High-Grade Transformation and Carcinosarcoma: A Review of Two Forms of Advanced Progression in the Salivary Gland

AciCC is a LG malignant neoplasm showing serous acinar differentiation; it comprises approximately 10% of SG carcinomas with more than 90% of cases originating in the parotid gland.²⁸  The conventional AciCC shows a female to male ratio of 1.5:1 and a median age of 47–52 years.^{17,18,28–30}  HGT in AciCC, which is defined as histologic progression and eventual loss of acinic cell differentiation, has been reported to occur in 9%–16% of cases, which also shows a female to male ratio of 1.5:1 but a median age of 61–66 years.^{17–19,30–33}  AciCC presents in a major SG in about 90%–95% of cases, with about 85%–90% involving the parotid, while HGT has almost exclusively been documented only in the parotid gland.^{17,19,30,32,34}  The median tumor size is 4 cm for HGT cases and 3 cm for conventional AciCC.^{17,19,20,30,31} 

The transformed areas are distinct and usually juxtaposed to conventional areas and show poor differentiation and can range from 5%–90% of the entire tumor.¹⁹  Conventional AciCC shows a solid follicular or microcystic pattern; the HG areas are characterized by presence of an infiltrative tumor border with a mainly large solid and trabecular and occasionally cribriform and cystic growth pattern.^17,19,30,31  The cells in HG areas show moderate to severe pleomorphism and nuclear atypia and lack acinar differentiation and the classic zymogen granules on PAS-diastase staining seen in conventional AciCC. The median mitotic count in conventional AciCC is 0/10 high-power fields (hpfs) (range, 0–18) while that in HGT is 11.5/10 hpfs (range, 6–27).³¹  Necrosis may be seen in up to 3%–4% of conventional AciCC cases, compared to 70%–85% of HGT cases.^17,18,31,34  Studies have also shown that lymphovascular invasion (LVI) and perineural invasion (PNI) are seen in 15%–25% of HGT cases compared to 0%–5% of classic AciCC cases.^17,19,31,34  In a recent study by Xu et al,¹⁸  the authors proposed that HG should be defined as presence of either a mitotic index of greater than or equal to 5/10 hpfs (>4/2 mm²) or by the presence of tumor necrosis.

Nuclear NR4A3 (neuron-derived orphan receptor 1 [NOR1]) immunohistochemistry, which identifies the translocation transcript protein, is retained in the HG areas.¹  Other markers such as SRY-box transcription factor 10 (SOX10) are retained, while GIST 1 (DOG1) and cytokeratin 7 (CK7) expression may be lost.¹  The HG areas show higher median positivity for p53, cyclin D1, and Ki-67 index (median, 45%; range, 10%–90%).^17,19,33  A study also showed that HGT cases show a higher amount of tumor-infiltrating lymphocytes and a higher proportion of tumor cells and inflammatory cells expressing programmed death ligand-1 (PD-L1) compared to conventional AciCC, which can potentially be useful for treatment in advanced cases.^20,35 

Most cases of AciCC show (t[4;9][q13;q31]), leading to upregulation of nuclear receptor subfamily 4 group A member 3 (NR4A3).²⁰  HG cases in addition show a cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss-of-function mutation in about 40% of cases.²⁰  Other alterations include mutation in ataxia telangiectasia mutated (ATM) and phosphatase and tensin homolog (PTEN) genes.²⁰  These mutations are also targetable and thus offer treatment opportunities.²⁰  Additional research is needed to identify genetic alterations, specifically in HGT cases.

HGT cases behave aggressively compared to LG AciCC and present at a higher stage and show more frequent relapse and lymph node (LN) and distant metastasis. LN metastasis is seen in 35%–50% of HGT AciCC cases compared to 5%–9% of conventional AciCC.^{17–19,31,33,34}  Therefore, it has been suggested that in addition to surgical resection these patients should undergo local LN dissection and should be evaluated for adjuvant chemoradiation.^1,31  Distant metastasis is noted in 50%–70% of HGT cases compared to 0%–10% of conventional AciCC.^{19,30,31,33,34,36}  Lung and brain are the most common sites of distant metastasis. This aggressive course is seen in cases even with a small focus of HG area.^20,30,31,35  The 5-year overall survival (OS) and recurrence-free survival (RFS) for HGT cases are 43% and 25%, respectively, compared to 97% and 82% for conventional AciCC.³¹  The mean OS is about 3–4 years for HGT cases compared to more than 10 years for conventional cases.^17,19,30  The Memorial Sloan Kettering Cancer Center (MSKCC) study by Xu et al¹⁸  showed that HGT significantly predicts OS, disease-specific survival (DSS), and disease-free survival (DFS) on univariate analysis.¹⁸  When they used their proposed grading system to identify HG AciCC, they found that HG cases had a 5-year OS of 50% and that HG was an independent factor to predict adverse OS and DFS. Interestingly, HGT did not reach statistical significance, and they concluded that HG rather than HGT is a better predictor of prognosis in AciCC.

