Management of the Neck Regarding the Novel Oncological Entities of the Salivary Glands

1. Introduction

The landscape of salivary gland neoplasms has undergone substantial evolution following the publication of the 5th edition of the World Health Organization (WHO) Classification of Head and Neck Tumors in 2022, necessitating a thorough reappraisal of established diagnostic and therapeutic paradigms [1,2]. This updated classification introduces novel benign and malignant oncological entities, requiring a more specialized and risk-stratified approach to cervical lymph node management in affected patients [3]. Given the intricate lymphatic network of the neck, its close anatomical proximity to primary tumor sites, and the well-established propensity of head and neck malignancies for regional dissemination, the cervical region carries paramount prognostic significance in salivary gland oncology. A comprehensive understanding of the updated 2022 classification, together with the clinical implications of surgical and adjuvant therapeutic interventions in this region, is therefore essential.

Appropriate cervical lymph node management in regionally metastasizing malignancies demands individualized therapeutic strategies, carefully tailored to the distinct histopathological characteristics of each tumor and the precise extent of nodal involvement [4]. The 2022 WHO Classification of Head and Neck Tumors represents a pivotal advance in acknowledging the broad spectrum of pathological processes affecting cervical lymph nodes and upper aerodigestive tract lymphoid tissue [3]. In total, six novel oncological entities have been introduced: four benign and two malignant. This evolving understanding of salivary gland tumors, their histopathological profiles and biological behavior—continues to guide contemporary treatment planning, with increasing emphasis on individualized patient care.

1.1. Novel Benign Salivary Gland Entities

According to the 2022 WHO classification, the newly recognized benign epithelial neoplasms of the salivary glands encompass the following entities:

• Sclerosing polycystic adenoma
• Keratocystoma
• Intercalated duct adenoma and hyperplasia
• Striated duct adenoma

1.2. Novel Malignant Salivary Gland Entities

The newly defined malignant salivary gland oncological entities introduced in 2022 WHO Classification include:

• Microsecretory adenocarcinoma
• Sclerosing microcystic adenocarcinoma

1.3. Neck Management in Novel Salivary Gland Oncological Entities

This review addresses the clinical challenge of neck management in patients with novel salivary gland oncological entities introduced in the 2022 WHO Classification, updating the 2017 edition. The primary objective is to evaluate the clinical indication for elective or therapeutic neck dissection and/or adjuvant regional radiotherapy, drawing on contemporary literature and established therapeutic recommendations, while accounting for the biological nature (benign vs. malignant), unique histopathological and molecular profiles, recurrence rates, degree of differentiation, and metastatic potential of each entity. Given the extreme rarity of these neoplasms, the limited number of published cases, and the consequent absence of consensus-based guidelines, this study systematically aggregates, reviews, and critically analyzes all available peer-reviewed evidence.

2. Novel Benign Salivary Gland Entities in the 2022 WHO Classification

2.1. Sclerosing Polycystic Adenoma

Sclerosing Polycystic Adenoma (SPA) was first described in 1996 by Smith et al. [5] as a pseudoneoplastic reactive lesion characterized by extensive fibrosis and epithelial proliferation resembling fibrocystic breast disease [6,7]. Originally designated as “sclerosing polycystic adenosis,” it was formally reclassified as a true neoplasm in the 4th edition of the 2017 WHO Classification, receiving its current designation [2]. This reclassification was supported by evidence of clonal cellular processes using the HUMARA assay, which demonstrated X-chromosome inactivation in 6 evaluated cases [8]. Additional clinicopathological features supporting its neoplastic nature with low-grade malignant potential include a local recurrence rate of 10–30% [8], intraductal epithelial dysplasia ranging from mild atypia to carcinoma in situ [7], and a rare, reported case of invasive carcinoma arising within SPA [9].

SPA arises predominantly within the parotid glands [10], accounting for approximately 70% of reported cases [8], followed by the submandibular glands [10]. Minor salivary gland involvement is exceptional, with only a single documented case in the upper lip mucosa [11]. Approximately 100 cases have been reported in the literature [10]. The tumor occurs across a wide age range (7–84 years), and its sex distribution varies across studies, with some authors reporting a female predilection [8] and others a higher incidence in males [7]. Clinically, SPA presents as a slowly growing, well-circumscribed, asymptomatic, indurated mass [7]. Initial fine-needle aspiration cytology frequently yields a misdiagnosis of pleomorphic adenoma.

The diagnosis of SPA rests on its characteristic histopathological architecture. The tumor typically presents as a well-circumscribed nodule with lobular architecture, surrounded by a fibrous capsule and set within a sclerotic stroma exhibiting zones of dense hyaline fibrosis [7] (Figure 1). The lesion contains a complex network of ducts lined by bilayered flattened epithelium with apocrine, vacuolated, and mucous metaplasia. Ductal dimensions vary considerably, ranging from small tubules to large ectatic cystic spaces containing intraluminal secretions and/or foamy macrophages [7,9]. Focal intraductal proliferations of epithelial cells forming solid, microcystic, and cribriform patterns (Figure 2) are consistently present, surrounded by a continuous myoepithelial cell layer. Neoplastic acini containing enlarged acinar cells with coarse, hypereosinophilic, PAS-positive, diastase-resistant granules or hyaline spherules are also observed [7]; these likely represent altered zymogen granules and, when identified, constitute a pathognomonic feature of SPA [7]. These intraductal formations share architectural and cytological similarities with ductal carcinoma in situ (DCIS) of the breast [9].

Immunohistochemically, SPA exhibits a complex composition of ductal, myoepithelial, and acinar components reflected in its immunophenotype [7]. Ductal and acinar cells show strong positivity for SOX10 and cytokeratins (AE1/3, CAM5.2). The attenuated myoepithelial layer is highlighted by SMA, p63, and calponin, while acinar cells containing hypereosinophilic granules are positive for GCDFP-15. DOG-1 expression is absent or only focally detectable within the neoplastic acini [7].

Next-generation sequencing (NGS) has identified a specific splice site alteration (ARV7) in the Androgen Receptor (AR) gene—a member of the nuclear hormone receptor family functioning as a ligand-dependent transcription factor. This alteration results in loss of the ligand-binding domain of the wild-type AR transcript, leading to constitutive, ligand-independent activation and marked AR protein overexpression (Figure 3); a mechanism commonly observed in castration-resistant prostate cancer and associated with resistance to conventional anti-androgen therapy [6]. Molecular analysis of AR expression in 35 salivary duct carcinoma specimens demonstrated AR protein overexpression in 70% of cases, implicating AR hyperactivation as a potential oncogenic driver in SPA pathogenesis [6].

A further recurrent somatic mutation in SPA involves a missense hotspot alteration in the HRAS proto-oncogene [c.182A>G (p.Q61R)], which impairs the intrinsic GTPase activity of the HRAS protein. This mutation leads to constitutive activation of downstream transcriptional cascades—predominantly the RAF/MEK/ERK and PI3K/AKT pathways—driving uninhibited cellular proliferation and survival [6]. Within salivary gland malignancies, HRAS mutations account for more than 90% of all RAS alterations and are most identified in epithelial-myoepithelial carcinoma and salivary duct carcinoma [6].

Somatic mutations in the PI3K/AKT/mTOR signaling pathway, specifically involving PTEN and PIK3CA, have also been implicated in SPA pathogenesis [6,8]. PTEN tumor suppressor mutations are prevalent, and a specific PIK3R1 missense alteration (c.1690A>G, p.N564D) induces loss of function of the regulatory subunit, leading to constitutive PI3K catalytic activation, AKT phosphorylation, and accelerated tumor growth—a mechanism validated in animal models [6]. Given that SPA harbors an identical spectrum of molecular alterations to those observed in salivary duct carcinoma and apocrine intraductal carcinoma, it is currently conceptualized as a clonal benign neoplasm and potential precursor lesion to these malignancies [6,8].

