Salivary acinic cell carcinoma: reappraisal and update
Epidemiologic and clinicopathologic features, therapeutic strategies, and prognosis for acinic cell carcinoma of the major and minor salivary glands are critically reviewed. We explore histopathologic, histochemical, electron microscopic and immunohistochemical aspects and discuss histologic grading, histogenesis, animal models, and genetic events. In the context of possible diagnostic difficulties, the relationship to mammary analog secretory carcinoma is probed and a classification is suggested. Areas of controversy or uncertainty, which may benefit from further investigations, are also highlighted.
KeywordsAcinic cell carcinoma Pathology Salivary glands Therapy Prognosis Mammary analog secretory carcinoma
The International Head and Neck Scientific Group regarded that a series of articles revisiting the major epithelial salivary malignancies in the light of contemporary knowledge would be of interest. In this respect, an article on adenoid cystic carcinoma  as well as on mucoepidermoid carcinoma has recently been published  and is now followed by the present article on acinic cell carcinoma (AcCC). This was deemed appropriate as both mucoepidermoid carcinoma and AcCC are characterized by innate acinar differentiation and an often favorable prognosis [2, 3], features interesting enough to result in intensive study and accumulating literature. The structure of the present article and the principles of our approach are similar to those of the previous [1, 2]. We review salivary gland AcCC, critically appraising the recent literature and integrating recent findings into the existing knowledge base, predicated on extensive clinical experience, epidemiological, clinicopathological, imaging and genomic aspects that determine our management decisions and consequent prognosis.
Definition and brief historical survey
The World Health Organization (WHO) currently defines salivary AcCC as “a malignant epithelial neoplasm of salivary glands in which at least some of the neoplastic cells demonstrate serous acinar cell differentiation, which is characterized by cytoplasmic zymogen secretory granules. Salivary ductal cells are also a component of this neoplasm” . Commitment to the characterisation of the secretory granules as zymogen and interpretation of the cells lacking obvious secretory granules as ductal cells may be criticized. The definition is, however, useful because it emphasizes the presence of a structural component other than serous-like acinar cells.
Godwin et al.  traced the earliest cases back to the 1890s, Nasse  being generally regarded as having described the first case in 1892 as a ‘blue dot tumor’, because of the appearance of what we now know are intracytoplasmic zymogen granules. It is likely that the serous cell phenotypes and apparent circumscription of the tumor accounted for the description of serous cell or acinar adenomas in the earlier literature . Buxton et al.  probably described the first cases of AcCC with a straightforward malignant behavior. Foote and Frazell  are usually credited with the “modern” morphological descriptions of the tumor, but it was oral pathologists who subsequently took the lead. Their efforts culminated in 1965 when a group led by Abrams published a detailed clinicopathologic study of 77 cases of AcCC of major salivary glands from the archives of the Armed Forces Institute of Pathology (AFIP), which defined particular growth patterns and tumor-cell types . In the 1970s, the publication of the World Health Organization (WHO) histological classification of salivary gland tumors  and also the seminal volume by Thackray and Lucas  spearheaded the now discarded term “acinic cell tumor” (with the suggestion to only use the term “carcinoma” if the tumor “happens to metastasize”) and general pathologists with a special interest in head and neck entered the field [12, 13, 14]. Oral pathologists responded by defining clinicopathologic features of AcCC in minor salivary glands [15, 16], revisiting the AFIP archives of 294 cases  and aptly presenting the experience in the AFIP atlas . The accumulating clinicopathologic experience together with investigative approaches using modalities such as electron microscopy, histochemistry, and immunohistochemistry substantially increased our understanding of AcCC. There seemed little wishing for and AcCC did not feature in reviews of advances in salivary pathology [19, 20]. However, the notion of AcCCs entirely composed of non-descript cells lacking secretory granules, illustrative per se of the inherent difficulties in precisely characterizing cells of simple phenotypes, should warrant a certain apprehension. This proved well founded in 2010 when the so-called mammary analog secretory carcinoma (MASC), a low-grade salivary malignancy that is histologically similar to AcCC of non-serous acinar cells and harbors the ETV6–NTRK3 translocation, was reported . Subsequently Bishop et al.  re-classified most non-parotid AcCC of non-serous cells as MASCs. Whether MASC is a distinct entity remains to be established, which is discussed below (see “Proposed classification”), but is a concept that should be considered when the earlier literature is reviewed.
