Salivary glands
Primary salivary gland neoplasms
Malignant
Adenocarcinoma, NOS
Author: Nazim Benzerdjeb, M.D., Ph.D.
Editorial Board Member: Marc Pusztaszeri, M.D.
Last staff update: 10 April 2025 (update in progress)
Copyright: 2003-2025, PathologyOutlines.com, Inc.
PubMed Search: Adenocarcinoma, NOS
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagnosis | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Practice question #1 | Practice answer #1 | Practice question #2 | Practice answer #2Cite this page: Benzerdjeb N. Adenocarcinoma, NOS. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/salivaryglandsadenocarcinomaNOS.html. Accessed April 29th, 2025.
Definition / general
- Salivary gland carcinoma, NOS (not otherwise specified) represents a heterogeneous spectrum of carcinomas forming epithelial, ductal or glandular structures; it is a diagnosis of exclusion, specifically exclusive of otherwise defined salivary gland carcinoma entities (Am J Surg Pathol 2021;45:753)
Essential features
- Nonspecific heterogeneous spectrum of carcinomas forming epithelial, ductal or glandular structures
- Diagnosis of exclusion, specifically exclusive of otherwise defined salivary gland carcinoma entities
- 2 recognized subtypes: oncocytic adenocarcinoma and intestinal type adenocarcinoma
- Oncocytic adenocarcinoma: oncocytic aspect with RA-
- Intestinal type adenocarcinoma: intestinal aspect with CDX2+ / CK20+
- Prognostic factors: histological grade (3 grades), histological subtype and clinical stage
Terminology
- Not recommended: unclassified adenocarcinoma, ductal adenocarcinoma, (papillary) cystadenocarcinoma
- Subtypes: oncocytic adenocarcinoma, intestinal type adenocarcinoma
ICD coding
- ICD-O: 8140/3 - adenocarcinoma, NOS
- ICD-11
- 2B67.Z - malignant neoplasms of parotid gland, unspecified
- 2B68.Z - malignant neoplasms of submandibular or sublingual glands, unspecified
- 2B60.Z - malignant neoplasms of lip, unspecified
- 2B65.Z - malignant neoplasms of palate, unspecified
- 2B66.Z - malignant neoplasms of other or unspecified parts of mouth, unspecified
Epidemiology
- Incidence is only 5 - 10% due to identification of new types of salivary adenocarcinoma (Oral Oncol 2011;47:677, Am J Surg Pathol 2021;45:753)
- Average age: 58 years with a wide age range; extremely rare in children (Oral Oncol 2002;38:706, Oral Oncol 2011;47:677, Am J Surg Pathol 2021;45:753)
Sites
- > 50% arise in the parotid gland
- 40% arise in minor glands, most often in the hard palate, buccal mucosa and lips
- References: Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:94, Oral Oncol 2002;38:706, Oral Oncol 2011;47:677, Am J Surg Pathol 2021;45:753
Pathophysiology
- Unknown
Etiology
- Unknown
Diagnosis
- Salivary carcinoma lacking morphological, immunohistochemical and molecular features of other salivary carcinomas
- Exclusion of metastasis is mandatory (ORL J Otorhinolaryngol Relat Spec 2001;63:233)
Prognostic factors
- Histological grade: 15 year survival rates for low, intermediate and high grade tumors of 54%, 31% and 3%, respectively (Am J Surg 1982;144:423, Am J Surg Pathol 2021;45:753)
- Histological subtype
- Significant cystic component is more favorable (Am J Surg Pathol 1996;20:1440)
- Intestinal type adenocarcinoma shows more aggressive behavior (Head Neck 2013;35:E234, Hum Pathol 2009;40:1798)
- Clinical stage (Head Neck 2016;38:1208, Cancer 2022;128:509)
Case reports
- 32 year old woman with adenocarcinoma of accessory parotid, metastasis to lung and complete response to nivolumab treatment (In Vivo 2022;36:2840)
- 53 year old woman with an anterior tongue mass of salivary carcinoma, NOS, intestinal type adenocarcinoma (Head Neck Pathol 2017;11:234)
- 54 year old woman with rapid enlargement of the right parotid gland (Autops Case Rep 2022;12:e2021357)
- 54 year old man presented with symptoms of fullness in his tongue, diagnosed as salivary carcinoma, NOS, intestinal type adenocarcinoma (Head Neck Pathol 2017;11:186)
- 61 year old man presented with a swelling in the left lower cheek, diagnosed as oncocytic adenocarcinoma of parotid gland (Acta Cytol 2003;47:1099)
- 66 year old woman with a case of oncocytic adenocarcinoma arising in parotid gland (World J Surg Oncol 2006;4:54)
- 68 year old woman with previous history of high grade adenocarcinoma of the parotid and metastasis to uterine leiomyoma (Cureus 2020;12:e6789)
Treatment
- Surgical procedure for salivary carcinoma, NOS (Cancer 2022;128:509, J Clin Oncol 2021;39:1909, ESMO Open 2022;7:100602)
- Complete removal in resectable case
- In cN0 patients with high grade or in cT3 - T4: elective treatment of the neck with either elective nodal dissection or elective neck irradiation since salivary carcinoma, NOS has a > 20% rate of clinically positive nodal involvement at presentation (Otolaryngol Head Neck Surg 2016;154:121)
