Which “P” Came First? The Parotid or the Pancreas? A Diagnostic Dilemma

Neoplasm of the salivary glands is rare and accounts for 3% to 6 % of all head and neck tumors, and about 85% occurs in the parotid glands. Metastatic disease to the salivary gland, in particular the parotid gland, is noted to be uncommon among solid tumors and has not been well described before. We report a patient who presented with an initial parotid swelling, only to ascertain, it was a metastatic lesion arising from an adenocarcinoma of the pancreas.


INTRODUCTION
Tumors of the salivary glands account for 3% to 6 % of all head and neck neoplasm in adults. Their clinical and histological appearances vary markedly.The World Health Organization describes 24 distinct malignant epithelial tumors of salivary origin (1).
About 85% of salivary gland tumors occur in the parotid glands, followed by the submandibular and minor salivary glands, and about 1% occurs in the sublingual glands. 75 to 80% are benign, slow-growing, movable, painless, usually solitary nodules beneath normal skin or mucosa (2).Malignant tumors of salivary glands are less common and can be characterized by rapid growth or a sudden growth spurt. Mucoepidermoid carcinoma, adenoid cystic carcinoma, and adenocarcinoma account for over 75% of all salivary gland carcinomas (3). Mucoepidermoid carcinoma is the most common malignant tumor of the parotid gland, accounting for 30% of parotid malignancies. Adenocarcinoma of the parotid develops from the secretory element of the gland. Histological appearances varying between low-grade well-differentiated papillary or mucinous patterns to high-grade, undifferentiated lesions(4).This is an aggressive lesion with potential for both local lymphatic and distant metastases. Approximately 33% of patients have nodal or distant metastasis present at the time of initial diagnosis.
The most common solid tumors to metastasize to the pancreas include carcinomas of the kidney, lung, breast, colon, stomach, esophagus, and melanoma (5). However, this case reveals an initial presentation of a metastatic lesion of the parotid gland, with a late detection of its primary, the adenocarcinoma of the pancreas.

CASE REPORT
A 63 year old gentleman, ex-smoker, with no known medical illness, presented with a painless left parotid swelling for 2 weeks which had increased in size.He denied other systemic symptoms at early presentation except for occasional pluritic chest pain. A thorough otorhinolaryngological (ORL) examination was performed which revealed a left parotid swelling, measuring 3cm x 3cm and firm in consistency. Other physical examinations were unremarkable. Fine Needle Aspiration Cytology (FNAC) of the parotid swelling was performed, which revealed the possibility of adenocarcinoma.
Subsequently, the patient underwent a Computed Tomography (CT) scan of the neck, thorax and abdomen, which showed a left parotid mass (Figure 1    Referrals to the respiratory team were made in view of the lung lesion to determine metastasis to the lungs. Furthermore, a CT guided biopsy of the right lung lesion was performed, and results showed non-small cell type of carcinoma.

Fluorine-18-Fluorodeoxyglucose
PositronEmissionTomography/Computed Tomography (F-18-FDG -PET/CT) scan was done and showed widespread malignancy involving the right lung, left parotid, left adrenal, pancreas, peritoneal nodules, nodes (cervical, supraclavicular, mediastinal and abdominal), bones and muscles. At this time,the primary malignancy was suspected to be originating from the right lung. (Figure 4a The patient's condition worsened as he showed signs of obstructive jaundice,complicated with hepatic encephalopathy. He underwent anotherCT scan of the pancreas, which showed a lesion at the head of pancreas, compressing on the common bile duct. Endoscopic Retrograde Cholangiopancreatography (ERCP) was performedand a biopsy of the pancreatic lesion was taken, which revealed adenocarcinoma of head of pancreas. Palliative chemotherapy was commenced; however patient deteriorated and further wentintoneutropenic sepsis. Further complications led tohis notable death.
Cause of death was determined as; advanced stage of head of pancreas adenocarcinoma with metastases to the lung, liver, bones, nodes, adrenal gland and the parotid gland.