Whereas most clinicians still associate AcCC to a good prognosis, recent studies increase our awareness of the propensity of this tumor for lymphatic invasion and distant metastases, developing in a protracted and unpredictable clinical course. Indeed, (late) distant metastases to the lungs, pleura, brain, peritoneum, paraaortic, paratracheal, and mediastinal lymph nodes, as well as cutaneous metastases, have been described, especially in the de-differentiated subgroup of AcCC, nowadays commonly referred to as “acinic cell carcinoma with high-grade transformation” [13, 23, 24, 25].
Unfortunately, the highly desirable population-based studies provide little information beyond incidence and survival [26, 27, 28]. Institution-based studies are more detailed, but report limited number (up to 35) of cases collected over a long period and treated without standardized protocols, which makes statistical evaluation difficult [29, 30, 31, 32].
In western countries, salivary gland carcinomas (SGCs) account for about 4 % of all head and neck cancers, approximately 80 % occurring in the parotid . About one out of six parotid cancers is AcCC , which is supported by a nationwide study in Netherlands, where 15 % of parotid malignancies were AcCC . A recent surveillance, epidemiology, and end results (SEER) analysis from 1973 to 2009 indicated that AcCC comprises 11 % of all salivary gland malignancies, with an average annual incidence of 0.13 cases per 100,000 patients per year during the 36 years the study encompassed . Incidence trend analysis, stratified for gender and race, indicated a significant annual increase (annual percentage change of 1.06 %) . Rather than being genuine, this trend is attributable to improved and increasingly widely known histopathologic diagnostic criteria. The SEER analysis also indicated a higher average annual incidence for females (0.15 cases per 100,000 patients) in comparison to males (0.11 cases per 100,000 patients). This correlates with a consistent slight female predominance in institutional [35, 36] and population-based series. The latter report female:male incidence ratios ranging from 1.43:1 to 1.57:1 [27, 28, 37].
The age distribution of AcCC seems quite even throughout all decades, with one-third of patients below the age of 40, one-third between 40 and 59, and one-third above 60 years . This corresponds to the findings in a series from the MD Anderson Cancer Center (MDACC) . With a median age at diagnosis of 52 years, AcCC tends to occur at a younger age than other SGCs . Children are very rarely affected by SGCs, but when they are, the most frequently observed histologic type is mucoepidermoid carcinoma, followed by AcCC [38, 39].
AcCC is predominantly diagnosed in whites (85 %) and less frequently in blacks (7 %) or other racial backgrounds (8 %) [28, 32]. Very little is known regarding risk factors for AcCC. Although familial predisposition and previous radiation exposure have been considered, no cases were noted among long-term atomic bomb survivors  and descriptions of familial occurrence are very sparse . One case has been reported in an individual with Cowden syndrome , and there is a recent case report of AcCC of the breast developing in a BRAC1 mutation carrier .
In the major salivary glands, the parotid is most commonly affected, the typical clinical presentation being a slow-growing swelling. Symptoms are often lacking, which often results in late diagnosis. Pain or fixation to surrounding tissues herald poor prognosis . Nodal metastasis is extremely uncommon at presentation. In the MDACC series mentioned above, only 12 of 155 patients (8 %) had nodal disease, even when 75 % presented with persistent or recurrent AcCC . In another series from the Memorial Sloan Kettering Cancer Center (MSKCC), three out of 35 patients (9 %) presented with nodal disease; also uncommon in this series were pain (n = 5; 13 %) and cranial nerve VII dysfunction (n = 1; 3 %) .
AcCC is far less common in minor salivary glands. A population-based report identified 736 cases of parotid AcCC (91 %) compared to only 42 cases (5 %) in other major and 35 cases (4 %) in minor salivary glands . In addition, AcCC of minor salivary glands accounts for about 9 % in a SEER database . The trend is also a feature of institutional series  and in case reports [45, 46]. Whether this relates to a generally decreased proportion of serous acinar cells in normal minor salivary glands, is unknown. In contrast to other types of minor SGCs, which mainly occur in the palate,  AcCC mainly occurs in the buccal mucosa and upper lip . A small minority of AcCC arises in the sinonasal area [44, 48] or the larynx , but these are outside the scope of the present article.
Bilateral AcCC is highly controversial. While some urge caution or are unconvinced,  others suggest that AcCC is the most frequently reported bilateral SGC [51, 52]. For completeness, non-salivary AcCC have been described in the lacrimal gland, pancreas, and breast. The tumors in the pancreas are referred to as acinar cell carcinoma [43, 53].
