Abstract
Salivary gland hybrid tumour, first described in 1996, is a very rare neoplasm for which exact morphological criteria have not been universally agreed upon. In contrast, the concept of high-grade transformation (HGT) in salivary neoplasms has been widely accepted during the last decade, and the number of reported cases is rapidly increasing. A review of the literature revealed 38 cases of hybrid tumour reported in 22 publications. During approximately the same time period, well over 100 cases of HGT in salivary neoplasms have been reported. There are important histological similarities between hybrid tumours and salivary tumours with HGT. In the latter, containing one tumour component of low-grade malignancy and the other of high grade, the two tumour components are not entirely separated and appear to originate in the same area. Virtually, all cases reported as hybrid tumour had no clear lines of demarcation between the two tumour types. We are inclined to suggest that most of the 38 cases of hybrid tumours described in the literature would today better be called tumour with HGT rather than hybrid tumour. The relative proportion of the two components may vary, and the high-grade component is sometimes very small, which emphasises the importance of very generous sampling of the surgical specimen. The molecular genetic mechanisms responsible for HGT, including what used to be called hybrid tumour, remain largely unknown. Abnormalities of a few genes (including p53, C-MYC, cyclin D1, HER-2/neu) have been documented. As insufficient data exist on gene abnormalities in these lesions, conclusions as to whether or not they have a common origin and which mechanisms are involved in transformation cannot be drawn. Due to the small number of cases reported, many of which lack follow-up details; indicators of prognosis of hybrid tumours are not available, but their behaviour seems to be similar to that of tumours with HGT, i.e. an accelerated aggressive course. HGT of salivary gland neoplasms greatly influences macroscopic and microscopic evaluation of the specimen but also, given the high incidence of metastases and morbidity, carries significant treatment implications.
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Introduction
The so-called salivary hybrid tumour, or hybrid carcinoma, is a very rare neoplasm and appears to have been reported in the English literature first in 1996 by Ballestin et al. [1]. The same year Seifert and Donath published their seminal paper, providing a detailed description of five cases. They defined hybrid tumour as “a neoplasm composed of two separate different tumour entities, each one of which conforms to an exactly defined tumour category, arising within the same topographical area. Both tumour entities are not separated but have an identical origin in the same topographical area” [2]. The exact criteria for a hybrid tumour/carcinoma have not been universally agreed upon and with the growing awareness of high-grade transformation; the validity of the term hybrid tumour might be questioned.
Two decades have passed since the observation of Seifert and Donath, but only some 33 further cases of hybrid tumour have been reported. During approximately the same period of time, the concept of high-grade transformation in salivary gland neoplasms became widely accepted, and the number of reported cases is rapidly increasing. Previous personal observations [3, 4] and increasing awareness of high-grade transformation in salivary gland cancers [5] prompted us to critically review published cases of hybrid tumour/carcinoma and compare them with salivary tumours with high-grade transformation. The concept of high-grade transformation (previously also called dedifferentiation) in neoplasms was introduced in 1971 when Dahlin and Beabout described a low-grade chondrosarcoma associated with a high-grade sarcoma [6]. High-grade transformation in salivary neoplasms most commonly creates a poorly differentiated adenocarcinoma or undifferentiated carcinoma (hence the older term dedifferentiation). Dedifferentiation is defined as the abrupt transformation of low-grade (LG) well-differentiated carcinoma into high-grade (HG) morphology, lacking the original distinct histological and immunohistochemical features [7]. The LG and HG areas may be clearly demarcated, but a transitional zone is usually present. In contrast to what has been published in bone and soft tissue sarcomas, in salivary gland tumours but also lymphomas, a line of demarcation is not always obvious. Therefore, high-grade transformation (HGT) seems a more appropriate term than dedifferentiation.
The present study is a critical review of published cases of salivary gland hybrid tumours and salivary gland tumours with HGT. Although HGT in a salivary tumour was first reported already in 1988 in an acinic cell carcinoma [8], we limited inclusion of hybrid tumours to those reported after the Seifert and Donath paper, the only exception being the case reported by Ballestin et al. [1] (a case of a combined acinic cell carcinoma and mucoepidermoid carcinoma). The paucity of hybrid tumour reports, and the histological similarities with salivary gland tumours with HGT do question the validity of the term hybrid tumour. Hybrid tumour was mentioned but not included as a separate entity in the latest 2005 WHO Classification [9]. Our hypothesis is that some cases, or perhaps most, reported as hybrid tumours may have represented HGT in a pre-existing salivary neoplasm, and a change in terminology may be warranted.
