Metastatic Neuroendocrine Tumors to Parotid Gland: Where Do They Come From?

Introduction

The typical presentation of a patient with salivary gland neuroendocrine tumor is that of a painless mass that has been growing slowly over several months. It is usually seen in older patients (50-70 years old) and more common in men (61.7%). ¹ A fine needle aspiration biopsy may be the initial step and once the diagnosis of neuroendocrine tumor is established, the patient should undergo a full metastatic evaluation since these lesions could represent primary malignancy or metastasis to the salivary gland. Primary salivary gland carcinomas with neuroendocrine differentiation are quite rare, accounting for 3.5% of all malignant minor salivary gland tumors and 1-3% or less of all parotid gland carcinomas.^2,3 Sublingual and minor salivary gland neuroendocrine tumors may exist but are difficult to distinguish from neuroendocrine tumors arising from the overlying surface mucosa of the upper aerodigestive tract. So salivary gland neuroendocrine tumors are considered mainly parotid origin and remaining from submandibular gland. The primary neuroendocrine tumors of the salivary glands include large cell neuroendocrine carcinoma and small cell neuroendocrine carcinoma with small cell neuroendocrine carcinoma being more common. Some of the parotid gland tumors are metastatic and for nearly half of these patients the initial presentation is reported to be symptoms from metastasis to the parotid gland. ⁴ Metastasis to the parotid gland occurs mostly from skin cancers of the head and neck region, such as squamous cell carcinoma and malignant melanoma. However, malignancies from breast, lung, prostate, kidney, and gastrointestinal tract can also metastasize to the parotid gland.

Metastatic neuroendocrine tumors to the parotid glands from the above-mentioned locations are rare and not well studied so far. They frequently pose challenges to pathologists in distinguishing metastatic disease to parotid form salivary gland primary neuroendocrine carcinomas due to low frequency of these tumors, similar tumor cytology, architectures and immunoprofile. However, it is important to differentiate metastatic neuroendocrine carcinomas from salivary gland primary tumors as the prognosis and treatment plans may differ. When metastasis to parotid gland is suspected an adequate metastatic work-up is imperative for the diagnosis of a primary neuroendocrine carcinoma. In addition, salivary gland primary neuroendocrine tumors usually have a more favorable prognosis than salivary gland metastasis. For example, small-cell carcinoma of the lung with distant metastasis has a 5-year survival rate of only 3%. Patients who receive supportive therapy alone only have a mean survival of 2 to 4 months. In contrast, the overall 2- and 5- year survival for small cell carcinoma of the major salivary glands is reported to be 70% and 46%, respectively. ⁵ To further investigate the clinical and pathologic features of metastatic neuroendocrine carcinomas to parotid, we undertook a retrospective study to review all the secondary neuroendocrine tumors to parotid glands diagnosed in our institution. The most common entities, primary tumor locations, their clinical presentations, pathological features and immunoprofiles are analyzed and presented here.

Materials and Methods

Results

The following is the overall patient characteristics: A total of 420 parotid gland neoplasms were recorded from 1995 to 2021. Benign parotid gland neoplasms accounted for about 71% of the total cases (300 of 420 cases). About 29% (120 of 420 cases) of parotid neoplasms were malignant, including 70 cases of parotid primary malignant tumors and 50 cases of metastases to parotid glands. Among metastatic tumors to the parotid, squamous cell carcinoma and malignant melanoma of the head and neck region together accounted for about 78% of the cases. Only 11 of 50 metastatic tumors to the parotid were neuroendocrine carcinomas (22%). The mean age of patients with metastatic neuroendocrine carcinoma was 71.4 (range 48 to 87 years) with approximately 82% of the patients being over 60 years old. Only two patients were found to be under the age of 60 (48 and 56 respectively). The patient group shows male gender predominance (9 of 11 patients, P = .026). Interestingly most of the metastases to parotid involved the left parotid gland (10 of 11 cases, P < .01). The average size of parotid metastases was about 1.8 cm in greatest dimension. Most of the parotid metastases presented on imaging as well-defined enhancing solid mass that frequently showed proximity to the facial nerve and retromandibular vein. (Table 1)

OPEN IN VIEWER

Table 1.

Selected Case Reports and Case Series of Metastatic Neuroendocrine Tumors to the Parotid.

