Abstract
Secretory carcinoma (SC) is a relatively new disease entity, separate from acinic cell carcinoma (AciCC), which frequently displays ETV6-NTRK3 gene fusion. However, the differences between SC and AciCC remain ambiguous. Genetic diversity makes its diagnosis complicated. In this regard combined expression of immunohistochemistry markers S100/Mammaglobin/SOX10 and DOG1 is need of the hour as alternative methodology. The current systematic review was to investigate the diagnostic utility of combined immunohistochemical expression of S100/Mammaglobin/SOX10/DOG1 in distinction of SC from AciCC histologically. An electronic search of databases was carried out using MEDLINE by PubMed, Google scholar, Scopus and Web of science. Articles inclusive of SC and AciCC were assessed with S100/Mammaglobin/SOX10/DOG1 immunohistochemistry and their predominant expression pattern, predictive values, sensitivity and specificity were gathered. Fourteen eligible articles were analysed, which revealed predominant immunostaining pattern of S100 + /Mammaglobin + /SOX10 + /DOG1- by nearly all ETV6::NTRK3 fusion prevalent SCs alongside with other gene fusions like RET, MET and MAML3 with 98.4% sensitivity as well as 86.1% specificity. The evidence supports that S100/Mammaglobin/SOX10/DOG1 combined immunostaining can serve as a reliable diagnostic method to differentiate secretory from acinic cell carcinoma.
Keywords: Acinic cell carcinoma (AciCC), ANOS (Adenocarcinoma not otherwise specified), Immunohistochemistry (IHC), LGCCC (Low Grade Cribriform Cystadeno carcinoma), Mammaglobin (MMG), Mammary analogue secretory carcinoma (MASC), Secretory carcinoma (SC), Sinonasal acinic cell carcinoma (SNAciC)
Introduction
Salivary gland tumors are elusive comprising innumerable histologic types, with mucoepidermoid carcinoma being frequently encountered followed by adenoid cystic and acinic cell carcinoma (AciCC) [1]. Secretory carcinoma (SC) of the salivary gland is considerably new disease phrase with vast histological commonalities with AciCC leads to misdiagnosed cases of SC [2]. SC possess the ETV6-NTRK3 gene akin to breast cancer, with paucity in other tumors highlighting its exclusivity to it. Previously diagnosed cases of AciCC may have a rephrased diagnosis of SC if tumor shows follicular, papillary-cystic or microcystic pattern [3, 4]. Numerous study articles propounded that to diagnose SC relying specifically on ETV6-NTRK3 is not sufficient as it shows greater genetic diversity [5]. Therefore, to lay emphasis on unknown fusion genes involving ETV6 and a gene other than NTRK3 term ETV6-X was adopted [6]. ‘X’ signifies MET, RET, or MAML3 gene mutation [7]. Therefore, owing to varied genetic expression immunohistochemistry (IHC) maybe an alternative approach to diagnose SC. SC is usually positive for mammaglobin (MMG) and S100 but negative for DOG-1 and p63 [8]. Baghai et al elaborated similar dual positivity expression for MMG and S100 in SC [9]. AciCC on the contrary exhibit strong positivity for SOX10 and DOG-1 on the luminal aspect of acini and ducts [10]. Thus characteristic pattern of staining for all enlisted immunohistochemical markers enable us to diagnose it accurately without using molecular techniques. It was suggested that a combined S100/MMG/SOX10/DOG-1 diagnostic panel could be a used to differentiate SG carcinomas such as SC from AciCC.
Thus, in the current systematic review an effort was made to evaluate the diagnostic usefulness of combined S100/MMG/SOX10/DOG-1 immunostaining to distinguish secretory from acinic cell carcinoma.
Material and Methods
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [11] and was registered at the International Prospective Register of Systematic Reviews database (CRD42022333590).
Review Question
Does S100/MMG/SOX10/DOG 1 immunoreactivity has diagnostic utility in the histopathological distinction of secretory and acinic cell carcinoma?
