Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Salivary Glands

Abstract

The salivary gland section in the 5th edition of the World Health Organization Classification of Head and Neck Tumours features a description and inclusion of several new entities, including sclerosing polycystic adenoma, keratocystoma, intercalated duct adenoma, and striated duct adenoma among the benign neoplasms; and microsecretory adenocarcinoma and sclerosing microcystic adenocarcinoma as the new malignant entities. The new entry also includes mucinous adenocarcinoma subdivided into papillary, colloid, signet ring, and mixed subtypes with recurrent AKT1 E17K mutations across patterns suggesting that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity that may be related to salivary intraductal papillary mucinous neoplasm (IPMN). Importantly, the number of entities in the salivary chapter has been reduced by omitting tumors or lesions if they do not occur exclusively or predominantly in salivary glands, including hemangioma, lipoma, nodular fasciitis and hematolymphoid tumors. They are now discussed in detail elsewhere in the book. Cribriform adenocarcinoma of salivary gland origin (CASG) now represents a distinctive subtype of polymorphous adenocarcinoma (PAC). PAC is defined as a clinically, histologically and molecularly heterogeneous disease group. Whether CASG is a different diagnostic category or a variant of PAC is still controversial. Poorly differentiated carcinomas and oncocytic carcinomas are discussed in the category “Salivary carcinoma not otherwise specified (NOS) and emerging entities”. New defining genomic alterations have been characterized in many salivary gland tumors. In particular, they include gene fusions, which have shown to be tightly tumor-type specific, and thus valuable for use in diagnostically challenging cases. The recurrent molecular alterations were included in the definition of mucoepidermoid carcinoma, adenoid cystic carcinoma, secretory carcinoma, polymorphous adenocarcinoma, hyalinizing clear cell carcinoma, mucinous adenocarcinoma, and microsecretory adenocarcinoma.

Introduction

The major and minor salivary glands are associated with a remarkable diversity of neoplasms. Given the number of already existing entities which show considerable overlap of histologic and immunohistochemical features between different salivary gland neoplasms, only very well documented new entities have been accepted in this edition [1]. Reported tumors and variant morphologies lacking consensus support and validation by independent investigators have not been included. This approach resulted in the introduction of microsecretory adenocarcinoma and sclerosing microcystic adenocarcinoma as the new malignant entities; and keratocystoma, intercalated duct adenoma, and striated duct adenoma within benign neoplasms. Further, the neoplastic nature of sclerosing polycystic adenoma moved the lesion from a non-neoplastic epithelial lesion [2] into the benign neoplasm category.

Since the last edition, molecular data has become widely reported, with many salivary gland neoplasms shown to harbour tumor type-specific rearrangements (Table 1). Molecular testing of salivary gland tumors for differential diagnostic accuracy and appropriate clinical management is becoming routine [3, 4]. Molecular alterations were included in the definition of the following entities: mucoepidermoid carcinoma, adenoid cystic carcinoma, secretory carcinoma, polymorphous adenocarcinoma, hyalinizing clear cell carcinoma, mucinous adenocarcinoma, and microsecretory adenocarcinoma [1].

Table 1.

Selected genetic alterations in salivary tumors (Adapted from Andreasen, et al., ref. No. [53])