Review of the literature
We found 22 publications together describing 38 cases of hybrid tumour [1, 2, 10–28]. Almost 70 % of reported cases were located in the parotid gland. Three cases were located in submandibular glands, one in a sublingual gland, five in the palate, two in the maxillary sinus, and one each in the upper lip, larynx, and lacrimal gland. A review of the literature of salivary neoplasms published as HGT so far revealed more than 100 cases, i.e. HGT in acinic cell carcinoma (ACC) [8, 29–34], adenoid cystic carcinoma (AdCC) [35–53], epithelial-myoepithelial carcinoma (EMC) [54–58], polymorphous low-grade adenocarcinoma (PLGA) [59–61], mucoepidermoid carcinoma (MEC) [62], myoepithelial carcinoma (MC) [63, 64], hyalinising clear cell carcinoma (HCCC) [65, 66] and mammary analogue secretory carcinoma (MASC) [67, 68].
Hybrid salivary gland tumour
Some clinicopathological features of the 38 cases of the so-called hybrid tumour are summarised in Table 1. Seifert and Donath retrieved and described five very rare tumours from the Salivary Gland Registry in Hamburg, at that time containing more than 6600 tumours, and outlined their definition and proposed the term hybrid tumour. All tumours were described as a single tumour mass, four were circumscribed and one even encapsulated and the tumour components were not separated from each other [2].
One of the cases in the original study by Seifert and Donath showed a combination of EMC and AdCC. Another nine cases with the same combination of EMC and AdCC have been reported subsequently [10, 12, 16, 18, 19, 21, 23, 27, 28]. Hence, in approximately 25 % of reported hybrid tumours, the two tumour components were EMC and AdCC. In another 11 cases, AdCC was mixed with another tumour component [2, 3, 11–13, 15, 17, 18, 24, 25]. AdCC therefore constituted one of the malignant components in more than 50 % of the 38 cases. SDC was the second most common carcinoma component and was found in 16 cases (44 %) [2, 11–13, 15, 17, 22, 24, 26] (Table 1). In one case, four malignant components were described (PLGA, ACC, AdCC and SDC) [15] and in another case in a single parotid tumour, three types of carcinoma, EMC, basal cell adenocarcinoma (BCAC) and AdCC [27]. Myoepithelial carcinoma (MC), ACC and mucoepidermoid carcinoma (MEC) have both been described in two cases, whilst squamous cell carcinoma (SCC), adenocarcinoma NOS (ANOS) and lymphoepithelial carcinoma (LEC) have occurred once only. Of the 38 cases, 24 (>60 %) were located in the parotid gland and five in the palate. The submandibular gland was the third most common site with three reported cases. There was male/female ratio of 1.6/1, and the age span was 26 to 81 years with a mean of 56 years (Table 1). The text and/or illustrations provided in the different publications rather convincingly showed all tumour components to be located within one single tumour mass without any clear separation or lines of demarcation between the different components. These descriptions of the growth pattern are compatible with HGT of one of the components. Woo et al. [19] reported a tumour that might have represented two malignancies arising as a carcinoma ex pleomorphic adenoma. The patient had an operation in the same area (right nasal cavity/maxillary sinus; tumour diagnosed as a pleomorphic adenoma), 2 years before the tumour described in the paper. The surgical specimen showed a carcinoma composed of EMC with an AdCC component, and the illustrations are compatible with the two components being intermingled. Development of carcinoma ex pleomorphic adenoma cannot totally be excluded in this case, although 2 years is a rather short period of time for such development, and the report does not mention any remnants of pleomorphic adenoma [19]. We are inclined to regard also this case as HGT of an EMC into AdCC.
High-grade transformation in salivary gland neoplasms
We were able to retrieve from the literature more than 100 cases of different salivary tumour with HGT. Histologically, salivary gland tumour HGT is characterised by a residual component of a conventional salivary gland tumour entity and another distinct more anaplastic cell population, often a poorly differentiated adenocarcinoma, or another tumour entity of higher degree of malignancy (e.g. epithelial-myoepithelial carcinoma transformed to foci of salivary duct carcinoma). The two (or more) components are intermingled (as seen in hybrid tumours), but smaller additional separate foci can be present. There is often an altered immunohistochemical marker profile as well as a considerably higher Ki-67 labelling index in the higher grade component. Mitoses are frequent and necrosis often extensive [7].
The first case of HGT in acinic cell carcinoma was described in 1988, and since then, more than 40 cases of ACC-HGT have been reported [8, 29–34]. In most cases, the high-grade component was a poorly differentiated adenocarcinoma (Fig. 1).
HGT in adenoid cystic carcinoma (AdCC-HGT) was first described in 1999 by Cheuk and associates who described three cases [35]. Since then, another 41 cases were published, and all were recently presented in great detail in multi-author review. Most of the 44 cases involved a submandibular gland, paranasal sinus or palate [69]. Also, in cases with AdCC-HGT, the HG component was usually a poorly differentiated adenocarcinoma with large pleomorphic cells, high mitotic rate and necrosis (Fig. 2).