Key pearls include identifying a separate nodule with HG architectural pattern such as solid and cribriform areas with necrosis and other HG cytologic features such as atypia, pleomorphism, and mitotic count, as key to the diagnosis. The immunohistochemical expression may differ from the LG areas but usually shows a high Ki-67. In small biopsies NOR1 immunohistochemistry may be helpful. The clinical and pathologic features of conventional AciCC and HGT AciCC have been summarized in Table 1.

AdCC is a biphasic tumor and second most common malignant neoplasm of the SG that shows MYB proto-oncogene, transcription factor::nuclear factor I B (MYB::NFIB) or MYB proto-oncogene–like 1::NFIB (MYBL1::NFIB) fusions in about 60% of cases.³⁷  It is characterized by slow but progressive growth with multiple recurrences and late distant metastasis.^5,7  AdCC on microscopy shows tubular, cribriform, and solid patterns.^5,37  AdCC with greater than 30% solid areas has a more aggressive clinical course.²⁸  Spotty necrosis, increased mitotic activity, and moderate atypia can be seen in cases with solid pattern.³⁷  HGT occurs in about 12% of cases and was first described by Cheuk et al⁷  as dedifferentiated AdCC.^7,37  About 60% of HGT cases arise on a background of solid AdCC.⁵ 

Median age of presentation for HGT in AdCC is 55–60 years, which is very similar to the median age of presentation for conventional AdCC.^5,37–39  The conventional type shows a female to male ratio of 1.4–1.6:1, while the HGT cases show a more even distribution, with a female to male ratio of 1.1.^38,40,41  While 60% of conventional AdCCs present in the major SGs only 35% of the HGTs occur in them.^28,38  HGT may be seen on initial presentation or in recurrences.⁷  Microscopically, the areas of HGT are either intricately mixed with the conventional areas or seen as a separate nodules.^5,7,37,42  These areas often lose their biphasic pattern and show cribriform, solid, or irregular nested growth of poorly differentiated adenocarcinoma or undifferentiated carcinoma.^5,7,42  In contrast to the conventional cribriform pattern, which actually consists of pseudoglandular spaces with myxohyaline stroma, the cribriform pattern in AdCC-HGT is purely ductal with true lumina. Micropapillary squamoid patterns have also been noted.⁵  Presence of spindle cell sarcomatoid areas has also been reported.^7,43  Rare punctate necrosis may be occasionally seen in solid AdCC; comedonecrosis or large geographic necrosis with calcification is seen in more than 50% of HGT cases.^5,7,42  A transition from myxohyaline stroma to true desmoplasia is another hallmark of AdCC-HGT. Mitotic activity is increased, with a mean of 17/10 hpfs (range, 5–67/10 hpfs) compared to the classic areas with a mean of 3.5/10 hpfs (range, 0–11/10 hpfs).^5,42  LVI and PNI, respectively, are seen in 55% and 95% of HGT cases compared to about 10% and 80% of conventional AdCC cases.^{5,37,41,42,44}  Immunohistochemistry staining shows loss of biphasic staining pattern. Focal to diffuse staining for cytokeratin (CK), cluster of differentiation 117, and epithelial membrane antigen is seen.^5,7  The myoepithelial markers like p63, calponin, smooth muscle actin (SMA), and S100 are lost focally or completely.⁵  HG areas may show overexpression of p53 and human epidermal growth factor receptor 2 (HER2).^5,42  Ki-67 is higher in the HG areas (50%–70% compared to 5%–30% in classic areas).^5,42  The HG areas also show the MYB::NFIB translocation, but in addition the HG areas show chromosomal gains while the conventional areas show chromosomal losses.^21,45 

LN metastasis is seen in about 40%–50% of cases with HGT compared to 5%–20% of cases in classic AdCC and about 25%–30% in solid AdCC.^5,37–39,42  LN metastasis is associated with worse 5-year OS (99.2% for pN0, 83.3% for pN1, and 62.9% for pN0) and 5-year DFS (60% for pN0, 25.6% for pN1, and 6.3% for pN2).³⁹  However, the study from MSKCC showed that presence of a solid component or HGT were not significant predictors of LN status.³⁷  Distant metastasis, seen in 25%–30% of patients with conventional AdCC, was seen in 50%–70% of patients with solid AdCC and HGT.^5,37–39  Lung was the most common site of distant metastasis, followed by brain, bone, and liver.^5,7,42  The MSKCC study showed recurrence in 39% of conventional AdCC, 73% of solid AdCC, and 67% of HGT AdCC, while death was noted in 10% of conventional AdCC, 26% of solid AdCC, and 31% of HGT AdCC.³⁷  Although HGT and solid growth pattern were significantly associated with worse DSS and RFS on univariate analysis, only solid growth was significant for RFS on multivariate analysis.³⁷  Other studies have also shown solid growth is also associated with worse DSS and OS on multivariate analysis, but they did not have HGT cases in their cohort.^39,44  The 5-year OS for conventional AdCC is 75%–90% compared to 36% for AdCC with solid growth and 25%–30% for AdCC with HGT (median OS: 36 months).^5,38,44 