Surgery is the first and most important step in the management, if technically feasible and if there are no medical contraindications. Pre-operative assessment of AcCC is similar to that of other tumors of the major salivary glands and involves imaging and needling procedures. Since AcCC often presents as a swelling, with little to suggest malignancy, pre-operative assessment aims at assessing localization, extent, indicators of malignancy, as in the case of parotid AcCC, these factors will determine the risk to the facial nerve during surgery . Imaging can be omitted without detriment to further management in mobile, circumscribed tumors where localization and extent are clinically obvious. It is strongly recommended when a glandular swelling is associated with impaired mobility or when involvement of deeper structures/cranial nerves is suspected [55, 56, 57, 58]. For AcCC, impaired mobility is typically seen in larger tumors or, more frequently, in local recurrences.
A recent study comparing US and CT indicated that most primary AcCCs show ‘benign’ imaging features reconcilable with the often favorable prognosis of the tumor. On US, AcCC appeared lobular, rather defined, hypoechoic, heterogeneous and poorly vascularized (Fig. 1); on CT, it appeared regular and variably defined with limited heterogeneous enhancement . The study supported the earlier findings of Suh et al. , who described CT qualities of AcCC in relation to histopathologic features.
MRI is superior to CT in assessing parotid, stylomastoid foramen and any facial nerve invasion/perineural extension (Fig. 2) [56, 57, 61, 62]. It is particularly indicated for patients with recurrent or residual AcCC and favored in tertiary centers where these patients are usually referred. As an example, 75 % of patients treated in MDACC had residual or recurrent disease; for these patients a meaningful statement on the feasibility of further treatment without an adequate was judged impossible without MRI .
PET with or without CT should be considered in clinically/radiologically suspected or needling-procedure proven, advanced stage, salivary malignancies, to exclude gross, distant disease. This is a very uncommon situation in AcCC . PET may be, however, recommended post-operatively when a histologic diagnosis of AcCC with high-grade transformation is established [63, 64, 65].
This remains the gold standard for the diagnosis of AcCC.
Structural organization of AcCC
Cell arrangements (solid, microcystic, cystic, follicular, papillary, mixed)
Cell phenotypes (serous, non-serous)
Tumors of minor salivary glands are centered in the submucosa where they are partly surrounded by salivary lobules; they may involve main ducts (Fig. 5a). Similar to mucoepidermoid carcinoma , ‘flooding’ of the lamina propria is unusual. Parotid AcCCs are often superficially located—hence, partly surrounded by glandular lobes (Fig. 5b, c).
Figure 5 also allows appreciation of various silhouettes of AcCC. Tumors irregularly penetrating salivary lobules, soft tissues or bone, ‘satellites’ invading far ahead of the main growth, perineurial invasion and necrosis are not frequent.
Morphological differences between solid, serous AcCC and normal parotid tissue
Serous cell phenotype
Hematoxyphilia of secretory granules
PAS, amylase reactivities of secretory granules
Arrangement of serous cells
Acini, trabeculae, sheets
Both serous and non-serous cells may show characteristic cytoplasmic ‘vacuoles’ that probably reflect cytoplasmic lumina (see “Histochemistry and electron microscopy” section (Figs. 6a, 7) and are diagnostically useful. They may coalesce in AcCCS composed of non-serous cells, which results in true lumina and microcystic areas eventually.
Histologic features of prognostic significance and grading
In contrast with adenoid cystic carcinoma and mucoepidermoid carcinoma, the WHO has not suggested a histologic grading system for AcCC . Features mentioned above would be useful in constructing such a system. Recently, a ‘proliferative grading system’ for AcCC has been suggested, which distinguishes high- and low-grade tumors based on the presence of an increased mitotic rate (>2 mitoses/10 HPFs), necrosis and presence of pleomorphic cells in combination with extracapsular extension and positive resection margins. Using this system, the authors classified 35 % of AcCC as high-grade . Histologic grading is of significance since high-grade AcCC seems associated with advanced stage disease, higher incidence of distant metastasis and poorer outcome [27, 32, 71, 78]. A population-based study analyzed the prognostic effect of histological grade of AcCC and reported that patients with low-, moderate or high-grade tumors showed a 20-year survival of 98, 83, and 38 %, respectively . Grading would also be useful for individualizing treatment; high-grade tumors would opt for high intensity management. While additional radiotherapy may be considered for high-grade tumors, patients with low-grade tumors would be spared from the morbidity of such intensified treatment .
Histochemistry and electron microscopy
Immunohistochemistry and related modalities
The literature is extensive and as in mucoepidermoid carcinoma, the WHO refrains from attempting a meaningful review [2, 3]. The present article is not intended as a conventional review of the immunohistochemistry of AcCC and the following brief discussion is based on references selected in view of the various arguments.
Studies concerned with comparing expression of various secretory components between AcCC and normal salivary glands, reported variable amylase, lactoferrin, secretory piece and proline-rich protein immunoreactivities in the tumor, whereas lysozyme is rarely expressed . Notably, despite histologic similarities between normal serous acini and serous-like tumor cells, amylase is not regularly expressed in AcCC.