- Postradiotherapy (Cancer 2022;128:509, J Clin Oncol 2021;39:1909)
- In high grade tumors: positive margins, perineural invasion, lymph node metastases, lymphatic or vascular invasion, T3 - T4 tumors or those that are not candidates for surgical resection
- Can be considered in cases of tumors with close margins or intermediate grade tumors
- Elective neck irradiation in patients with cN0 disease for the following indications: T3 - T4 cancers or high grade malignancies or those that are not candidates for surgical resection
- Chemotherapy (Cancer 2022;128:509, J Clin Oncol 2021;39:1909, Head Neck 2016;38:1208, ESMO Open 2022;7:100602)
- May be considered for initiation of systemic therapy in the following circumstances
- Metastatic deposits are symptomatic and not amenable to palliative local therapy
- Growth has the potential to compromise organ function
- Lesions have increased in size > 20% in the preceding 6 months
- May be considered for initiation of systemic therapy in the following circumstances
- Immunotherapy (Cancer 2022;128:509,J Clin Oncol 2021;39:1909, In Vivo 2022;36:2840)
- Not routinely offered at this time except for patients with selected molecular alteration (high tumor mutational burden, MSI-H)
Gross description
- Tumors are partly circumscribed but usually irregular with infiltrative appearance
- Cut surface of tumors: commonly tan or yellow, sometimes with areas of necrosis and hemorrhage (Arch Pathol Lab Med 2004;128:1385)
Microscopic (histologic) description
- Lacks the characteristic histomorphology of other salivary adenocarcinomas
- Wide range of ductal or glandular proliferation with or without a cystic component or necrosis (Arch Pathol Lab Med 2004;128:1385)
- Architectural variety of growth patterns: glandular, papillary, cystic, cribriform, solid, lobular, nest-like, strand-like differentiation and small confluent nests or cords, large islands (Arch Pathol Lab Med 2004;128:1385)
- Variety of tumor cells: cuboidal, columnar, polygonal, clear, mucinous, oncocytoid or plasmacytoid (Arch Pathol Lab Med 2004;128:1385)
- Proof of an intraductal component favors salivary origin (Virchows Arch 2006;449:159)
- Subtypes
- Oncocytic (Am J Surg Pathol 1996;20:1440)
- Intestinal type (Head Neck Pathol 2012;6:250, Head Neck 2013;35:E234)
Microscopic (histologic) images
Contributed by Marino Leon, M.D.
Parotid oncocytic carcinoma with vascular invasion
Cytology description
- Smears show adenocarcinoma usually with high grade nuclei in a necrotic background and lacking features of other salivary gland carcinomas, resulting in a differential diagnosis of metastases from colon and lung
- Oncocytic and intestinal types are recognized (Am J Surg 1982;144:423)
Positive stains
- CK7+ / CK20- (Mod Pathol 2004;17:407)
- p63+ / p40+ in oncocytic subtype: predominately in basal cell type distribution (Am J Surg Pathol 2009;33:409, Head Neck Pathol 2007;1:123)
- CDX2+ / CK20+ in intestinal type subtype (Head Neck 2013;35:E234, Head Neck Pathol 2012;6:250)
- MMR proficient
Negative stains
- IHC is helpful in distinguishing from
- Acinic cell carcinoma: positive for NR4A3 and DOG1 (Pathol Res Pract 2002;198:777)
- Salivary duct carcinoma: positive for androgen receptor (AR) (Clin Cancer Res 2014;20:6570, Head Neck Pathol 2013;7:S48, Am J Surg Pathol 2003;27:1070)
- Context of metastasis: positive for site specific markers (Mod Pathol 2004;17:407)
Electron microscopy description
- For oncocytic subtype: abundant mitochondria to the exclusion of most other organelles
- Mitochondria are varied in shape from spherical to ovoid, with elongated, lamelliform cristae
- Rough endoplasmic reticulum and free ribosomes are rare (Acta Cytol 2003;47:1099)
Molecular / cytogenetics description
- No specific molecular alterations
- Not needed for diagnosis (Clin Cancer Res 2016;22:6061)
Sample pathology report
- Parotid gland, left, inferior, partial parotidectomy:
- Adenocarcinoma carcinoma, NOS, 2 cm (see comment)
- Comment: There is a lobulated and unencapsulated biphasic primary neoplasm. The tumor shows a nodular growth pattern. The tumor is composed of a bilayered arrangement of small to large luminal cells with eosinophilic cytoplasm and outer myoepithelial cells. Immunohistochemically, the inner epithelial cells are positive for AE1 / AE3 and EMA, while the outer myoepithelial layer shows staining for p63, smooth muscle actin and S100. The rest of the staining is negative for CK20, DOG1, AR and PLAG1 / HMGA2. There is no evidence of necrosis or high grade transformation. The molecular analysis is negative for PLAG1, HMGA2, MAML2, PRKD fusions and PRKD1 mutation.
