Bone marrow metastases in salivary duct carcinoma of the parotid gland

Abstract

Salivary duct carcinoma (SDC) is a rare and extremely aggressive salivary gland cancer. An 81-year-old woman with SDC underwent a total parotidectomy with facial nerve sacrifice and a neck dissection. Following surgery, she was diagnosed with disseminated bone marrow metastases. She underwent chemotherapy and trastuzumab for palliation. We present a case of SDC of the parotid which was diagnosed with disseminated bone marrow metastasis following surgery for the primary. This case also highlights the importance of having a high index of suspicion while evaluating highly aggressive tumours like SDC for any atypical findings during workup.

Background

Salivary duct carcinoma (SDC) was first described by Kleinsasser et al.¹ SDC is a rare (1%–3% of all malignant salivary tumours), aggressive, high grade salivary gland cancer which frequently presents as advanced stage with early facial nerve involvement, frequent lymph node involvement and distant metastasis.^{2 3} The incidence of distant metastasis at presentation is approximately 13%.⁴ The 5-year mortality is greater than 50%.^{5 6} SDC has a predilection for men, 60–70 years old, with the parotid gland being the most common site.² The standard treatment for resectable tumours is a total parotidectomy including a neck dissection followed by adjuvant radiotherapy with or without chemotherapy. We present a case of SDC of the parotid who was diagnosed with disseminated bone marrow metastasis following surgery for the primary.

Case presentation

An 81-year-old Caucasian woman was first seen in our hospital in August 2017 for a rapidly growing, painful right parotid mass. No facial nerve weakness was noted on examination. Workup and treatment at an outside hospital noted atypical oncocytic neoplasm on fine-needle aspiration biopsy and excision was attempted but aborted when the mass was found to be ill defined, involving the sternocleidomastoid muscle and the greater auricular nerve. An incisional biopsy at this point returned as adenocarcinoma of the parotid.

Investigations

The patient was then referred to us and an MRI confirmed a mass in the superficial and deep lobe of the right parotid (figure 1A) along with enhancement of the facial nerve at the stylomastoid foramen (figure 1B). ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT performed postaborted incisional biopsy did not report any definite locoregional nodal or distant metastases. There were areas of uptake locally in the periparotid and right upper neck region that were deemed to be related to recent surgical intervention in this region. However, there were multiple areas of heterogeneous osseous FDG uptake that appeared to be intramedullary/bone marrow related (figure 2A,B) with a differential of myelodysplastic syndrome, and other haematopoietic disorders (with osseous metastases less likely or not favoured based on the overall appearance). Although metastatic disease was a rare possibility, the patient was designated as M0 (given lack of locoregional nodal metastases and no concerning liver or lung lesions). The patient was staged M0 as per the tumour, node, metastases classification (American Joint comission on cancer (AJCC) eighth edition) due to equivocal findings.⁷ The clinical staging was cT4aN0M0.

Figure 1.

(A) MRI showing mass in the superficial and deep lobe of the parotid (shown by red arrows). (B) MRI showing enhancement in the stylomastoid foramen (shown by red arrows).

Figure 2.

(A) Preoperative positron emission tomography (PET) scan showing diffuse uptake in bone marrow (red arrows). (B) PET scan showing bone marrow uptake in the extremities (white arrow).

Treatment

The patient underwent right total parotidectomy with facial nerve sacrifice, right modified radical neck dissection type II (sacrificing internal jugular vein and sternocleidomastoid muscle), that is, excision of nodal levels I–V with a gold weight implant and a rotational skin flap for reconstruction of the skin defect. Intraoperatively, the facial nerve was found to be grossly and microscopically involved by the malignancy (positive for SDC on frozen section) and hence the facial nerve was sacrificed.

The final histopathology returned as SDC of the parotid gland with metastasis to levels Ib, II, III, IV and V lymph nodes with extracapsular extension. The pathological staging was pT4aN2b. Immunohistochemistry performed on the specimen showed positivity for androgen receptor (AR), gross cystic disease fluid protein-15 (GCDFP-15), Her-2 neu (3–4+) and transcription factor GATA-3. The Ki 67 index was very high at 40%–50%. The molecular cytogenetics did not detect any mutations in the targeted epidermal growth factor receptor (EGFR) regions (figure 3A,B).

Figure 3.

(A) Ductal carcinoma in situ type histology with comedo necrosis (×10) (shown by black arrows). (B) Immunostaining showing Her-2 neu expression (×10) (shown by black arrows).

Outcome and follow-up

The patient did well during her postoperative course. Adjuvant radiation with chemotherapy was recommended due to the presence of extracapsular extension in multiple lymph nodes and given the overall aggressive pathology. While being evaluated for adjuvant therapy, the heterogeneous uptake in the bone marrow was evaluated. Although this was felt to be related to an entity like myelodysplastic syndrome and osseous metastases was deemed unlikely based on overall appearance, the medical oncologist addressing the adjuvant chemotherapy wanted a better understanding of the bone marrow status given that chemotherapy can affect the bone marrow. Hence, it was decided to pursue a bone marrow biopsy as the exact underlying aetiology could potentially affect the choice and tolerance of the chemotherapeutic agent. However, the pathology was reported as extensive replacement of the marrow by a metastatic neoplasm with oncocytic features, in a known primary of SDC (figure 4A,B). In view of disseminated bone marrow metastasis, she was treated with Taxol-based chemotherapy (60 mg/m² weekly) for 3 weeks, followed by 1 week of trastuzumab (4 mg/kg day 1 then 2 mg/kg weekly). Taxol was administered for 12 treatments and trastuzumab was continued in a maintenance fashion. The PET/CT scan after the therapy showed a significant interval response in the previously noted irregular osseous activity with improved and generally modest and diffuse bone/bone marrow activity. There were no other definite abnormal foci of characteristic FDG avid foci elsewhere in the body (figure 5A,B).