Search Strategy
The following databases were searched namely MEDLINE by PubMed, Google Scholar, Scopus,Web of Science till 31st October 2022. The search strategy was as following: [Salivary gland tumors of head and neck AND S-100/MMG/SOX10/DOG 1 IHC].
Article Screening and Eligibility Evaluation
Titles and abstracts of all articles published in english language were screened by 2 independent authors (G.S. and M.K.) and the articles that did not meet the eligibility criteria were excluded. Then, the same 2 authors proceeded with the eligibility evaluation by reading the full text of the articles and recorded the reasons for exclusions. Disagreements were resolved first by discussion and then by consulting a third author in a consensus meeting (R.K.).
Inclusion and Exclusion Criteria
Eligibility criteria Articles were included if they met the following eligibility criteria: (1) full-length original immunohistochemistry (IHC) study design published in english language and (2) studies that included quantitative analysis of S100/MMG/SOX10/DOG 1 immunoreactivity in secretory and acinic cell carcinoma of the head and neck region.
Study Selection and Data Extraction
Data were extracted by one author (G.S.) and revised by a second author (M.K.) to warrant the integrity of the contents. The following information was extracted: the country of origin, author(s), year of publication, salivary gland tumor studied, clinical details if available, pattern of IHC expression in acinic and secretory carcinoma, sensitivity, specificity and positive and negative predictability.
Summary Measures, Data Synthesis, and Analysis
The main outcome was the analysis of different immunohistochemical patterns of S-100/MMG/SOX10/DOG 1 in histopathological differentiation of secretory and acinic cell carcinoma. As these tumors are histological mimickers of each other, they may vary greatly in treatment modality, prognosis and outcome. The quantitative data were tabulated and processed in Microsoft Excel version 2016 (version 16.44, Microsoft Corporation).
Quality Assessment
To assess the risk of bias for each study, Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool, which was developed for diagnostic accuracy studies was applied. Checklist items included for risk bias and applicability concerns were patient selection, index test, reference standard, and flow and timing. Studies with the judgment of low risk of bias on all domains of the tool, rated as “low risk of bias” or low concern regarding the applicability, those with a judgment of high or unclear on one or more domains, rated as “high risk of bias” or as having concerns regarding applicability. The quality of case reports was evaluated by the Joanna Briggs Institute critical appraisal tools (JBI), (one point for each). The qualities of studies with < 70% raw score were recognized as low, those with 50–69% raw score as moderate, and those with > 70% raw score as high risk. Two reviewers (G.S. & M.K.) independently assessed the methodological quality of the included articles and then a third author was consulted for arbitration (R.K.). The Review Manager special software (RevMan v5.4, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used to output the result of QUADAS-2 and JBI tools.
Results
Studies Selection
The exploration strategy identified 160 articles published through in various scientific databases. After duplicate articles were removed, 67 records remained. These were further screened by reading the titles and abstracts, resulting in 14 articles being selected for eligibility evaluation, which were further assessed by reading the full text. Finally, 14 articles [4, 5, 9, 12–22] were considered inclusive of 78 cases (Fig. 1) out of which 45 were SCs, 29 AciCC (27 conventional,1 high grade and I low grade each), 3 ANOS (Adenocarcinoma not otherwise specified), 1 salivary duct carcinoma which were re-diagnosed as 69 SC cases (66 conventional, 3 high grade),7 AciCC(6 conventional, 1 high grade) and 2 LGCCC (Low Grade cribriform cystadeno carcinoma) and finally included in quantitative synthesis.
Fig. 1.
Flowchart of study selection adapted from Preferred Reporting Items for Systematic Reviews and Meta-analyses
Methodological Characteristics of the Studies
Data extracted from all 14 studies [4, 5, 9, 12–22] including details on the country of origin, authors, total number and type of SGTs included in study, clinical details, and pattern of S100/MMG/SOX10/DOG-1/IHC expression is provided in Table 1 and 2. The included studies were conducted between 2015 and 2022, in 8 different countries: 4 in the United States, 2 in Japan, 2 in Czech Republic, 2 in Australia, 1 in New Zealand, 1 in Iran, 1 in Malaysia, 1 in Philippines.