The results of immunohistochemically assessing cytoskeleton/cytoplasmic filaments correspond with the patterns of tumor differentiation (see “Histogenesis and animal models”). Cytokeratin (CK) ‘cocktails’ are gradually superseded by staining for individual CKs. The basic CK7 and acid CK19, which are of low molecular weight and reflect simple glandular phenotypes, are often expressed in AcCCs of intercalated duct-like cells in microcystic, cystic, follicular or papillary architectural arrangements; based on CK7 staining and analogous to CK7 expression in normal salivary gland epithelia, three distinct histogenetic subtypes of AcCC are recognized: acinar differentiation as seen in blue dot tumors (CK7-negative), ductal differentiation as seen in papillary-cystic tumors (diffuse CK7-positive) and mixed ductulo-acinar (10–66 % CK7-positive cells) differentiation . Staining for CK7 is not seen in solid AcCCs of serous-like cells . AcCC (both low- and HG components) stain with the same intensity using pankeratin antibodies AE1/AE3 and CK18. Cytokeratins CK5/6, CK7, and CK19 are expressed in low-grade AcCC, but not in HG components. CK14 and CK20 are absent in AcCC . Abundant secretory granules in the latter may, however, effect attenuation/displacement of the cytoskeleton and affect detection of immunoreactivities. Myofilament-associated smooth muscle actin or calponin immunoreactivities have not been reported in AcCC , which accords with the results of TPL-histochemistry and inconspicuous EMT in AcCC [75, 79]. Vimentin also seems absent .
Novel markers have recently reinforced the particular patterns of differentiation in AcCC. The chloride channel DOG1 (Anoctamin-1, described in gastrointestinal stromal tumors—GIST1), selectively expressed in the luminal plasmalemma of serous acinar and intercalated ductal cells and the transcriptional activator SOX10 expressed in nuclei of those cells, are variously immunolocalized in AcCC [91, 92]. Positive DOG1 staining can be an admixture of apical membranous, cytoplasmic, and complete membranous staining, and would support AcCC versus many differential diagnoses. This differential diagnosis includes MASC, but biphasic tumors like, e.g. adenoid cystic carcinoma and epithelial-myoepithelial carcinoma can also express DOG1, although to a lesser degree and lower intensity than AcCC [91, 93].
Controversy surrounds the expression of plasmalemma-anchored, epithelial membrane antigen (MUC1) in AcCC. While Gusterson et al.  did not record any immunoreactivity, later studies reported regular staining . Of other plasmalemmal molecules, AcCC shows variable membranous staining for CD44 and integrin αvβ3 .
It is generally regarded that S-100 protein is not expressed in AcCC . The significance of this rather unpretentious feature is now increasingly appreciated (see “Differential diagnosis” and “Proposed classification”).
Immunohistochemistry confirmed aberrant neuroendocrine differentiation in few AcCCs [87, 99, 100, 101, 102]. This may result in a paraneoplastic syndrome , but is probably a pathological curiosity.
Except for the S-100 protein immunoreactivities, the above features seem largely academic. The following molecular biological aspects can, however, be useful in grading and prognosis.
Molecules associated with the cell cycle are firstly considered. We have already commented on the significance of the Ki67 index (see “Histologic features of prognostic significance and grading”). The Ki-67 index, an independent prognosticator for all SGCs [76, 104, 105], is markedly increased (Ki-67 index up to 60 %) in AcCC with high-grade transformation, where high expression of cyclin D1 is also seen . In contrast with the Ki-67 index, argyrophilic nucleolar organizer region-associated proteins (AgNORs) have not been found of prognostic value in AcCC . Apoptosis assessed by immunohistochemistry for bcl-2 protein and TUNEL, seems more pronounced in Stage I AcCC and overexpression of p53 (nuclear staining >10 %) is low . Recently, the mammalian target of rapamycin (mTOR), significant in the homonymous signaling pathway that regulates cell cycle and promotes proliferation, has been variously immunolocalized in AcCC [108, 109].
Growth factor receptors are now considered. A study using a tissue microarray reported epidermal growth factor receptor (EGFR, HER-1) immunoreactivity in 30 out of 168 AcCCs (17.9 %), which varied from weak to strong , whereas a conventional immunohistochemical study reported weak staining in three out of 6 tumors . Overexpression of epidermal growth factor receptor 2 (HER-2/neu, ErbB-2) is less common (one out of 170, 0.59 %) . In situ hybridization, however, suggests that HER-2/neu is overexpressed at the mRNA level in AcCC . In an in vitro situation, targeting overexpressed Her-2 with Gefitinib has resulted in cytostasis in one AcCC derived cell line .
