see also: Salivary Gland Swelling - Classification by Disease Processes Affecting the Glands

protocol by Zach Fleishhacker BS with assistance from Henry Hoffman MD 

Initially compiled 05-26-2022 by Fleishhacker and Hoffman with future adaptations per additional contributors

Definitions

Lymphadenoma: Referring to an abnormally enlarged lymph node. An adenoma is an abnormal benign tumor of glandular origin.

Sebaceous: Referring to the gland of the skin that secretes a lipid-predominant, fatty substance.

Non-Sebaceous Lymphadenoma (NSL) of the Parotid Gland

1. Rare, benign tumor of the salivary glands (predominantly parotid) first characterized by Auclair in 1994 with ~50 cases reported in the English literature (Auclair 1994, Kara et al 2020).

2. Clinical Presentation and Characteristics (Kara 2020, Morales et al 2021)

   • Slow-growing, well-defined mass

   • Usually painless

   • No impact on facial nerve or salivary gland function

   • Majority of cases involve the parotid gland, with two cases each reported in the submandibular glands and cervical lymph nodes (Seethala et al 2012), as well as a single case arising from the lacrimal duct (Pau et al 2018).

   • Benign with no reports of invasion into adjacent structures or recurrence after excision. Single case report of transformation into an undifferentiated carcinoma of the salivary glands (Kara 2020).

3. Demographics (Kara 2020, Seethala 2012)

   • Slight preponderance among females (25 of 45 cases reported)

   • Average age at presentation of 52 (ranging 10-80), 4 cases reported in children 10-15 years old

4. Pathophysiology

   • Unknown, two theories have been proposed in the literature

   • The first suggests that this tumor develops from embryonic salivary inclusions in the intra/peri-parotid lymph nodes (Weiler et al 2012)

     • Support for this theory is based on findings of hilus structures containing embryonic parenchymal inclusions within samples of the tumor

     • Additionally, comparisons are drawn between other parotid-predominant benign tumors such as Warthin's tumor and Sebaceous lymphadenoma that arise from intra/periglandular lymph nodes unique to the parotid gland

     • Critics of this theory observe that many case reports of NSL do not demonstrate these hilus structures. It is noted that this may be due to incomplete tumor sampling or effacement of these structures due to tumor growth.

   • The second theory postulates that these tumors arise from reactive lymphoid proliferation secondary to the neoplastic epithelial component discussed below (Auclair 1994, Ishii et al 2013)

     • Support for this theory is based on numerous case reports of NSL without histologic evidence of lymph node involvement (hilus structure, nodal capsule)

     • Additionally, NSL has been found in the submandibular and lacrimal glands which do not generally contain intraglandular lymph nodes (Fives et al 2017)

5. Histopathology and Immunohistochemistry

   • Histopathology (Seethala 2012, Ma et al 2002)

     • Well-encapsulated tumor with characteristic epithelial and lymphoid components

       • Proliferated, normal to mildly atypical appearing epithelium in the form of solid cords, trabeculae, tubules, glands, basaloid islands, and rarely squamous differentiation and keratinization

       • Cystic components may or may not be present

       • The lymphoid component consists of mixed T and B cell infiltrates with infrequent stromal cell foreign body granulomatous reactions observed

     • Absence of sebaceous differentiation

     • Absence of oncocytic epithelial lining

     • Mitotic figures not present

   • Immunohistochemistry (Yang et al 2007, Gallego et al 2009)

     • Strong expression in tumor cells of Cytokeratin (CK) 7 and 8/18 suggesting epithelial cell columnar differentiation (Chu et al 2002)

     • Presence of CK 5/6 which is typically expressed in basal cells

     • Positive staining for CK 19 in only the luminal cells suggests dual luminal and abluminal cell differentiation

     • Rare to absent staining with SMA, Vimentin, and S-100 indicate that myoepthilial cells are not involved with this neoplasm

6. Diagnosis

   • Criteria first published by Dardick et al in 2007 requires histologic analysis:

     • Absence of sebaceous differentiation

     • Absence of oncocytic epithelium

     • Presence of predominant lymphocytic component (T cells, B cells, and/or plasma cells) with or without germinal centers

     • Presence of solid, glandular, or cystic epithelial nests

     • Well-defined tumor or mass

   • Clinical findings of painless, slow growing (months to years) salivary gland mass without facial nerve weakness (Morales 2021)