Table 1.
Demographic and clinical data extracted from the included studies
| S. no | Country | Study (Author/Year) | Gender | Mean age (Years) | Mean size (mm) | Location | Cases included in study for IHC | Total No of cases |
|---|---|---|---|---|---|---|---|---|
| 1 | Japan | Urano M et al./2015 [14] | M 9 | 52.33 ± 17.90 | 28 × 20;30 × 20;12 × 11;20 × 20;20 × 15;13 × 8;17 × 13;20 × 17;20 × 13;15 × 10;18 × 15;12 × 8;30 × 25;55 × 50;25 × 25;20 × 15;15 × 5;10 × 5 | P 15; Ac P 1; Lip 1; Ph 1 | SC 12; Aci CC 6 | SC 12; Aci CC 6 |
| F 9 | ||||||||
| 2 | Australia | Woo WY /2017 [17] | F 1 | 52.0 | NA | Rt P 1 | SC 1 | 1SC |
| 3 | Iran | Baghai F et al./2017 [9] | M 6 | 46.9 ± 19.62 | 7;2.5;1.5;1.5;4;1;4;5;2;4 | P 9; Upr Lip 1 | SC 8 | SC |
| F 4 | H G SC 2 | 37 | ||||||
| 4 | Czech Republic | Baneckova M/2018 [19] | F2 | 58 ± 9.90 | 1.5 × 1.5 × 0.4;4 × 4 × 1.5 | Rt N Sep 1; Rt N Cav 1 | SC 2 | 2 SC |
| 5 | USA | Rooper LM/2018 [5] | F 1 | 59.0 | 47 | Lt Submand Reg 1 | H G SC1 | 1 H G SC |
| 6 | Czech Republic | Skalova A et al./2018 [4] | M 7 | 74.18 ± 17.13 | 15;23;30;70;10;40;70;12;17;19 | P 7; Submand 2; Lip 1 | SC 10 | 30 SC |
| F 3 | ||||||||
| 7 | USA | Karabachev A/2020 [13] | M 1 | 18.0 | 16 × 12 × 13 | Lt Submand Reg 1 | SC 1 | 1SC |
| 8 | Japan | Shibata E /2020 [18] | F1 | 59.0 | 30 | Lt P 1 | SC 1 | 1 SC |
| 9 | Australia | Wu B/2020 [22] | M1 | 72.0 | 8 × 4 | Lt N Cav 1 | SC 1 | 1 SC |
| 10 | New Zealand | Li YH/2021 [12] | M 2 | 50 ± 21.21 | 25 × 15 × 15;80 × 27 × 25 | Lt P 2 | SC 2 | 2 SC |
| 11 | Philippines | Uy TC/2022 [15] | F 1 | 29.0 | 18 × 12 × 10 | Rt infra aur Reg 1 | SC 1 | 1 SC |
| 12 | Malaysia | Kallarakkal TG/2022 [16] | F 1 | 64.0 | NA | Lt S palat 1 | H G Aci CC 1 | H G 1 Aci CC |
| 13 | USA | AlKaabba F/ 2022 [20] | M 1 | 22.0 | 2.8 | Rt P 1 | SC 1 | 1SC |
| 14 | USA | Wiles AB/2022[21] | M 7 | 52.0 | NA | P 18; Neck 4; Submand 2; Subment 2; Oral 2 | SC 28 | 40 SC |
| F 21 |
Ac Accessory; Aci CC Acinic cell carcinoma; Infra aur Reg Infra auricular region; N Cav nasal cavity; N Sep nasal septum; P Parotid; Ph Pharynx; SC Secretory carcinoma; Submand Submandibular; Subment Submental; S palat Soft palate; Rt Right; Lt Left; Upr Upper; H G High Grade
Table 2.