HGT of polymorphous low-grade adenocarcinoma (PLGA) was first described in 1995, but only a few cases have been reported since [59–61]. More than 20 cases of HGT in epithelial-myoepitelial carcinoma (EMC) have been reported since 1999 [5, 54–58]. HGT was also reported in low-grade mucoepidermoid carcinoma (MEC) [62, 64], myoepithelial carcinoma (MC) [63], hyalinising clear cell carcinoma [65, 66] and mammary analogue secretory carcinoma (MASC) [67, 68] (Fig. 3).
Discussion
The diagnosis of hybrid tumour or HGT in a salivary gland tumour is almost always reached only after examination of the postoperative surgical specimen, which has been meticulous and often of the entire specimen is included for histological examination. Hybrid tumours as defined by Seifert and Donath [2] differ from biphasically differentiated salivary neoplasms (e.g. epithelial-myoepithelial carcinoma and adenoid cystic carcinoma), collision tumours (the meeting of two neoplasms arising at independent topographical sites; usually a carcinoma and a sarcoma and/or lymphoma, e.g. observed in multiple sites such as cardia, cervix and urinary bladder) and synchronous and multiple (often recurrent) salivary gland tumours and to a certain extent, carcinomas with metaplastic changes. Rare cases of primary salivary tumours with metastatic localization of extra-salivary primaries exist, e.g. pleomorphic adenoma in a parotid next to metastasis from renal carcinoma, but such cases are beyond the scope of this review.
HGT in AdCC may occur first in recurrent AdCC [35]. There should be a clear distinction between a solid type of AdCC and AdCC-HGT, and to this end, histological criteria were outlined by Seethala et al. [43]. Most reports indicate that the prognosis for AdCC-HGT is even worse than for a solid type of conventional AdCC [43, 5, 69, 70], and therefore, HGT recognition is important for management of the individual patient. The cells in the solid type of AdCC have small hyperchromatic nuclei and a basaloid appearance, whilst the cells in AdCC-HGT have larger and more pleomorphic vesicular nuclei. Moreover, the cells in a solid type AdCC express some of the myoepithelial immunohistochemical markers. The HG component, which usually is either a poorly differentiated adenocarcinoma or, less commonly, an undifferentiated carcinoma, shows cells with large pleomorphic nuclei and a high mitotic rate. The nuclei contain vesicular chromatin with conspicuous nucleoli. Necrosis (also comedonecrosis) is common as is desmoplastic stroma and tumour calcification. Squamous areas and micropapillary growth are unique patterns seen exclusively in AdCC-HGT as compared to conventional AdCC [43]. There are suggestions that AdCC-HGT has a high propensity for lymph node metastasis, which have been reported in up to 57 % of patients compared to 5–25 % of patients with conventional AdCC [43]. The risk for tumour extension into lymph nodes in AdCC-HGT is distinctly higher than in conventional AdCC, as lymph nodes in conventional AdCC are often involved by direct extension from the primary tumour rather than by metastasis. In the study of AdCC-HGT by Seethala et al. in all cases with cervical lymph node metastases, these were not single but multiple and all with extracapsular spread [43]. HGT in salivary tumours of low-grade malignancy, such as acinic cell carcinoma (ACC), is associated with a higher propensity for local recurrence and lymph node metastasis along with worse prognosis. While ACC has the best prognosis of all salivary malignancies (10-year survival of almost 90 %), in patients with ACC-HGT, the mean survival has been reported as short as 4.3 years [31, 34, 71]. A recent review of the head and neck AdCC-HGT concluded that its clinical course is progressive with a high propensity for lymph node metastasis, drastically different from that of conventional AdCC. The study concludes that elective neck dissection in patients with AdCC-HGT is mandatory [69].
In some cases, particularly in cases of EMC and basal cell adenoma, the possibility of multidirectional differentiation, mediated through intercalated duct hyperplasia, has been suggested [72–75]. We tend to consider in such cases multidirectional differentiation also as a form of HGT. Grenko et al. [76] described three AdCCs and two EMCs and discussed criteria for hybrid tumours. They showed in AdCCs regions of clear cell change of basal/myoepithelial cells and prominent ductal structures mimicking EMC. Conversely, EMCs had AdCC-like regions. The authors concluded that AdCC-like regions in EMC and EMC-like regions in AdCC should be regarded as anomalous differentiation but not as hybrid tumour. They further suggested that the only two tumour types that might be included in the hybrid tumour category to be adenosquamous carcinoma and carcinosarcoma [76]. It is noteworthy that in 10 of the 38 cases of hybrid tumour described in the literature, the two tumour components were EMC and AdCC (Table 1). Further support for a common differentiation pathway, i.e. HGT, comes from a case report of a salivary gland type hybrid carcinoma arising within a Bartholin’s gland adenoma, in which the tumours consisted of an EMC and an AdCC [77]. In this context, one should bear in mind that occurrence of areas of EMC within an AdCC is not extremely unusual, as is MC associated with EMC (these tumour entities share a common origin). In our optinion, cases with these two carcinoma components that have been called hybrid tumour should possibly regarded as HGT carcinomas.