The differential diagnosis of SPA primarily includes chronic sclerosing sialadenitis (Kuttner’s tumor), which is distinguished by a dense lymphoplasmacytic infiltrate with prominent lymphoid follicles and reactive germinal centers, in the absence of the acinar hyperplasia and intraductal proliferations characteristic of SPA [7].

The definitive treatment of SPA is complete surgical excision with clear margins. Given the benign nature of this neoplasm, there is no indication for elective or therapeutic neck dissection or adjuvant regional radiotherapy in the absence of documented nodal involvement [8,10,12].

2.2. Keratocystoma

Keratocystoma is an exceedingly rare benign salivary gland neoplasm, with fewer than 15 cases reported in the literature [7]. The term was formally introduced in the 5th edition of the 2022 WHO Classification of Head and Neck Tumors [1,2,7] as a distinct neoplastic entity.

The tumor arises predominantly within the parotid gland; a single case involving the minor salivary glands of the soft palate has been reported. It affects a wide age range (2–70 years) [13] and presents clinically as a firm, slowly enlarging, asymptomatic mass, without associated facial nerve palsy, pain, hemorrhage, dysphagia, odynophagia, otalgia, pyrexia, or cervical lymphadenopathy [14,15,16]. Gross examination typically reveals a multilocular cystic lesion containing solid, grayish, keratinous material [7] (Figure 4).

Microscopically, the tumor is composed of multiple cystic spaces lined by stratified squamous epithelium with parakeratinized or orthokeratinized surfaces and a complete absence of a granular cell layer [7,16] (Figure 5). Basophilic keratohyalin granules may be observed in orthokeratinized foci [15]. No cellular atypia or atypical mitotic figures are present [2,16]; furthermore, the tumor does not invade adjacent structures or metastasize [17], corroborating its benign nature. Tubular or glandular structures, sebaceous differentiation, and adnexal elements beneath the epithelium are characteristically absent [15,16]. According to Skalova et al. [2], a homogeneous stratified squamous epithelium lacking a granular layer, combined with distinctly demarcated epithelial cell islands, constitutes the diagnostic hallmark of keratocystoma. A dense lymphoid stromal element [16] and a foreign-body giant-cell reaction to extruded keratin, manifesting as granulomas, are frequently observed [7,16].

Immunohistochemistry demonstrates diffuse positivity for cytokeratins AE1/AE3 and CK5/6 [15,16,18], focal positivity for CK7, strong nuclear expression of p63 and p40 [16,18], and weak, scattered p53 staining [16]. The Ki-67 proliferation index is below 1% and confined to the basal epithelial layer [15,17,18,19], consistent with benign behavior. At the molecular level, a recurrent IRF2BP2:RUNX2 gene fusion has been identified in seven cases—a rearrangement not described in any other salivary gland neoplasm, underscoring the molecular uniqueness of keratocystoma as a distinct entity [7].

The differential diagnosis includes primary or metastatic squamous cell carcinoma (SCC), mucoepidermoid carcinoma (MEC), the infarcted variant of Warthin’s tumor, pleomorphic adenoma, necrotizing sialometaplasia, and dermoid or epidermoid cysts [2,7,15]. Distinguishing keratocystoma from SCC is of paramount importance, as SCC—a high-grade malignancy with prominent necrosis, perineural and lymphovascular invasion, and significant metastatic potential—demands entirely different therapeutic protocols. Moreover, SCC within the parotid gland most frequently represents metastasis from cutaneous malignancy to intraparotid lymph nodes, a scenario far more prevalent than keratocystoma. In contrast, keratocystoma lacks cellular atypia and exhibits only rare mitotic figures confined to the basal layer [7,15].

Discrimination from mucoepidermoid carcinoma relies on the complete absence of mucus-secreting, intermediate, or clear cells in keratocystoma [7,15]. The infarcted Warthin’s tumor variant features squamous metaplasia and necrosis yet retains a bilayered oncocytic epithelium and a lymphoid stroma with germinal centers—features absent in keratocystoma [7]. Comparison with pleomorphic adenoma is straightforward, as the latter contains ductal, myoepithelial, and myxochondroid elements [15]. Necrotizing sialometaplasia is distinguished by its lobular architecture and coagulative necrosis without perineural invasion [15], and dermoid or epidermoid cysts are excluded by the presence of a granular cell layer and adnexal structures [13].

To date, 13 cases have been documented in the literature: 7 in male patients (age range: 18–70 years) and 6 in female patients (age range: 8–70 years). The parotid gland was the site of involvement in 12 cases (7 left-sided, 5 right-sided), with only one case arising in the minor salivary glands of the soft palate [13]. In all reported cases, the definitive treatment was complete surgical excision via superficial or subtotal parotidectomy, without concurrent neck dissection or adjuvant radiotherapy or chemotherapy. Postoperative follow-up ranged from 8 months to 7 years, with no published case reporting local recurrence or malignant transformation [13].

2.3. Intercalated Duct Adenoma and Hyperplasia

Intercalated duct adenoma is a benign epithelial neoplasm that, according to Skalova et al. [2], originates from bilayered salivary ducts, exhibiting cytomorphological features and an immunohistochemical profile closely resembling those of normal intercalated ducts. It is characterized by a proliferation of ductal cells with minimal cytological atypia [20]. Together with intercalated duct hyperplasia, these lesions constitute a continuous biological spectrum—collectively termed “intercalated duct lesions”—sharing overlapping histopathological features [2,21].

The 5th edition of the WHO Classification classifies both intercalated duct hyperplasia and adenoma as benign neoplasms [20]; however, their true neoplastic nature remains incompletely established, and whether hyperplasia and adenoma represent distinct evolutionary stages of the same entity remains debated [20]. Their precise etiology is unknown, but an association has been reported with chronic sclerosing sialadenitis [7,22], acinar atrophy, sialolithiasis, and prior radiotherapy [22].

Intercalated duct lesions most commonly arise within the parotid gland, followed by the submandibular gland; minor salivary gland involvement is rare [7]. They affect a broad age range (19–80 years) with a statistically significant female predominance (ratio 1.7:1) [7]. Accurate histopathological diagnosis is essential given the morphological overlap with several salivary gland neoplasms and the documented association of these lesions with specific malignancies, particularly basal cell adenocarcinoma (BCAC) and epithelial-myoepithelial carcinoma (EMC) arising within the parotid gland [2,7,22,23].

In general, intercalated duct lesions display three distinct histomorphological growth patterns [7,20]:

• Hyperplastic Pattern: The first pattern, typically observed in hyperplasia, consists of crowded small ductal proliferations with minimal intervening stroma and a complete absence of a fibrous capsule. This pattern frequently interdigitates with surrounding serous acini and mucous cells of the normal salivary gland parenchyma [7].
• Adenomatosis Pattern: The distinction of an adenoma from hyperplasia relies on the presence of a discrete, well-circumscribed, and partially or completely encapsulated tumor mass that completely disrupts the pre-existing lobular architecture of the surrounding normal salivary parenchyma [2]. This represents the second growth pattern, also termed the adenomatous pattern [7].
• Hybrid Pattern: The third pattern is hybrid, comprising partially circumscribed, adenoma-like nodules alongside poorly defined areas featuring purely hyperplastic characteristics [7].