Tumor type	Chromosomal region	Gene and mechanism	Prevalence
Pleomorphic adenoma	8q12	PLAG1 fusions/amplification	> 50%
	12q13-15	HMGA2 fusions/amplification	10–20%
Basal cell adenoma	3p22.1	CTNNB1 mutations	37–80%
	16q12.1	CYLD mutations	36%
	16p13.3	AXIN1 mutations	9%
	5q22.2	APC mutations	3%
Myoepithelioma, oncocytic subtype	8q12	PLAG1 fusions	40%
Sialadenoma papilliferum	7q34	BRAF V600E mutations	50%-100%
Sclerosing polycystic adenoma	3q26.32 PIK3CA mutation high
Mucoepidermoid carcinoma	t(11;19) (q21;p13)	CRTC1-MAML2	40–90%
	t(11;15) (q21;q26)	CRTC3-MAML2	6%
	9p21.3	CDKN2A deletion	25%
Adenoid cystic carcinoma	6q22-23	MYB fusion/activation/amplification	~ 80%
	8q13	MYBL1 fusion/activation/amplification	~ 10%
	9q34.3	NOTCH mutations	14%
Acinic cell carcinoma	9q31	NR4A3 fusion/activation	86%
	19q31.1	MSANTD3 fusion/amplification	4%
Secretory carcinoma	t(12;15) (p13;q25)	ETV6-NTRK3 fusion	> 90%
	t(12;10) (p13;q11)	ETV6-RET fusion	2–5%
	t(12;7) (p13;q31)	ETV6-MET fusion	< 1%
	t(12;4) (p13;q31)	ETV6-MAML3 fusion	< 1%
	t(10;10) (p13;q11)	VIM-RET fusion	< 1%
Microsecretory adenocarcinoma	t(5q14.3) (18q11.2)	MEF2C-SS18 fusion	> 90%
Polymorphous adenocarcinoma
Classic subtype	14q12	PRKD1 mutations	73%
Cribriform subtype	14q12	PRKD1 fusions	38%
	19q13.2	PRKD2 fusions	14%
	2p22.2	PRKD3 fusions	19%
Hyalinizing clear cell carcinoma	t(12;22) (q21;q12)	EWSR1-ATF1 fusions	93%
		EWSR1-CREM fusions	< 5%
Basal cell adenocarcinoma	16q12.1	CYLD mutations	29%
Intraductal carcinoma
Intercalated duct subtype	10q11.21	RET fusions	47%
Apocrine subtype	3q26.32	PIK3CA mutations	High
	11p15.5	HRAS mutations	High
Salivary duct carcinoma	17q21.1	HER2 amplification	31%
	8p11.23	FGFR1 amplification	10%
	17p13.1	TP53 mutation	56%
	3q26.32	PIK3CA mutation	33%
	11p15.5	HRAS mutation	33%
	Xq12	AR copy gain	35%
	10q23.31	PTEN loss	38%
	9p21.3	CDKN2A loss	10%
Myoepithelial carcinoma	8q12	PLAG1 fusions	38%
	t(12, 22) (q21;q12)	EWSR1 rearrangement	13%
Epithelial-myoepithelial carcinoma	11p15.5	HRAS mutations	78%
Mucinous adenocarcinoma	14q32.33	AKT1 E17K mutations	100%
	17p13.1	TP53 mutations	88%
Sclerosing microcystic adenocarcinoma	1p36.33	CDK11B mutation	1 case
Carcinoma ex pleomorphic adenoma	8q12	PLAG1 fusions/amplification	73%
	12q13-15	HMGA2 fusions/amplification	14%
	17p13.1	TP53 mutations	60%
Sebaceous adenocarcinoma	2p21	MSH2 loss	10%

Cytological findings have been included in most sections, in recognition of the importance of fine needle aspiration (FNA) as an initial diagnostic approach, and the Milan system is recommended [5]. While FNA has emerged as an important component in the diagnostic workup of salivary gland tumors, core needle biopsies are still performed occasionally, especially after non-diagnostic aspirates. While offering more architectural information than FNAs, most core biopsies do not allow for assessment of the interface between the tumor and surrounding tissues, and thus are insufficient in distinguishing between benign tumors and low grade malignancies (i.e. myoepithelioma vs myoepithelial carcinoma). Only fully resected tumor specimens allow for diagnostic clarity in such cases.