Pattern of S100/Mammaglobin/SOX10/DOG-1 immunostaining and molecular diagnostic results from the included studies
| S. no | Study | Type of Salivary gland Tumors | Total | Immunohistochemistry | Molecular Findings | Final/Revised Diagnosis | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| S100 | SOX 10 | DOG1 | MMG | FISH | RT-PCR | NGS | |||||
| 1 | Urano M/2015 Japan | AciCC 18 | 18 | (P)17/18 | (P)3/18 | (P)3/18 | (P)13/18 |
ETV6-NTRK3 10 ND 8 |
ETV6-NTRK3 7 ND 11 |
ETV6-NTRK3 10 ND 8 |
SC 10; Aci CC 6; LGCCC 2 |
| 2 | Woo WY/2017 Australia | SC 1 | 1 | (P)1/1 | (P)1/1 | (P)0/1 | (P)1/1 | NA | NA | NA | SC 1 |
| 3 | Baghai F/2017 Iran | AciCC 7 | 10 | (SD)7/7 | (SD)7/7 | (FP)1/10 | (SD)7/7 |
ETV6 8 ND 1 NA 1 |
ETV6-NTRK3 7 ND 3 |
NA | SC 8 |
| ANOS 3 | (FP-2; SD-1) 2/3 | (SD)3/3 | (FP)2/10 | (SD)3/3 | SC HG 2 | ||||||
| 4 | Baneckova M/2018 Czech Republic | SC | 2 | (DP-1; FP-1) 2/2 | (DP)2/2 | 0/2 | (DP-1; FP-1) 2/2 | ETV6 1 | ETV6-NTRK3 ND | ETV6-NTRK3 1 (Exon 5–15) | SC 2 |
| ETV6-NTRK3 1 | ETV6-NTRK3 1 | NA | |||||||||
| 5 | Rooper LM/2018 USA | H G Aci CC 1 | 1 | (DP)1/1 | 0/1 | 0/1 | (FP)1/1 | ETV6 12p13.1 | NA |
ETV6-MET 1 (Exon 4–14) |
HG SC 1 |
| 6 | Skalova A/2018 Czech Republic | SC 10 | 10 | (P)5/6 | (P)6/10 | 0/10 | (SD)10 | ETV6-NTRK3 ND 10, ETV6-RET 10 | ETV6 7 |
ETV6-RET 10 (Exon 6–12) |
SC 10 |
| 7 | Karabachev A/2020 USA | LGAciCC | 1 | (DP)1/1 | (DP)1/1 | 0/1 | 0/1 | ETV6 12p13.2 | NA | NA | SC 1 |
| 8 | Shibata E/2020 Japan | Salivary DC | 1 | (FP)1/1 | (FP)1/1 | (FP)1/1 | (DP)1/1 | ETV6 | ETV6-NTRK3 1 | NA | SC 1 |
| 9 | Wu B/2020 Australia | AciC 1 | 1 | (DP)1/1 | (PW)1/1 | (PP)1/1 | (DP)1/1 | ETV6 | ND |
ETV6-MET 1 (Exon 4–14) |
SC 1 |
| 10 |
Li YH/2021 New Zealand |
SC 2 | 2 | (P)2/2 | (P)1/2 | 0/2 | (P)2/2 | ND | NA | NA | SC 2 |
| 11 |
Uy TC/2022 Philippiness |
SC 2 | 1 | (SD)1/1 | (SD)1/1 | 0/1 | (SD)1/1 | NA | NA | NA | SC 1 |
| 12 |
Kallarakkal TG/2022 Malaysia |
Aci CC 1 | 1 | (DP)1/1 | (DP)1/1 | (FP)1/1 | 0/1 | NA | NA | NA | AciCC HG 1 |
| 13 |
AlKaabba F/2022 USA |
SC 1 | 1 | (P)1/1 | (P)1/1 | 0/1 | (P)1/1 | NA |
mRNA fusion -5/15 (ETV6- NTRK3) |
mRNA fusion -5/15 | SC 1 |
| 14 |
Wiles AB/2022 USA |
SC | 28 | (P)23/24 | (P)3/3 | (P)0/7 | (P)17/17 | ETV6, NTRK- 33 | NA | t(12,15)(p13:q25) 1 | SC 28 |
Aci CC Acinic cell carcinoma; ANOS Adenocarcinoma not otherwise specified; DP Diffuse positive; DC Duct cyst; FP Focal positive; FISH Fluorescence insitu hybridization; HG High grade; LGCCC Low grade cribriform cystadeno carcinoma; NGS Next generation sequencing; P Positive; PP Partial positive; PW Partial weak; RT-PCR Real time polymerase chain reaction; SC Secretory carcinoma
Demographic and Clinical Data
The demographic and clinical details were extracted from 14 studies [4, 5, 9, 12–22]. Of the 78 cases, the clinical details were specified for only 14 cases. Forty-four female (56%) and 34 male patients (43%) were affected with a female: male ratio of 1.29:1. The mean age of patients ranged from 18 to 74.18 years. The most affected site was the parotid (54), upper lip (3), accessory parotid (1), pharynx (1), nasal septum (1), nasal cavity (2), submandibular region (6), neck(4), soft palate (1), submental (2), oral (2), right infra-auricular region (1). The mean tumor size ranged from 2.8–55 mm (Table 1).