All three growth patterns are composed of small, uniform ductal structures lined by cuboidal epithelial cells with amphophilic to weakly eosinophilic cytoplasm and small, regular, centrally located nuclei lacking prominent nucleoli [2,7]. Clinically, these lesions present as small incidental findings, ranging from 1 to 8 mm; multifocal or diffuse involvement has also been reported [7]. Despite their characteristically small dimensions, true intercalated duct adenomas may occasionally reach palpable mass proportions [2].

Immunohistochemically, intercalated duct lesions exhibit diffuse positivity for CK7 and S100 protein, with focal expression of estrogen receptors and lysozyme [2,7]. Diffuse S100 positivity is a diagnostically useful feature, as normal salivary gland acinar cells do not share this expression pattern [7]. Next-generation sequencing has identified distinct pathogenetic mutations: CTNNB1 mutations in hyperplastic and hybrid-type lesions [7]—mutations also identified in up to 80% of basal cell adenomas and adenocarcinomas—and HRAS mutations in true adenomas, which are characteristically found in epithelial-myoepithelial carcinoma in up to 78% of de novo cases [20].

As noted above, the primary differential diagnoses are basal cell adenocarcinoma and epithelial-myoepithelial carcinoma, with which strong molecular, genetic, and morphological overlap exists [7]. Benign basal cell adenoma is also considered; it is consistently larger (>10 mm) and features a prominent outer myoepithelial layer with strong S100 positivity, contrasting with the focal or absent S100 expression in the outer cell layer of intercalated duct lesions [2].

Given the shared molecular signatures with malignant counterparts and the frequent topographic co-occurrence with basal cell adenocarcinoma and epithelial-myoepithelial carcinoma, intercalated duct lesions are increasingly regarded as clonal precursor lesions for these specific malignancies—a manifestation of the “hybrid tumor phenomenon” [2,7,20]. True adenoma serves as a direct precursor to malignancy less frequently than the hyperplastic variant [22]. A compelling case documenting histomorphological transition from focal intercalated duct hyperplasia directly into invasive basal cell adenocarcinoma has been reported [23].

Clinical management of intercalated duct lesions consists of complete surgical excision with clear margins. There is no indication for neck dissection or adjuvant radiotherapy, as no regional or distant metastases have been reported in any published case [7,20].

2.4. Striated Duct Adenoma

Striated duct adenoma is an exceedingly rare benign salivary gland neoplasm, first described in 1996 by Dardick as a duct-derived adenoma lacking an outer myoepithelial layer [24]. It was formally established under its current nomenclature by Weinreb et al. [23] following comprehensive immunohistochemical profiling demonstrating morphological and functional similarities to normal striated ducts and was incorporated as a distinct entity in the 2022 WHO Classification [2].

Approximately 20 cases have been reported [25], predominantly arising in the parotid gland (13 cases), followed by the palate (3 cases), buccal mucosa (1 case), and upper lip mucosa (1 case) [25]. The tumor typically presents in the seventh decade of life (mean age: 62 years) with no definitive sex predilection [2,25]. Clinically, it manifests as an asymptomatic palpable firm mass [2,25], with one reported case involving associated pain and erythema at an intraoral minor salivary gland site [25]. Reported dimensions range from 0.5 to 3 cm [7].

Histopathologically, the tumor is well-circumscribed and typically enveloped by a distinct fibrous capsule separating it from adjacent normal parenchyma [2,7], though three unencapsulated variants with direct intermingling of neoplastic and normal cells have been reported [25]. It is composed of a monophasic population of uniform cuboidal to columnar epithelial cells with abundant eosinophilic cytoplasm arranged in tight tubular configurations [7] (Figure 6), varying from the dimensions of normal striated ducts to larger ectatic spaces [2], and frequently containing hypereosinophilic serous secretions [7]. The intervening stroma is usually minimal; when present, it is typically focal and associated with hemorrhagic or adipose elements [2,7,23].

Immunohistochemically, striated duct adenomas are diffusely and strongly positive for S100 protein, CK7, SOX10 [7,24], and CK5 [2], and entirely negative for DOG1, SMA, SMMHC, and calponin [7]. Focal p63 positivity may be observed in scattered cells and should not be interpreted as evidence of a continuous myoepithelial layer [7]. A pathognomonic molecular advance was established by Rooper et al. [26], who demonstrated that robust immunohistochemical expression of mutant IDH1/2 correlates directly with specific IDH2 R172X somatic mutations, identified in all 9 evaluated cases. Although IDH1/2 mutations are classically associated with high-grade malignancies, striated duct adenoma provides a notable example of a benign neoplasm harboring an oncogenic driver mutation insufficient, in isolation, to confer a malignant phenotype [25].

The differential diagnosis includes canalicular adenoma, oncocytoma, intercalated duct adenoma, and basal cell adenoma [2]. The primary distinction is from canalicular adenoma, which occurs almost exclusively in the minor salivary glands of the upper lip, exhibits a characteristic “beads-on-a-string” pattern of anastomosing cellular cords embedded in a loose myxoid stroma [2,7], and lacks the IDH2 mutations characteristic of striated duct adenoma [7,26]. Oncocytoma is differentiated by its diffuse oncocytic cytoplasm, predominantly solid growth, and absent S100 protein expression [2,27]. Intercalated duct adenoma is distinguished by its smaller basaloid cytomorphology and a well-defined outer myoepithelial cell layer [2].

None of the published cases of striated duct adenoma have displayed histopathological features suggestive of malignancy, such as atypical mitotic figures, atypical cellular pleomorphism, or coagulative necrosis [25]. In every documented instance, definitive clinical management consisted strictly of complete surgical excision with negative margins, without the implementation of concurrent elective neck dissection or pre- and postoperative adjuvant regional radiotherapy. Across a maximum documented postoperative follow-up period of 46 months and a mean follow-up of 26 months [25], no case of local recurrence, regional lymph node metastasis, or malignant transformation has been reported, further confirming the stable and completely benign nature of this neoplasm [2,7,25].

3. Novel Malignant Salivary Gland Entities in the 2022 WHO Classification

3.1. Microsecretory Adenocarcinoma

Microsecretory adenocarcinoma (MSA) is a newly recognized low-grade malignant salivary gland neoplasm formally incorporated into the 2022 WHO Classification, having been first described by Bishop et al. in 2019 [28]. Its defining molecular hallmark is a recurrent MEF2C::SS18 gene fusion [28,29].

Historically, MSA was classified within the broad diagnostic category of adenocarcinoma, not otherwise specified (NOS), due to the absence of sufficient defining criteria for independent recognition [28]. Its identification as a distinct pathological entity followed the characterization of its unique morphological, immunohistochemical, and molecular features [28].

This breakthrough established specific histopathological criteria mandatory for the definitive diagnosis of microsecretory adenocarcinoma [7,30]:

• A distinct growth pattern dominated by a striking proliferation of microcysts.
• Uniform, monotonous neoplastic cells resembling those of normal intercalated ducts, featuring pale eosinophilic to entirely clear cytoplasm.
• Oval, hyperchromatic nuclei with inconspicuous, non-distinct nucleoli.
• Abundant, basophilic intraluminal secretions.
• A highly cellular, fibromyxoid connective tissue stroma.
• Well-demarcated, rounded tumor borders that paradoxically display localized infiltration into adjacent anatomical structures (Figure 7 and Figure 8) [7,30].