Histologic grading of salivary gland carcinomas has been shown to be an independent predictor of behavior and plays a role in optimizing therapy. Still, most salivary gland carcinomas have an intrinsic biologic behavior, and attempts to apply universal grading schemes are not recommended [6, 7]. Carcinoma types for which validated grading systems exist include adenoid cystic carcinoma, mucoepidermoid carcinoma, and adenocarcinoma, not otherwise specified [8]. High-grade transformation (HGT) has been shown to be an important concept in tumor progression in salivary gland carcinomas [9]. Tumors demonstrating HGT show an aggressive clinical course that differs significantly from the usual behavior of a given tumor type. Therefore the phenomenon of HGT is included in the description of the appropriate entities [1].

The following controversial issues remain unresolved in the new edition of the WHO Blue Book [1]:

• Mucinous adenocarcinoma (MA) subdivided into papillary, colloid, signet ring, and mixed subtypes is characterized by recurrent AKT1 E17K mutations across the various patterns suggesting that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity [10]. Intraductal papillary mucinous neoplasm (IPMN) is an emerging entity comprising duct-centric tumors with low-grade mucinous morphology; they share with MA frequent occurrence of AKT1 mutations [11]. It is still not established whether IPMN should be classified separately or within the MA spectrum as a potential precursor [12, 13].

• Intraductal carcinoma (IC) is a salivary gland malignancy characterized by papillary, cribriform, and solid proliferations that are entirely or predominantly intraductal. Despite the name „intraductal“, frank invasive growth with loss of myoepithelial cells can be seen occasionally in IC [14, 15]. Moreover, one recent study has shown that the layer of myoepithelial cells is part of the tumor and so ICs may actually be biphasic neoplasms rather than truly in-situ neoplasms [16].

• There is no consensus whether oncocytic carcinoma exists. Oncocytic appearance is a common change encountered in many different salivary gland tumors. In the past, carcinomas consisting entirely of oncocytes were frequently diagnosed as oncocytic carcinoma. Molecular studies have now shown that many such tumors are oncocytic variants of other salivary carcinomas [17–19] and it is uncertain if any purely oncocytic carcinomas exist that are not morphologic variants of other carcinomas. For this reason, oncocytic carcinoma has been moved into the emerging entities chapter.

• Carcinosarcoma has remained as a separate entity in this edition, but it is not clear whether the sarcomatous component represents a true sarcoma or a result of an epithelial-mesenchymal transition.

New Entries Included in the 5th Edition WHO

Sclerosing Polycystic Adenoma

Sclerosing polycystic adenoma (SPA) is a rare sclerosing tumor of salivary glands with a characteristic combination of histological features, somewhat reminiscent of fibrocystic changes, sclerosing adenosis and adenosis tumor of the breast. The histologic findings in SPA include fibrosis, cystic alterations, apocrine metaplasia, and proliferations of ducts, acini composed of the cells with abundant eosinophilic cytoplasmic granules, and myoepithelial cells in variable proportions (Fig. 1A–G) [20]. Recurrent mutations in the PI3 kinase pathway, most frequently PTEN, confirm its neoplastic nature and suggest links with apocrine intraductal carcinoma (IC) and salivary duct carcinoma (SDC) [21–24].

Fig. 1.

Sclerosing polycystic adenoma (SPA). SPA is well circumscribed and encapsulated tumor composed of proliferations of ducts and acini within fibrotic stroma sometimes intermixed with foci of mature adipose tissue (Fig. 1A). The halmark of SPA is a presence acinic cells with abundant large eosinophilic cytoplasmic granules (Fig. 1B). Ductal structures are surrounded by periductal concentric layers of stromal hyalinization (Fig. 1C). SPA frequently harbors intraductal epithelial proliferations with variable degree of atypia. Low-grade atypia is composed of intercalated duct-like epithelium positive for SOX10 (Fig. 1D, E) and high-grade atypia with atypical nuclear features and complex growth pattern of micropapillary structures with luminal apocrine epithelium positive for AR (Fig. 1F, G). Invasive carcinoma arising in SPA is presented in Fig. 1H–J. Well circumscribed predominantly polycystic SPA divided from parotid gland by fibrous pseudocapsule is seen in the left upper part of the picture (Fig. 1H) while Figs. 1I andJ show invasive salivary duct carcinoma and apocrine intraductal carcinoma, respectively