Immunohistochemical Results
Data regarding IHC expression of S-100/ MMG / SOX10/ DOG 1 staining from all 14 studies that satisfied the eligibility criteria of the present review are elaborated in Table 2.
S100 + /MMG + /SOX10 + /DOG 1 + immunohistochemical co-expression was reported in 5 of 78 (6.41%) cases.
S100 ± /MMG + /SOX10 + /DOG 1- immunohistochemical co-expression was reported in 33 of 78 (42.3%) cases.
S100 + /MMG + /SOX10-/DOG1- immunohistochemical co-expression was reported in 8 of 78 (10.2%) cases.
S100 + /SOX10 ± /MMG-/DOG1 ± immunohistochemical co-expression was reported in 3 of 78 (3.84%) cases.
Sensitivity and Specificity of S100/MMG/ SOX10/ DOG 1
Information regarding sensitivity and specificity of all included studies is provided in Table 3. The sensitivity involving ETV6:NTRK3 and RET and MET all ranged from 50% to 98.4% and the specificity was 50% to 86.1% among all studies. Positive predictive value ranged from 69.23% to 80% for all fusions as well as NTRK3 fusions, whereas negative predictive value varied from 80 to 100% for all fusions.
Table 3.
Sensitivity, Specificity, Positive predictive value and Negative predictive value of combined expression of S100, SOX10, MMG, and DOG1 in differentiating Secretory carcinoma from other salivary gland lesions
| S. no | Study | Total no. of Test/control Cases | Varying patterns of immunoreactivity | TP | FN | FP | TN | Sensitivity | Specificity | Positive Predictive value (%) | Negative Predictive value (%) | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| S100 ± SOX10 + DOG1-MMG + | S100 + SOX10 + DOG1 + MMG + | S100 + SOX10-DOG1-MMG + | S100 + SOX10 ± DOG1 ± MMG- | |||||||||||
| 1 | Urano M/2015 Japan | 10/8 | 9 | 0 | 0 | 1 | 9 | 1 | 4 | 4 | 90.00% | 50.00% | 69.23% | 80.00% |
| 2 | Woo WY/2017 Australia | 1/1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 75.00% | 50.00% | 100.00% | 0.00% |
| 3 | Baghai F/2017 Iran | 0/37 | 7 | 3 | 0 | 0 | 0 | 0 | 10 | 27 | 50.00% | 72.40% | 0.00% | 100.00% |
| 4 | Baneckova M/2018 Czech Republic | 0/17 | 2 | 0 | 0 | 0 | 0 | 0 | 2 | 15 | 50.00% | 86.10% | 0.00% | 88.24% |
| 5 | Rooper LM/2018 USA | 1/0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 75.00% | 50.00% | 100.00% | 0.00% |
| 6 | Skalova A/2018 Czech Republic | 30/0 | 30 | 0 | 0 | 0 | 30 | 0 | 0 | 0 | 98.40% | 50.00% | 100.00% | 0.00% |
| 7 | Karabachev A/2020 USA | 1/0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 75.00% | 50.00% | 100.00% | 0.00% |
| 8 | Shibata E/2020 Japan | 1/0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 75.00% | 50.00% | 100.00% | 0.00% |
| 9 | Wu B/2020 Australia | 1/0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 75.00% | 50.00% | 100.00% | 0.00% |
| 10 | Li YH/2021 New Zealand | 2/0 | 1 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 83.30% | 50.00% | 100.00% | 0.00% |
| 11 | Uy TC/2022 Philippiness | 1/0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 75.00% | 50.00% | 100.00% | 0.00% |