Immunohistochemically, MSA exhibits a characteristic immunophenotype with diffuse positivity for S100 protein, p63, and SOX10, and complete negativity for p40, calponin, c-KIT (CD117), and mammaglobin [7,31]. Aggressive histopathological features such as tumor necrosis, marked cytological atypia, or brisk mitotic activity are absent in the vast majority of documented cases [7]. Perineural invasion has been noted in isolated series, including that of Lu et al. [32], in the absence of regional lymph node metastasis.

Rare aggressive clinical phenotypes have nonetheless been documented. Gui et al. [34] reported a case of high-grade transformation characterized by comedo-like necrosis, severe cytological atypia, increased mitotic activity, solid growth architecture, and regional lymph node metastases. Additionally, Jurmeister et al. [35] reported local recurrence followed by distant pulmonary metastasis occurring more than a decade after initial resection, illustrating the indolent yet potentially protracted course of this malignancy, the only published case in the literature requiring surgical re-intervention during long-term follow-up. All published cases are summarized in Table 1.

The differential diagnosis includes secretory carcinoma (SC), polymorphous adenocarcinoma (PAC), adenoid cystic carcinoma (AdCC), the secretory variant of myoepithelial carcinoma, and adenocarcinoma NOS [2]. SC is distinguished by its abundant granular eosinophilic cytoplasm, strong mammaglobin positivity with p63 negativity, and the pathognomonic ETV6::NTRK3 fusion [7]. PAC shares a nearly identical immunophenotype and infiltrative growth pattern with MSA but exhibits broader architectural diversity and a characteristic concentric targetoid perineural infiltration pattern [7].

Adenoid cystic carcinoma may exhibit tubular and cribriform patterns with intraluminal secretions mimicking MSA; however, AdCC is distinguished by its highly invasive clinical behavior, dual-cell architecture, and characteristic MYB, MYBL1, or NFIB rearrangements [7]. Myoepithelial carcinoma is excluded by its diffuse immunoreactivity for definitive myoepithelial markers including calponin, SMA, and p40 [2]. Differentiation of MSA from AdCC is of clinical importance, given that AdCC requires radical surgical resection and mandatory adjuvant treatment—in contrast to the more conservative approach warranted for MSA.

The definitive clinical management of microsecretory adenocarcinoma consists of wide surgical excision with negative margins. The implementation of a concurrent therapeutic neck dissection and adjuvant postoperative chemotherapy has only been reported in the unique high-grade transformed case by Gui et al. [34]. Surgical re-intervention for local recurrence was isolated to the single case described by Jurmeister et al. [35]. Ultimately, the aggressive variant documented by Gui et al. [34] underscores the inherent capacity of otherwise low-grade salivary gland malignancies to undergo high-grade transformation and progress into highly aggressive, metastatic phenotypes.

3.2. Sclerosing Microcystic Adenocarcinoma

Sclerosing microcystic adenocarcinoma (SMAC) is an exceedingly rare low-grade malignant neoplasm arising exclusively from the minor salivary glands of the oral cavity [44] (Figure 9), with approximately 23 cases reported in the literature to date [7,44].

The historical use of overlapping terminology—including “microcystic adnexal carcinoma of the head and neck mucosa” and “sclerosing sweat duct-like carcinoma”—reflects the prior uncertainty surrounding its histogenesis and the broad topographic distribution of this tumor across non-cutaneous mucosal sites of the head and neck [7,45].

Histopathologically, SMAC closely mimics cutaneous microcystic adnexal carcinoma (MAC), characterized by nests, cords, strands, and small tubules of neoplastic cells embedded within a dense hyalinized or desmoplastic stroma in which collagenous elements predominate [2,7]. The tumor exhibits a dual-cell architecture comprising an inner luminal layer of cuboidal ductal cells with clear cytoplasm and an outer peripheral layer of flattened myoepithelial cells [2]. Nuclei are uniform, round-to-oval, and clear, with occasional small nucleoli [2]. High-grade cytological parameters—prominent mitoses, marked nuclear atypia, pleomorphism, or necrosis—are characteristically absent [7]. Paradoxically, perineural invasion is present in a high proportion of cases and is considered a diagnostic hallmark, frequently accompanied by infiltration into adjacent skeletal muscle and surrounding structures [7] (Figure 10).

A notable clinicopathological feature of SMAC is its recurrent association with iatrogenic or disease-related immunosuppression, which is hypothesized to contribute to its pathogenesis [46] and may correlate with the somatic mutational burden [7]. Across published series, a significant proportion of patients reported prior malignancies or immunologically driven conditions: in the original series by Mills et al. [45], two patients had received prior systemic chemotherapy and regional radiotherapy; R. Zhang et al. [47] reported a patient on long-term immunosuppressive therapy for multiple sclerosis; Tan et al. [48] described a patient with prior radiotherapy for nasopharyngeal carcinoma; and Jiang et al. [49] documented a patient with intensive immunosuppression for psoriatic arthritis. Other reported associated conditions include adenoid cystic carcinoma, acute myeloid leukemia, benign ovarian mucinous cystadenoma, squamous cell carcinoma, and membranoproliferative glomerulonephritis [46].

Immunohistochemically, routine staining profiles and molecular characteristics are often considered of limited diagnostic utility on their own due to overlapping signatures [7]. However, they cleanly delineate the dual-cell architecture: the inner luminal ductal cells demonstrate diffuse positivity for pan-cytokeratin and CK7, whereas the outer peripheral myoepithelial cells consistently express S100 protein, p63, p40, and smooth muscle actin (SMA) [7] (Figure 11). At the molecular level, whole-exome sequencing of a index SMAC case revealed a distinctive mutational profile characterized by loss-of-function mutations targeting the CDK11B gene [7]. Crucially, SMAC consistently lacks the somatic alterations affecting CDKN2A/B, TP53, or JAK1 that are identified in up to 20% of cutaneous MAC cases, thereby firmly establishing sclerosing microcystic adenocarcinoma as a distinct, independent oncological entity and underscoring its unique biological pathogenesis [7].

The differential diagnosis encompasses several malignant oral cavity neoplasms. The most critical is squamous cell carcinoma (SCC), which represents the closest histopathological mimic to SMAC [46] yet demands entirely different—and more aggressive—therapeutic protocols. SMAC is distinguished from SCC by the complete absence of keratinization, its low-grade cytomorphology, and the preservation of a dual-cell epithelial-myoepithelial architecture [7], as well as the absence of surface epithelial dysplasia, keratin pearls, and dyskeratotic cells characteristic of SCC invasion fronts [46].

Hyalinized clear cell carcinoma (HCCC) enters the differential due to its hyalinized stroma and cord-like architecture; however, HCCC features a monophasic population of clear cells with diffuse high-molecular-weight cytokeratin and p63/p40 positivity, lacks an outer myoepithelial layer, and does not produce intraluminal secretions [7].

The tubular variant of adenoid cystic carcinoma (AdCC) exhibits dual-cell architecture and perineural invasion but is distinguished by its highly aggressive clinical behavior, cribriform architectural patterns, basophilic mucinous secretions, and angulated hyperchromatic nuclei [46]. MYB gene rearrangement testing and CD117 immunohistochemistry—which is robustly positive in AdCC—serve as valuable ancillary diagnostic tools [7,46]. The distinction of SMAC from both SCC and AdCC is clinically critical, as both represent high-grade malignancies requiring markedly more aggressive resection margins and mandatory adjuvant treatment.

Polymorphous adenocarcinoma (PAC) is another low-grade mimic, characterized by well-circumscribed borders and high cellularity—contrasting with the diffusely infiltrative, paucicellular growth pattern of SMAC [46]. Architecturally, PAC demonstrates extensive structural diversity including cords, tubules, solid sheets, and papillary projections in a characteristic targetoid perineural arrangement, in contrast to the predominantly tubular and microcystic architecture of SMAC [46]. The cellular myxoid stroma of PAC further contrasts with the dense acellular hyalinized stroma of SMAC, and PAC demonstrates uniform S100 positivity across all cellular compartments—a feature not observed in the dual-cell framework of SMAC [46].