   • CT with contrast can be employed to more accurately characterize the extent and consistency of a new mass (Morales 2021)

   • Ultrasound may be used to diagnose a new mass as primarily cystic vs solid, as well as in guiding fine needle aspiration (FNA) (Morales 2021)

   • FNA is not diagnostic by itself but may provide additional information regarding benign vs malignant nature of a new mass

     • FNA findings include (Castelino-Prabhu et al 2010)

       1. Hypercellular smears of basaloid epithelial cells with naked, round to oval nuclei

       2. Numerous lymphocytes

       3. Strands of stromal matrix in a branching pattern

       4. Absence of myoepithelial cells and oncocytic cells

7. Differential Diagnosis (Kara 2020, Ma 2002)

   • Other benign, painless, slow-growing tumors/cysts of the parotid gland such as lymphoepithelial cysts, myoepithelial sialadenitis, Whartin's tumor and Sebaceous lymphadenoma must be considered

     • Unlike myoepithelial sialadenitis

       • NSL does not contain myoepithial components in significant proportions

       • NSL epithelial cell islands are more densely packed and numerous

       • NSL is discrete and well-circumscribed

     • Unlike Sebaceous lymphadenoma, which may have similar histologic architecture

       • NSL does not contain any sebaceous components

       • NSL less frequently has a squamous cell component

     • Unlike Whartin's tumor

       • NSL does not have oncocytic epithelial lining

       • NSL does not have papillary formations

     • Unlike lymphoepithelial cysts

       • NSL has a less prominent lymphoid/follicular hyperplasia component

       • NSL is predominantly solid, with more rare/intermittent cysts

   • Malignant entities that must be considered include lympoepithelial carcinoma, lymphoma, acinic cell carcinoma, and metastatic carcinoma

     • Clinical features such as facial nerve weakness or invasion of adjacent structures on imaging suggest a malignant etiology versus benign NSL

     • Histologically, absence of nuclear atypia and invasion aid in ruling out metastatic carcinoma and other malignancies

     • Low-grade lymphoepithelial carcinoma is more difficult to rule out, but can be accomplished by observing an absence of mitotic activity, sinuses, and EBV association

     • Acinic cell carcinoma is characterized by a microcystic growth pattern and cells with a granular cytoplasm that does not occur in NSL

     • The presence of both T-cells and B-cells in NSL as well as lack of staining with traditional lymphoid markers differentiates the tumor from that of a lymphoma

8. Clinical Approach

   • Patients initially suspected based on clinical symptoms of growing mass in the parotid or other salivary gland

     • Patients are often suspected of having more common tumors such as pleomorphic adenomas (Morales 2021)

   • As with other masses of the salivary glands, malignancy must be excluded

     • Presenting symptoms concerning for malignancy include fast onset/growth, facial nerve involvement, and cervical lymphadenopathy

     • Imaging CT and/or US with or without FNA can provide further information of invasion into surrounding structures or concerning cell morphology

   • If benign, assessment of impact must be completed

     • Appearance and interference with activities such as chewing

   • Elective resection of the tumor with superficial parotidectomy and facial nerve preservation is the treatment and end-diagnostic of choice for NSL (Morales 2021)

     • There has been only one report of malignant transformation of NSL (Kara 2020)

     • Informed consent regarding parotidectomy includes disclosure of the risks of general anesthesia, facial nerve injury, altering the facial contour, Frey's syndrome, numbness to ear/face

     • Tissue should be sent for pathological analysis 

9. Conclusion

   • Nonsebaceous Lymphadenoma is a rare, slow-growing, benign neoplasm of predominantly the parotid salivary gland this is characterized by structures of abnormal epithelial cells and lymphocytic infiltration without the presence of sebaceous and/or oncocytic components that is typically treated with facial nerve-sparing superficial parotidectomy. 

References

Auclair PL. Tumor-associated lymphoid proliferation in the parotid gland. A potential diagnostic pitfall. Oral Surg Oral Med Oral Pathol. 1994 Jan;77(1):19-26. doi: 10.1016/s0030-4220(06)80102-7. PMID: 8108090.