Of proteins involved in DNA damage repair, p53 protein is usually not detected in LG components, but strongly expressed (>50 %) in the HG areas of AcCC. P63, a p 53 homologue, has recently been proposed to differentiate AcCC (no expression) from MEC (nearly always positive) . The MEC-specific CRTC1–MAML2 gene fusion is another useful biomarker that distinguishes MEC from AcCC .
Little is known about expression of sex hormone receptors in AcCC, which precludes from assessing any therapeutic/prognostic correlations. An institutional study reported immunoreactivity for androgen receptors in two out of ten tumors .
Cytophotometry and flow cytometry
In contrast with mucoepidermoid carcinoma [2, 117], cytophotometry quantified DNA does not correlate with the clinical course of AcCC [117, 118]. In addition, prognosis seems similar for tumors with diploid or aneuploid DNA assessed by flow cytometry [106, 119].
We have already alluded to potential problems (see “Histology”). Diagnosis of solid AcCC with largely serous-like cells would not pose significant problems for the aware general pathologist with adequate exposure to salivary pathology while in training. AcCC of non-serous cell in various architectural arrangements is completely the opposite. Even novices in oral/head and neck pathology would experience difficulties and frustration. Detection of cytoplasmic vacuoles would almost be diagnostic for the experienced specialist and other clues (e.g., hemosiderin pigmentation) would be helpful. Standard references offer appropriate advice on the traditional differential diagnosis of AcCC from the perspective of trainees/non-specialists [18, 69] and we further comment on particular aspects. Largely unicystic, AcCC with stromal lymphoid aggregates may be misinterpreted as lymphoepithelial cyst on casual inspection [60, 67], but any invasive growth in the ‘wall’ of the cystic structure and/or intraluminal papillations should be alerting. Difficulties in distinguishing follicular and/or papillary AcCC from salivary metastases of thyroid carcinomas may have been overemphasized; such metastases are rare; when in doubt the characteristic nuclear features of papillary thyroid carcinomas (overlapping, ‘empty’ appearance, grooves, pseudoinclusions) should be sought and immunohistochemistry (thyroglobulin etc.) may not be even necessary. In our opinion, unduly attention has been paid to the role of immunohistochemistry for p63 and CK5/6 in differentiating AcCC from salivary oncocytoma;  recognition of oncocytic features is rather straightforward on hematoxylin and eosin stained sections of good quality and solid AcCCs of non-serous, eosinophilic cells are rare. Occasionally, however, there are difficulties in distinguishing microcystic and follicular AcCC from mucoepidermoid carcinoma with inconspicuous mucous/squamoid cells as both tumors may appear variously cystic/papillary with simple, eosinophilic cells and stromal, lymphoid aggregates. In this case, immunohistochemistry for p63 is recommended, as staining would be present in intermediate/non-descript cells of mucoepidermoid carcinoma and usually absent from AcCC [114, 121].
Currently, the greatest diagnostic challenge is differentiating AcCC from MASC. As MASC is histologically similar to microcystic/papillary AcCC of non-serous cells, [21, 22, 122, 123, 124, 125, 126, 127, 128] distinction usually relies on special techniques. It has been reported that MASC cells lack PAS-positive secretory granules [122, 126], but this is a matter of dispute. In addition, pathologists trained in the present era, where diagnostic immunohistochemistry and molecular testing reign, may have difficulties in interpreting conventional mucosubstance histochemistry. Immunohistochemistry seems more helpful as staining for vimentin, S-100 protein, proteins related to secretory mechanisms (STAT5a and mammaglobin) and adipophilin (a component of milk lipid globule membranes) is usually positive in MASC, though negative in AcCC [21, 123, 127, 129]. Immunostaining should always be interpreted in conjunction with routine histology as S-100 protein and mammaglobin immunoreactivities are features of other SGCs [130, 131]. In addition, nuclear staining for the transcription factor GATA3 is another feature associated with MASC, but not with conventional AcCC . Caution should also be exerted as regards staining with adipophilin  and cross-immunoreactivity with lipid-rich residues of lysosomal events/phagy (see “Histochemistry and electron microscopy” and “Immunohistochemistry and related modalities”) should be considered. A definite diagnosis of MASC can only be established via demonstration of the chromosomal t(12;15) (p13;q25) translocation, which results in fusion between the ETV6 gene on chromosome 12 (a transcription regulator) and the NTRK3 gene on chromosome 15 (a membrane receptor kinase influencing cell proliferation and survival) . This genetic re-arrangement, usually demonstrated by means of ETV6 fluorescence in situ hybridization (FISH) [124, 127, 128], is not found in other SGCs [21, 133, 134, 135]. Chiosea et al.  detected ETV6 translocation in so-called ‘zymogen granule poor AcCCs’, but they subsequently re-classified them as MASC.
