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ORIGINAL ARTICLE  
Year : 2022  |  Volume : 26  |  Issue : 4  |  Page : 589
 

Immunohistochemical analysis of cathepsin-D in benign and malignant salivary gland neoplasms. Evaluation of its role as a prognostic indicator


Department of Oral Pathology and Microbiology, Amrita School of Dentistry, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Kochi, Kerala, India

Date of Submission09-Sep-2020
Date of Decision25-Nov-2021
Date of Acceptance25-Dec-2021
Date of Web Publication22-Dec-2022

Correspondence Address:
Mridula Mohan
Department of Oral Pathology and Microbiology, Amrita School of Dentistry, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, AIMS Campus, Kochi - 682 041. Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jomfp.jomfp_370_20

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   Abstract 


Background: Salivary gland tumors are histologically the most heterogeneous group of tumors. Traditional diagnostics and grading of these tumors often fail to provide any insight into patient's clinical course. Cathepsin-D is a lysosomal acid protease secreted in increased levels in several malignancies. However, its role in salivary gland tumors has not been studied extensively. The present study aims to assess the expression of cathepsin-D in malignant and benign salivary gland tumors and to compare its expression in these tumors.
Materials and Methods: A total of 40 salivary gland tumors which included 10 cases each of adenoid cystic carcinoma, mucoepidermoid carcinoma, pleomorphic adenoma and Warthin's tumor were evaluated immunohistochemically for cathepsin-D expression. Intergroup comparison of cathepsin-D expression was done between the benign and malignant groups using the Mann–Whitney U-test. Intragroup comparison was also done using Kruskal–Wallis test.
Results: A statistically significant difference in the expression of cathepsin-D was observed between the benign and malignant groups. The malignant group showed a considerably higher cathepsin-D expression (mean value 6.284 ± 4.377) when compared to the benign group (mean value 2.281 ± 2.459). The differences in the immunopositivity between the malignant and benign groups were found to be highly significant (P = 0.004).
Conclusions: Increased expression of cathepsin-D is observed in the malignant salivary gland neoplasms. This may prove to be a useful marker for the aggressive biologic behavior as well as invasive potential of salivary gland neoplasms.


Keywords: Cathepsin-D, malignant and benign, prognosis, salivary gland neoplasms


How to cite this article:
Mohan M, Suresh R, Janardhanan M, Savithri V, Aravind T. Immunohistochemical analysis of cathepsin-D in benign and malignant salivary gland neoplasms. Evaluation of its role as a prognostic indicator. J Oral Maxillofac Pathol 2022;26:589

How to cite this URL:
Mohan M, Suresh R, Janardhanan M, Savithri V, Aravind T. Immunohistochemical analysis of cathepsin-D in benign and malignant salivary gland neoplasms. Evaluation of its role as a prognostic indicator. J Oral Maxillofac Pathol [serial online] 2022 [cited 2023 Feb 3];26:589. Available from: https://www.jomfp.in/text.asp?2022/26/4/589/364807





   Introduction Top


Salivary gland tumors have considerable diagnostic and prognostic assessment difficulties owing to the rarity of these tumors, the diversity of tumors and frequent overlap between tumor types. Classical hematoxylin and eosin staining is still considered to be the gold standard in diagnosis of salivary gland tumors. Generally, the histopathological diagnosis of salivary gland tumors is made carefully through the assessment of the growth pattern of the tumor borders, histological architecture, cellular structure and differentiation and components of the tumor stroma, along with the clinical information.[1] Prognostic assessment is even more cumbersome using the conventional histological examination. With this background, additional immunophenotypical markers would be valuable in prognostic assessment of these tumors. Based on the studies from other types of tumors, particularly breast cancer, the expression and function of certain molecules such as cathepsin D, DF3, estrogen receptors, etc., have been studied and applied to diagnosis and treatment.[2]

In this study, we have aimed at assessing and comparing the expression of cathepsin D in malignant and benign salivary gland neoplasms. We have also tried to correlate its expression with the biologic behavior of the tumor.


   Materials and Methods Top


Paraffin-embedded blocks of previously diagnosed and histopathologically reported cases of mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), Warthin's tumor (WT) and pleomorphic adenoma (PA) were selected from the departmental archives.