Although no patient with SPA has developed metastases or died of disease, reports indicate that at least three patients had invasive carcinoma with apocrine ductal phenotype arising from SPA [23–25]. In a recent study, a unique case of a parotid gland tumor composed of SPA, apocrine IC and high grade SDC harbored an identical mutation in PI3K/Akt pathway in all tumor three components [25] (Fig. 1H-J). Taken together, recent findings not only strongly support that SPA is a neoplastic disease, but suggest a close relationship between SPA, apocrine IC and high-grade invasive SDC. In fact, SPA may represent a precursor lesion for the development of apocrine IC and occasionally even invasive SDC [25].

Keratocystoma

Keratocystoma is a benign salivary gland tumor characterized by multicystic spaces, lined by stratified squamous epithelium, containing keratotic lamellae and focal solid epithelial nests [26]. Essential diagnostic criteria include a bland stratified squamous epithelial lining without a granular layer within the multicystic structures and the presence of sharply defined solid squamous epithelial cell islands (Fig. 2). All reported tumors arose in the parotid gland. Differential diagnosis includes primary and metastatic squamous cell carcinoma, mucoepidermoid carcinoma, metaplastic Warthin tumor, and necrotizing sialometaplasia. The absence of necrosis, invasion, and cytologic atypia speaks against malignancy.

Fig. 2.

Keratocystoma. Keratocystoma is composed of multicystic spaces (Fig. 2A), lined by stratified squamous epithelium, containing keratotic lamellae (Fig. 2B). Squamous epithelium shows a parakeratotic or orthokeratotic surface, usually without a granular cell layer (Fig. 2C). (courtesy of Dr. Toshitaka Nagao)

Intercalated Duct Adenoma

Intercalated duct adenoma (IDA) is a benign proliferation of bilayered ducts with a cytological appearance and immunoprofile of normal intercalated ducts (Fig. 3A, B) [27]. IDAs are part of intercalated duct lesion (IDL) spectrum together with intercalated duct hyperplasia (IDH) [27]. Both IDHs and IDAs show proliferation of small ducts with eosinophilic to amphophilic cytoplasm and small bland nuclei. Although myoepithelial cells can be shown to be present using immunohistochemistry for myoepithelial markers, they are usually not conspicuous on routine H&E slides. The ductal cells show diffuse staining for cytokeratin 7, focal positivity for lysozyme and estrogen receptor, and diffuse staining for S100 in the majority of cases [27]. Occasional acinic cells can be seen within the lesions. The distinction of IDA from IDH was proposed to be based on the presence of a discrete, well-defined, partially or completely encapsulated tumor which does not respect the pre-existing lobular architecture of the background salivary parenchyma [27]. Although intercalated duct lesions tend to be small and are frequently found incidentally in resections of other lesions, IDAs can reach sizes that bring them to direct clinical attention. The association of IDLs with other salivary neoplasms such as epithelial-myoepithelial carcinomas, basal cell adenomas, basal cell adenocarcinomas and others, has lead some authors to propose that IDL may in fact be a precursor lesion for other neoplasms [27, 28]. This hypothesis is supported by published cases of hybrid tumors showing and IDL component next to a morphologically distinct tumour such as basal cell adenoma or epithelial-myoepithelial carcinoma [27, 28]. The main differential diagnosis of IDA is basal cell adenoma, which tends to be larger (typically over >10 mm) showing obvious bilayering, prominent spindle cell stroma, and a prominent S100 expression in the stromal spindle cells, while in the luminal cells it is weak and patchy [27].

Fig. 3.