One argument that has been used in favour of the term hybrid tumours/carcinomas has been the consistent presence of a transitional feature between the two, suggesting that the two components have an identical origin [2, 11, 17]. This feature can also be found in HGT of salivary gland neoplasms. In the 36 so-called hybrid tumours (Table 1) with at least one malignant component, AdCC was the high-grade component in 21 cases (58 %). Salivary duct carcinoma was the high-grade component in 16 (45 %) of these 36 cases. The latter finding makes it tempting to draw parallels with the development of carcinoma in situ ex pleomorphic adenoma and carcinoma ex pleomorphic adenoma, where SDC is one of the more common malignant components [78, 79].
The molecular genetic mechanisms responsible for the development of hybrid tumours and for HGTs remain largely unknown. Very few genomic studies have been performed on hybrid tumours. The nine cases of hybrid tumour studied by Nagao et al. [40] reported diffusely positive p53 immunoreactivity in four cases, restricted to the more aggressive component. Molecular analysis showed that of the p53-positive cases, three had loss of heterozygosity at a p53 microsatellite locus and one TP53 gene point mutation, only in the p53-immunoreactive carcinoma component. The authors suggest that such molecular-genetic events might induce the transformation from histologically lower to higher grade tumour during the development of a hybrid carcinoma [40]. We tend to interpret this statement as “hybrid tumours are examples of HGT.” In cases of HGT of salivary gland neoplasm abnormalities, a few genes have been documented, for example TP53 gene mutation and C-MYC amplification [38, 46, 64, 70]. Cyclin D1 overexpression, as well as p53 abnormalities in combination with HER-2/neu overexpression or loss of pRb expression, has been implicated in HGT of AdCC [35, 38, 40]. Some studies have implicated C-MYC amplification but also oncogenes on chromosome 17q23 in HGT of AdCC, and these warrant further investigation [70, 80]. One study of AdCC-HGT reported that MYB/NFIB translocation is not necessarily an early event in or fundamental for HGT in AdCC [47]. Skálová et al. [67] recently reported the HG component of MASC to have strong immunostaining for EGFR, Beta-catenin, S-100 and cyclin D1, whereas HER-2/neu was absent. Analysis of TP53 and CTNNB1 gene mutations in the HG component of MASCs as well as detection of copy number aberration of EGFR and CCND1 gene did not harbour any abnormalities. However, both high- and low-grade components of MASC contained the ETV6-NTRK3 fusion transcript. Overall, only TP53 alterations have been shown in both hybrid tumours and HGT, and this is insufficient evidence to firmly conclude that hybrid tumours in fact represent HGT.
Our review of hybrid tumours and HGT in salivary tumours emphatically demonstrates the importance of very generous sampling of the surgical specimens and meticulous microscopic examination, as the HG component may represent as little as 5–10 % or even less of the tumour. Ideally, the entire surgical specimen should be examined. Virtually, all cases reported as hybrid tumours had no clear lines of demarcation between the different tumour types. We contend that most, if not all (apart from the two cases with two benign tumour entities—see Table 1) of the 38 cases of hybrid tumour described in the literature, would today probably better be called tumours with HGT. We suggest that the term hybrid tumour is reserved for those rare occasions, as originally proposed, of two benign tumours (or also perhaps as suggested by Grenko et al. [76], adenosquamous carcinoma and carcinosarcoma) arising in the same topographical area and are not separated from each other (which is not the same as a collision tumour). The concept of HGT in salivary gland tumours has important consequences for macroscopic and microscopic evaluation of a specimen, but also carries significant treatment implications given the high incidence of metastases [81].
We conclude that salivary hybrid tumours and salivary gland neoplasms with HGT share many morphological and clinical similarities and conclude that hybrid tumours do exist and that the concept is valid, but also that most cases published so far are not true hybrid tumours but salivary neoplasms with HGT. Careful examination including generous sampling of the surgical specimen is essential, as missing the high-grade component has important implications for treatment and prognosis. Further, molecular genetic studies are necessary to unambiguously determine whether or not salivary hybrid tumours and salivary gland neoplasms with HGT are distinct entities or biologically identical.