It should be appreciated that FISH and antibodies for mammaglobin or DOG1 may not be available to all pathology laboratories. We therefore recommend that all salivary tumors with a histologic appearance of non-serous, microcystic/papillary AcCC are routinely immunostained for S-100 protein. If staining is negative, a diagnosis of AcCC should be established; if staining is positive and in the absence of more specific tests, the pathologist should raise the possibility of MASC and explain the situation in his/her report. The nuances in distinction may be academic to clinicians as both conventional AcCC and MASC share a similar outcome .
Histogenesis and animal models
Although proliferative capacity lies with all types of salivary glandular cells , the origin of AcCC has been traditionally sought among purported, ‘semipluripotential reserve’ or ‘stem’ cells located at the acinar-intercalated ductal region of salivary glands; proliferation and abnormal cytodifferentiation of those cells would result in AcCC [7, 23, 136, 137]. Chaudhry et al.  attributed ‘pluripotential reserve/stem’ qualities to simple tumor cells with a high nuclear:cytoplasmic ratio and few organelles. Overall interpretations of electron microscopical observations [82, 84] and the immunohistochemical localization of DOG1 and SOX10 in AcCC [92, 94], as discussed above, suggest that the histogenesis of AcCC simulates events at the ends of branching rudiments during salivary embryogenesis. In this regard, we may envisage the histology of AcCC (see above) as a continuum. At one end would be AcCC of simple duct-like cells (intercalated duct-like or incompletely differentiated acinar) in microcystic or other architectural arrangements, whereas at the other end would be solid AcCC of differentiated serous-like cells; AcCC of varying proportions of duct-/serous-like cells possibly occupies a middle position and myoepithelial differentiation is not prominent. Interestingly, the acinar differentiation seems functional as in vitro tumor cells secrete amylase when stimulated by adrenalin [48, 138, 139]. The features in S1 can be reconciled with this histogenetic model; AcCC may spread to involve main ducts and acini emptying into proximal extralobular ducts have been described in mammalian salivary glands .
Little is known about naturally occurring, animal models for the study of human salivary tumors. However, 70 % of male transgenic (MMTV/v-Ha-ras) mice develop tumors in their parotids, which show electron microscopic features and immunohistochemical expression of amylase similar to those of AcCC . The model is of interest, but has not enjoyed widespread endorsement and further application. Of greater clinical potential appears the deletion of both the Adenomatous Polyposis Coli (APC) and Phosphatase and tensin homologue (PTEN) tumor suppressor genes in mice, which results in activation of the mTOR pathway and formation of salivary gland tumors resembling human AcCC with 100 % penetrance; treatment with the rapamycin inhibited mTOR and led to complete regression of tumors, which indicates dependence of growth on sustained signaling . The results allow pondering whether treatment with mTOR inhibitors may benefit AcCC patients, given immunohistochemical confirmation of activated mTOR signaling in human AcCC [108, 109].
The genetic landscape of AcCC is insufficiently explored. In the Mitelman database of Chromosome Aberrations and Gene Fusions in Cancer there are only 11 cases with cytogenetic alterations published (http://cgap.nci.nih.gov/Chromosomes/Mitelman). Early investigations showed alterations, often loss of heterozygosity, in 84 % out of 25 AcCCs frequently altered regions being on 4p and 17p, followed by 5q and 6p . The only recurrent changes observed are extra copies of chromosome 8 and deletions or translocations with breakpoints in 6q13-q24. Terminal 6q-deletions are a typical feature of all major subtypes of SGCs . A single AcCC showed deletions in the tumor suppressor CDKN2A and proapoptotic cofactor of p53-encoding PPP1R13B; and mutations in the cell growth regulator EP300 . Given the possible significance of the PTEN-activated mTOR signaling pathway (see “Immunohistochemistry and related modalities” and “Histogenesis and animal models”) [108, 109, 141], the sporadic association of AcCC with the effected by germline mutations of PTEN, Cowden syndrome (see “Epidemiology”)  is of interest. The situation regarding the ETV6–NTRK3 fusion is still evolving (see “Differential diagnosis” and “Proposed classification”).