Intercalated duct adenoma (IDA) (Fig. 3A, B) and striated duct adenoma (SDA) (Fig. 3C, D). IDA is composed of bilayered ducts with a cytological appearance and immunoprofile of normal intercalated ducts (Fig. 3A). High power image shows spindle shaped abluminal myoepithelial cell layer (Fig. 3B). SDA is composed of ducts lined by a monolayer of cells resembling normal striated ducts (Fig. 3C) and do not contain myoepithelial or basal cells. Only occasional abluminal cells are decorated by smooth muscle actin (Fig. 3D)

Striated Duct Adenoma

Striated duct adenoma is a rare benign tumor composed of ducts lined by a monolayer of cells with cytological appearance resembling normal striated ducts (Fig. 3C, D) [29]. Unlike the intercalated duct adenomas, striated duct adenomas do not contain myoepithelial or basal cells. The tumors are encapsulated and composed of closely apposed ducts with little or no stroma. Some ducts show cystic dilation up to 0.1 cm. The cells have eosinophilic cytoplasm and prominent cell membranes resembling striations seen in normal striated ducts. Immunoprofile is positive for S100, cytokeratin 7, and cytokeratin 5, and negative for smooth muscle actin. The p63 staining may show single positive cells. Occasional tumors may show nuclear grooves and intranuclear pseudoinclusions, mimicking the nuclear features of papillary thyroid carcinoma [30]. Given the oncocytic cytoplasm and the ductal architecture, the differential diagnosis of striated duct adenoma includes oncocytoma, intercalated duct adenoma, basal cell adenoma, and canalicular adenoma. Lack of bilayering, basophilic cytoplasm, and basement membrane connective tissue distinguishes striated duct adenoma from basal cell adenoma. Canalicular adenomas show a beading pattern of anastomosing cords of cells, which striated duct adenomas lack. The cells of oncocytoma show more prominent oncocytic cytoplasm while forming fewer ducts and more solid islands than striated duct adenoma. Finally, intercalated duct adenomas have basophilic cytoplasm and a myoepithelial layer on immunohistochemistry, both of which lack in striated duct adenoma. Fewer than ten cases of striated duct adenomas have been published to-date, highlighting its rarity. Lack of recognition may also contribute to its low incidence, whereby inclusion of striated duct adenoma in the 5th edition of World Health Organization Classification of Head and Neck Tumours, may inspire more pathologists to report it.

Microsecretory Adenocarcinoma

Microsecretory adenocarcinoma (MSA) is a newly identified low-grade salivary adenocarcinoma characterized by distinctive morphology and a specific MEF2C::SS18 fusion [31]. Its discovery stemmed from efforts to further subclassify the heterogeneous group of salivary carcinomas collectively termed as “adenocarcinoma, not otherwise specified” (NOS). Next generation sequencing of such adenocarcinomas showed a recurrent MEF2C::SS18 gene fusion in a subset of tumors with consistent morphologic features, including small tubules and microcysts lined by flat intercalated duct-like cells, and containing abundant basophilic luminal secretions (Fig. 4) [32]. The nuclei are uniform, oval, and lack prominent nucleoli. MSAs lack myoepithelial and basal cells placing them within the group of monophasic salivary tumors. Despite a fairly good circumscription within a myxohyaline stroma, these tumors lack a capsule and tend to show focal infiltration into surrounding tissues, leading to their classification as carcinomas. Despite this, none of the 24 cases identified to-date has shown recurrence, or locoregional or distant metastasis [31]. The SS18 gene rearrangement is so far unique among salivary gland tumors and it can be demonstrated by fluorescence in situ hybridization (FISH). The SS18 FISH is available in many laboratories, since the same gene is rearranged in synovial sarcomas, albeit with different partners [33]. Alternative testing strategies include next generation sequencing (NGS) and polymerase chain reaction (PCR) [31]. Tumor cells show diffuse positivity for S100, SOX10, and p63, but are negative for p40, calponin, SMA, and mammaglobin [31]. Differential diagnosis includes adenoid cystic carcinoma, secretory carcinoma, polymorphous adenocarcinoma, secretory variant of myoepithelial carcinoma, and adenocarcinoma, NOS. Adenoid cystic carcinoma is a biphasic neoplasm, which can be demonstrated by immunohistochemistry for myoepithelial markers, CEA and EMA. Secretory carcinoma lacks the myxoid stroma and shows strong mammaglobin positivity. Polymorphous adenocarcinoma tends to lack the microsecretory pattern and the myxoid stroma and its cells show much more abundant cytoplasm. Myoepithelial carcinoma shows positivity for myoepithelial markers such as calponin, smooth muscle actin and p40, which are absent in MSA. Finally, all these tumors lack the MEF2C::SS18 gene fusion.

