Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Tumors of the Salivary Gland

Secretory Carcinoma

Mammary analogue secretory carcinoma (MASC), first descibed in 2010, is a salivary gland malignancy that was essentially culled from acinic cell carcinomas and adenocarcinomas not otherwise specified [3, 4]. It is named for its recapitulation of secretory carcinoma of breast, along with its shared ETV6-NTRK3 gene fusion. Given this similarity and in an effort to standardize nomenclature across organ sites, the official designation for this entity is now simply “secretory carcinoma.”

Acinic cell carcinoma serves as the best point of comparison for secretory carcinoma. Secretory carcinoma differs from acinic cell carcinoma epidemiologically in that the sex predilection is more equal, and secretory carcinoma arise in minor salivary sites more frequently than acinic cell carcinoma [3, 5]. Histologically, secretory carcinoma share nearly identical growth patterns to acinic cell carcinoma (Fig. 1a, b), but instead show a multivacuolated eosinophilic cytoplasm, often with luminal and intracytoplasmic mucin and no true zymogen granules. Papillary cystic architecture is now consider rare in true acinic cell carcinoma, being far more common in secretory carcinoma. Both secretory carcinoma and acinic cell carcinoma may show PAS positivity after diastase treatment, but the pattern in secretory carcinoma is globular (indicative of mucin) while that in acinic cell carcinoma is granular (Fig. 1a, b inset). Secretory carcinoma is S100, and mammaglobin positive, and typically negative for DOG1, while acinic cell carcinoma shows the opposite staining profile (Fig. 1c–f) [6].

As noted above, secretory carcinoma usually harbors a t(12;15)(p13;q25) resulting in an ETV6-NTRK3 gene fusion [4]. A subset that are more infiltrative and sclerosing show ETV6 rearrangements with a yet unknown fusion partner [7]. Secretory carcinoma is typically indolent like acinic cell carcinoma, but may show a slightly higher lymph node metastatic rate (up to 25%) than true acinic cell carcinoma [8]. Prognostic features include stage and high-grade transformation (see below) [9]. With the expansion of selective TRK inhibitors, recognition of advanced stage cases of secretory carcinoma may eventually have direct therapeutic relevance [10].

Sclerosing Polycystic Adenosis

While sclerosing polycystic adenosis (SPAN) was described long before the 3rd edition of the salivary gland section,[11] it is a new entry and represents a major entity in the new “Other epithelial lesions” category in the 4th edition. SPAN is named for its resemblance to fibrocystic change and sclerosing adenosis of the breast. The age range is broad (typically 4th decade), with a slight female predilection. The vast majority are parotid lesions.

The characteristic appearance is that of a well circumscribed tubulocystic proliferation of glands within a sclerotic stroma (Fig. 2a). Duct morphology ranges from intercalated duct like to apocrine (Fig. 2b). A characteristic feature is the presence of acini with aberrant coarse red zymogen granules (Fig. 2c). SPAN is occasionally multifocal.

Studies of the X-chromosome inactivation pattern have suggested that SPAN is a clonal process suggesting that perhaps this entity is more appropriately placed in the neoplastic category [12]. The recurrence rate is as high as 11%, likely secondary to incomplete excision and multifocality. SPAN ductal components may become proliferative with an appearance similar to intraductal carcinoma [13]. However, only one case of a salivary duct carcinoma arising after a multiply recurrent SPAN has been described [14].

Remaining “Other Epithelial Lesions”

Intercalated duct hyperplasia (IDH) is a proliferation of intercalated duct caliber tubules that is mainly of interest given its reported association with other salivary gland tumors [15]. It is thought that IDH may represent a precursor lesion, particularly to basal cell adenoma and perhaps epithelial-myoepithelial carcinoma [15–17]. IDHs are most frequently parotid gland lesions, and are as a rule less than 1 cm. They are usually found incidentally, and only rarely present as masses. Subclassification of intercalated duct lesions has been proposed. Well demarcated/encapsulated nodular lesions are designated as intercalated duct adenoma (Fig. 3a) while the term IDH is retained for unencapsulated, expansile proliferations that retain the lobular architecture of the ductoacinar unit.