In summary, the HG areas show solid and sheet patterns with necrosis, increased mitotic count, and nuclear pleomorphism. Loss of biphasic pattern, which is better highlighted by immunohistochemistry, helps in identifying HGT. The clinical and pathologic features of conventional AdCC, solid AdCC, and HGT AdCC have been summarized in Table 2.

EMC is a biphasic LG malignant neoplasm possibly originating from the intercalated ducts and occasionally arising from a precursor pleomorphic adenoma or intercalated duct hyperplasia or adenoma.²²  About 70%–90% of the cases originate in the major SG, particularly in the parotid gland.^16,46  They present in the sixth to seventh decades of life with a mean age of 60–63 years and slight female preponderance (1.4:1).^16,28,46  HGT has been reported in 3%–6% of EMCs, which present at a mean age of 70–75 years and a female to male ratio of 1.6:1.^16,46–49  The average size of the tumor in HGT cases is about 6 cm and presents most commonly as a parotid mass in 75% of patients and frequently shows extraglandular extension and dermal invasion while the average tumor size is 3 cm in conventional EMC and also presents as parotid mass in 65%–80% of cases.^16,46–49  Occasionally, HGT in EMC can be seen in submandibular gland and minor SGs.^48,49 

EMC on histology is characterized by multinodular growth with a biphasic arrangement of inner ductal and outer clear myoepithelial cells, and an HGT can arise from either, but occasionally lacks differentiation (Figure 1, A and B). Cases reported in literature have sometimes also referred to it as dedifferentiation or anaplastic component in EMC.^16,28,47  The HGT cases show either a sharp transition from LG to HG areas or a gradual transition to or intermixing with anaplastic cells.^1,16  Like AdCC-HGT, HG areas in EMC-HGT often show a loss of biphasic arrangement (Figure 1, C through E). However, unlike AdCC-HGT, which almost always involves progression of the ductal phenotype, EMC can show HGT of either ductal or myoepithelial cells, and rarely both populations. The separate nodules are solid and composed of pleomorphic cells with atypia, large nucleoli, increased mitotic activity, and necrosis (Figure 1, C through E).^16,47  The HG areas arising from myoepithelial overgrowth show clear cell change, squamous differentiation, spindling, whirling, or a plasmacytoid appearance but may also lack a myoepithelial differentiation.^22,47  Transition to nonclear cells with rare gland formation and comedonecrosis is suggestive of an HG epithelial component.^22,47  Cases with sarcomatoid transformation have also been reported.⁴⁹  The mitotic activity in conventional EMC is approximately 3/10 hpfs while the HGTs show 10/10 hpfs (range, 6–40).^{9,16,47,50,51}  Focal necrosis may be noted in about 18%–20% of EMC cases but are present in more than 95% of HGT cases and frequently are the large geographic or comedo types.^16,22,47,51  The conventional EMC shows LVI in 10%–11% of cases and PNI in 20%–25% of cases.^16,51  There are no significant data regarding LVI and PNI in HGT ENC cases in literature, but such invasion has been reported in 2 cases.^48,52  The HG areas by immunohistochemistry show focal to diffuse positivity for CK and CK7.^9,47  S100, SMA, p63, and calponin are either negative or show focal reaction.^{9,47,49,50,52}  High-molecular-weight CK stains the squamoid areas if present.⁴⁷  Ki-67 (Figure 1, F) is higher (30%–70%) compared to the conventional EMC (10%–20%).^9,16,49–52  p53 overexpression may be seen, but HER2 overexpression has not been reported in HGT cases.^16,48,50 

Conventional EMC may show pleomorphic adenoma gene 1 (PLAG1) zinc finger/high-mobility group AT-hook 2 (PLAG1/HMGA2) rearrangement or HRas proto-oncogene, GTPase (HRAS) mutation depending on the precursor and have been demonstrated in cases with HGT.²²  Alterations of other genes like SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1 (SMARCB1), tumor protein p53 (TP53), and F-box and WD repeat domain containing 7 (FBXW7) have been demonstrated exclusively in HGT cases.²²  They are also unlikely to show MYB fusion.⁵³ 