| 12 | Kallarakkal TG/2022 Malaysia | 0/1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 50.00% | 75.00% | 0.00% | 100.00% |
| 13 | Alkaabba F/2022 USA | 1/0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 75.00% | 50.00% | 100.00% | 0.00% |
| 14 | Wiles AB/2022 USA | 3/0 | 1 | 0 | 6 | 0 | 3 | 0 | 0 | 0 | 87.50% | 50.00% | 100.00% | 0.00% |
FP False positive; FN False negative; MMG Mammaglobin; TP True positive; TN True negative
Molecular Genetic Findings
Data particular to specific gene rearrangements were sufficient, as detailed in the Table 2. ETV6:NTRK3 fusion transcript was detected by RT-PCR in 17 of 78 cases (21.7%) of SC whereas only ETV6 transcript was detected in 1 case. FISH detected ETV6:NTRK3 fusion transcript in 44 of 78 cases (56.8%). 13 cases were positive for only ETV6 gene out of 78 cases (16.6%). ETV6: RET gene fusion transcript observed in 10 cases out of 78(12.8%). Next generation sequencing (NGS) detected 2 cases with ETV6-MET fusion.
Survival and Follow-up
Data particular to survival and follow up was sufficient. Out of 78 cases, 64 of 78 cases (82%) were alive with no evidence of disease on 5 year follow up, 6 of 78 cases (7%) died of disease due to metastasis, 4 of 78 cases (5%) were lost to follow-up and details of 4 cases (5%) were not available.
Other IHC Markers in Differentiation
Pan-TRK antibody has recently upsurged its popularity in detection of NTRK rearranged epithelial as well as mesenchymal tumors [23]. Although it is a sensitive marker to discriminate SC from AciCC mainly by targeting NTRK3 gene fusion but it lacks the sufficient sensitivity in subset of secretory carcinomas that harbor the non-NTRK fusion partners such as RET, MET and MAML3 necessitating the use of a reliable diagnostic IHC panel for the same.
Quality Assessment (Risk of Bias and Applicability Concern)
According to the assessment by the QUADAS-2 and JBI checklist (Figs. 2 and 3), we assigned a low risk of bias to 4 studies [4, 9, 14, 19] and a high risk of bias to 1 study [21] among the 5 original studies [4, 9, 14, 19, 21]. In 9 case reports [5, 12, 13, 15–18, 20, 22] all were classified with overall low risk of bias. An Open Meta analyst for sierra (10.12) software was used to perform the meta-analysis. Pooled sensitivity, specificity and diagnostic odds ratio (DOR) were calculated following a bivariate random-effects regression model. Forest plots of each study and pooled estimates for sensitivity and specificity with 95% confidence intervals (95% CI) were presented. The heterogeneity between eligible studies was calculated by inconsistency indexes (IÇ), I2 > 50% were considered indicators of substantial heterogeneity. A p value < 0.05 was considered statistically significant (Fig. 4).
Fig. 2.
Summary of the risk of bias of the included (a) case–control and (b) cross sectional studies, based on QUADAS-2 criteria
Fig. 3.
Schematic representation of applicability concerns
Fig. 4.
