however, showed a gradual increase after reaching a nadir (0.25 ng/ml) two months after the initiation of CAB therapy. Responses to anti-androgen withdrawal syndrome were not seen. After PSA levels increased to 5.27 ng/ml, abiraterone was given at the standard dose of 1000 mg once daily with prednisone 5 mg twice daily. Tolerance was good and PSA dropped to 1.48 ng/ml.

During treatment with CAB, the routine imaging surveillance of the patient revealed no disease progression of SDC. Changes in the serum PSA, NSE, total testosterone level, treatment course, and metastasis lesion are shown in Fig. 2.

Fig. 2.

Changes of the patient’s serum PSA, NSE, total testosterone level, treatment course, and metastasis lesion from time of diagnosis with prostate cancer PSA Prostate-Specific Antigen, NSE Neuron-Specific Enolase, SD Stable Disease, PD Progressive Disease

Discussion

SDC is a rare and aggressive subtype of salivary gland malignancy: SDC was first described by Kleinsasser in 1986 [3]. The treatment of choice in the case of a resectable tumor is surgery; in unresectable SDC, primary radiotherapy is recommended [4]. Palliative chemotherapy is also offered to patients with unresectable diseases, but its efficacy remains uncertain.

Histologically, SDC shows morphologic resemblance to invasive ductal carcinoma of the breast and the presence of AR is common [2, 5]; thus, ADT in patients with recurrent or disseminated disease may be beneficial. As an illustration, a retrospective cohort study in which patients with stage 4a AR-positive SDC were offered adjuvant ADT after tumor resection showed that AR-positive SDC patients who received adjuvant ADT had a favorable outcome compared with patients in the control group [6]. Likewise, Heidy C. J, et al. reported the series of 10 patients with AR-positive SDC using ADT in 2011: the clinical benefit in the case series seemed to be 50% with a median duration of 12 months which is more durable than the results mentioned in the literature concerning chemotherapy [7].

Since SDC is a rare disease, it has been impossible to conduct large definitive randomized trials to establish standard approaches to treatment. In particular, for recurrent unresectable and/or metastatic SDC, the following treatment options are available, but there are no randomized trials that have established the most effective therapy; taxane (paclitaxel or docetaxel) plus platinum (carboplatin) chemotherapy, AR-targeted therapy, HER2-targeted therapy, and immune checkpoint inhibitor therapy [8]. Nevertheless, targeting AR is one of the most promising new therapeutic strategies for SDC, and the latest version of the National Comprehensive Cancer Network guidelines recommends the evaluation of AR status before treatment [9].

The AR-targeted therapy generally includes methods based on surgery and methods based on drugs. Surgical castration, or orchiectomy, is a method of removing the testicles, the organ where androgens are synthesized.

Orchiectomy is the most radical treatment for ending the production of androgens, and it is the easiest and least expensive one: however, castration based on drugs may be preferred to surgical castration as it keeps the testes intact.

There are two different medicines commonly used for chemical castration; luteinizing hormone (LH) releasing hormone agonists and antagonists. Both drugs lower the amount of testosterone produced by the testicles by inhibiting the formation of LH in the pituitary gland. In this report, the ADT with goserelin acetate, an LH releasing hormone agonist, well contributed to the control of SDC; however, his unrecognized prostate cancer progressed as castrate-resistant prostate cancer (CRPC) on the ADT.

In the urology practice, ADT is the standard of care for patients with biochemical recurrence after definitive primary therapy, locally advanced disease, or metastatic disease, has been demonstrated to provide an initial benefit, but the majority of patients will progress to CRPC within 2–3 years [9]. The mechanism by which prostate cancer progresses to CRPC is said to be due to the adaptation of prostate cancer cells to ADT for survival and growth, and the activation of epithelial-mesenchymal transition, neuroendocrine transdifferentiation, and cancer stem cell-like gene programs [10].

Conclusion

To the best of our knowledge, ours is the first documented case of a CRPC diagnosed during the ADT for metastatic SDC. The present case highlights the importance of screening for prostate cancer at the initiation of ADT treatment and during treatment.

Abbreviations

ADT

Androgen deprivation therapy

AR

Androgen receptors

CAB

Combined androgen blockade

CRPC

Castration-resistant prostate cancer

CT

Computed tomography

DWI

Diffusion-weighted magnetic resonance image

HER2

Human epidermal growth factor receptor 2

LH

Luteinizing hormone

MR

Magnetic resonance

MRI

Magnetic resonance imaging

NSE

Neuron-specific enolase

PET

Positron emission tomography

PD

Progressive disease

PSA

Prostate-specific antigen

SD

Stable disease

SDC

Salivary duct carcinoma

Author Contributions

SY wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

Funding

Not applicable

Data Availability

The data that support the findings of this study are available from the corresponding author, Shugo Yajima, upon reasonable request.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

Ethical approval to report this case was obtained from National Cancer Center Institutional Review Board.

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