Though HGT and conventional EMC both have a similar local recurrence rate of about 30%–40%, the LN and distant metastatic potential is vastly different.^16,47,51,52  LN metastasis is identified in 40%–50% of HGT cases compared to 2%–4% of conventional EMC while distant metastasis is identified in 30%–35% HGT cases and 4%–5% of conventional EMC.^{16,46–48,52}  Based on minimal available data, it appears that HGT cases have a 5-year OS of 50%–75% compared to 90%–95% for conventional EMC; median DFS is 13 months in HGT and 11.3 years for conventional cases.^{16,46–48,52}  Neck dissection and locoregional radiotherapy and chemotherapy have shown variable results.^47–49 

Key take-home points for HGT in EMC are to identify loss of the classic biphasic pattern with presence of necrosis, increased mitotic count, and atypia. Immunohistochemistry helps in highlighting the loss of biphasic architecture. The clinical and pathologic features of conventional EMC and HGT EMC have been summarized in Table 3.

HCCC is a LG malignant neoplasm that consistently shows Ewing sarcoma RNA binding protein 1::activating transcription factor 1 (EWSR1::ATF1) gene fusion and occurs predominantly in the minor SGs.^54,55  It occurs at a mean age of 55–60 years with a female to male ratio of 1.5:1 and presents as a 1–4.5-cm mass (mean, 2–2.5 cm) predominantly in the oral cavity and oropharynx (70%).^28,54–56  There are extremely rare cases of HGT in HCCC. The 4 reported cases occurred in 3 women and 1 man with an age range of 57–77 years (mean, 66 years) with a 3–4-cm (mean, 3.5-cm) tumor involving the base of tongue in 2 patients and oropharynx and submandibular gland in 1 each.^8,56–58  The classic HCCC shows clear to eosinophilic cells arranged in cords, trabeculae, or cribriform pattern surrounded by basement membrane material and hyalinized stroma. PNI is seen in 60% of cases but necrosis and mitotic activity (<1/10 hpfs) are rare.^54,55  The HG areas showed proliferation of pleomorphic and anaplastic cells with nuclear atypia and high nucleus/cytoplasm ratio. Tumor necrosis, high mitotic count, and atypical mitosis are almost always seen.^8,56–58  Unlike some of the other SG neoplasms with HGT, the HG areas in HCCC are seen intermixed with the LG areas. The immunohistochemical pattern is similar to the conventional HCCC, and the tumor cells are positive for CK7, p63, p40, and CK5/6 and are negative for S100, SMA, calponin, and SOX10. Ki-67 is higher than classic HCCC and p53 shows a wild staining pattern.^55–58 EWSR1::ATF1 gene fusion is present in HGT cases and recently a HGT case with EWSR1::LARP4 (La ribonucleoprotein 4) gene fusion was described.^56–58 

In conventional HC, LN metastasis is seen in 0%–10%, distant metastasis in 0%, and a near 100% survival with a mean follow-up of 47.6 months (range, 2–195 months).^55,56,58  HGT cases present with higher disease stage. They show LN and distant metastasis in 75% of cases and local recurrence in 66% of cases; the 2 patients with follow-up both died of disease in 10–36 months.^8,56–58 

Microsecretory adenocarcinoma is a recently described LG malignant neoplasm defined by the presence of myocyte-specific enhancer factor 2C::synovial sarcoma 18 (MEF2C::SS18) fusion and mainly originates from the minor SGs of buccal mucosa and palate.^28,59,60  They can occasionally arise in the skin.¹⁴  It equally involves both the sexes and affects the adults (mean age, 49.5 years; range, 17–83 years).

On microscopy, microsecretory adenocarcinoma presents as a circumscribed lesion with peripheral infiltrative areas and a microcystic, loose cribriform, or cordlike pattern. The cells are monotonous, flattened, or epithelioid with moderate eosinophilic to clear cytoplasm and oval hyperchromatic nuclei. Basophilic to amphophilic secretion is characteristically present and is highlighted by mucicarmine. LVI and PNI are extremely rare^59,60  They are positive for S100, SOX10, and p63 and are negative for p40, mammaglobin, and calponin. No recurrence or metastasis has been reported in these cases.²⁸  Only 2 cases of HGT have been described until now.^14,61 

HGT was reported in patients in their 70s.^14,61  The transformed areas show tubular and cribriform architecture composed of large atypical cells and nuclear pleomorphism with necrosis, increased apoptosis, and mitotic count 10/10 hpfs.^14,61  LVI, PNI, and LN metastasis have been reported in literature. The HG areas show loss of p63 and Ki-67 of about 25% compared to 2% in the LG areas.^14,61  Long-term follow up is not available currently.^14,61 