Nodular oncocytic hyperplasia and lymphoepithelial lesion are well characterized entities that now have their own entries in the current edition. Nodular oncocytic hyperplasia is almost exclusively a lesion of the parotid and peaks in the 5th to 6th decade. It consists of multiple unencapsulated solid to tubulotrabecular patterned nodules of oncocytes, occasionally with marked clear cell change (Fig. 3b, so called clear cell oncocytosis), the latter being more frequently bilateral and prone to recurrence [18]. In contrast to oncocytoma, there is no dominant encapsulated lesion. Clear cell predominance may mimic the appearance of metastatic renal cell carcinoma, though nodular oncocytic hyperplasia does not show the hemorrhage or vascularity typically seen in renal cell carcinoma [19]. Lymphoepithelial lesions are pathognomonic for lymphoepithelial sialadenitis that is seen in Sjögren syndrome [20]. Both cystic and non-cystic versions may mimic a tumor. Lymphoepithelial lesions are characterized by metaplastic ducts infiltrated by lymphocytes. The lymphoid component effaces the surrounding acini and contains germinal centers. When cystic, lymphoepithelial lesions may overlap with the cystic lymphoid hyperplasia seen in immunosuppressed patients [21]. When malignant transformation occurs, it is most frequently the lymphoid component, resulting in MALT lymphoma [22].

Soft Tissue Lesions

In addition to hemangioma, which is the most common parotid tumor in infancy, the new edition now includes lipoma and nodular fasciitis. Lipomas are rare in salivary gland (<0.5%) and usually involve the parotid. They are well circumscribed and are designated as sialolipoma if they have an intratumoral ductal component. Oncocytic lipoadenoma appears to be a distinctive subtype of sialolipoma with oncocytes and sebaceous rests [23]. Nodular fasciitis may rarely involve the superficial parotid gland. As with other sites, these tend to occur in young adults (3rd to 4th decade) and show a characteristic rapid growth mimicking an aggressive neoplasm [23]. Histologically similar to nodular fasciitis at other sites, parotid lesions consist of a well demarcated but focally permeative myofibroblastic proliferation that is cellular but with little atypia. Cells vary from spindled to more stellate like. Nodular fasciitis is indolent and may regress spontaneously. The majority are now known to harbor an USP6 gene fusion [24]. Nodular fasciitis must be distinguished from more aggressive spindle cell sarcomas, as well as spindle cell myoepithelial cell rich neoplasms [23]. Other considerations in this region include schwannoma and solitary fibrous tumor.

Categorical Lumping

Both sebaceous and non-sebaceous lymphadenomas are benign non-Warthin lymphoid stroma rich tumors with variable mixtures of ductal, squamous, and myoepithelial elements; the main morphologic distinction is the presence or absence of sebaceous elements (Fig. 4a, b). While non-sebaceous lymphadenomas do have a stronger female predilection, they are overall biologically similar. Only rare cases of malignant transformation are described [28].

Inverted ductal papillomas appear to arise at the junction between minor salivary excretory duct and squamous mucosa and shows a nested transitional type epithelial proliferation with overlying surface ductal columnar epithelium, reminiscent of a Schneiderian type inverted papilloma. Intraductal papillomas appear to arise more distally in the duct and consist of papillary proliferations of bland columnar ductal cells [29].

With improved classification, the terms cystadenocarcinoma [30] and mucinous adenocarcinoma [31] have become diagnoses of exclusion and are now part of adenocarcinoma, not otherwise specified. Similarly, the exceptionally rare entity sebaceous lymphadenocarcinoma [32] has been subsumed under the malignant transformation portion of the “Lymphadenoma” chapter.

Metastasizing Pleomorphic Adenoma

The prior edition of this section classified metastasizing pleomorphic adenoma (MPA) under the “Malignant tumors” given its aggressive biologic behavior [32]. MPA is a tumor that is histologically identical to PA, but has metastasized regionally or distantly. It arises after multiple recurrences and typically spreads to lung and bone and as many as 40% of patients die with disease [33]. However, in the 4th edition, MPA has been relegated to subcategory status under the benign, “pleomorphic adenoma” section, since these are histologically indistinguishable. Thus, a word of caution regarding current edition is that despite this reorganization, MPA is still considered biologically aggressive.

Polymorphous Adenocarcinoma

Polymorphous low-grade adenocarcinoma, now shortened to polymorphous adenocarcinoma (PAC) is without a doubt the most contentious entity for this iteration of the WHO classification for salivary gland tumors. While described earlier, the term polymorphous low-grade adenocarcinoma was first used in 1984 by Evans and Batsakis [34] to describe an infiltrative salivary tumor with a variety of growth patterns but bland nuclei. The growth pattern and stromal characteristics mimic those of adenoid cystic carcinoma and have been historically diagnostically challenging to differentiate. The importance of distinction however lies in the much more indolent behavior of PAC as compared to adenoid cystic carcinoma.