Molecular diagnostics further assist in separating SMAC from other low-grade translocation-associated salivary malignancies: low-grade mucoepidermoid carcinoma (CRTC1/3::MAML2 fusion), secretory carcinoma (ETV6::NTRK3 fusion), and AdCC (MYB::NFIB fusion) [46]. Loss-of-function CDK11B mutations represent a key molecular signature of SMAC [49]. Adenocarcinoma NOS remains a diagnosis of exclusion and is readily separated from SMAC based on the latter’s reproducible histomorphological criteria [46]. Necrotizing sialometaplasia, a benign reactive condition, is distinguished by its preserved lobular architecture and absence of perineural or skeletal muscle invasion [46].

Although the majority of reported SMAC cases have been managed conservatively with surgical excision alone, isolated cases have undergone elective neck dissection and adjuvant radiotherapy and/or chemotherapy. Importantly, no published case has demonstrated histologically positive regional lymph nodes or distant metastases, reinforcing the stable, low-grade biological behavior of this entity despite its characteristically infiltrative local growth. All published cases are summarized in Table 2.

4. Management of Salivary Gland Tumors

4.1. Clinical Practice Algorithms of the European Society for Medical Oncology (ESMO)

The ESMO–EURACAN clinical practice guideline provides management algorithms for a parotid gland tumor with suspicion of malignancy (Figure 12) and for a tumor of the minor or sublingual salivary glands with suspicion of malignancy (Figure 13) [60].

4.2. American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines

4.2.1. Clinical Question 1: What Is the Appropriate Preoperative Evaluation for Patients with Suspected Salivary Gland Malignancy?

• Recommendation 1.1: Healthcare providers should perform baseline diagnostic imaging (neck ultrasonography, contrast-enhanced computed tomography [CT] with intravenous [IV] contrast, and/or magnetic resonance imaging [MRI] of the neck and the primary site) in patients with a clinical suspicion of malignant salivary gland cancer. (Strong recommendation)
• Recommendation 1.2: Healthcare providers should perform a contrast-enhanced neck CT (with IV contrast) for patients with suspected malignant salivary gland cancer when adjacent osseous invasion or bone involvement is clinically or radiographically suspected. (Strong recommendation)
• Recommendation 1.3: Healthcare providers should perform a contrast-enhanced neck and skull base MRI, including diffusion-weighted imaging (DWI) sequences, for patients with suspected salivary gland malignancy and suspected perineural invasion (PNI) and/or skull base involvement. (Strong recommendation)
• Recommendation 1.4: Healthcare providers may perform positron emission tomography/computed tomography (PET/CT) from the skull base to the mid-thigh for patients diagnosed with advanced-stage or high-grade salivary gland malignancies. (Low recommendation)
• Recommendation 1.5: Healthcare providers should perform a preoperative tissue biopsy—utilizing either fine-needle aspiration biopsy (FNAB) or core needle biopsy (CNB)—to definitively assist in differentiating malignant salivary gland cancers from benign salivary gland lesions. (Strong recommendation)
• Recommendation 1.6: Healthcare providers may perform a core needle biopsy (CNB) if the initial fine-needle aspiration biopsy (FNAB) yields inadequate or non-diagnostic material, or if the anatomical localization of the tumor precludes an optimal FNAB approach, such as in deeply seated minor salivary gland lesions. (Moderate recommendation)
• Recommendation 1.7: Pathologists should report the risk of malignancy (ROM) utilizing a standardized risk stratification scheme for salivary gland fine-needle aspiration biopsies (FNAB), paying meticulous attention to cytomorphological features indicative of a high-grade malignancy. (Strong recommendation)
• Recommendation 1.8: Pathologists may perform ancillary diagnostic testing (such as immunohistochemical stains or molecular studies) on FNAB and core needle biopsy specimens to further refine the specific diagnosis and estimate the risk of malignancy. (Low recommendation)

4.2.2. Clinical Question 2: What Are the Appropriate Surgical Interventions for Salivary Gland Malignancies?

• Recommendation 2.1: Surgeons should recommend open surgical resection as the definitive primary management for histologically confirmed malignant salivary gland lesions. (Strong recommendation)
• Recommendation 2.2: Surgeons may utilize intraoperative frozen section analysis to guide immediate intraoperative management modifications, such as modifying the extent of surgical resection or evaluating the necessity of a concurrent neck dissection. However, irreversible surgical decisions resulting in major morbidity—such as sacrificing the facial nerve—should not be based solely on equivocal preoperative or intraoperative diagnoses. (Low recommendation)
• Recommendation 2.3: Surgeons may perform a partial superficial parotidectomy for low-grade, early-stage (T1 or T2) salivary gland carcinomas that are favorably localized within the superficial lobe of the parotid gland. (Low recommendation)
• Recommendation 2.4: Due to the elevated risk of occult intraparotid lymph node metastases in high-grade or advanced-stage (T3–T4) parotid malignancies, surgeons should perform at least a superficial parotidectomy—with a low threshold for extension to a subtotal or total parotidectomy—for any high-grade or advanced-stage parotid cancer. (Strong recommendation)
• Recommendation 2.5: Surgeons should preserve the facial nerve in patients presenting with normal, intact preoperative facial nerve function when a clear dissection plane can be oncologically established between the tumor mass and the nerve trunk or its branches. (Strong recommendation)
• Recommendation 2.6: Surgeons should perform a segmental resection of the involved facial nerve branches in patients presenting with impaired preoperative facial function, or when the nerve branches are found intraoperatively to be directly encased, embedded, or macroscopically invaded by a confirmed malignancy. (Moderate recommendation)
• Recommendation 2.7: Surgeons should offer elective neck treatment (elective neck dissection) rather than clinical observation alone for patients with a clinically negative neck (cN0) presenting with advanced-stage (T3 or T4) primary tumors or high-grade malignancies. (Moderate recommendation)
• Recommendation 2.8: For the surgical elective management of the neck in salivary gland cancers, an ipsilateral elective neck dissection should be performed, with the specific lymph node levels tailored according to the primary anatomical site. For parotid malignancies, the dissection should routinely encompass lymph node levels II through IV. (Moderate recommendation)
• Recommendation 2.9: In the setting of a clinically node-positive neck (cN+), surgeons should perform a comprehensive ipsilateral therapeutic neck dissection encompassing all involved and high-risk levels, with the latitude to extend the dissection to adjacent levels, up to and including levels I through V. (Moderate recommendation)
• Recommendation 2.10: In cases of resectable, locally recurrent disease without evidence of distant metastasis, and regardless of prior therapeutic modalities, patients should be offered the option of salvage surgical re-resection combined with appropriate reconstructive strategies. (Strong recommendation)
• Recommendation 2.11: In the setting of resectable, locally recurrent disease presenting with concurrent distant metastases, management may include palliative re-resection and appropriate surgical reconstruction, provided that the metastatic burden is not rapidly progressive or indicative of an imminent terminal outcome. (Moderate recommendation)
• Recommendation 2.12: Patients undergoing surgical re-intervention for recurrent salivary gland cancer must be multidisciplinary evaluated for potential adjuvant or systemic therapies. (Moderate recommendation)

4.2.3. Clinical Question 3: What Are the Indications and Appropriate Techniques for Radiation Therapy In patients with Salivary Gland Malignancies?