References
Ballestin C, Lopez-Carreira M, Lopez JI (1996) Combined acinic cell mucoepidermoid carcinoma of the parotid gland. Report of a case with immunohistochemical study. APMIS 104:99–102
Seifert G, Donath K (1996) Hybrid tumours of salivary glands. Definition and classification of five rare cases. Eur J Cancer B Oral Oncol 32B:251–259
Murphy JGP, Lonsdale R, Premachandra D, Hellquist HB (2006) Salivary hybrid tumour: adenoid cystic carcinoma and basal cell adenocarcinoma. Virchows Arch 448:236–238
Hellquist H, Skalova A (2014) Hybrid tumour in: histopathology of the salivary glands. Springer, Heidelberg, New York, Dordrecht, London, pp. 415–418
Costa AF, Altemani A, Hermsen M (2011) Current concepts of dedifferentiation/high-grade transformation in salivary gland tumors. Patolog Res Int. doi:10.4061/2011/325965
Dahlin DC, Beabout JW (1971) Dedifferentiation of low-grade chondrosarcomas. Cancer 28:461–466
Nagao T (2013) “Dedifferentiation” and high-grade transformation in salivary gland carcinomas. Head Neck Pathol 7(Suppl 1):S37–S47
Stanley RJ, Weiland LH, Olsen KD, Pearson BW (1988) Dedifferentiated acinic cell (acinous) carcinoma of the parotid gland. Otolaryngol Head Neck Surg 98:155–161
Barnes EL, Eveson JW, Reichart P, Sidransky D (eds.) Pathology & genetics of head and neck tumours. World Health Organization Classification of Tumours, IARC Press, Lyon, 2005.
Seifert G, Simpson R (1997) Pitfalls in salivary gland pathology: hybrid epithelial-myoepithelial carcinoma and adenoid cystic carcinoma (abstract 067). Pathol Res Pract 193:342
Kamio N, Tanaka Y, Mukai M, Ikeda E, Kuramochi S, Fujii M, Hosoda Y (1997) A hybrid carcinoma: adenoid cystic carcinoma and salivary duct carcinoma of the salivary gland. An immunohistochemical study. Virchows Arch 430:495–500
Croitoru CM, Suarez PA, Luna MA (1999) Hybrid carcinomas of salivary glands. Report of 4 cases and review of the literature. Arch Pathol Lab Med 123:698–702
Snyder ML, Paulino AF (1999) Hybrid carcinoma of the salivary gland: salivary duct adenocarcinoma and adenoid cystic carcinoma. Histopathology 35:380–383
Chetty R, Medley P, Essa A (2000) Hybrid carcinomas of salivary glands. Arch Pathol Lab Med 124:494–496
Zardawi IM (2000) Hybrid carcinoma of the salivary gland. Histopathology 37:283–284
Hayashi K, Shimamoto F, Takata T, Yasui W (2001) Epithelial-myoepithelial carcinoma of the parotid gland with adenoid cystic carcinoma-like features: a case report with immunohistochemical study. Hiroshima J Med Sci 50:101–104
Nagao T, Sugano I, Ishida Y, Asoh A, Munakata S, Yamazaki K, et al. (2002) Hybrid carcinomas of the salivary glands: report of nine cases with clinicopathologic, immunohistochemical, and p53 gene alteration analysis. Mod Pathol 15:724–733
Ruiz-Godoy LM, Mosqueda-Taylor A, Suarez-Roa L, Poitevin A, Bandala-Sanchez E, Memeses-Garcia A (2003) Hybrid tumours of the salivary glands. A report of two cases involving the palate and a review of the literature. Eur Arch Otorhinolaryngol 260:312–315
Woo JS, Kwon SY, Jung KY, Kim I (2004) A hybrid carcinoma of epithelial-myoepithelial carcinoma and adenoid cystic carcinoma in maxillary sinus. J Korean Med Sci 19:462–465
Piana S, Damiani S, Asioli S, Magrini E, Barberi W, Cavazza A (2004) Epstein-Barr positive lymphoepithelial carcinoma and epi-myopeithelial cell carcinoma of the parotid gland: a hitherto unreported example of hybrid tumour. Virchows Arch 445:425–428
Mosqueda-Taylor A, Cano-Valdéz AM, Ruiz-González JD, Ortega-Gutiérrez C, Luna-Ortiz K (2010) Hybrid salivary gland tumor of the upper lip or just an adenoid cystic carcinoma? Case report. Med Oral Patol Oral Cir Bucal 15:e43–e47
Kainuma K, Oshima A, Suzuki H, Fukushima M, Shimojo H, Usami S (2010) Hybrid carcinoma of the parotid gland: report of a case (epithelial-myoepithelial carcinoma and salivary duct carcinoma) and review of the literature. Acta Otolaryngol 130:185–189
Falbo V, Floridia G, Censi F, Marra M, Foschini MP, Taruscio D (2011) Three cases of rare salivary gland tumours: a molecular study of TP53, CDKN2A/ARF, RAS, BRAF, PTEN, MAPK2 and EGFR genes. Oncol Rep 26:3–11