	Number of cases	Age of patients	Type of tumor	Grade	Primary location	Other locations involved	History of NEC
Yu, et al	1	64	Neuroendocrine carcinoma	SCLC	Lung	Right submandibular lymph nodes	No
Gulati, et al	1	56	Neuroendocrine tumor	Atypical carcinoid	Lung	Left adrenal gland	Yes
Salzman, et al	1	72	Neuroendocrine tumor	Carcinoid	Middle ear	Cervical lymph nodes	Yes
Koraitim, et al	1	68	Neuroendocrine tumor	Carcinoid	Lung	Lip	Yes
Ulubas, et al	1	59	Neuroendocrine carcinoma	SCLC	Lung	Multiple bone metastases	No
Salama, et al	1	82	Neuroendocrine carcinoma	SCLC	Lung	Brain, skin	Yes
Salama, et al	1	54	Neuroendocrine carcinoma	SCLC	Lung	Cervical lymph nodes	No
Kr Das, et al	1	48	Medullary thyroid carcinoma	N/A	Thyroid	Cervical lymph nodes	No
Conway, et al	1	61	Medullary thyroid carcinoma	Low-grade	Thyroid	Cervical lymph nodes, brain, bone, adrenal gland	No
Gajdzis, et al	1	47	Medullary thyroid carcinoma	N/A	Thyroid	Eye, bone, lung	No
Day, et al	14	Mean age 75.9	Merkel cell carcinoma	N/A	Head and neck	Cervical lymph nodes in 6 of 10 cases	10 of 14 cases
Basati, et al	1	69	Merkel cell carcinoma	N/A	Eyebrow	None	Yes
Nuyens, et al	1	84	Merkel cell carcinoma	N/A	Eye lid	Cervical lymph nodes	Yes

Abbreviations: NEC, neuroendocrine carcinoma; SCLC, small cell lung cancer.

The most common primary was poorly differentiated neuroendocrine carcinoma of lung (5 of 11 cases), including 4 cases of small cell carcinomas and one case of large cell neuroendocrine carcinoma. All four cases of small cell carcinoma presented with enlarging parotid mass as the first manifestation of disease and subsequent clinical work up revealed synchronous small cell lung cancer. Only the patient with large cell neuroendocrine carcinoma was initially diagnosed 5 years before the parotid metastasis. Three of the four small cell lung cancers also showed metastases to other locations, including liver, forehead skin and nasal cavity. All five cases of metastasis involved the left parotid and were unifocal lesions. Three metastases were in the superficial aspect of the parotid gland and one metastatic small cell carcinoma was found within an intra-parotid lymph node. Three patients received parotidectomy and two patients were treated with carboplatin and etoposide regimen. Two of the three parotidectomy had positive regional lymph nodes, lymphovascular invasion and positive resection margins and one case showed perineural invasion as well. H&E stained histologic sections showed sheets of small to medium sized oval blue cells with minimal cytoplasm, finely dispersed chromatin and no distinct nucleoli. Tumor necrosis and numerous apoptotic bodies were evident. Nuclear molding and smudging were focally present. (Figure 1A) All metastatic neuroendocrine carcinomas from the lung were positive for keratin 8/18, keratin 7, thyroid transcription factor (TTF)1 and synaptophysin on immunohistochemistry. (Figure 1B and C) monoclonal antibody against recombinant parts of the Ki-67 antigen1 mitotic index was usually more than 80%. Three of the five cases also had parotid fine needle aspiration (FNA) cytology, all of which showed poorly differentiated carcinoma with neuroendocrine features. The diff-quick stained cytology smears showed hypercellular smear with three dimensional clusters and numerous medium sized isolated tumor cells with scant to absent cytoplasm, fine chromatin and indistinct nucleoli. Absence of lymphoglandular bodies and a thin rim of cytoplasm distinguished the tumor cells from lymphocytes. Extensive nuclear molding and crushing artifact were evident. (Figure 1D)

OPEN IN VIEWER

Figure 1.

Histology and immunohistochemistry of metastatic small cell carcinoma of lung. (A and B) Poorly differentiated neuroendocrine carcinoma, small cell type. Tumor shows necrosis and numerous apoptotic bodies. Nuclear molding and smudging are focally present. (C) Immunostain for TTF-1 shows strong nuclear positivity. (D) Synaptophysin strongly stains the cytoplasm of tumor cells. (E) The cytology diff-quick stained smears show poorly differentiated tumor cells with extensive nuclear molding and crush artifact.