Fig. 4.

Microsecretory adenocarcinoma (MSA). MSA is small tubules and microcysts lined by flat intercalated duct-like cells, and containing abundant basophilic luminal secretions (Fig. 4A, B). Tumor cells show diffuse positivity for p63 (Fig. 4C), S100 protein (Fig. 4D) and SOX10 (Fig. 4E). Next generation sequencing of MSA shows a recurrent MEF2C::SS18 gene fusion (Fig. 4F). (courtesy of Dr. Justin Bishop)

Sclerosing Microcystic Adenocarcinoma

Sclerosing microcystic adenocarcinoma (SMA) is a rare malignancy occurring in salivary glands with characteristic morphology resembling the cutaneous microcystic adnexal carcinoma. Reports of such tumors occurring in the oral cavity and other mucosal H&N sites [34–36] led to proposals for recognition of SMA as a new type of salivary carcinoma rather than simply a microcystic adnexal carcinoma occurring in extracutaneous sites [36, 37]. The name sclerosing microcystic adenocarcinoma highlights its key morphological features, and “adnexal” was removed as adnexal structures are absent from mucosal sites where these tumors occur [37]. SMA has so far been described in minor salivary glands only, and unlike its cutaneous counterpart, the salivary tumor has a good outcome with no documented local recurrence or distant metastasis [37, 38].

SMAs consist of small infiltrative cords and nests embedded in thick fibrous or desmoplastic stroma, which tends to dominate the tumor volume. The tumor is biphasic with bland luminal cuboidal ductal cells with eosinophilic or clear cytoplasm, and flat peripheral myoepithelial cells. The nuclei are bland, round to oval, with occasional nucleoli. The ducts contain focal eosinophilic secretions. Perineural invasion is common while mitoses are rare (Fig. 5). Immunohistochemistry shows that the luminal cells are positive for cytokeratin 7 while the abluminal myoepithelial cells are positive for smooth muscle actin, S100, p63, and p40. The differential diagnosis includes squamous cell carcinoma (SCC), hyalinizing clear cell carcinoma, adenoid cystic carcinoma and myoepithelial carcinoma. Lack of keratinization, low grade cytology and biphasic architecture distinguish SMA from SCC. Hyalinizing clear cell carcinoma shares the dense connective tissue stroma and trabecular architecture, but it lacks lumina, secretions, and myoepithelial cells. Myoepithelial carcinoma is a monophasic neoplasm without the ductal component. Adenoid cystic carcinoma shares the biphasic nature and the propensity for perineural invasion; however, in typical cases the myoepithelial component dominates and is easily seen. It also tends to lack the dense connective tissue deposition. In difficult cases, molecular testing for the MYB gene rearrangement may be helpful.

Fig. 5.

Sclerosing microcystic adenocarcinoma (SMA). SMAs consist of small infiltrative cords and nests embedded in thick fibrous or desmoplastic stroma (Fig. 5A). Perineural invasion is common (Fig. 5B). (courtesy of Dr. Abbas Agaimy)