Eichhorn W, Precht C, Wehrmann M, Hickmann E, Eichhorn M, Zeuch J, Löning T, Friedrich RE, Heiland M, Hoffmann J (2013) First description of a hybrid tumor of the sublingual gland. Anticancer Res 33:4567–4571
Karasmanis I, Goudakos JK, Vital I, Zarampoukas T, Vital V, Markou K (2013) Hybrid carcinoma of the larynx: a case report (adenoid cystic and adenocarcinoma) and review of the literature. Case Rep Otolaryngol. doi:10.1155/2013/385405
Atay G, Cabbarzade C, Gedikoglu G, Hosal AS (2014) Hybrid carcinoma of the parotid gland: ductal carcinoma and myoepithelial carcinoma. Kulak Burun Bogaz Ihtis Derg 24:46–49 [Turkish with English Abstract]
Sabri A, Bawab I, Khalifeh I, Alam E (2015) Hybrid tumor of the parotid gland: a case report and review of the literature. Case Rep Otolaryngol. doi:10.1155/2015/192453
Tran TAN, Jennings T, Carlson JA (2015) Dedifferentiated salivary hybrid carcinoma of the maxillary sinus with Pagetoid spread to the overlying lining mucosa. Head Neck Pathol 9:293–299
Henley JD, Geary WA, Jackson CL, Wu CD, Gnepp DR (1997) Dedifferentiated acinic cell carcinoma of the parotid gland: a distinct rarely described entity. Hum Pathol 28:869–873
Di Palma S, Corletto V, Lavarino C, Birindelli S, Pilotti S (1999) Unilateral aneuploid dedifferentiated acinic cell carcinoma associated with bilateral low grade diploid acinic cell carcinoma of the parotid gland. Virchows Arch 434:361–365
Skálová A, Sima R, Vanecek T, Muller S, Korabecna M, Nemcova J, Elmberger G, Leivo I, Passador-Santos F, Walter J, Rousarova M, Jedlickova K, Curik R, Geierova M, Michal M (2009) Acinic cell carcinoma with high-grade transformation: a report of 9 cases with immunohistochemical study and analysis of TP53 and HER-2/neu genes. Am J Surg Pathol 33:1137–1145
Ilayaraja V, Prasad H, Anuthama K, Sruthi R (2014) Acinic cell carcinoma of minor salivary gland showing features of high-grade transformation. J Oral Maxillofac Pathol 18:97–101
Thompson LD, Aslam MN, Stall JN, Udager AM, Chiosea S, McHugh JB (2015) Clinicopathologic and immunophenotypic characterization of 25 cases of acinic cell carcinoma with high-grade transformation. Head Neck Pathol 10:152–160
Chintakuntlawar AV, Shon W, Erickson-Johnson M, Bilodeau E, Jenkins SM, Davidson JA, Keeney MG, Rivera M, Price DL, Moore EJ, Olsen KD, Kasperbauer JL, Foote RL, Price KA, Garcia JJ (2016) High-grade transformation of acinic cell carcinoma: an inadequately treated entity? Oral Surg Oral Med Oral Pathol Oral Radiol 121:542–549
Cheuk W, Chan JKC, Ngan RKC (1999) Dedifferentiation in adenoid cystic carcinoma of salivary gland. An uncommon complication associated with an accelerated clinical course. Am J Surg Pathol 23:465–472
Moles MA, Avila IR, Archila AR (1999) Dedifferentiation occurring in adenoid cystic carcinoma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88:177–180
Terasaki M, Tokutomi T, Maruiwa H, Sugita Y, Harada H, Shigemori M (2000) High-grade adenoid cystic carcinoma originating from the lacrimal gland. Brain Tumor Pathol 17:159–163
Chau Y, Hongyo T, Aozasa K, Chan JK (2001) Dedifferentiation of adenoid cystic carcinoma: report of a case implicating p53 gene mutation. Hum Pathol 32:1403–1407
Ide F, Mishima K, Saito I (2003) Small foci of high-grade carcinoma cells in adenoid cystic carcinoma represent an incipient phase of dedifferentiation. Histopathology 43:604–606
Nagao T, Gaffey TA, Serizawa H, Sugano I, Ishida Y, Yamazaki K, Tokashiki R, Yoshida T, Minato H, Kay PA, Lewis JE (2003) Dedifferentiated adenoid cystic carcinoma: a clinicopathologic study of 6 cases. Mod Pathol 16:1265–1272
Brackrock S, Krüll A, Röser K, Schwarz R, Riethdorf L, Alberti W (2005) Neutron therapy, prognostic factors and dedifferentiation of adenoid cystic carcinomas (ACC) of salivary glands. Anticancer Res 25:1321–1326
Sato K, Ueda Y, Sakurai A, Ishikawa Y, Kaji S, Nojima T, Katsuda S (2006) Adenoid cystic carcinoma of the maxillary sinus with gradual histologic transformation to high-grade adenocarcinoma: a comparative report with dedifferentiated carcinoma. Virchows Arch 448:204–208