A preliminary survey was conducted to assess the frequency of salivary gland neoplasms reported at our institution. The most prevalent lesions were included in our study. Ten cases from each group were selected with a total sample size of 40. The selected cases were categorized into two major groups, i.e., malignant and benign. The relevant clinical data pertaining to each case selected was recorded in a data sheet wherein the age and sex of the patient, the site of lesion, the histologic pattern or grade in the case of malignant neoplasms, involvement of lymph nodes if any, distant metastasis if observed as well as any recorded history of recurrence during the follow-up. Only those cases which were followed up for a minimum of 2-year period were included in the study. Sections were subjected to immunohistochemical (IHC) staining with anti-cathepsin-D antibody (BioGeneX, USA). Breast carcinoma was used as positive control during the IHC staining procedure.

Sections stained with cathepsin-D antibody were examined under light microscope. The cells were considered positive for cathepsin-D if they revealed cytoplasmic granular staining. Quantitative scores as well as Staining Intensity Scores for positive cathepsin-D expression were recorded for each of the stained sections using the immunoreactive scoring system. Stained cells were counted in five high-power field and scored as shown in [Table 1].
Table 1: Scoring criteria for immunoreactive scoring

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The mean scores for five high-power fields in each section were noted.

The mean immunoreactive score (MIS) for each slide was calculated as follows:

MIS = Mean Quantitative Score × Mean Staining Intensity Score

As part of the statistical analysis, the comparison of cathepsin D expression between the two broad study groups – malignant and benign groups was analyzed using the MannWhitney U-test and cathepsin D expression scores between all the four subgroups – MEC, ACC, WT and PA were statistically analyzed using the Kruskal–Wallis test, with the help of a computer software, IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.


   Results Top


The malignant group showed a considerably higher cathepsin D expression (6.284 ± 4.377) when compared to the benign group, with a mean value of 2.281 ± 2.459.

The differences between the mean immunoreactive scores (IRS) of the malignant and benign groups were found to be highly significant (P = 0.004) [Table 2].
Table 2: Depicts the mean immunoreactive scores for cathepsin-D expression between the two broad groups

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The percentage positivity of cathepsin-D expression in the two broad groups was also noted. The malignant group showed a positivity of 95% (19 cases of the total of 20 cases) as compared to the 80% positivity in the benign group (16 of 20 cases).

The differences in cathepsin-D expression among all the four subgroups were found to be statistically significant (P = 0.001). The cathepsin D expression was also found to be progressively increasing from PA to WT to ACC to MEC.

It was observed that among the four subgroups, MEC showed the highest expression of cathepsin-D. Of the 10 cases of MEC (which included two high-grade variants and four each of low-grade and intermediate grades), all the cases, irrespective of the tumor grade, showed a similar intense cytoplasmic staining by the tumor cells for cathepsin-D [Figure 1]. ACC, in comparison to MEC, showed a lower expression and lesser staining for cathepsin-D, although its expression was much higher than the benign neoplasms. Among the 10 cases of ACC (which included six cribriform and two each of tubular and solid patterns), one case did not show any positive staining for cathepsin-D. All the other nine cases showed a similar cytoplasmic staining, which in places were focal or patchy, irrespective of the tumor pattern. Areas of positive cytoplasmic staining for cathepsin-D were seen admixed with those tumor cells which took up faint or no stain [Figure 2].
Figure 1: Immunohistochemistry of cathepsin-D expression in Mucoepidermoid carcinoma (×40)

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Figure 2: Immunohistochemistry of cathepsin-D expression in adenoid cystic carcinoma (×40)

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Among the two subgroups in the benign group, WT showed a more intense staining and a higher expression of cathepsin-D than the PA subgroup. Of the 10 cases of WT, all showed a positive staining of tumor cells – patchy and intense cytoplasmic staining. It was also observed that some focal positivity for cathepsin-D was present in the lymphoid stroma [Figure 3]. PA showed the least positive staining and expression of cathepsin-D among all the four subgroups. Of the 10 cases, four were negative for cathepsin-D expression. The positive staining was very weak which was seen only in a few tumor cells in focal areas [Figure 4].
Figure 3: Immunohistochemistry of cathepsin-D expression in Warthin's tumor (×40)

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Figure 4: Immunohistochemistry of cathepsin-D in pleomorphic adenoma (×40)