MEC is the most common salivary malignancy, involving a major SG in 60% and a minor SG in 40% of cases.⁶²  It is usually a LG carcinoma affecting all age groups with slight female predilection. Various grading systems using features like mitotic count, necrosis, cystic component, anaplasia, and PNI have been used through the years.^28,62  Depending on the system used, about 3%–20% of cases are HG MEC.⁶²  Despite HG MEC being not an uncommon entity, HGT of LG MEC has rarely been reported in the literature.^10,63,64 

The HG component described in these cases is a separate region from the LG areas with focal intermingling of cells in the transition. The HG areas are solid and sheetlike. The cells are pleomorphic with nucleoli. Clear cells with mucin may be seen but do not clearly show a glandular or squamous differentiation. Anaplastic cells and sarcomatoid areas have also been documented. Necrosis was noted in all the cases and the mitotic count varied between 5 and 50/10 hpfs.^10,63,64 

Immunohistochemistry is nonspecific and the HG components stain variably with CK and p63.^10,63,64  p53 overexpression may be seen.^63,64  Ki-67 is 50%–80% in HG areas compared to less than 5% in the LG areas.^10,63,64  HER2 or cyclin D1 overexpression has not been reported.^10,64  Lee et al⁶³  reported presence of mastermind-like transcriptional coactivator 2 (MAML2) translocation in the LG and HG areas with additional MAML2 polyploidy in HG areas. Subramaniam et al⁶⁴  reported 2 TP53 variants in the normal SG and the LG component, and additional 4 TP53 variants in the HG component.⁶⁴ 

The HGT has been reported in young and elderly patients with a median age of 55 years (range, 11–73 years) with a female to male ratio of 2:1.^10,63,64  The average tumor size is about 3 cm and has been reported to occur at sites like parotid, trachea, and palate.^10,63,64  They are known to recur locally in 66% of cases.^10,63,64  They show lymph node metastasis in 66% of cases and distant metastasis in 33% of cases.^10,63,64  The follow-up data are limited due to rarity of these cases but survival is about 3–7 months in patients who develop metastasis.^10,63,64 

MyC is an underrecognized entity and earlier studies that showed that it represented 2% of SG malignancies are likely to be conservative estimates.¹⁵  It occurs in children and adults (median age, 59 years) and affects both the sexes equally.^65,66  The parotid is the most common site followed by the palate and submandibular gland and it frequently arises in a preexisting pleomorphic adenoma.^65,66 

MyC shows varied cell types and architectural patterns with poor diagnostic criterias.^1,66  LVI and PNI can be seen in 10%–12% of cases while necrosis is seen in 24%–38% of cases. Mitotic count is usually low, less than 2/10 hpfs, but variable (0–9/10 hpfs).^15,66  There is no well-established grading system and studies have used 2-tier and 3-tier systems.^65,66  HG features include necrosis and high mitotic activity (>5/10 hpfs [2.4 mm²]).^65,66  LVI and PNI can be seen in 10%–12% of cases. They tend to show more frequent distant metastasis (3%–25%) compared to LN metastasis (8%–14%).^66,67  HG disease is an independent risk factor for survival by multivariate analysis.⁶⁷ 

To the best of our knowledge, there are 2 reported cases of an HGT in a LG MyC, 1 of which was an ex-PA.^11,68  Both the cases showed a separate HG tumor nodule adjacent to an LG area. The nodules were solid with diffuse infiltration and were composed of large pleomorphic and spindle cells.^11,68  Increased mitotic activity and atypical mitosis are identified.^11,68  The HG areas were positive for CK but negative for myoepithelial markers like S100, SMA, and GFAP. They showed a high Ki-67 proliferation index and overexpression of p53 and cyclin D1.^11,68  The case reported by Rupp et al⁶⁸  also had overexpression of HER2 but absent androgen receptor. PLAG1 and to a lesser extent HMGA2 gene fusions have been demonstrated in de novo and ex-PA MyC.^1,65 TGFBR3-PLAG1 which was thought to be seen exclusively in de novo MyC was demonstrated in MyC ex-PA with HGT.^65,68 

One of the HGT cases recurred twice in 9 months while the other patient was free of disease at 27 months.^11,68  Both the patients received adjuvant radiotherapy following surgical excision.^11,68 

PAC is a malignant neoplasm mainly arising in the minor SG.^69,70  The cases show a female to male ratio of 2:1 and are seen in adults (median, 60 years; range, 16–94 years).^28,70  Rare HGT has been documented in the literature occurring at a mean age of 55.7 years with a female to male ratio of 1.25:1.^12,71–76  Both the conventional and the HGT cases present as a 2–3-cm mass and are centered around palate and maxilla.^28,69,76,77  Eight cases of HGT have presented around hard or soft palate while 1 case was in the nasal cavity.^12,71–76  In about 50% of the cases the HG component is present in the recurrence with median time of recurrence of 17 years (range, 10–28 years).^12,71–75 