Seethala RR, Hunt JL, Baloch ZW, Livolsi VA, Barnes EL (2007) Adenoid cystic carcinoma with high-grade transformation: a report of 11 cases and a review of the literature. Am J Surg Pathol 31:1683–1694
Handra-Luca A, Planchard D, Fouret P (2009) Docetaxel-cisplatin-radiotherapy in adenoid cystic carcinoma with high-grade transformation. Oral Oncol 45:e208–e209
Malhotra KP, Agrawal V, Pandey R (2009) High grade transformation in adenoid cystic carcinoma of the parotid: report of a case with cytologic, histologic and immunohistochemical study. Head Neck Pathol 3:310–314
Bonfitto VL, Demasi AP, Costa AF, Bonfitto JF, Araujo VC, Altemani A (2010) High-grade transformation of adenoid cystic carcinomas: a study of the expression of GLUT1 glucose transporter and of mitochondrial antigen. J Clin Pathol 63:615–619
Costa AF, Altemani A, Vékony H, Bloemena E, Fresno F, Suárez C, et al. (2011) Genetic profile of adenoid cystic carcinomas (ACC) with high grade transformation versus solid type. Cell Oncol 34:369–379
Panarelli JF, Zoumalan CI, Mukkamala K, Maher EA, Iacob C, Della Rocca DA (2011) Dedifferentiated adenoid cystic carcinoma of the lacrimal gland. Ophthal Plast Reconstr Surg 27:e119–e121
Boland JM, McPhail ED, García JJ, Lewis JE, Schembri-Wismayer DJ (2012) Detection of human papilloma virus and p16 expression in high-grade adenoid cystic carcinoma of the head and neck. Mod Pathol 25:529–236
Argyris PP, Pambuccian SE, Cayci Z, Singh C, Tosios KI, Koutlas IG (2013) Lacrimal gland adenoid cystic carcinoma with high-grade transformation to myoepithelial carcinoma: report of a case and review of the literature. Head Neck Pathol 7:85–92
Bayle RM, D’Mello S, Makaria S, Hosthor SS (2013) Dedifferentiation in adenoid cystic carcinoma. J Oral Maxillofac Pathol 17:474–477
Ly CK, Cheng HM, Vermeulen T (2013) High grade transformation in a case of adenoid cystic carcinoma associated with Epstein-Barr virus expression. Pathology 45:693–695
Sayar H, Sarioȗğlu S, Bakaris S, Yildirim I, Öztarakçi H (2013) High-grade transformation of adenoid cystic carcinoma delineated with a fibrous rim: a case report. Balkan Med J 30:333–336
Alos L, Carrillo R, Ramos J, Baez JM, Mallofre C, Fernandez PL, Cardesa A (1999) High-grade carcinoma component in epithelial-myoepithelial carcinoma of salivary glands clinicopathological, immunohistochemical and flow-cytometric study of three cases. Virchows Arch 434:291–299
Seethala RR, Barnes EL, Hunt JL (2007) Epithelial-myoepithelial carcinoma: a review of the clinicopathologic spectrum and immunophenotypic characteristics in 61 tumors of the salivary glands and upper aerodigestive tract. Am J Surg Pathol 31:44–57
Kusafuka K, Takizawa Y, Ueno T, Ishiki H, Asano R, Kamijo T, Iida Y, Ebihara M, Ota Y, Onitsuka T, Kameya T (2008) Dedifferentiated epithelial-myoepithelial carcinoma of the parotid gland: a rare case report of immunohistochemical analysis and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 106:85–91
Roy P, Bullock MJ, Perez-Ordoñez B, Dardick I, Weinreb I (2010) Epithelial-myoepithelial carcinoma with high grade transformation. Am J Surg Pathol 34:1258–1265
Aydin S, Taskin U, Ozdamar K, Yücebas K, Sar M, Oktay MF, Tetikkurt ÜS (2014) Case study of a parotid gland adenocarcinoma dedifferentiated from epithelial-myoepithelial carcinoma. Case Rep Otolaryngol. doi:10.1155/2014/629054
Lloreta J, Serrano S, Corominas JM, Ferrés-Padró E (1995) Polymorphous low-grade adenocarcinoma arising in the nasal cavities with an associated undifferentiated carcinoma. Ultrastruct Pathol 19:365–370
Pelkey TJ, Mills SE (1999) Histologic transformation of polymorphous low-grade adenocarcinoma of salivary gland. Am J Clin Pathol 111:785–791
Simpson RH, Pereira EM, Ribeiro AC, Abdulkadir A, Reis-Filho JS (2002) Polymorphous low-grade adenocarcinoma of the salivary glands with transformation to high-grade carcinoma. Histopathology 41:250–259
Nagao T, Gaffey TA, Kay PA, Unni KK, Nascimento AG, Sebo TJ, et al. (2003) Dedifferentiation in low-grade mucoepidermoid carcinoma of the parotid gland. Hum Pathol 34:1068–1072