The second most common metastatic neuroendocrine tumor was Merkel cell carcinoma (4 of 11 cases, 36%) including one case of direct invasion from overlying skin. Two of the four Merkel cell carcinomas had synchronous metastases to parotid glands and one patient had more than one year history of skin cancer. All the primary Merkel cell carcinomas were in the head and neck region, such as scalp, auricular and temporal skin. One of the metastatic Merkel cell carcinomas also involved the temporal bone. All four patients received parotidectomy with one case having a positive resection margin, three cases with positive regional lymph nodes and two cases with multifocal tumor. One of the parotid metastases was confined to an intra-parotid lymph node. H&E stained histologic sections showed sheets of diffusely infiltrative small round blue cells with high N/C ratio, round to oval nuclei, salt and pepper like chromatin, indistinct nucleoli and scant cytoplasm. Mitoses, apoptotic bodies and areas of tumor necrosis were readily identified. There were variable nuclear molding and crush artifact. (Figure 2A and B). On immunohistochemistry, all metastatic Merkel cell carcinomas were positive for keratin 20, Synaptophysin, chromogranin and CD56 (Figure 2C and D).

OPEN IN VIEWER

Figure 2.

Histology and immunohistochemistry of metastatic Merkel cell carcinoma. (A and B) Metastatic Merkel cell carcinoma shows small round blue cells with high N/C ratio, round to oval nuclei, salt and pepper like chromatin and indistinct nucleoli. (C) The tumor shows variable nuclear molding and crush artifact. (D) Merkel cell carcinoma almost always stains with keratin 20 in contrast to metastatic small cell carcinoma. (E) Synaptophysin weakly stains the cytoplasm of tumor cells.

The third most common metastatic neuroendocrine tumor was medullary carcinoma of the thyroid (2 of 11 cases, 18%). Both patients had more than 5-year history of medullary thyroid cancer. Besides metastasis to the parotid gland, one patient also had metastatic tumor to the left humerus, and central neck soft tissue and the other patient had metastasis to the breast. One patient received parotidectomy. Surgical pathology specimen showed metastatic medullary carcinoma in three intra-parotid lymph nodes with lymphovascular invasion. The parotid parenchyma was free of medullary carcinoma. H&E stained histologic sections showed nests of medium to large cells with plasmacytoid appearance, moderate to abundant eosinophilic cytoplasm and oval to elongated nuclei with moderate nuclear atypia. The cells had coarsely clumped chromatin with inconspicuous or multiple small nucleoli. Occasional bizarre nuclear atypia was seen. Area of tumor necrosis was evident. Mitotic figures were readily identified. No amyloid material was present in this specific case. (Figure 3A and B). Both patients had parotid FNA cytology specimens which were diagnosed as poorly differentiated carcinoma and metastatic medullary carcinoma respectively. The thin-prep cytology was cellular and showed numerous isolated spindle cells with occasional loose clusters. The cells were uniform in size with elongated and eccentrically placed nuclei and long cytoplasmic tail. The nuclei had fine chromatin and small to inconspicuous nucleoli. The cytoplasm was scant to moderate and finely granular in texture. (Figure 3C) On immunohistochemical stains, the tumor cells were positive for keratin 7, keratin 8/18, carcinoembryonic antigen (CEA), calcitonin, synaptophysin and chromogranin (Figure 3D).

OPEN IN VIEWER

Figure 3.

Histology and immunohistochemistry of metastatic medullary thyroid carcinoma. (A and B) H&E stained section shows metastatic medullary thyroid carcinoma in intra-parotid lymph nodes. (C) The tumor cells are medium to large sized with plasmacytoid appearance, eosinophilic and granular cytoplasm and oval to elongated nuclei with moderate nuclear atypia. (D) The thin-prep cytology shows numerous isolated spindle cells with elongated and eccentrically placed nuclei and long cytoplasmic tail. (E) On immunohistochemistry, the tumor cells are diffusely positive for calcitonin.

Discussion

Metastatic tumors to the parotid glands are rare. Most parotid metastases are secondary to malignancies from the head and neck origin. The most common type of metastasis is squamous cell carcinoma, followed by cutaneous malignant melanomas from the head and neck region.^6,7 Metastasis to the parotid glands sometimes can be the initial presentation of undiagnosed malignancy, or they can arise years after initial treatment of the primary malignancy.^6,8 In addition, about 10-20% of parotid metastases are from distant organs, such as the lungs, breast and gastrointestinal tract. ⁶