Differential diagnosis
- Salivary duct carcinoma (Clin Cancer Res 2014;20:6570, Head Neck Pathol 2013;7:S48, Am J Surg Pathol 2003;27:1070):
- Mucoepidermoid carcinoma, oncocytic variant:
- Polymorphous adenocarcinoma (Am J Surg Pathol 2016;40:1526, Cancer Cytopathol 2018;126:275):
- Mostly in minor salivary glands or seromucous glands of the upper aerodigestive tract
- Tumor proliferation with cytological uniformity, histological diversity and an infiltrative growth pattern
- Foci of oncocytic, clear, squamous, apocrine or mucous cells
- p40- / p63+
- PRKD1 p.Glu710Asp hotspot mutation or translocation of one of the PRKD1, PRKD2 or PRKD3 genes
- High grade transformation of other types of salivary carcinoma (Mod Pathol 2004;17:407):
- High grade morphology
- Specific molecular alteration of other types of salivary carcinoma (PLAG1, HMGA2, MAML2, etc.)
- Mucinous adenocarcinoma (Histopathology 2010;57:395, Am J Surg Pathol 2021;45:1337):
- Metastasis from other body sites (e.g., lung, colon) (StatPearls: Malignant Salivary Gland Tumors [Accessed 28 March 2025]):
- Colorectal carcinoma is positive for villin, CDX2 and CK20 and negative for CK7, CD117 and MYB (World J Clin Cases 2021;9:5238)
Practice question #1
Which of the following statements is true regarding salivary carcinoma, NOS?
- It is defined by its peculiar morphological, immunohistochemical and molecular features
- It is the most common differential diagnosis of mucoepidermoid carcinoma
- Nodal dissection is systematic regardless of the imaging
- Oncocytic subtype is the most aggressive
- TP53 mutation is never identified
Practice answer #1
B. It is the most common differential diagnosis of mucoepidermoid carcinoma. Answer C is incorrect because elective nodal dissection is performed if the imaging study identifies lymph nodes suspected of metastasis in low grade carcinoma. Answer D is incorrect because the oncocytic subtype is commonly associated with low grade carcinomas. Answer A is incorrect because the oncocytic subtype is defined by its lack of peculiar morphological, immunohistochemical and molecular features. Answer E is incorrect because TP53 mutation can be identified, along with others such as PI3KCA, NRAS and HRAS.
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Reference: Adenocarcinoma, NOS
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Reference: Adenocarcinoma, NOS
Practice question #2
Which of the following statements is true regarding salivary carcinoma, NOS?
- Abundant intracellular or extracellular mucin can be observed
- CK20 is not consistently found
- Lymph node metastases never occur
- Principal differential diagnosis of metastatic colorectal carcinoma must be addressed
- This histological subtype is specific for MMR deficiency
Practice answer #2
D. The principal differential diagnosis of metastatic colorectal carcinoma must be addressed. Answer B is incorrect because CK20, like CDX2, is commonly observed as positive in immunostaining. Answer A is incorrect because only mucinous adenocarcinoma exhibits these features with significant mucinous differentiation, abundant intracellular or extracellular mucin, CK7+ / CK20- and commonly the AKT1 p.E17K mutation. Answer C is incorrect because lymph node metastases can occur. Answer E is incorrect because MMR proficiency is identified, in contrast to the GI tract.
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Reference: Adenocarcinoma, NOS
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