Figure 4.

(A) Pancytokeratin immunostaining showing complete replacement of bone marrow with poorly differentiated carcinoma (shown by black arrows). (B) High-resolution image showing bone marrow replaced with poorly differentiated carcinoma in the setting of a treated salivary duct carcinoma of the parotid (shown by black arrows).

Figure 5.

(A) Postsystemic therapy positron emission tomography (PET) scan showing excellent response. (B) Postsystemic therapy PET scan showing excellent response.

She is doing well 3 months after completion of chemotherapy while on maintenance trastuzumab. She has not progressed on CT scan of the chest done 3 months from the last date of Taxol. A follow-up PET scan is scheduled to monitor the response in 3 months.

Discussion

Due to the rarity and dismal prognosis of SDC, there is a dearth of literature regarding the clinical characteristics, treatment protocols and long-term clinical outcomes. Single institution studies, case series and case reports form majority of the literature.^8–14 Parotid gland is commonly involved by SDC. Imaging findings are suggestive of an aggressive mass, with ill-defined borders with frequent involvement of adjacent tissue. CT scans and MRI are both helpful in determining the extent of the disease. MRI gives a better soft-tissue delineation and is vital to assess perineural spread. These tumours are aggressive and frequently involve the facial nerve due to propensity to spread perineurally.¹⁵ Facial nerve paralysis is observed in about 40%–60% of cases.³ Perineural spread was observed in the case presented. However, there was no facial palsy at presentation. Histopathologically, SDC resembles ductal carcinoma of the breast. Differential diagnoses include mucoepidermoid carcinoma, adenocarcinoma not otherwise specified, metastatic adenocarcinoma and oncocytic carcinoma. The most distinguishing feature is the presence of an intraductal component which is relatively specific of the diagnosis. Variants include sarcomatoid, mucin rich, low-grade SDC and micropapillary SDC.^16–18 The presence of flat sheets of irregular tumour cells, with invasive features and with intraductal components are characteristic features of SDC.¹⁹ SDC can occur as the malignant component of carcinoma ex pleomorphic adenoma.²⁰

Tumour cells of SDC are immunoreactive for the AR (43%–92%), GCDFP-15, CK8118, Her-2 neu, CK5/6, keratin and cerbB2 with very low expression of oestrogen receptor (ER) (1.3%) and progesterone receptor (PR) (6%).^{18 21 22} In our case, immunohistochemistry of the tumour showed positivity for AR, GCDFP-15, Her-2 neu (3–4+) and GATA-3 and negative for ER and PR. Most often these tumours have a very high cell proliferation index (Ki-67). The patient did not have a history of breast cancer.

SDC being an aggressive tumour frequently presents with regional and distant metastasis. Regional metastasis ranges from 20% to 73% and distant metastasis from 25% to 80%.^{11 23 24} Lung, bone and brain are the most common sites of distant metastasis.²⁵

A recent surveillance, empidemiology and end results (SEER) database review which analysed 228 patients provided a comprehensive overview of survival outcomes and prognostic factors.²⁶ Once again regional metastasis significantly led to poorer survival (HR 2.43; 95% CI 1.35 to 4.39; p=0.003). Otsuka et al conducted a large multi-institutional study including 141 patients.²⁷ The 3-year overall survival and disease-free survival rates were 70.5% and 38.2%, respectively. The most common treatment failure was distant metastases (39.0%). The most common sites of distant metastasis were the lungs, followed by the bones, liver and brain. This is similar to the findings of other studies.^{8 26}

The treatment for SDC of the parotid is surgery followed by radiotherapy in advanced cases. Surgery entails total parotidectomy without or with facial nerve sacrifice if involved and, ipsilateral neck dissection. Perineural invasion, inadequate resection margins, extraparotid extension, lymphovascular invasion and nodal disease are all poor prognostic factors. Adjuvant postoperative radiotherapy should be considered with these poor prognostic features.

Systemic therapy is generally reserved for metastatic disease. Trastuzumab (TCH), targeting Her-2 neu which is overexpressed in 20%–66% of cases has been documented to provide clinical response in some patients.²⁸

Limaye et al concluded that Her-2 neu status should be tested in all patients with SDC. In their small series of five patients, all had clinical response to TCH.²⁹ One patient had a complete response at 52 months. As a randomised trial is not feasible due to rarity of the disease, various case series and case reports have concordant results.²⁸

Our patient has achieved favourable response to cisplatin and TCH, clinically and on the post-therapy PET scan and is planned for two times weekly TCH until progression.

SDC is a rare, aggressive tumour most commonly involving the parotid gland. There should be a high index of suspicion for distant metastases, especially in patients who present with regional metastasis. Since FDG CT-PET is now the standard of care for assessing advanced head and neck malignancies, any atypical findings on FDG PET/CT in these patients should be viewed suspiciously and confirmed by tissue sampling, when feasible. As demonstrated in this case, bone/bone marrow metastases can mimic lymphoproliferative disorders, especially in cases of intramedullary/marrow involvement where the appearance may not be typical of sclerotic/lytic/mixed osseous metastases. Finally, this case adds to the paucity of literature in a rare salivary gland tumour.

Learning points.

• There should be a high index for suspicion for distant metastasis while treating highly aggressive malignancies like salivary duct carcinoma (SDC) of the parotid and any equivocal findings should be further investigated.

• Regional lymph node metastases are often present in highly aggressive malignancies like SDC. Relatively low intensity of fluorodeoxyglucose uptake and recent surgical intervention in the region should not influence against a high level of suspicion for metastasis (regional or distant).

• Trastuzumab which targets the Her 2-neu overexpression has shown good response when used as a palliative agent in certain cases.