New concepts, Variant Morphologies, Controversial Issues, and Emerging Entities

Intraductal Carcinoma

In the 2017 World Health Organization Classification of Head and Neck Tumours [39], the tumor entity originally described as “low-grade salivary duct carcinoma” [40] and later called “low-grade cribriform cystadenocarcinoma” [41] was renamed as intraductal carcinoma (IC). IC is a rare low-grade salivary gland malignancy with histomorphologic features reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast. The tumor is, in typical cases, characterized by intraductal and intracystic proliferation of luminal ductal cells exhibiting solid, cribriform, and papillary patterns. Its in situ intraductal nature is demonstrated by an intact surrounding myoepithelial cell layer highlighted by antibodies to p63 protein, calponin, and/or cytokeratin 14. IC typically shows an intercalated duct phenotype demonstrating S100 protein and SOX10 positivity of luminal cells (Fig. 6A, B), while a subset of IC shows apocrine morphology supported by androgen receptor (AR) positivity (Fig. 6C, D) [42]. Most ICs harbor recurrent RET gene rearrangements. NCOA4::RET fusion has been identified in 47% of intercalated duct type ICs [14, 43], while TRIM27::RET fusion is often observed in an apocrine type or hybrid type IC [15, 43]. Recently, novel TUT1::ETV5, KIAA1217::RET [15], and STRN::ALK [44] fusions have been identified in rare cases of IC with invasive growth pattern. A recent report proposed that oncocytic ICs that harbor BRAF V600E mutations and TRIM33::RET fusion are a fourth distinct subtype of IC [45].

Fig. 6.

Intraductal carcinoma (IC). IC typically shows an intercalated duct phenotype demonstrating SOX10 positivity of luminal cells (Fig. 6A, B), while a subset of IC shows apocrine morphology supported by androgen receptor positivity (Fig. 6C, D)

It remains a controversial issue how to classify a tumor which has morphology, immunoprofile and molecular signature typical of IC, but if there is also invasive growth [14, 15]. Moreover, one recent study reported that the myoepithelial and ductal cells of IC harbor the same fusion, thus indicating that the myoepithelial cell layer is part of the tumor, and consequently ICs may be biphasic, occasionally invasive neoplasms rather than true in-situ neoplasms [16].

Polymorphous Adenocarcinoma and Cribriform Adenocarcinoma

Polymorhous adenocarcinoma (PAC), (previously known as polymorphous low-grade adenocarcinoma), is a malignant epithelial tumor characterized by cytological uniformity, morphological diversity, and an infiltrative growth pattern, and it is predominantly seen in minor salivary glands [1]. Polymorphous adenocarcinoma, cribriform subtype (cribriform adenocarcinoma of salivary glands; CASG) was initially reported at the base of the tongue [46] and later in other minor salivary gland sites [47]. CASG is characterized by a multinodular growth pattern separated by fibrous septa, relatively uniform solid, cribriform and microcystic architecture, and optically clear nuclei. Glomeruloid and papillary structures, peripheral palisading and clefting may be observed (Fig. 7). Compared with classic PAC, CASG is associated with a propensity to base of the tongue location and a higher risk of lymph node metastasis. Activating protein kinase D1 (PRKD1) gene point mutations have been identified in more than 70% of the classic variant of PACs [48, 49]. Rearrangements in PRKD1, PRKD2, or PRKD3 genes rather than point mutations have been noted in about 80% of the CASG subtype of PACs [50]. The PRKD1 E710D hotspot mutation and PRKD1/2/3 gene rearrangements are useful as an ancillary diagnostic markers to differentiate PACs from other salivary gland tumors, such as adenoid cystic carcinoma, the rare SC and canalicular adenoma [48, 51]. The classic subtype of PACs most often exhibit a PRKD1 point mutation, whereas the CASG subtype of PACs mostly exhibit PRKD1/2/3 translocations. The PRKD1 E710D hotspot mutation and the gene fusions involving the PRKD1/2/3 genes are mutually exclusive [48].

Fig. 7.