PAC has 2 subtypes, conventional and cribriform. The conventional subtype shows an infiltrative growth with various patterns including single file, trabecular, tubular, microcystic, and solid, and the cells are monomorphic, uniform, and bland.^28,70  PNI leading to a targetoid appearance is common.^69,70  The HG areas are usually a separate focus with some junctional intermixing.^71,72  They are composed of large pleomorphic cells in sheets, nests, cribriform pattern, and cords. The cells have eosinophilic to amphophilic cytoplasm with nuclear atypia, coarse chromatin, and prominent nucleoli.^{12,71–73,76}  Mitotic count is high with a mean of 17/10 hpfs (6–40/10 hpfs) compared to 1–3/10 hpfs in the conventional PAC.^{12,69,71,73,76,78,79}  In the conventional PAC, necrosis is rare but spotty focal necrosis may be seen in 10% of cases while in HGT large areas of necrosis is noted in 90% of cases.^{12,69,71–75,79}  LVI and PNI are seen in about 6% and 60%–75%, respectively, in the conventional PAC while with HGT both are present in a range of 40%–50%.^69,71,73,76  By immunohistochemistry, a typical PAC shows positivity for CK7, S100, and SOX10 with a p63+/p40− pattern, and a Ki-67 of approximately less than 10%.^69,70  The HGT areas also show positivity for CK and S100 with variable p63 and Ki-67 of 20%–40%.^71,72,75,76  Two cases of HGT were positive for androgen receptors.^71,76 

The cribriform subtype also shows uniform monomorphic cells arranged in cribriform, solid, glomeruloid, and microcystic patterns. The nuclei classically show clear chromatin resembling papillary thyroid carcinoma.⁷⁰  Mitosis and necrosis are rare while LVI may be seen in 35% of patients.^70,80,81  The immunohistochemical features are similar to conventional PAC.⁷⁰  The only case of HGT of cribriform subtype described in literature was a 7.5-cm mass involving the maxilla of a 59-year-old male.⁸²  On microscopy, the HG area was next to an LG area and showed a solid architecture with peripheral palisading of tumor cells, comedonecrosis, and numerous mitosis. The cells were positive for CK7, focally for S100, and were negative for p40.⁸² 

By molecular analysis, the classic PAC shows activating mutation of the protein kinase D1 (PRKD1) gene and rare fusion involving PRKD1, PRKD2, and PRKD3 genes while the cribriform PAC shows fusion involving PRKD1, PRKD2, or PRKD3 genes with the most common partner genes being AT-rich interaction domain 1A (ARID1A) or DEAD-box helicase 3 X-linked (DDX3X) and a rare activating mutation of PRKD1 gene.^70,74  The only case of classic PAC with HGT where molecular data are available showed PRKD2 gene rearrangement.⁷⁴  The only cribriform subtype with HGT showed PRKD1 gene fusion albeit with a novel partner, striatin 3 (STRN3).⁸² 

Local recurrence and local and distant metastasis are uncommon in conventional PAC and are seen in 5%–15%, 3%–15%, and 2%–3% of cases, respectively.^69,77–79  The HGT cases show a recurrence in more than 50% of cases and show LN metastasis in 50%–60% of cases and distant metastasis in 25%–30% of cases.^12,71–76  Conventional PAC has an excellent prognosis and more than 95% of patients show 10-year DSS and about 85% show 10-year RFS.⁷⁰  Although follow-up is limited in most the HGT cases, none of the patients died of disease.⁷⁶  The cribriform subtype, unlike the conventional subtype, shows LN metastasis in about 40%–60% of cases. The only case of HGT in the cribriform PAC showed an LN metastasis and the patient was disease free 10 months after surgery and radiotherapy.⁸² 

SC is a rare SG tumor initially defined by the presence of ETS variant transcription factor 6::neurotrophic receptor tyrosine kinase 3 (ETV6::NTRK3) fusion.¹  It shows slight male predominance and presents at a mean age of 46.5 years (range, 7–94 years).^13,28,83  About 80% of the cases present in the major SG with a tumor size of 1.5–2 cm.^13,83,84  HGT is rare and is seen in 7%–9% of cases.^13,83  HGT is seen at a mean age of 55–60 years with a male to female ratio of 5:1.^23,85–90  It also presents mainly as a parotid mass with a tumor size of 3–4 cm. Rare cases involve the palate, sinonasal region, and oral cavity.^83,88,89 

