|Year : 2019 | Volume
| Issue : 1 | Page : 11-17
Application of the Milan system of reporting salivary cytopathology – A retrospective cytohistological correlation study
Ramya Katta1, Devi Padmavathi Chaganti2
1 Department of Pathology, Dr. PSIMS and RF, Chinoutpalli, Gannavaram Mandal, Andhra Pradesh, India
2 Department of Pathology, Guntur Medical College, Guntur, Andhra Pradesh, India
|Date of Submission||15-Apr-2019|
|Date of Acceptance||15-Apr-2019|
|Date of Web Publication||26-Apr-2019|
Dr. Ramya Katta
Sai Balaji Residency, 1st lane, Jaya Prakash Nagar, LIC Colony, Vijayawada - 520 008, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Context: Fine needle aspiration cytology for salivary gland lesions has shown to be adequately sensitive and specific for diagnosing and treating salivary gland pathologies. The Milan System for Reporting Salivary Gland Cytopathology was developed and introduced to provide enhanced communication and improved overall care.
Aims: The present study was taken up to assess the accuracy (sensitivity, specificity, positive and negative predictive values) and risk of malignancy of various diagnostic categories when the Milan system is applied and particular emphasis has been laid on cases that showed varied cytohistopathological correlation to highlight the analytical intricacies.
Settings and Design: The present study is a two-year retrospective descriptive study conducted in a tertiary care hospital, Vijayawada.
Methods and Material: Fine needle aspiration smears, relevant clinical details, histopathological slides and final reports were retrieved from the Departmental archives. The FNA results of the present study were re-categorized according to the Milan system and number of false positives, false negatives, true positives and true negatives were assessed in comparison with the final histopathological diagnosis and thus the accuracy and risk of malignancy of each diagnostic category were calculated.
Results: The overall cytological diagnostic accuracy for differentiating malignant from benign tumors in the present study is 90%, with a sensitivity of 73.34%, specificity of 95.56%, positive and negative predictive values of 84.62% and 91.49% respectively.In the present study the highest risk of malignancy was seen in Atypia of undetermined significance (category III-100%) according to the Milan system.
Conclusions: Use of The Milan System of Reporting salivary gland Cytopathology can increase the overall effectiveness and communication with clinicians and between institutions thus improving the overall patient care.
Keywords: Cytology, FNAC salivary gland, histopathology correlation, Milan system
|How to cite this article:|
Katta R, Chaganti DP. Application of the Milan system of reporting salivary cytopathology – A retrospective cytohistological correlation study. J NTR Univ Health Sci 2019;8:11-7
|How to cite this URL:|
Katta R, Chaganti DP. Application of the Milan system of reporting salivary cytopathology – A retrospective cytohistological correlation study. J NTR Univ Health Sci [serial online] 2019 [cited 2019 Dec 14];8:11-7. Available from: http://www.jdrntruhs.org/text.asp?2019/8/1/11/257167
| Introduction|| |
Fine-needle aspiration cytology (FNAC) for salivary gland lesions has shown to be adequately sensitive and specific for diagnosing and treating salivary gland pathologies., However, the inherent morphological heterogeneity of the lesions, technical expertise of the performer, and quality of the cytological smear preparations and finally the experience of the cytopathologist in reviewing and diagnosing the lesions alter the ultimate diagnosis, treatment protocol, and outcome.,,, Usage of a single-category-based system of reporting provides enhanced communication between the pathologist and the clinician, between various institutions and improved overall care of the patient as already established in thyroid FNAC (The Bethesda System for Reporting Thyroid Cytopathology) and cervical Pap smear More Detailss (The Bethesda System for Reporting Cervical Cytopathology). The Milan System for Reporting Salivary Gland Cytopathology was developed and introduced with a similar rationale. This study was taken up to assess the accuracy (sensitivity, specificity, positive, and negative predictive values) and risk of malignancy of various diagnostic categories when the Milan system is applied and particular emphasis has been laid on cases that showed varied cytohistopathological correlation to highlight the analytical intricacies.