PAC almost exclusively occur in minor salivary sites with palate being the most frequent. They predominate in the 5th decade and show a female predilection of 2:1 [35–37]. Histologically they are infiltrative and may show a spectrum of tubular, fascicular, cribriform, papillary or solid architecture. Classically they demonstrate considerable neurotropism and often show a targetoid appearance (Fig. 5a). However, as noted above, tumor cells are monomorphic and monotypic with a (terminal) ductal phenotype, consisting of uniform ovoid vesicular nuclei and scant to moderate lightly eosinophilic cytoplasm (Fig. 5b). S100 is diffusely strongly positive in these tumors,[35, 37] but they do not have a prominent basal or myoepithelial component. The frequent finding of p63 immunoreactivity may at times cause confusion. However, the staining is not patterned as seen with truly biphasic tumors such as adenoid cystic carcinoma and pleomorphic adenoma, and if necessary, the more myoepithelial cell specific ΔNp63 antibody, p40 will still be negative [38].

As a whole PAC show local recurrence rates of 10–33% and regional metastases in 9–15%. Distant metastases and death from disease are exceptionally rare [35–37]. However, even early on in the existence of this entity, papillary patterned tumors were thought to behave more aggressively with a greater capacity for regional and distant spread [36]. Additionally, at base of tongue sites a distinctive cribriform architecture was noted along with more overtly cleared (papillary thyroid carcinoma-like) nuclei initiating the proposal for reclassification of this subset of tumors as cribriform adenocarcinoma of tongue, and subsequently cribriform adenocarcinoma of (minor) salivary gland (CAMSG) (Fig. 5c, d) [39, 40]. Despite the presence of cribriform in the proposed name for this tumor, the growth pattern is actually mainly papillary glomeruloid, thus incorporating the previously noted morphologic feature of aggression. CAMSG morphology does tend to show more cytonuclear atypia and a greater capacity for regional and possibly distant metastasis, though no differences in survival have been documented to date. Aside from this morphology, overt high-grade transformation has been described as well (see also below) [41].

These developments raised two major issues with the term polymorphous low-grade adenocarcinoma. First, are these tumors always low-grade? Based on data summarized above, this is not necessarily the case, thus justifying removal of the term low-grade as a default. Thus on a case by case basis, PAC can be assigned a grade which in the vast majority of cases would still be low-grade, but this allows for recognition when a tumor deviates from the norm. The point of contention here, however, is that there is no structured evidence based grading scheme for PAC, unlike other tumor types such as mucoepidermoid carcinoma. Additionally, since the vast majority are still low-grade, the necessity of a name change is questionable.

The second issue raised is whether sufficient evidence exists to justify separating CAMSG as a distinct entity from PAC. Proponents for this separation point to the difference in site distribution, preponderance of papillary/glomeruloid or cribriform morphology, exaggerated nuclear features, and regional aggressiveness as sufficient evidence to establish this as a new entity. Furthermore, recent studies indicate that rearrangements of PRKD1-3, including ARID1A-PRKD1 and DDX3X-PRKD1 gene fusions, are seen in ~80% of cases with CAMSG morphology, and in less than 10% of cases with classic PAC morphology [42]. In contrast, PRKD1 E710D mutations are largely restricted to classic PAC, with only about 10% of CAMSG type tumors showing a mutation [43, 44]. The counterpoints to these arguments are that the findings in the literature are numerically insufficient, there is still some morphologic and genotypic overlap, and despite the regional aggressiveness, survival differences have not yet been established. Thus despite extensive debate, the decision was to retain a more conservative and unifying approach and leave CAMSG within the PAC subheading for this edition. This is also in line with the fact that both PAC and CAMSG are driven by genes in the same family, indicating that they are variants of one spectrum.

Grading in Mucoepidermoid Carcinoma

The 4th edition is less dogmatic about application of grading in mucoepidermoid carcinoma (MEC). In contrast to the 3rd edition,[45] in which the Goode et al. [46] (a.k.a AFIP) system was featured, the 4th edition does not endorse a specific grading scheme. Several grading schemes exist in the literature each with advantages and limitations, specifically with respect to intermediate-grade tumors [46–50]. Furthermore, studies are variably prone to misclassification artifact in the high-grade category as well. Given the lack of consensus on optimal grading criteria, only the general features of low-, intermediate-, and high-grade tumors are outlined.

High-Grade Transformation

New relative to the prior edition of this chapter is the term high-grade transformation (HGT). HGT is the preferred terminology (over dedifferentiation) for progression of a (usually) lower grade carcinoma with conventional morphology into a pleomorphic high-grade carcinoma [51]. The rationale for recognition of this morphology lies in its aggressive behavior and thus potential differences in clinical management. Tumors for which this phenomenon is well characterized include acinic cell carcinoma, adenoid cystic carcinoma, and epithelial-myoepithelial carcinoma (Fig. 6a–d). For acinic cell carcinoma with HGT a side by side comparison with conventional acinic cell carcinoma confirms a more aggressive behavior even when corrected for age. Secretory carcinoma and PAC have also been reported to rarely undergo high-grade transformation, which was part of the impetus to drop the term “low-grade” from PAC [9, 41].