Neuroendocrine carcinomas arising in the salivary glands are rare, accounting for only about 1% to 3% of parotid malignancies.^9,10 The majority of salivary gland neuroendocrine carcinomas occur in the sixth to eighth decade of life, and affect predominantly males, with a male to female ratio of 2.0-3.0/1. ³ They involve predominantly the parotid gland and rarely the submandibular gland, while the presence of primary salivary gland neuroendocrine carcinomas of the sublingual gland and the minor salivary glands is questionable. ¹¹ The primary neuroendocrine tumors of the salivary glands are usually high-grade carcinomas. Most of these tumors are small cell carcinomas; however, cases of neuroendocrine differentiation in large cell carcinoma of the major salivary glands have been reported as well.^12,13 The diagnosis of primary neuroendocrine carcinoma can be made after metastatic neuroendocrine carcinoma and other primary salivary gland tumors with similar morphology are excluded. The majority of primary salivary gland neuroendocrine carcinomas occur in the parotid glands, but cases arising in the submandibular glands have also been reported. ¹⁴ Rare cases have been reported as high-grade salivary neuroendocrine carcinomas arising from lower grade salivary gland tumors, such as small cell carcinomas arising from ex pleomorphic adenoma and low grade acinic cell carcinoma.^15,16 On immunohistochemistry, the tumor cells usually stain for synaptophysin, chromogranin and CD56. Small cell neuroendocrine carcinoma occasionally shows perinuclear dot-like positivity for pancytokeratins and even keratin 20, like the pattern typically seen in cutaneous Merkel cell carcinoma, making the diagnosis challenging.

Lung neuroendocrine carcinomas account for about 25% of the lung carcinomas. ¹⁷ Neuroendocrine tumors of the lung are a distinct group of neoplasms. The 2015 WHO tumor classification categorizes this group of tumors as typical carcinoid (low-grade malignant tumor), atypical carcinoid (intermediate-grade malignant tumor), small cell lung carcinoma and large cell neuroendocrine carcinoma (both are considered high-grade malignant tumors). Although all classified as neuroendocrine tumors, there are notable differences in their clinical presentation and tumor behavior. Small cell carcinoma and large cell neuroendocrine carcinoma almost always arise in the smokers. Typical carcinoids are not correlated to tobacco smoking, although reports of atypical carcinoids are more frequent in smokers. ¹⁸ Typical and atypical carcinoids can occur in patients with multiple endocrine neoplasia syndrome type 1 (8%) and have been found to have MEN1 mutations in about 40% of sporadic cases. ¹⁹ Both small cell carcinoma and large cell neuroendocrine carcinoma are considered to arise from the same endodermal origin as the rest of the respiratory epithelium and they display similar pattern of metastasis when tumor spreads. They tend to spread to regional intrathoracic and supraclavicular lymph nodes first, and can further metastasize to distant organs, such as liver, bone, brain and adrenal glands. Parotid gland metastasis from lung neuroendocrine carcinomas is rare and only a few cases have been reported in literature to date. Interestingly, a parotid mass frequently presented as the first sign of underlying malignancy in the few reported cases. ²⁰ Sometimes metastasis from lung primary neuroendocrine carcinomas can involve bilateral parotid glands. ²¹

As mentioned above, primary neuroendocrine carcinomas of the parotid gland can be difficult to distinguish from metastatic Merkel cell carcinoma due to overlapping morphology, immunophenotype and molecular profile. Both entities generally show small round blue cell morphology with high N:C ratio, round or oval nuclei, finely dispersed chromatin (salt and pepper), indistinct nucleoli and scant cytoplasm. Clinical history is often relied upon to differentiate primary salivary tumors from metastatic Merkel cell carcinoma but may not be helpful in all cases. Among high-grade neuroendocrine carcinomas, keratin 20 positivity, often in a perinuclear “dot-like” pattern, is considered sensitive (∼ 95%) and fairly specific for cutaneous Merkel cell carcinomas, as <5% of lung small cell carcinomas are keratin 20 positive.^22,23 However, salivary gland primary high-grade neuroendocrine carcinomas also frequently show dots like perinuclear positivity for keratin 20 which mimics the keratin 20 pattern seen in Merkel cell carcinoma. ²⁴ The oncogenic Merkel cell carcinoma polyomavirus (MCPyV) is found in approximately 70-80% of Merkel cell carcinomas, and a few cases of salivary gland high-grade neuroendocrine carcinomas have been reported to be positive for MCPyV. ²⁵ In addition, mutations in Retinoblastoma 1 gene have been found in both Merkel cell carcinomas and salivary gland high-grade neuroendocrine carcinomas. ²⁶ Merkel cell carcinoma commonly occurs in the head and neck skin of older adults and frequently metastasizes to intra-parotid lymph nodes or involves the parotid gland through direct spread. The similarity of immunophenotype and molecular profile, such as MCPyV positivity makes it reasonable to speculate that those MCPyV positive cases are actually occult metastasis with spontaneously regressed cutaneous primary Merkel cell carcinoma. Further studies are needed to better characterize the origin and frequency of these tumors.