| Materials and Methods|| |
This study is a 2-year retrospective descriptive study conducted in a tertiary care hospital, Vijayawada. All salivary gland pathology cases that were registered between March 2016 and February 2018 were included in the study. Cases with no cytohistopathological correlation were excluded from the study. Fine-needle aspiration smears, relevant clinical details, histopathological slides, and final reports were retrieved from departmental archives. Direct percutaneous or transoral aspiration was done using a 22- or 24-gauge needle after taking informed consent from the patients. Smears were routinely fixed, processed, and stained using hematoxylin and eosin stains, and Leishman's stain was used wherever required.
The Milan System for Reporting Salivary Gland Cytopathology is an evidence-based reporting system that has been developed by an international consortium of qualified healthcare experts and has a total of six diagnostic categories including nondiagnostic, non-neoplastic, atypia of undetermined significance, neoplasm (benign or salivary gland neoplasm of uncertain malignant potential), suspicious for malignancy, and malignant.
The FNA results of this study were recategorized according to the Milan system, and number of false positives, false negatives, true positives, and true negatives were assessed in comparison to the final histopathological diagnosis, and thus the accuracy and risk of malignancy of each diagnostic category were calculated.
| Results|| |
A total of 69 cases of salivary gland pathology, all of those with histopathological correlation, were included in the study. The most common site was the parotid gland constituting 66.67% of cases. Salivary gland pathologies were most common in the fifth decade of life constituting 37.68% of cases, with a male preponderance (M:F ratio = 1.15:1) as depicted in [Table 1].
The cytological diagnoses have been tabulated in [Table 2], with particular mention of those with discordant histopathological diagnoses. Three cases had paucicellular yield even after repeat aspiration and hence were categorized as nondiagnostic. Non-neoplastic lesions constituted 13.04% of the cases, in which chronic sialadenitis was the most common diagnosis (four cases); along with one case each of retention cyst, lymphoepithelial lesion, benign cellular aspirate, chronic granulomatous lymphadenitis, and acute reactive lymphadenitis. However, when correlated with histopathology, one of the cases reported as retention cyst turned out to be a low-grade mucoepidermoid carcinoma (false negative for malignancy), and a case reported as benign cellular aspirate was a pleomorphic adenoma. The remaining 57 cases were categorized as neoplastic with the most common diagnosis being pleomorphic adenoma (34 cases). Of the 34 cases reported as pleomorphic adenoma on cytology, 3 cases turned out to be malignant – 2 cases of adenoid cystic carcinoma [Figure 1]a and [Figure 1]b and 1 case of intermediate grade mucoepidermoid carcinoma [Figure 2]a, [Figure 2]b, [Figure 2]c (false negative for malignancy). On cytology, a total of six cases were reported to have atypical features, uncertain malignant potential, or suspicious malignant features. These cases were concluded as low-grade mucoepidermoid carcinoma [Figure 3]a, [Figure 3]b, [Figure 3]c, high-grade mucoepidermoid carcinoma [Figure 4]a, [Figure 4]b, [Figure 4]c, pleomorphic adenoma [Figure 5]a, [Figure 5]b, [Figure 5]c (false positive for malignancy), intermediate grade mucoepidermoid carcinoma, adenoid cystic carcinoma, and oncocytoma [Figure 6]a and [Figure 6]b (false positive for malignancy), respectively, on histopathology. On the whole, four false negative for malignancy and two false positive for malignancy were reported [Table 3].