Acinic cell carcinoma, secretory carcinoma and PAC are monotypic/monophasic tumors that progress to nondescript pleomorphic cribriform to solid adenocarcinoma types. Adenoid cystic carcinoma and epithelial myoepithelial carcinomas are biphasic. To date adenoid cystic carcinoma with HGT reflects progression of the ductal component beyond solid growth pattern alone to an adenocarcinoma morphologically similar to the transformed components of the aforementioned carcinoma types. Given this overlap, distinction between these entities, and even adenocarcinoma not otherwise specified would require documentation of a conventional component, or a defining molecular alteration (i.e., ETV6-NTRK3 for secretory carcinoma with HGT). Epithelial myoepithelial carcinoma is somewhat unique in that the transformed phenotype may range from myoepithelial to ductal to undifferentiated [52]. Tumors with HGT may mimic salivary duct carcinoma, and in fact, most non-apocrine androgen receptor negative “salivary duct carcinomas” are in fact unrecognized HGT of another tumor type [53].

Carcinoma Ex Pleomorphic Adenoma

Carcinoma ex pleomorphic adenoma (CAxPA) represents a malignancy arising in a pleomorphic adenoma [54, 55]. It is a well-recognized phenomenon accounting for ~12% of all salivary carcinomas. Peak incidence is in the 6th to 7th decade (about 1–2 decades later than that of pleomorphic adenoma) [55, 56].

The major changes in this iteration of the salivary gland tumor classification center on how key features and concepts are framed. Importantly, in this edition it is explicitly stated that CAxPA should no longer be considered a standalone diagnosis, biology is determined by both extent and carcinoma subtype. While the majority are now recognized as salivary duct carcinomas, other morphologic subtypes including myoepithelial carcinoma and epithelial-myoepithelial carcinoma also exist and have less aggression than the prototypical CAxPA [57]. The concept of stratification by extent of invasion was previously introduced and expanded in this edition. CAxPA can be classified as intracapsular, minimally invasive and (widely)-invasive. Ironically with this edition, the definition of minimal invasion is less certain. The initial cut-off of 1.5 mm to delineate minimal invasion has been deemed arbitrary and too restrictive (Fig. 7), [58] as several studies have justified a 4–6 mm cut-off as still prognostically relevant [57, 59–61]. The current edition is realistic in the approach suggesting that the optimal cut-off to define minimal invasion requires further validation.

Intraductal Carcinoma

The entities, low-grade cribriform cystadenocarcinoma,[25] also known as “low-grade salivary duct carcinoma,” and (conventional) salivary duct carcinoma in-situ are now collectively categorized as intraductal carcinomas, low-grade and high-grade respectively. The bulk of this section focuses on low-grade intraductal carcinomas which, as a rule, are parotid tumors, and only rarely noted at other sites. They show a variety of growth patterns, both solid and cystic, ranging from cribriform to solid to micropapillary reminiscent of low-grade ductal carcinoma in situ or atypical ductal hyperplasia of the breast (Fig. 8a) [62]. Tumor cells are monomorphic and ovoid and evenly spaced with round nuclei and scant eosinophilic cytoplasm (Fig. 8b). Oncocytic and apocrine change and intermediate grade cytonuclear features are uncommon. Focal infiltration may be noted, but overall, low-grade intraductal carcinoma behaves as expected for a non-invasive tumor, with no reported recurrences. Intraductal carcinomas are delimited by a basal/myoepithelial layer, which is p63 and often muscle marker positive (Fig. 8c).

While not explicitly stated, low-grade intraductal carcinomas and high-grade intraductal carcinomas are biologically distinct. Low-grade tumors are S100 positive (Fig. 8d), and typically negative for androgen receptor [62]. High-grade intraductal carcinomas, have the same phenotype as salivary duct carcinomas,[63] and have well developed apocrine features (Fig.8e, f) and are androgen receptor positive and S100 negative. There appears to be very little overlap between these phenotypes. Additionally, high-grade intraductal carcinoma should be diagnosed cautiously and on resections, thorough sampling must be performed to exclude an invasive component. Here, the stakes are potentially higher if invasion (i.e., salivary duct carcinoma) is noted.

Conflict of interest

The authors have no financial or other conflicts of interest to report.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.