Kara H, Sönmez S, Bağbudar S, Güllüoğlu M, Başaran B. Malignant Transformation of Parotid Gland Non-sebaceous Lymphadenoma: Case Report and Review of Literature. Head Neck Pathol. 2020;14(4):1123-1128. doi:10.1007/s12105-020-01133-3

Morales Morales CA, Ramos Mayo AE, Gonzalez-Urquijo M, Barbosa Quintana Á, Guzmán Huerta EA. Non-sebaceous Lymphadenoma of the Parotid Gland Mimicking a Pleomorphic Adenoma. Clin Pathol. 2021;14:2632010X21996338. Published 2021 Feb 23. doi:10.1177/2632010X21996338

Seethala RR, Thompson LD, Gnepp DR, Barnes EL, Skalova A, Montone K, Kane S, Lewis JS Jr, Solomon LW, Simpson RH, Khan A, Prasad ML. Lymphadenoma of the salivary gland: clinicopathological and immunohistochemical analysis of 33 tumors. Mod Pathol. 2012 Jan;25(1):26-35. doi: 10.1038/modpathol.2011.135. Epub 2011 Sep 2. PMID: 21892186.

Pau M, Brcic L, Seethala RR, Klein-Theyer AK, Magyar M, Reinbacher KE, Schweiger M, Wallner J, Jakse N. Non-sebaceous lymphadenoma of the lacrimal gland: first report of a new localization. Virchows Arch. 2018 Jul;473(1):127-130. doi: 10.1007/s00428-018-2322-4. Epub 2018 Feb 19. PMID: 29460186.

Weiler C, Agaimy A, Zengel P, Zenk J, Kirchner T, Ihrler S. Nonsebaceous lymphadenoma of salivary glands: proposed development from intraparotid lymph nodes and risk of misdiagnosis. Virchows Arch. 2012 May;460(5):467-72. doi: 10.1007/s00428-012-1225-z. Epub 2012 Apr 4. PMID: 22476402.

Ishii A, Kawano H, Tanaka S, Yamamoto Y, Nakamoto T, Hirose Y, Yamashita H, Morinaga S, Ikeda E. Non-sebaceous lymphadenoma of the salivary gland with serous acinic cell differentiation, a first case report in the literature. Pathol Int. 2013 May;63(5):272-6. doi: 10.1111/pin.12061. PMID: 23714255.

Fives C, Feeley L, Sadadcharam M, O'Leary G, Sheahan P. Incidence of intraglandular lymph nodes within submandibular gland, and involvement by floor of mouth cancer. Eur Arch Otorhinolaryngol. 2017 Jan;274(1):461-466. doi: 10.1007/s00405-016-4205-0. Epub 2016 Jul 23. PMID: 27450469.

Ma J, Chan JK, Chow CW, Orell SR. Lymphadenoma: a report of three cases of an uncommon salivary gland neoplasm. Histopathology. 2002 Oct;41(4):342-50. doi: 10.1046/j.1365-2559.2002.01528.x. PMID: 12383217.

Yang S, Chen X, Wang L, Zhang J. Non-sebaceous lymphadenoma of the salivary gland: case report with immunohistochemical investigation. Virchows Arch. 2007 May;450(5):595-9. doi: 10.1007/s00428-007-0393-8. Epub 2007 Mar 13. PMID: 17431672.

Gallego L, Junquera L, Fresno MF. Non-sebaceous lymphadenoma of the parotid gland: immunohistochemical study and DNA ploidy analysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Apr;107(4):555-8. doi: 10.1016/j.tripleo.2008.11.018. Epub 2009 Feb 6. PMID: 19201224.

Chu PG, Weiss LM. Keratin expression in human tissues and neoplasms. Histopathology. 2002 May;40(5):403-39. doi: 10.1046/j.1365-2559.2002.01387.x. PMID: 12010363.

Dardick I, Thomas MJ. Lymphadenoma of parotid gland: Two additional cases and a literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008 Apr;105(4):491-4. doi: 10.1016/j.tripleo.2007.08.035. PMID: 18329584.

Castelino-Prabhu S, Li QK, Ali SZ. Nonsebaceous lymphadenoma of the parotid gland: cytopathologic findings and differential diagnosis. Diagn Cytopathol. 2010 Feb;38(2):137-40. doi: 10.1002/dc.21158. PMID: 19670220.