Polymorphous adenocarcinoma, cribriform subtype (CASG). CASG is characterized by a multinodular growth pattern separated by fibrous septa, with predominant glomeruloid, cribriform and microcystic architecture (Fig. 7A, B). Optically clear nuclei with resemblance to “Orphan Annie Eyes” and papillary structures (Fig. 7C) are typically observed but in contrasat to papillary thyroid cancer, the tumor cells are S100 protein positive (Fig. 7D)

Whether CASG is a different diagnostic category or a variant of PAC is still controversial, and currently PAC is defined as a histologically and molecularly heterogeneous disease group [48]. Our knowledge of the relationship between PRKD gene changes and prognosis is limited. The PRKD1 E710D hotspot mutation may be associated with good, metastasis-free survival, while the fusion-positive CASGs, however, appear to be more aggressive clinically. CASGs are usually located in the base of the tongue, and they have a high risk of nodal metastasis, and may require additional treatments (e.g., neck dissection) [52].

Mucinous Adenocarcinoma Versus Intraductal Papillary Mucinous Neoplasm (IPMN)

Mucinous adenocarcinoma (MA) is a primary salivary adenocarcinoma that displays prominent intracellular and/or extracellular mucin and lacks diagnostic features of other salivary carcinomas. A variety of patterns have been observed including papillary, signet ring, colloid, and mixed subtypes. MA occurs typically in oral minor salivary glands. Molecular profiling has shown a recurrent AKT1 E17K mutation in MA regardless of the pattern [10]. The same mutation has been reported in low grade proliferations of intraductal epithelium with mucinous component, for which a collective term “intraductal papillary mucinous neoplasm” (IPMN) has been proposed in analogy with the pancreatic duct mucinous lesions [11]. IPMN is an emerging entity whose place in the classification of salivary tumors is uncertain at this time, although a recent study showed that IPMN may be distinct from sialadenoma papilliferum, with the former harboring AKT1 E17K mutation and the latter BRAF V600E mutation [13]. Nevertheless, it is currently unknown whether IPMN is (1) a separate entity from MA, possibly related to ductal papilloma; (2) a precursor lesion to MA analogous to pancreatic IPMN, or (3) an intraductal variant of MA. Additional studies are needed to clarify these questions.

Oncocytic Neoplasms

There is no consensus on whether oncocytic carcinoma exists. Oncocytic appearance is a common change encountered in many different salivary gland tumors. In the past, carcinomas consisting entirely of oncocytes were frequently diagnosed as oncocytic carcinoma. Molecular studies have now shown that many such tumors represent oncocytic variants of other salivary carcinomas [17–19]. For this reason, oncocytic carcinoma is not classified as an independent entity, but it has been included in the category of emerging entities [1].

Conclusions

Molecular pathology of salivary tumors has seen numerous advances in recent years, and they have allowed for better classification of the previously heterogenous categories of adenocarcinoma, NOS and oncocytic carcinoma, and have led to the discovery of novel tumor types such as secretory carcinoma (mammary analogue) and microsecretory adenocarcinoma. Additional neoplastic entities will almost certainly be defined as characteristic molecular alterations are discovered in tumors with reproducible morphologies. Nevertheless, the synthesis of morphological patterns and molecular alterations driving them is rarely straightforward. In addition to the issues discussed above, questions remain concerning the classification of neoplasms with morphologies matching known types but the tumors lacking the recognized molecular alterations. Is mucoepidermoid carcinoma without MAML2 gene rearrangement still a mucoepidermoid carcinoma or a convincing mimic? Is a secretory carcinoma with an atypical VIM::RET fusion still a secretory carcinoma? As more molecular and clinical data accumulates about these tumors, such questions may be answered and the tumor classification adjusted accordingly in future editions.

Authors Contributions

Conceptualization, literature search, data analysis, writing original draft [AS, MH], review and editing [AS, IL].

Funding

This work was supported by the grant from the Finnish Cancer Society, Helsinki [Ilmo Leivo].

Data Availability

Data supporting the findings are available from the corresponding author [A.S.], upon reasonable request.

Code Availability

Not applicable.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical Approval

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Consent to Participate

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Consent for Publication

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