• Recommendation 3.1: Postoperative radiation therapy (RT) should be routinely offered to all patients following the surgical resection of adenoid cystic carcinoma (ACC). (Strong recommendation)
• Recommendation 3.2: Postoperative radiation therapy (RT) should be offered to patients presenting with adverse clinicopathological features, including: high-grade malignancy, positive or close surgical margins, perineural invasion (PNI), regional lymph node metastases, lymphovascular or microvascular invasion, and advanced primary tumor stage (T3–T4). (Strong recommendation)
• Recommendation 3.3: Postoperative radiation therapy (RT) may be offered to patients with intermediate-grade tumors or those with inadequate or close surgical margins. (Low recommendation)
• Recommendation 3.4: In the postoperative setting, the high-dose target volume must comprehensively encompass the primary surgical bed of the salivary gland along with the adjacent high-risk lymph node echelons. (Strong recommendation)
• Recommendation 3.5: In cases demonstrating documented perineural invasion, the course of the involved cranial nerves may be targeted with elective or intermediate radiation doses tracked proximally toward the skull base. (Moderate recommendation)
• Recommendation 3.6: Elective nodal irradiation may be offered for patients presenting with T3–T4 primary tumors and high-grade malignancies. (Moderate recommendation)
• Recommendation 3.7: Postoperative radiation therapy should ideally be initiated within 8 weeks following definitive surgical resection. (Moderate recommendation)
• Recommendation 3.8: Particle therapy—including proton beam, neutron beam, and carbon ion therapy—may be utilized for patients with salivary gland cancers. Currently, there is insufficient high-level evidence to definitively mandate the routine use of heavy particle therapy over modern photon or electron modalities. (Low recommendation)
• Recommendation 3.9: Elective nodal irradiation may be offered to patients with a clinically node-negative neck (cN0) who present with specific high-risk indications, namely advanced T-stage (T3–T4) or high-grade malignancies. (Moderate recommendation)
• Recommendation 3.10: Primary radiation therapy must be offered to patients with salivary gland cancer who are deemed unresectable due to the extensive anatomical constraints of the disease or severe medical comorbidities. (Moderate recommendation) Note: The high-dose target volume must encompass all macroscopic disease within the salivary gland and involved regional nodal levels.

4.2.4. Clinical Question 4: What Is the Role of Systemic Therapy in the Management of Salivary Gland Malignancies?

Note: Systemic therapy is defined as cytotoxic chemotherapy, molecularly targeted therapies, and immunotherapy.

• Recommendation 4.1: For patients undergoing adjuvant radiation therapy, the routine, unselected addition of concurrent chemotherapy should not be offered on a standard basis outside the strict infrastructure of a clinical trial. (Moderate recommendation)
• Recommendation 4.2: For patients undergoing definitive radiation therapy for unresectable salivary gland cancer, the addition of concurrent chemotherapy should not be offered on a routine basis outside the context of a clinical trial. (Moderate recommendation)
• Recommendation 4.3: In patients harboring salivary gland tumors that robustly express the androgen receptor (AR) and/or HER2/neu, adjuvant endocrine (androgen deprivation) or HER2-targeted therapy should not be offered routinely outside the framework of a clinical trial. (Moderate recommendation)

4.2.5. Clinical Question 5: What Is the Appropriate Post-Treatment Surveillance and Evaluation for Patients with Salivary Gland Malignancies?

• Recommendation 5.1: Clinical post-treatment surveillance incorporating a thorough medical history and directed physical examination must be performed on a regular schedule, with the frequency of visits gradually tapering as the time elapsed from the completion of definitive therapy increases. (Moderate recommendation)
• Recommendation 5.2: Baseline post-treatment diagnostic imaging of the primary site—utilizing contrast-enhanced CT or MRI (in the absence of medical contraindications)—and/or a systemic PET/CT, should be obtained approximately 3 months following the completion of all planned therapeutic modalities. (Moderate recommendation)
• Recommendation 5.3: Routine surveillance imaging of the primary site with contrast-enhanced CT or MRI, coupled with a chest CT, may be performed every 6 to 12 months for the first 2 years post-treatment. (Moderate recommendation)
• Recommendation 5.4: Routine surveillance imaging of the primary site and chest from year 3 through year 5 post-treatment should be guided primarily by patient-reported symptoms and clinical findings on physical examination. Annual imaging may be offered in cases characterized by high-grade histology or other poor prognostic clinicopathological features. (Moderate recommendation)
• Recommendation 5.5: Long-term surveillance extending beyond 5 years post-treatment with an annual clinical evaluation should be offered to all salivary gland cancer patients. An annual surveillance chest CT may also be offered, particularly in patients with high-grade malignancies or adverse clinicopathological features prone to late distant failure. (Moderate recommendation)

4.2.6. Clinical Question 6: What Are the Therapeutic Options for Patients with Recurrent or Metastatic Salivary Gland Malignancies?

• Recommendation 6.1: Patients presenting with documented distant metastatic disease should be evaluated for further therapeutic interventions, including localized ablative modalities or systemic therapies. These options must be discussed via a shared decision-making process and are dependent on patient-specific factors and tumor biology. (Low recommendation)
• Recommendation 6.2: In the specific clinical scenario of Adenoid Cystic Carcinoma (ACC) and/or low-grade tumors exhibiting an indolent biological behavior and oligo-metastatic disease (defined as ≤5 metastatic lesions), localized ablative therapies—such as surgical metastasectomy or stereotactic body radiotherapy (SBRT)—may be offered to delay localized disease progression. (Low recommendation)
• Recommendation 6.3: Patients should be considered for the initiation of systemic therapy in the following scenarios: (1) when metastatic lesions are symptomatic and amenable to palliative localized therapy, (2) when the kinetic growth of the tumor poses an imminent threat to vital organ function, or (3) when target lesions demonstrate a volumetric increase of greater than 20% within the preceding 6 months. (Moderate recommendation)
• Recommendation 6.4: For patients with advanced adenoid cystic carcinoma (ACC) who are candidates for systemic therapy, a multi-targeted tyrosine kinase inhibitor (TKI) such as Lenvatinib or Sorafenib may be offered if an appropriate clinical trial is unavailable. (Moderate recommendation)
• Recommendation 6.5: For systemic therapy candidates presenting with non-ACC salivary gland carcinomas, targeted therapy tailored to specific driver molecular alterations (such as AR-positivity, HER2-amplification, or NTRK fusions) should be offered if a clinical trial is unavailable. (Moderate recommendation)
• Recommendation 6.6: Combination cytotoxic chemotherapy regimens may be offered to patients presenting with highly symptomatic, rapidly progressive visceral disease. (Low recommendation)
• Recommendation 6.7: For patients who are candidates for systemic therapy, immune checkpoint inhibitors should not be offered on a routine, unselected basis, except for patients harboring tumors with validated molecular biomarkers, such as a high tumor mutational burden (TMB-H) or high microsatellite instability (MSI-H). (Low recommendation)
• Recommendation 6.8: For patients presenting with histological subtypes known to harbor a high prevalence of actionable molecular alterations (e.g., AR expression in salivary duct carcinoma, or NTRK3 fusions in secretory carcinoma), target-specific confirmatory biomarker testing must be performed. (Strong recommendation)
• Recommendation 6.9: Patients who are potential candidates for systemic therapy presenting with histological subtypes associated with a low prevalence of targetable alterations and an unknown driver mutation status should undergo molecular testing utilizing a comprehensive next-generation sequencing (NGS) panel. Subsequently, for patients whose tumors are negative for common driver fusions, target-specific testing (such as AR and NTRK3) may be considered. (Low recommendation)

The foregoing clinical practice recommendations are based on the guidelines published by Geiger et al. [61].