The acinic-intercalated ductal carcinoma family
Solid acinic cell carcinoma of serous-like cells (‘Serous cell adenocarcinoma’)
Carcinomas of various proportions of acinic and intercalated duct-like cells
Carcinomas of intercalated duct-like cells in microcystic, papillary, follicular, cystic and mixed architectural arrangements
S-100 protein (–) → consider immunohistochemistry for DOG1
S-100 protein (+)/MASC → consider immunohistochemistry for mammaglobin, ETV6 FISH
Surgery: the primary tumor
As AcCCs are often anatomically accessible tumors and patients do not show distant metastases at presentation, the treatment of choice would be complete resection aiming at achieving free margins, thereby avoiding post-operative morbidity [35, 54]. AcCC may be, however, initially underestimated, as indicated by the high number of redo-cases in a recent study .
Surgery alone will likely be curative for low-grade AcCC. The extent of the operation should parallel the loco-regional anatomical extent of the tumor as influenced by the site of origin. Although superficial parotidectomy often effects complete removal, more extended, conservative parotidectomy is indicated if the deep lobe is involved. A pre-operatively functioning facial nerve can be preserved without loss of oncologic control, even if there would be no margin between tumor and nerve, and any microscopic, residual disease seems treatable with post-operative radiotherapy . A more aggressive, initial approach would be required for locally advanced AcCCs, especially pre-operatively known high-grade tumors in risk of positive margins, bone/nerve invasion, and nodal metastases. A pre-operatively paralyzed or grossly invaded/surrounded facial nerve should be resected and reconstructed with an interposition graft from the greater auricular or sural nerve. Advanced cases may also require resection of skin, posterior mandible/masseter or lateral temporal bone, followed by a free flap reconstruction. In AcCC of minor salivary glands, local anatomy will dictate the best surgical approach .
Surgery: the neck
Elective ND in patients with AcCC is usually not recommended because of a relatively low incidence of regional lymph node metastasis (10 %). The MDACC study, however, observing that addition of an ND to the surgical strategy decreases the rate of regional recurrences, suggests that patients with large tumor volume or tumors with high-grade features in the pre-operative biopsy would likely benefit from elective ND of levels II, III and IV .
Clinically positive cervical lymph nodes at presentation are an adverse prognosticator necessitating therapeutic ND as part of the surgical approach and should raise suspicion of an AcCC with HG transformation.
Low grade, low stage (I and II), and adequately resected AcCCs are not considered for radiotherapy, as their prognosis is excellent with surgery alone [54, 146]. This is supported by a recent SEER analysis specifically assessing any oncologic benefits of additional radiotherapy . The study did not demonstrate an effect of post-operative radiotherapy on stage I and II, low-grade AcCC; no disease-specific deaths were recorded in 50 stage I, low-grade tumors treated with surgery alone.
Criteria for additional radiotherapy do not differ from those for other SGCs  and include salvage surgery for recurrent disease; advanced T-classification (T3/T4); positive surgical margins; pathologically positive, cervical lymph nodes; perineural invasion; and high-grade/highly proliferative tumors [28, 32, 36]. Patients with prognostically worse AcCC selected to undergo post-operative radiotherapy through application of those criteria, doubled their chance of staying disease-free when thus treated (HR of 2, p = 0.04) in multivariate analysis).
Conversely, the SEER analysis undertaken by Biron et al.  concludes that ‘radiotherapy probably is not effective in AcCC’; the study even suggests and that after multivariate correction for stage and grade, radiotherapy implied a death hazard ratio of 2. Caution should be, however, exerted as it is imprudent to retrospectively assess the value of a ‘treatment’. It is noted that the SEER analysis does not correct for involved resection margins or initially inadequate treatment, which account for a substantial part of AcCC patients  and would probably end up being radiated. Missing data in the variables corrected for, are further weakening the conclusions; for instance, although the analysis spanned from 1973 to 2009, precise TNM classification had only been obtained for patients from 2000 to 2005 . In other words, even after corrected “roughly” for stage and grade, significant selection and information bias still is likely present in the retrospective SEER data, resulting from the reality that hard-to-capture prognostic factors have usually been incorporated in a clinical decision to add radiotherapy to the treatment of early stage AcCC that worries the treating oncologist.
Little is known regarding chemotherapy in AcCC. The potential value of mTOR inhibitors has already been mentioned (see “Histogenesis and animal models”), but no specific chemotherapeutic agents have been currently approved. Nevertheless, an observed distant metastasis rate of 1 in 5 (most commonly in the lungs) indicates the need for developing such treatment .