Schematic representation of the forest plot for meta-analysis
Meta-Analysis
Fourteen case control studies [4, 5, 9, 12–22] were included for meta-analysis. The pooled sensitivity and specificity of combined expression of S100, SOX10, MMG, and DOG1in predicting secretory carcinoma were 0.82 (95% CI: 0.66 ± 0.91) and 0.69 (95% CI: 0.57 ± 0.79), respectively. The positive likelihood ratio was 1.75 (95% CI, 1.11 ± 2.76) and the negative likelihood ratio was 0.29 (95% CI, 0.18 ± 0.46). The summary Diagnostic Odds Ratio (DOR) was 5.21(95% CI: 1.60 ± 16.91). There was null heterogeneity among the studies (I2 = 0%, p = 1.00) (Fig. 4).
Discussion
Precise detection of tumors in the modern age substantially depends upon advancements at molecular level which makes it possible to distinguish original tumors from their histological mimickers. Though perplexing pathologies like SGCs with conjoint histopathology make the diagnosis tedious, yet IHC and molecular methods remain the mainstay comprehensive diagnostic approaches. The tumor of curiosity among the newly allocated SGCs is SC which was previously considered as AciCC based on histology. Differential diagnosis encompass intraductal carcinoma, low-grade mucoepidermoid carcinoma and pleomorphic adenoma [23, 24]. Retrospectively previously reported zymogen poor AciCC were rediagnosed as SC [3]. Cases of SC with high-grade transformation were also well documented with lower mean survival rate. [23] Thus, for adequate treatment, correct diagnosis of SC and its discrimination from histopathological mimicker such as AciCC is of utmost significance. Although detection of ETV6:NTRK3 fusion by molecular techniques like FISH, RTPCR and NGS is considered as a definite method to confirm the diagnosis of SC but they being expensive with sensitive procedures renders them usually unavailable and unaffordable. Changes at every exon is not always detected by these techniques making it cumbersome. It could be avoided by involving diverse detection methods in which combined IHC panel forms a major part.
SC is recently introduced terminology initially listed in the fourth edition of World Health Organization (WHO) classification (2017). The term “mammary analogue secretory carcinoma (MASC)” was frequently used before SC was first described by Skalova et al. [4]. SC harbors a chromosomal translocation t (12; 15) (p13; q25) [25]. Despite parotid gland being the favoured site for its occurrence, SC could also arise in the oral cavity, submandibular and accessory parotid gland [12, 25–28]. Frequency of SC usually varies and may account for up to one-third to one-half of the tumors conventionally considered AciCC. AciCC is one of the major salivary gland carcinomas which are rare tumors, whereas SC is not rarer than expected. SC is well characterized not only by histologic and immunohistochemical features but also by the ETV6-NTRK3 gene fusion. However, a negative test for ETV6- NTRK3 gene fusion does not rule out the diagnosis of SC. Experts have now recognized that the diagnosis of SC may be rendered in the presence of classic histomorphology with dual positivity for MMG and S-100 immunostains, independent of molecular testing [29]. SC can be confused with other salivary gland tumors, including AciCC and ANOS (adenocarcinoma not otherwise specified). More than half of cases previously diagnosed as zymogen granule-poor AciCC were positive for ETV6 translocation on view and therefore reclassified as SC, and most tumors previously diagnosed as AciCC of the minor salivary glands also represent SC [5]. Urano et al. [13] stated that MMG and S-100 immunoreactivity are used to differentiate SC from its mimics such as AciCC and cystadenocarcinoma. Pinto et al. [26] showed MMG positivity to be 100% sensitive for SC of the salivary gland; however, it may also be positive in other salivary gland tumors. The high sensitivity for diffuse S-100 positivity in SC is a useful diagnostic characteristic, particularly since S-100 staining in acinic cell carcinoma has been reported to be positive in only 10% of cases. The SRY-related HMG-box 10 (SOX10) is known as a novel marker of acinar and intercalated duct differentiation in salivary glands [14]. SOX10 positivity, however alone cannot be used to differentiate SC from its mimics, as SOX10 expression is widely present in many