4.3. Recommendations of REFCOR: Surgical Management

The REFCOR (Réseau d’Expertise Français sur les Cancers ORL Rares; French Network of Rare Head and Neck Tumors) recommendations were produced using the formal consensus method [62,63].

4.3.1. General Principles of Surgical Management

• Recommendation 1: The primary definitive treatment modality for major salivary gland carcinomas remains surgical resection. (Strong recommendation)
• Recommendation 2: Surgical margins must be oncologically negative to the greatest extent possible, maximizing the excision margins from the primary tumor bulk. (Strong recommendation)

4.3.2. Surgical Management of Parotid Carcinoma

• Recommendation 1: The gold standard surgical procedure for parotid carcinoma is a total parotidectomy. The operative objective mandates complete tumor extirpation with negative margins, concurrently incorporating the removal of all intraparotid lymph nodes. (Strong recommendation)
• Recommendation 2: In cases involving strictly low-grade malignancies, a partial parotidectomy with a planned wide local excision of the tumor mass is acceptable, even if the definitive malignant diagnosis is established postoperatively on the final histopathological analysis. (Strong recommendation)
• Recommendation 3: In the event of histologically positive margins on final pathology, the feasibility of surgical re-resection must be rigorously evaluated and executed whenever anatomically achievable. (Strong recommendation)

4.3.3. Management and Preservation of the Facial Nerve

• Recommendation 1: A meticulous preoperative clinical assessment is mandatory to detect any signs of facial nerve compromise, including facial paresis or complete paralysis. Advanced diagnostic imaging can further assist in assessing macroscopic facial nerve involvement. (Strong recommendation)
• Recommendation 2: In the absence of preoperative clinical signs of facial nerve weakness, every effort must be made to preserve the facial nerve trunk and its branches, provided an oncological dissection plane can be safely established between the lesion and the nerve. If the tumor is intraoperatively noted to be completely inseparable from the nerve architecture, sacrifice of the nerve may be required. (Strong recommendation)
• Recommendation 3: If preoperative facial nerve compromise is present and intraoperative findings confirm macroscopic direct tumor invasion, segmental resection of the invaded nerve segment alongside the tumor bulk is indicated. Intraoperative frozen section analysis of the proximal and distal nerve stumps should be utilized to ensure clearance up to histologically negative nerve margins, particularly in cases of adenoid cystic carcinoma (ACC) prone to perineural tracking. (Strong recommendation)
• Recommendation 2.4 (Note on Counseling): In all clinical scenarios, patients must be thoroughly counseled preoperatively regarding the potential necessity of facial nerve sacrifice if direct macroscopic invasion is encountered. This potential outcome must be comprehensively discussed with the patient, considering patient age, clinical context, and overall oncological prognosis. (Strong recommendation)
• Recommendation 5: Whenever facial nerve sacrifice is performed, immediate intraoperative facial nerve reconstruction or reanimation should be attempted, regardless of the specific surgical technique chosen. (Strong recommendation)

4.3.4. Surgical Management of Parapharyngeal Space Salivary Tumors

• Recommendation 1: For salivary gland carcinomas arising within or extending into the parapharyngeal space, complete surgical excision with negative margins is recommended, utilizing surgical approaches carefully tailored to the complex regional anatomy. (Strong recommendation)

4.3.5. Surgical Management of Submandibular Gland Carcinoma

• Recommendation 1: Lymph node level Ib must be systematically dissected and cleared concurrently during the surgical excision of a malignant submandibular gland tumor. (Strong recommendation)
• Recommendation 2: In the event of positive surgical margins on final histopathological analysis, surgical re-resection must be evaluated for feasibility and executed if anatomically viable. (Strong recommendation)
• Recommendation 3: The marginal mandibular branch of the facial nerve must be anatomically preserved, provided it is clinically functional preoperatively and displays no intraoperative evidence of direct neoplastic invasion. (Strong recommendation)
• Recommendation 4: In cases demonstrating direct invasion or close adherence to the mandible, a formal mandibulectomy, either a marginal or segmental cortical resection—must be integrated into the surgical plan. (Strong recommendation)

The foregoing surgical management recommendations are derived from the consensus statement by Barry et al. [62] (Figure 14).

4.4. Recommendations of REFCOR: Neck Management

• Recommendation 1: In the presence of regional lymph node involvement documented during baseline diagnostic imaging evaluation (cN+), a therapeutic ipsilateral neck dissection is strongly recommended. (Strong recommendation)
• Recommendation 2: In the absence of regional lymph node involvement on baseline diagnostic imaging evaluation (cN0), an elective ipsilateral neck dissection is recommended. Exceptions to this rule include tumors with a well-documented low biological risk for subclinical or occult nodal metastasis—such as histologically confirmed low-grade malignancies, early-stage (T1 or T2) primary tumors, and early-stage (T1 or T2) adenoid cystic carcinomas (ACC) that do not directly invade the overlying oral mucosa. (Strong recommendation)
• Recommendation 3: If adverse histopathological features indicating a high risk for subclinical or occult nodal metastasis are identified on the final post-surgical pathology report, adjuvant regional neck treatment is recommended. This therapeutic paradigm should consist of either a secondary completion ipsilateral neck dissection or prophylactic regional irradiation of the ipsilateral neck echelons. (Strong recommendation)

The foregoing neck management recommendations are derived from the consensus statement by Baujat et al. [63] (Figure 15).

5. Materials and Methods

A comprehensive search of the peer-reviewed literature was conducted across PubMed, Google Scholar, Web of Science, and Scopus databases. The search was performed in both English and Greek using the following MeSH terms and keywords: “Striated duct adenoma”, “Keratocystoma”, “Intercalated duct adenoma - hyperplasia”, “Sclerosing polycystic adenoma”, “Microsecretory adenocarcinoma”, “Sclerosing microcystic adenocarcinoma”, “neck dissection”, and “salivary gland tumor”.

5.1. Inclusion Criteria

• Studies reporting clinical, molecular, genetic, histological, immunohistochemical, or epidemiological data pertaining to the salivary gland oncological entities under investigation.
• For the primary literature framework, peer-reviewed articles published between 2016 and 2025 were selected.
• Note: Due to the inherently small sample size of documented cases in world literature, 8 cases of Sclerosing Microcystic Adenocarcinoma published between 1982 and 2011, 1 case of Sclerosing Polycystic Adenoma, 4 cases of Keratocystoma, and 1 case of Intercalated Duct Adenoma published prior to 2016 were exceptionally included. This was deemed necessary to provide a comprehensive and rigorous presentation of the historical data regarding these rare entities and their regional management.
• Articles and publications containing the designated search terms in either English or Greek.
• Case reports with well-documented histopathological or molecular confirmation of diagnosis.
• Publications in peer-reviewed scientific journals.

5.2. Exclusion Criteria

• Studies lacking relevant clinical, molecular, genetic, histological, immunohistochemical, or epidemiological data pertaining to the entities of interest.
• Articles not containing the predefined search keywords.
• Publications in non-peer-reviewed or non-scientific sources.

Following application of these criteria, a total of 63 articles were selected to constitute the final reference list of this review.

6. Results

6.1. Evidence Base

A total of 63 peer-reviewed publications were identified and included following application of the predefined inclusion and exclusion criteria, comprising case reports, case series, retrospective cohort studies, and clinical practice guideline documents.