Conventional SC is circumscribed and lobulated with microcystic/solid, papillocystic, follicular architecture. The cells are LG with pale eosinophilic and bubbly cytoplasm and small round to oval nuclei.^13,28,83  In HGT, a sharp transition between conventional and HG areas is identified.^1,90  The HG areas show solid sheet, irregular islands, or trabecular architecture.^83,90  They are also more likely to show invasive borders, hyalinization, and fibrosis.^13,90  The cells show HG features like pleomorphism, nuclear atypia, prominent nucleoli, and lack cytoplasmic vacuolations (Figure 2, A through D).^13,83,90  In conventional SC, mitotic activity (0–2/10 hpfs), and necrosis are extremely rare while LVI may be seen in 0%–7% of cases and PNI in 0%–20% of cases.^83,84,91  The HGT cases increased mitotic activity (>5/10 hpfs) and necrosis (Figure 2, D), mostly comedo type, which is almost always seen (95% of cases), LVI is seen in about 30% of cases and PNI in 70% of cases.^{23,83,85–90}  Two-tiered and 3-tiered grading systems have recently been proposed in the literature.^13,83  In the 2-tiered system, the HG is defined by presence of a mitotic count greater than or equal to 5/10 hpfs and/or tumor necrosis while in the 3-tier system the HG is defined by presence of sheetlike growth with comedonecrosis, pleomorphic cells with absence of intracytoplasmic vacuoles, mitosis greater than or equal to 10/2 mm², atypical mitosis, and high Ki-67, greater than or equal to 31%.^13,83  The conventional SCs are positive for CK7, SOX10, S100, and mammaglobin; are negative for p63, p40, NR4A3, and DOG1; and exhibit Ki-67 of 5%–28%.^28,84  The HG areas show a similar immunohistochemical profile and are positive for CK7 and S100, variable for mammaglobin, and have Ki-67 of 40%–70% (Figure 2, E and F).^13,85,87,90  Subsequently, other rare translocations like ETV6-RET (ret proto-oncogene), ETV6-MET (mesenchymal epithelial transition factor), and vimentin (VIM)-RET have been documented. ETV6::NTRK3 or one of the other rare translocations is identified in the LG and HG areas. A case with CDKN2A/B loss and adenomatous polyposis coli (APC) mutation has also been described.²³ 

In conventional SC, LN metastasis is seen in 5%–10% and distant metastasis in 3%–10% of cases while LN metastasis in HGT cases is seen in 40%–45% of cases and distant metastasis is seen in 60%–65% of cases with lung being the most common site (80%).^{13,23,83–92}  The 5-year OS in HGT cases is about 35%–50% compared to 82%–97% for conventional SC.^{13,23,84–88}  Patients with HGT SC have an 8.3 times greater risk of recurrence or dying of disease and HGT SC is an independent predictor of DFS by multivariate analysis.^13,83  A significant number of the HGT patients undergo LN dissection and radiation in addition to surgery. NTRK fusion is a potential biomarker and larotrectinib and entrectinib have been used as an alternative with good response.^13,83,86 

Keys to identifying HGT in SC are identification of solid and irregular islands with necrosis, increased mitotic count, atypia, and pleomorphism. Immunohistochemistry is nonspecific. ETV6 translocation may be helpful in small biopsies. The clinical and pathologic features of conventional SC and HGT SC are summarized in Table 4.

CS is an extremely rare malignant neoplasm comprising carcinomatous and sarcomatous components.⁹³  These tumors in the past have been referred to as “true malignant mixed tumors.”^24,93  Historically some of the HG myoepithelial carcinoma and carcinoma ex PA with myxochondroid matrix may have been misclassified as CS. These cases can mimic a CS but should be differentiated by presence or absence of cytologically malignant mesenchymal elements.⁹⁴  Recently, Ihrler et al²⁴  showed that they arise almost exclusively on a background of a pleomorphic adenoma. They occur mainly in elderly patients (mean and median of 60–65 years) affecting males and females almost equally but rare cases in children and young adults have been reported.^24,95  They present as a slow-growing mass and occasionally as a rapidly growing mass averaging about 3.9 cm (frequently >6 cm) (Figure 3, A) involving the parotid in about 70%–80%, followed by submandibular gland in 15%–20%, and occasionally in the minor SGs in 10%–12% of patients.^24,95–97 

By microscopy, as the name suggests, both carcinomatous and sarcomatous components are identified. The carcinomatous component is a salivary duct carcinoma in 30%, undifferentiated carcinoma in 25%, squamous cell carcinoma in 20%, and MEC in 5% of cases (Figure 3, B through D).^24,95  The heterologous component is detected in about 75% of cases and the common heterologous sarcomatous components include chondrosarcoma (35%–50%), osteosarcoma (25%–30%), fibrosarcoma (15%), spindle-cell sarcoma (5%–25%), pleomorphic sarcoma (3%–8%), and rhabdomyosarcoma (3%–7%) (Figure 3, E and F).^24,95,96,98  Frequently, more than 1 type of carcinoma or sarcoma component may be identified.²⁴  A precursor PA can be demonstrated by histology in at least 80% of patients and by molecular methods in the remainder of the patients.^24,25,95  Intraductal carcinoma is seen in greater than 50% of cases and intracapsular carcinoma and sarcoma in 70% and 50% of cases, respectively.²⁴  The intracapsular malignancy is usually a carcinomatous component, and the extracapsular malignancy is dominated by the sarcomatous component. The intraductal and the invasive carcinoma may show overexpression of AR, p53, and HER2.