other salivary neoplasms, such as adenoid cystic carcinoma, sialoblastoma and basal cell adenoma/adenocarcinoma [30]. DOG1 is a calcium activated chloride channel protein that was initially identified in gastrointestinal stromal tumor. DOG-1 expression in salivary gland tissue is localised mainly in salivary acini to a lesser extent in mucinous acini [31]. DOG1 expression was not seen in the myoepithelial cells, striated and excretory ducts [32]. Dual expression of S100 protein and SOX10 has been reported in AciCC, while positivity for MMG and S-100 has been noted in a subset of low-grade IDC and PAC (polymorphous adenocarcinoma) which further lessens the reliability of these markers if used alone [33]. Thus, to overcome such difficulties with single diagnostic markers conjoint panel is necessitated. Pinto et al. indicated that negativity for DOG1 with positivity for S-100, MMG and SOX10 staining is a useful screening tool for MASC [26]. SC may be differentiated from AciCC by lack of basophilic zymogen cytoplasmic granules in the tumor cells, diffuse expression of S100 and MMG as well as absence of DOG1 expression on immunohistochemistry [15, 16, 33]. Kallarakal in their case reported positivity for SOX10, S100, DOG1 and negative expression for MMG and gave a diagnosis of it as AciCC with high grade transformation [16].Wai Yun Woo elaborated IHC findings for secretory carcinoma with consistent positivity for MMG, SOX10 and S100 and negative expression for DOG-1in majority of cases and focal positivity in few SC cases [17, 18]. SC of the salivary gland is a rare entity that may pose diagnostic challenges. Awareness of its morphologic interpretation must be supported by an immunohistochemical profile and molecular studies to confirm a diagnosis of SC [18–22]. Thus, to minimize a diagnostic bias and to enhance the accuracy to discriminate SC from AciCC, a conjoint diagnostic panel (S100/MMG/SOX10/DOG1) should be used rather any individual immunohistochemical marker.
Advantages and Limitations of S100/Mammoglobin/SOX10/DOG-1 IHC in Diagnosing SCs
Conjoint panel renders several benefits like low financial burden, high sensitivity and specificity. S100/MMG/SOX10/DOG-1 IHC diagnostic panel can detect ETV6: RET/MET/MAML-3 fusions along with conventional ETV6:NTRK3 gene which is not possible with other IHC markers like pan-TRK which can only detect ETV6-NTRK3. Thus, the diagnostic precision of this panel improves patients' overall disease-free survival by focusing on all important genetic variations, enabling effective treatment to be provided. Thus combined IHC panel is more accurate and sensitive to overcome diagnostic inaccuracies. IHC however, has its own limitations, it being a technique sensitive procedure so procedures must be carried out diligently to avoid false positive or negative results.
Conclusion
On the basis of data compilation, predominant co-expression of S100 ± /MMG + /SOX10 + /DOG-1 immunoreactivity revealed by majority of cases is a sensitive (98.4%) and specific (86.1%) methodology that could be employed as a reliable diagnostic agent to identify both ETV6-NTRK3 positive and RET/MET/MAML3 positive secretory carcinomas. Similarly accurate identification and targeting these novel gene fusions with help of c-met and pan-TRK inhibitors are valuable in meticulous therapeutic scheming.
Authors' Contributions
Guarantor of the integrity of the study: SG. Literature research: SG, KM. Data acquisition: SG and KM, RK. Manuscript preparation: SG and KM. Manuscript editing: NA, DA. Manuscript review: VG.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
Articles including “Diagnostic Utility of Expression Pattern of S100/Mammaglobin/SOX10/DOG 1 Immunohistochemistry in Differentiation of Secretory and Acinic Cell Carcinoma” examined in databases of MEDLINE by PubMed, Google Scholar, Scopus, Cochrane library and EMBASE until 31 October 2022.
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Associated Data
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Data Availability Statement
Articles including “Diagnostic Utility of Expression Pattern of S100/Mammaglobin/SOX10/DOG 1 Immunohistochemistry in Differentiation of Secretory and Acinic Cell Carcinoma” examined in databases of MEDLINE by PubMed, Google Scholar, Scopus, Cochrane library and EMBASE until 31 October 2022.