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The mean IRS scores for cathepsin-D expression were also compared with certain clinical parameters in the malignant salivary gland neoplasms taken for the study. The mean IRS scores for the MEC group and ACC group were compared with the presence or absence of lymph node involvement, distant metastasis or recurrence [Table 3]. It was observed that MEC, which showed the highest mean IRS for cathepsin-D expression, however, did not have any of the selected cases showing lymph node involvement, distant metastasis during the follow-up period or any reported recurrences. ACC, which showed lower cathepsin-D expression than MEC had three cases of reported recurrence. However, these three cases did not show a cathepsin-D expression score which was different from the cases of ACC which did not show recurrence.
Table 3: Depicts the mean immunoreactive scores for cathepsin-D expression among the four subgroups

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   Discussion Top


Salivary gland neoplasms constitute a heterogeneous group of lesions which can often pose a considerable amount of difficulty in diagnostic and prognostic assessment based on their histopathologic features alone. The salivary gland carcinomas comprise 5%–7% of all head-and-neck cancers and represent one of the most heterogeneous groups of neoplasms.[3] The histopathologic assessment of salivary gland tumors, especially the malignancies, has its own difficulties and limitations. Additional immunophenotypical markers would be valuable to predict the biological behavior and prognosis of salivary gland neoplasms.[4]

Our quest for an alternate marker led us to a few studies done on cathepsin-D, a lysosomal aspartyl protease that is involved in intracellular protein turnover.[5]

Cathepsins comprise a large class of lysosomal proteases involved in catabolism of proteins.[6],[7] Among them, cathepsin-D has a wide tissue distribution. It is secreted in small amounts in normal cells, while increased levels or its overexpression has been reported in several malignant neoplasms.[8],[9] Cathepsin-D is secreted as 52 kd precursor which is processed in the lysosome to an intermediate active enzyme (48 kd) and then to a mature form (34kd). It is active in acidic pH. It has both direct and indirect modes of action. It acts directly by digesting the extracellular matrix or indirectly by initiating the proteolytic cascade which is thought to be responsible for the breakdown of basement membrane.[10],[11] Cathepsin-D is also thought to be mitogenic by releasing certain growth factors and activating several growth factor receptors.[12]

Cathepsin-D expression has been extensively studied in breast carcinoma. Its overexpression has also been studied in carcinomas of the prostate, colorectal region, lungs, larynx, thyroid and oral squamous cell carcinoma.[7],[13],[14],[15],[16],[17],[18] However, studies of cathepsin-D expression in salivary gland tumors are very limited. There are only four or five studies which have explored the expression of cathepsin-D in salivary gland tumors, of which only one has actually carried out a comparative study of cathepsin-D expression in benign and malignant salivary gland neoplasms.

In the present study, the expression of cathepsin-D in benign and malignant salivary gland neoplasms is compared. We also compared the cathepsin-D expression in the malignant neoplasms with their reported incidence of lymph node involvement, recurrence and distant metastasis, while comparing the expression with the histologic grades/pattern of the tumors. Our study groups comprised two broad groups – malignant and benign. MEC and ACC made up the malignant group, while WT and PA were included under the benign group. Ten cases each were selected for the study from the Departmental archives to make a total sample size of 40 cases.

Expression of cathepsin-D between the malignant and benign tumors was found to be statistically highly significant (P = 0.004). This is in agreement with those reported in an earlier study carried out by Vigneswaran et al.[2] They studied the cathepsin-D expression in benign and malignant salivary gland tumors and observed a significantly higher expression in malignant tumors as compared to benign tumors. An individual intragroup comparison of cathepsin-D expressions was also carried out between MEC and ACC of the malignant group and between WT and PA of the benign group. MEC showed a higher expression of cathepsin-D (8 ± 3.601) when compared to ACC (4.464 ± 3.804). In the benign group, WT showed a higher expression (3.256 ± 2.679) as compared to PA (1.306 ± 1.871). A previous study by Vigneswaran et al., however, has reported equal expression of cathepsin-D by MEC and ACC. A more recent study by Punnya et al. showed a near equal expression of cathepsin-D by all cases of MEC and ACC.[19] Of the 10 MEC cases selected for our study, four cases were of low grade and intermediate grade while two were of high grade. Of the 10 ACC cases in our study group, six showed cribriform pattern while two cases showed tubular and solid patterns. We observed that there was no significant difference in the cathepsin-D expression between the different grades of MEC or between the different histologic patterns of ACC. This again, was contrary to the results reported by Punnya et al., who observed a positive correlation of cathepsin-D expression with the histologic grades of the tumor. They reported a higher expression of cathepsin-D in the solid variant of ACC as well as the high-grade variant of MEC, while the expression was much lower in the cribriform and tubular variants of ACC and the low-grade variant of MEC.