DISCUSSION
This clinical case shows a dilemma between the primary source of the adenocarcinoma, as the initial presentation did not complement the origin of the cancer. Carcinomas most commonly metastasize via the lymphatic system; first to the regional lymph nodes and then into the general circulation. Dependent upon the primary site of the tumour, metastases from carcinomas commonly occur to the lungs, liver and bones. It is important to be able to distinguish the origin of the mass as the management will depend significantly on the histological type and staging of the disease. It is rare for soft-tissue metastases to be a presenting sign of an occult cancer as by the time these appear, the patient has commonly developed symptoms pertaining to the primary tumour (6).
Evaluating the origin of metastatic disease could be difficult and confusing in many cases because of the presence ofconcomitant sites of involvement. In our case, although the origin of metastatic disease preliminary diagnosis was considered to be of salivary gland origin, the chance of having a second malignancy or primary could not be completely ruled out.
The incidence of distant metastasis in head and neck cancer and especially in salivary gland cancer is relatively low in comparison to other malignancies. Furthermore, the presence of distant metastasis heralds a poor prognosis in head and neck cancer, with a median survival of 4.3-7.3 months(6).
A report in 2014, was the first case which showed presentation of acinic cell carcinoma of the parotid with metastatic spread to the pancreas even after years of treatment of the initial diagnosis. Overall, metastases to the pancreas are uncommon in solid tumors, with autopsy studies showing pancreatic involvement as a diffuse metastatic disease in 3-12% of all patients (7).
However in this clinical case, it has shown to be vice versa. There is a similarity between the structure of the salivary glands and the pancreas. The duct system made up of acinar and duct cells ensconced in a sheet of myoepithelial cells. The acinar cells line the intercalated and striated ducts through which the saliva travels before it is expulsed into the mouth. While the salivary glands themselves are mesodermal in origin, endocrine cells may be found within these glands, most likely derived from embryonic neural crest cells of the diffuse neuroendocrine system. It is likely that such cells give rise to neuroendocrine tumors in this location, although it has been proposed that pluripotential stem cells capable of dual epithelial and endocrine differentiation may be the source of the tumor (8). However, there has been no conclusive evidence in regards to adenocarcinoma tumours in particular.
With regards to imaging appearance, benign parotid tumors are generally well circumscribed, uniformly enhancing focal lesions while malignant tumors usually have poorly defined margins and enhance inhomogeneously (9). Lobulated appearance, and presence of vascularity within the tumour suggest benignity. Cystic or haemorrhagic components may be found in larger benign tumours, whereas calcifications are usually seen in long standing benign tumours. On the other hand, malignant or metastatic parotid tumours are often ill defined, with heterogeneous enhancement, as seen in this patient. Other features of malignancy include local infiltration to the parapharyngeal space, encasement of the carotid vessels, perineural spread, and bone and lymph node involvement (9).
Adenocarcinomas can be classified according to their histological findings: Grade 1 (low-grade) tumours are circumscribed and minimally invasive, Grade 2 (intermediate-grade) tumours are in between Grade 1 and Grade 3, whereas Grade 3( high-grade) tumours are more solid with a greater mitotic rate. Survival rates are reported to be poorer for high-grade tumours(10).
Metastases to salivary glands are mainly observed in the parotid gland due to the presence of intraglandular lymph nodes, which drain the face, external ear, and scalp. Skin malignancies (melanoma, squamous cell carcinomas) are the most common primary tumours metastasizing to the salivary glands, therefore careful clinical examination has to be performed. In addition, other malignancies, such as renal cell carcinomas, lung, breast and gastrointestinal carcinomas can also metastasize to the parotid gland or periparotid lymph nodes (9)(10)(11).
The most common primary tumours which give rise to pancreatic metastases are lung cancer, breast cancer, renal cell carcinoma, malignant melanoma, carcinoma of gastrointestinal origin and prostate cancer. Less commonly metastases from osteosarcoma, leiomyosarcoma, chondrosarcoma, and Merkel cell carcinoma, have also been reported (12).
A review of resection for metastases to the pancreas found renal cell carcinoma to be the most frequent primary histopathology (62%), followed by non-small-cell lung cancer, and melanoma(13). Moreover, metastatic from the parotid gland is extremely rare. In view of its rarity, other lesions that were reported in the CT scan were quickly addressed and sent for biopsy to assure the source of the primary lesion.
CT is an excellent modality for the detection and characterization of pancreatic lesions. However, differentiation of primary pancreatic neoplasm from metastases is often difficult.Pancreatic metastases are usually hypovascular, and this can appear similar to pancreatic ductal adenocarcinoma (PDAC). Unlike PDAC, most metastases are generally well circumscribed(14). Multiplicity of lesions is more commonly seen in metastases than in primary neoplasm. However, there are reported cases of multiple lesions in PDAC, possibly synchronous primary tumours or intra-glandular metastases(15).In this case, there were multiple rim-enhancing hypodense lesions in the pancreaswith ill-defined margins, suggestive of primary neoplasm.
Metastatic spread to the lungs may be haematogenously, resulting in multiple lung nodules of varying sizes located peripherally, or via lymphatic drainage, resulting in diffuse interstitial thickening (16). These radiologic findings are best seen on CT. Radiological features of adenocarcinoma metastases include air-space nodules, ground-glass opacities, consolidation, and nodules with CT halo signs16. Cavitation is frequently present, as seen in this case.

CONCLUSION
Evaluating the origin of metastatic disease could be difficult in many cases because of the presence of concomitant sites of involvements. Although the possibility of a primary adenocarcinoma of the parotid gland should be considered, the management should include recognition of possibilities of metastatic spread to uncommon anatomical sites. This case demonstrated the importance of thorough investigations and radiological imaging which helped to solve the diagnostic dilemma.