6.2. Benign Entities

For all four novel benign entities introduced in the 2022 WHO Classification—Sclerosing Polycystic Adenoma, Keratocystoma, Intercalated Duct Adenoma and Hyperplasia, and Striated Duct Adenoma—the synthesized evidence consistently demonstrates the complete absence of regional lymph node metastasis or distant spread across all documented cases. Accordingly, elective or therapeutic neck dissection is not indicated for any of these entities; surgical management is limited to complete local excision with clear margins.

6.3. Microsecretory Adenocarcinoma

A total of 14 cases with salivary gland localization and 9 cases with cutaneous localization were identified and analyzed (Table 1). The majority were managed with surgical excision alone. In the largest published series [27], comprising 24 cases, follow-up was available for 14 patients, with a disease-free interval ranging from 1 month to 18 years. One case [34] demonstrated high-grade transformation with cervical lymph node metastases—the only reported instance of regional spread in the entire MSA literature—supporting the overall low metastatic potential of this entity.

6.4. Sclerosing Microcystic Adenocarcinoma

A total of 23 published cases were identified and analyzed (Table 2). The predominant management strategy was surgical excision with or without adjuvant radiotherapy. Lymph node involvement was not observed in any documented case, consistent with the indolent clinical behavior of this tumor.

6.5. Management Guidelines Synthesis

Three major international clinical practice guidelines were analyzed: the ESMO-EURACAN Clinical Practice Guidelines [60], the ASCO Clinical Practice Guidelines [61], and the REFCOR Recommendations [62,63]. All three guidelines converge on complete surgical resection as the primary treatment modality. Notable discrepancies exist regarding management of the clinically node-negative neck (cN0) in low-grade tumors, reflecting the limited high-quality evidence available for this clinical scenario.

6.6. Therapeutic Algorithms

Based on the synthesized evidence and guidelines reviewed, two distinct neck management algorithms were formulated—one for primary tumors of the parotid gland and one for tumors of the minor salivary glands—presented in Figure 16 and Figure 17 below.

7. Discussion

The ESMO, ASCO, and REFCOR guidelines share broad consensus regarding the primacy of surgical resection with negative oncological margins as the definitive treatment modality for salivary gland malignancies [60,61,62].

Notable divergence exists, however, in the management of the clinically node-negative neck (cN0) for parotid gland primaries. ESMO employs a risk-stratified approach based on tumor stage and patient age, whereas ASCO and REFCOR provide more uniform elective neck management recommendations.

In the setting of a clinically node-positive neck (cN+) or high-grade primary tumor, all three organizations are in complete agreement, uniformly advocating for comprehensive neck dissection followed by adjuvant regional radiotherapy.

8. Conclusions

In conclusion, this review identifies a notable absence of formalized, consensus-based clinical practice guidelines for neck management in patients with the novel salivary gland oncological entities introduced in the 2022 WHO Classification.

For the four novel benign entities—Sclerosing Polycystic Adenoma, Keratocystoma, Intercalated Duct Adenoma and Hyperplasia, and Striated Duct Adenoma—the available evidence demonstrates a consistent absence of regional or distant metastatic risk. Complete surgical excision with negative margins is the definitive treatment, and cervical lymph node intervention is not indicated.

By contrast, neck management for the two novel malignant entities differs substantially, governed by primary tumor site, histopathological grade, and clinical nodal status.

Both Microsecretory Adenocarcinoma and Sclerosing Microcystic Adenocarcinoma are intrinsically low-grade malignancies characterized by an indolent clinical course, limited metastatic potential, and favorable prognosis following complete surgical resection [7,33,45].

Accordingly, two distinct, evidence-based therapeutic algorithms are proposed based on the primary anatomical site of origin:

8.1. Primary Localization within the Parotid Gland

For suspected resectable parotid malignancy, the initial operative step is parotidectomy with intraoperative frozen section analysis, performed with oncologically safe margins [62], with definitive management guided by final histopathological findings.

Following histopathological confirmation of malignancy in a clinically node-negative (cN0) neck with low-risk features (T1–T2, age ≤54 years), adjuvant irradiation of the primary bed may be considered without upfront neck dissection, in accordance with ESMO recommendations [60].

In the absence of adverse prognostic features on final pathology—including high-risk histological subtype, intermediate or high-grade differentiation, extraglandular extension, perineural invasion, lymphovascular invasion, or positive surgical margins—active surveillance is recommended [60,61].

If adverse prognostic features are identified, the patient should undergo therapeutic neck dissection and/or adjuvant radiotherapy; an ipsilateral selective neck dissection of levels I–V followed by adjuvant radiotherapy to levels I–V is recommended [61].

In the presence of preoperative high-risk features (T3–T4 or age >54 years), elective dissection of level II is recommended. If pathologically node-negative (pN0), no further treatment is required; if node-positive (pN+), dissection is extended to levels I–V with adjuvant radiotherapy [60,61].

For a clinically node-positive neck (cN+), there is uniform consensus supporting comprehensive neck dissection of levels I–V with adjuvant regional nodal irradiation. The rate of pathologically positive nodes in a cN+ neck ranges from 10–40% (Van Herpen et al. [60]) to 47–89% (Baujat et al. [63]). Levels II and III are most frequently involved (73% and 48%, respectively), while levels I and V demonstrate metastatic involvement in 33% and 37% of cases, respectively [63], and must be included in the dissection.

For anatomically unresectable parotid carcinomas—attributable to extensive local invasion, advanced disease stage, or prohibitive medical comorbidity—neck management consists of clinical observation or palliative regional radiotherapy. Routine concurrent systemic chemotherapy is not recommended outside the context of clinical trials.

8.2. Primary Localization within the Minor Salivary Glands

For primary tumors of the minor salivary glands, wide surgical excision with negative oncological margins is recommended, achievable via open, transoral endoscopic, or robotic approaches [62].

Minor salivary glands exhibit marked anatomical heterogeneity, and neck management is determined by the specific subsite. For tumors of the larynx, sinonasal tract, external auditory canal, or lacrimal gland, the incidence of regional nodal involvement is sufficiently low to preclude elective neck dissection [60]. For oral cavity primaries, the estimated occult metastasis rate approaches 20%, supporting elective dissection of levels I–IV; for oropharyngeal primaries, levels II–IV are targeted [60].

Preoperatively, imaging of the neck with contrast-enhanced CT and/or MRI is performed once a low-grade minor salivary gland malignancy is confirmed. Surgical excision of the primary lesion with safe oncological margins is then performed, with or without concurrent neck dissection based on clinical nodal status.

Neck management is determined by the presence or absence of regional nodal disease:

• Clinically Node-Positive Neck (cN+): Per ESMO [60] and REFCOR [63] recommendations, comprehensive five-level neck dissection (levels I–V) is indicated. Pathologically node-positive (pN+) disease mandates adjuvant radiotherapy to levels I–V; pathologically node-negative (pN0) disease warrants observation.
• Clinically Node-Negative Neck (cN0): Elective neck dissection is recommended, with the level selection tailored to the primary subsite [60]. Levels I–IV are targeted for oral cavity primaries; levels II–IV for oropharyngeal primaries. For other minor salivary gland subsites requiring transcervical surgical access, the extent of dissection is adjusted accordingly.

The subsequent management is identical across all scenarios: pN+ disease mandates regional nodal irradiation of levels I–V, while pN0 disease requires no additional treatment.

In the absence of formalized clinical practice guidelines for neck management of these newly recognized salivary gland malignancies, the two algorithms proposed herein represent a synthesis of the best available evidence from ESMO, ASCO, and REFCOR guidelines, adapted to the distinctive biological behavior and clinical characteristics of MSA and SMAC.