Endorsing the outlined therapeutic strategies (see “Management”), AcCC is generally considered to have the best survival rate among SGCs, although the subgroup with high-grade transformation has a poorer prognosis ; [27, 148, 149]. AcCC is by no means an innocent tumor. Earlier studies reported that the cure rate decreased from 76 to 89 % at 5 years to 55 % at 15 years and 56 % at 20 years , similar trends being noted by others [12, 13]. The evidence suggests a protracted clinical course with recurrences occurring years or even decades after initial diagnosis and treatment (mean time to recurrence, 92 months) [32, 35, 66]. Clearly, this can be an aggressive tumor that should be treated accordingly and appropriate initial treatment would thus obviously affect prognosis. Mere enucleation is totally inadequate [12, 151] and this has been recently corroborated by multivariate analysis . The effects of selectively applied post-operative radiotherapy have been discussed above (see “Management”) [54, 146, 152]. A recent institutional study indicates a median survival of 28.5 years, with only 13 out of 155 patients (8.4 %) dying of their disease (mean time to death from disease, 3.8 years; range, 0.7–11.2 years) . Selection/referral bias obviously affects institutional results as large tertiary/referral centers a usually end with prognostically worse cases and a higher proportion of patients with either residual or recurrent disease after suboptimal initial treatment. Nevertheless, better results are now being reported. Recent population-based studies indicate overall 5-, 10-, and 20-year survival of 97, 94, and 90 %, respectively; survival dropped to 22 % in patients with distant metastasis .
Adverse prognosticators in AcCC
Univariate identification of prognostic value of factor for different outcomes
Multivariate confirmation of prognostic value of factor for different outcomes
Pain at presentation
OS (28, 35, 36, 44)
OS (28, 36, 44)
Minor salivary gland origin
OS (30, 32, 36, 71, 158)
DFS (12, 13, 36)
DSS (27, 28, 35)
DFS (13, 32)
OS (28, 36)
DFS (30, 71)
Macroscopic invasion beyond glandular capsule
DFS (13, 32)
Macroscopic invasion of VIIth nerve
Skull base invasion
Proliferative grading (32)
Increased mitoses (13, 35)
OS (28, 32, 71)
DFS (32, 35)
DSS (44, 158)
Histological extracapsular extension
OS (32, 36)
Desmoplastic stromal reaction/lymphoid stroma
DFS (30, 32)
Previous inadequate treatment
DFS (13, 35)
Additional radiotherapy (controversial findings)
DSS worse (44)
DSS better survival for high grade AcCC if additional radiotherapy (27)
DFS better (36)
DFS worse (44)
Invasion of the anterior skull base is uncommon and typically associated with the rare sinonasal AcCC. Anterior skull base invasion is infrequently seen, typically in the rarely occurring sinonasal AcCC. However, sinonasal origin as such does not seem to carry a worse prognosis, as evidenced from the 18 cases in the SEER database that were matched to major salivary gland AcCC . A general idea of the effect of UICC/AJCC stage on outcome in the largest series reported to date is that Stage I tumors carry a 93.5 % 20 years DSS, Stage II tumors a 98 % 20 years DSS, Stage III tumors and Stage IV tumors a 64 % 20 years DSS . Disease-specific deaths are not uncommon in the course of AcCC; In a recent series, 76.9 % of those were attributable to distant metastases .
Of the factors considered above, the MDACC multivariate analysis regards the following factors as influencing overall and disease-free survival in AcCC: gender, inadequate previous treatment (these patients have a significantly higher chance of succumbing to disease and a hazard Ratio of recurrence twice as high as that of advanced vs low stage disease), extent of disease (T-classification, UICC/AJCC stage), positive resection margins and age at diagnosis . With the exception of gender, these factors had already been identified and confirmed in other studies dealing with all types of SGCs [26, 155, 156]. Gender did not feature as a significant prognostic factor in the SEER analysis of Biron et al. . In the latter analysis, the factors remaining in multivariate analysis were advanced stage (HR 2), minor salivary gland subsite (HR 3) and HG (HR 3.3 for grade III and 8.1 for grade IV).
Our perception of salivary AcCC has been repeatedly modified over the 12 decades since its description. Successes include the introduction of modern imaging modalities in the assessment of patients; application of various morphological methodologies to characterize cellular phenotypes/events suggestive of distorted embryonic development; and multivariate analyses of population-based datasets/institution-based series indicative of factors influencing prognosis, management, and outcome. In addition, molecular methodologies introduced the concept of MASC and prompted further thinking and research. Uncertainties, however, remain. Links between particular genetic alterations and cellular phenotypes reflecting abnormal events at the ends of branching salivary rudiments should be explored; the role of the S-100 protein in salivary pathobiology should be clarified; and high-grade transformation and patterns of nodal metastasis should be precisely characterized. Prospects are good, but would require continuous research efforts in the hope that non-invasive therapies and gene manipulation may become available in future.
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