Among the salivary glands, the parotid gland is especially rich in lymph node tissue, which is usually located superficially or in the parenchyma. This feature makes the intra-parotid lymph nodes frequent sites for metastasis from the head and neck region. In our series, one of the four cases of metastatic Merkel cell carcinoma was confined to intra-parotid lymph nodes and one patient had direct spread from overlying facial skin. The remainder of the cases were intraparenchymal metastasis from the head and neck Merkel cell carcinoma. UV signature mutations are new biomarkers that can help distinguish metastatic Merkel cell carcinomas from primary neuroendocrine carcinomas. The UV signature mutations are present in MCPyV-negative Merkel cell carcinomas, thus supporting a solar damage induced mechanism of pathogenesis. ²⁵ On the contrary, UV signature mutations should not be present in salivary gland primary high-grade neuroendocrine carcinomas since the salivary glands are not sun exposed areas. Chernock et al studied the UV signature mutations in four cases of MCPyV-negative high-grade neuroendocrine carcinomas of the parotid and compared them with positive UV signature mutation controls (cutaneous melanoma) and negative controls (lung neuroendocrine carcinoma). ²⁵ Their results demonstrated that these high-grade neuroendocrine carcinomas had UV signature mutations with a mutational profile similar to cutaneous melanomas, while lung small cell neuroendocrine carcinomas did not show evidence of UV induced mutagenesis. They concluded that UV signature mutations in salivary high-grade neuroendocrine carcinomas are strong evidence for a sun damage induced mechanism of pathogenesis and thus suggests cutaneous rather than salivary origin. On the other hand, MCPyV-positive Merkel cell carcinomas have a lower mutational burden and are almost never associated with UV signature mutations. ²⁷ As a result, MCPyV positivity and UV signature mutations in high-grade neuroendocrine carcinomas would strongly suggest occult Merkel cell carcinoma with salivary gland metastasis.

Another cutaneous neoplasm that shows neuroendocrine features and can rarely metastasize to parotid is endocrine mucin producing sweat gland carcinoma (EMPSCG). It is a rare, low-grade cutaneous adnexal neoplasm with evidence of neuroendocrine differentiation, predominantly involving the eyelids of elderly. The tumor can show solid, cystic, cribriform and trabecular architectures. The cells are usually small to intermediate sized, with scant amphophilic cytoplasm and monomorphic round to oval nuclei with fine chromatin and inconspicuous nucleoli, resembling low grade neuroendocrine tumor. Besides neuroendocrine markers like chromogranin and synaptophysin, the tumor cells are usually positive for mammary gland markers, such as estrogen receptor, progesterone receptor, GATA-3, mammaglobin and GCDFP-15 which help differentiate from parotid primary and other metastatic neuroendocrine tumors.^28,29

Medullary thyroid carcinoma is a malignant neoplasm of the thyroid gland showing C-cell differentiation. It accounts for 5% to 10% of all malignant thyroid tumors. ³⁰ Up to 25% of these tumors are hereditary, caused by gain of function germline mutations in the ret proto-oncogene, with an autosomal dominant mode of inheritance. ³¹ The etiology of sporadic medullary thyroid carcinoma is unknown. Medullary thyroid carcinoma tends to metastasize early, especially to cervical lymph nodes. The tumor metastasizes by hematogenous spread most frequently to bone, liver, and lungs. Distant metastases are reported to occur in 15-25% of medullary thyroid carcinomas and patients may present with nodal metastases in about 50% of cases.^31,32 Few cases of metastatic medullary thyroid carcinoma to parotid gland are reported. Rarely a parotid mass presents as the first clinical manifestation of metastatic medullary thyroid carcinoma. ³³ On immunohistochemistry, the tumor is positive for calcitonin, CEA, chromogranin A, synaptophysin, TTF-1 and low molecular weight keratins. Positivity for calcitonin helps differentiate metastatic medullary thyroid carcinoma from salivary gland primary high-grade neuroendocrine carcinoma.

Our results show that metastatic neuroendocrine carcinomas to the parotid gland account for about 22% of all metastatic tumors to the organ. Lung is the most common primary location. It is not uncommon for metastatic neuroendocrine carcinomas to present as the first sign of systemic clinical manifestation. Merkel cell carcinoma is the second most common entity that metastasizes to parotid, followed by medullary carcinoma of the thyroid.