Classic PA translocation involving PLAG1 or HMGA2 genes has been identified in a majority of cases even in absence of histologic evidence of a PA. Other translocations of unknown significance that have been identified include tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon:: G protein subunit beta 1 (YWHAE::GNB1) and lysine demethylase 5A::calcium voltage-gated channel subunit alpha1 C (KDM5A::CACNA1C).²⁴  A high degree of molecular concordance is observed between intracapsular and extracapsular components.²⁴ 

CS presents at high T category (pT3/T4 in 70% of cases) with LN metastasis in about 50% of cases.²⁴  Follow-up data are limited but 40%–45% of patients have local recurrence, 50% have metastases, and 27%–50% die of disease due to metastasis to lung, liver, and bones with a mean OS of 3.6 years.^24,95 

Ihrler et al,²⁴  in their recent paper, concluded that CS develops from 2 pathways: intraductal and myoepithelial, as an intraductal component was absent in cases where MEC was the carcinomatous component and was almost always combined with chondrosarcoma. While the intraductal pathway shows salivary duct or undifferentiated carcinoma with various sarcomas, the 2 pathways do not show significant differences.²⁴  Ihrler et al²⁴  also concluded that CS follows an adenoma-carcinoma-sarcoma path and therefore the correct terminology should be sarcomatoid carcinoma as the sarcomatous component represents epithelial-to-mesenchymal transition and not a true sarcoma. This conundrum was acknowledged in the recent proceedings of the North American Society of Head and Neck Pathology, but CS was retained as a separate category in the 5th edition of the WHO Classification of Tumours.^27,28 

HGT likely involves additional complex genetic changes that are poorly understood as of now. Its presence in SG carcinoma is being increasingly recognized. It is more common in some of the entities, such as AdCC, compared to others. Presence of solid areas with pleomorphic atypical cells, necrosis, and elevated mitotic count are the most common histologic features. Ki-67 is higher than in the classic areas.^{5,13,15,17–19} 

It is a clinically significant phenomenon, and presence of transformed areas have a heightened potential for metastasis.^5,22,31,56  HGT therefore impacts prognosis and treatment options. It presents a unique challenge to the pathologist and the treating physicians.^31,47  For the pathologist, it is critical to identify the HGT, and a small biopsy from such an area would be diagnostically challenging. For the treating surgeons and oncologists, a simple excision may not suffice in such cases and may require LN dissection and adjuvant therapy.³¹  This also opens up avenues for research to identify the molecular changes. Few molecular alterations have been identified and in the future, hopefully, more targets with therapies can be identified to improve patient survival.^20–22 

Carcinosarcoma, as discussed, likely follows the adenoma-carcinoma-sarcoma pathway and could be renamed or reclassified, possibly as sarcomatoid carcinoma, in the future.^24,27  However, its genesis exclusively from a PA and almost never from a de novo salivary duct carcinoma is curious. As a hypothesis, PLAG1 and HMGA2, which play a role in development of “benign mixed tumor,” possibly also play a role in development of “malignant mixed tumor.” More data may be needed to conclude one way or the other.

Diagnosing HGT in a biopsy poses unique challenges. The biopsy may be composed of only HG features like pleomorphic cells, necrosis, and increased mitosis, and lack the conventional cytologic and architectural features of the underlying entity. Immunohistochemistry may be nonspecific but markers such as NOR1 and mammaglobin may be helpful if positive. A molecular analysis is more likely to be helpful in such cases. In resections, extensive sampling can help identify the areas of conventional morphology, thus aiding in making a diagnosis. It is important for a pathologist not to miss a small focus on HGT in a case with predominantly conventional morphology, as the HG area will drive the management and prognosis. The approach should be to identify solid, cribriform, or other unusual architectural and cytologic patterns distinct from the conventional areas, recognizing areas of necrosis at low power and closely examining these areas on high power for other HG features. If the suspicious area for HGT is small, additional sections should be evaluated to confirm and quantify the HG areas. Immunohistochemical markers may be helpful to demonstrate the differential staining pattern between the conventional and HG areas.