Ogawa I, Nishida T, Miyauchi M, Sato S, Takata T (2003) Dedifferentiated malignant myoepithelioma of the parotid gland. Pathol Int 53:704–709
Subramaniam MM, Ng SB, Seah SB, Anuar D, Soong R, Lee VK (2009) Molecular characterization of dedifferentiated mucoepidermoid carcinoma of the trachea using laser microdissection-based PT53 mutation analysis. Histopathology 55:4722–4475
O'Regan E, Shandilya M, Gnepp DR, Timon C, Toner M (2004) Hyalinizing clear cell carcinoma of salivary gland: an aggressive variant. Ral Oncol 40:348–350
Jin R, Craddock KJ, Irish JC, Perez-Ordonez B, Weinreb I (2012) Recurrent hyalinizing clear cell carcinoma of the base of tongue with high-grade transformation and EWSR1 gene rearrangement by FISH. Head Neck Pathol 6:389–394
Skalova A, Vanecek T, Majewska H, Laco J, Grossmann P, Simpson RHW, et al. (2014) Mammary analogue secretory carcinoma of salivary glands with high grade transformation: report of three cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR and CCND1 genes. Am J Surg Pathol 38:23–33
Luo W, Lindley SW, Lindley PH, Krempl GA, Seethala RR, Fung K-M (2014) Mammary analog secretary carcinoma of salivary gland with high-grade histology arising in hard palate, report of a case and review of the literature. Int J Clin Exp Pathol 7:9008–9022
Hellquist H, Skálová A, Barnes L, Cardesa A, Thompson LDR, Triantafyllou A, et al. (2016) Cervical lymph node metastasis in high-grade transformation of head and neck adenoid cystic carcinoma: a collective international review. Adv Ther 33:357–368
Seethala RR, Cieply K, Barnes EL, Dacic S (2011) Progressive genetic alterations of adenoid cystic carcinoma with high-grade transformation. Arch Pathol Lab Med 135:123–130
Hellquist H, Skalova A (2014) Acinic cell carcinoma in: histopathology of the salivary glands. Springer, Heidelberg, New York, Dordrecht, London, pp. 261–281
Di Palma S (1994) Epithelial-myoepithelial carcinoma with co-existing multifocal intercalated duct hyperplasia of the parotid gland. Histopathology 25:494–496
Chetty R (2000) Intercalated duct hyperplasia: possible relationship to epithelial-myoepithelial carcinoma and hybrid tumours of salivary gland. Histopathology 37:260–263
Weinreb I, Seethala RR, Hunt JL, Chetty R, Dardick I, Perez-Ordoñez B (2009) Intercalated duct lesions of salivary gland: a morphologic spectrum from hyperplasia to adenoma. Am J Surg Pathol 33:1322–1329
Naunheim MR, Lin HW, Faquin WC, Lin DT (2012) Intercalated duct lesion of the parotid. Head Neck Pathol 6:373–337
Grenko RT, Abendroth CS, Davis AT, Levin RJ, Dardick I (1998) Hybrid tumors of salivary gland tumors sharing common differentiation pathways? Reexamining adenoid cystic and epithelial-myoepithelial carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 86:188–195
Padmanabhan V, Cooper K (2000) Concomitant adenoma and hybrid carcinoma of salivary gland type arsing in Bartholin’s gland. Int J Gynecol Pathol 19:377–380
Hellquist H, Skalova A (2014) Carcinoma ex pleomorphic adenoma in: histopathology of the salivary glands. Springer, Heidelberg, New York, Dordrecht, London, pp. 283–296
Petersson F (2015) High-grade transformation (“dedifferentiation”) – malignant progression of salivary gland neoplasms, including carcinoma ex pleomorphic adenoma. Pathology Case Reviews 20:27–37
Costa AF, Altemani A, García-Inclán C, Fresno F, Suárez C, Llorente JL, Hermsen M (2014) Analysis of MYB oncogene in transformed adenoid cystic carcinomas reveals distinct pathways of tumor progression. Lab Investig 94:692–702
Gupta R, Balasubramanian D, Clark JR (2015) Salivary gland lesions: recent advances and evolving concepts. Oral Surg Oral Med Oral Pathol Oral Radiol 119:661–674
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Hellquist, H., Skalova, A. & Azadeh, B. Salivary gland hybrid tumour revisited: could they represent high-grade transformation in a low-grade neoplasm?. Virchows Arch 469, 643–650 (2016). https://doi.org/10.1007/s00428-016-2018-6
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DOI: https://doi.org/10.1007/s00428-016-2018-6