In the benign group, WT showed a clearly higher expression of cathepsin-D than PA cases, although the values were not statistically significant. There are no studies that exist in the literature which have done a similar comparison in the benign group of salivary gland tumors. An interesting observation in our study was the comparatively higher expression (though not significant) of cathepsin-D in WT than in PA cases. Since there are no similar studies in the literature to compare our results, we can only presume that the intense lymphoid stroma that comprises lymphocytic aggregates in the WT may have an influence on the expression of cathepsin-D. There are few studies which have reported an increased cathepsin-D expression in lymphocyte-rich inflammatory and delayed hypersensitivity reactions.[20],[21],[22] Probably in a similar role, the presence of the lymphoid stroma may have some bearing on the cathepsin-D expression in the WT cases. Moreover, the fact that WT has been suggested to be a delayed hypersensitivity reaction, our finding gives more credential to the fact that cathepsin-D expression has been reported earlier in delayed hypersensitivity reactions.[23],[24]

The overall cathepsin-D expression in our study groups shows a progressive increase in its expression from ACC to MEC and then from PA to WT. Although studies on salivary gland neoplasms are very limited, the cathepsin-D expression has been extensively studied in breast carcinomas. Overexpression of cathepsin-D in these lesions has been found to be associated with early recurrence, regional and distant metastasis and shorter overall survival.[25],[26],[27] The increased levels of cathepsin-D expression noted in the malignant group as compared to the benign tumors in our study could probably be attributed to the proteolytic role of cathepsin-D which results in degradation of extracellular matrix, thereby helping and facilitating invasion in the malignant neoplasms.[19] In addition to this, cathepsin-D is known to be mitogenic and is thought to activate certain oncogenes. It is also thought to stimulate growth factors brought about by its interaction with growth factor receptors such as EGFR and IGFR. It is also thought to stimulate angiogenesis and these facts are corroborated by several studies which have demonstrated increased growth factors, oncogenes as well as angiogenesis in malignant salivary gland carcinomas.[28],[29],[30],[31]

To explore a possible correlation with lymph node involvement, distant metastasis and recurrence in the malignant study group, we compared these parameters with the corresponding cathepsin-D expression scores in MEC and ACC. It was observed that only three cases of ACC showed reported recurrence. There were no other cases of either MEC or ACC which showed any of the positive clinical parameters which were listed above. However, all cases of MEC clearly showed a higher cathepsin-D expression than the ACC cases. Nevertheless, the increased expression of cathepsin-D in the malignant group needs to be given due importance as there are confirmed reports which states that overexpression of cathepsin-D in breast carcinomas have been proved to be associated with early recurrences, shorter survival and distant metastasis even in those cases which showed lymph node-negative initial presentation. In our study, none of the 20 cases of the malignant group have reported an initial lymph node involvement as per the medical-archival records, in spite of the relatively high expression of cathepsin-D, especially in the MEC group. This can well be kept in mind for more elaborate future studies on cathepsin-D expression in salivary gland carcinomas where a longer follow-up period would need to be taken for the study to observe the long-term recurrence or distant metastasis in those cases where there was no initial lymph node involvement.


   Conclusions Top


Our present study was performed to assess the expression of cathepsin-D in benign and malignant salivary gland neoplasms by IHC and to compare the expression values with the histologic grade/tumor pattern, lymph node involvement, distant metastasis and recurrence to derive a possible correlation between the overexpression of cathepsin-D and tumor grade and prognostic parameters. There is a significantly high expression of cathepsin-D in malignant neoplasms as compared to the benign ones. MEC gave the highest expression while PA gave the lowest. Thus, the expression of cathepsin-D is definitely higher in malignant salivary gland neoplasms.

We conclude that in both MEC and ACC, we did not observe any positive correlation between the high expression of cathepsin-D and the prognostic parameters. Of the 10 cases of MEC and 10 cases of ACC, only three had a reported recurrence during the follow-up period. There was no initial lymph node involvement or distant metastasis in any of these cases, all of which showed a high and uniform expression of cathepsin-D.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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