|Figure 1: False negative-(a) On cytology diagnosed as pleomorphic adenoma. (b) On Histopathology revealed to be adenoid cystic carcinoma|
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|Figure 2: False negative-(a, b) On cytology diagnosed as pleomorphic adenoma. (c)On Histopathology revealed to be Intermediate grade mucoepidermoid carcinoma|
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|Figure 3: (a, b) On cytology diagnosed as Suspicious of malignancy. (c) On Histopathology revealed to be Intermediate grade mucoepidermoid carcinoma|
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|Figure 4: (a, b) On cytology diagnosed as Suspicious of malignancy (c) Histopathology revealed to be High grade Mucoepidermoid carcinoma|
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|Figure 5: False positive- (a) On cytology diagnosed as Atypia of unknown significance (c) On Histopathology revealed to be pleomorphic adenoma|
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|Figure 6: False positive- (a) On cytology diagnosed as atypia of unknown significance (b) on Histopathology revealed to be oncocytoma|
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|Table 3: Depiction Of False Negatives And False Positives For Malignancy|
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On statistical analysis, the overall cytological diagnostic accuracy for differentiating malignant from benign tumors in this study is 90%, with a sensitivity of 73.34%, specificity of 95.56%, and positive and negative predictive values of 84.62% and 91.49%, respectively.
When the FNA results were categorized according to the Milan system, the most common category was benign neoplasms (category IVa), constituting 43 cases. The risk of neoplasm and risk of malignancy were calculated for each category separately as depicted in [Table 4].
In this study, the highest risk of malignancy was seen in atypia of undetermined significance (category III – 100%) followed by the malignant category (category VI – 87.5%), and the least risk of malignancy was seen in benign neoplasm category (category IVa – 6.9%) followed by the non-neoplastic category (category II – 11.1%).
| Discussion|| |
Specimen adequacy (both qualitative and quantitative aspects) in salivary lesions' FNACs has not yet been clearly defined. Several factors such as aspiration technique, gauge of the needle used, experience of the performer, target lesion characteristics, obscuring elements, smearing, and staining artifacts play an important role in the diagnosis, and hence the treatment protocol and the final outcome of the patient., Furthermore, considerable overlap in morphological patterns and cytomorphological heterogeneity within the same tumor can bring about difficulty in differentiating and exact subgrouping of tumors even in aspirates with abundant cell yield. Also, some typical qualitative aspects such as presence of chondromyxoid background and hyaline globules can help identify some diagnoses even when the cellularity is low. Thus, several studies have affirmed that use of rapid on-site evaluation (ROSE) technique can provide an obvious benefit in restraining the number of false negatives due to undersampling of lesions and also trim down the number of passes used to get the adequate sample for diagnosis., It has been shown that the ROSE technique can also reduce the total turnaround time and costs. The most important disadvantage of this technique is the need for a proficient on-site expert. Griffith et al. have proposed adequacy criterion of more than four high-power fields of epithelial cells. However, the Milan system has recommended using the adequacy criteria of TBSRTC – a minimum of 60 lesional cells in the diagnosis of salivary lesion as well for the time being.,
In addition, it has been postulated that diagnostic errors in reporting of salivary gland lesions could be a consequence of minimal communication between the pathologist and the treating doctor and inadequate knowledge of cytological diagnostic overlap and pitfalls. Studies have established that use of specialized head and neck FNAC request forms which provide adequate clinical and radiological information can improve the diagnostic accuracy of salivary gland FNACs.
The next important diagnostic pitfall is cystic salivary gland lesions. Cystic lesions can range from a non-neoplastic lesion like simple retention cyst to benign tumors like Warthin's tumor to malignant tumors like mucoepidermoid carcinomas. Most cystic lesions aspirations yield fluids which are poorly cellular making cytological diagnosis very tricky. Studies have suggested that diagnostic yield can be increased by reaspiration under radiological guidance.
Some authorities claim that use of image-guided core biopsies have better accuracy in diagnosing salivary gland lesions when compared with FNAC. Nevertheless, the risk of false negatives due to tumor heterogeneity and presence of cystic component cannot be overcome. Also, there is an additional risk of tumor seedling along the larger needle track in case of malignant lesions as stated by Supriya et al. However, use of robust ancillary techniques such as flourochromes, automated digital imaging, immunocytochemistry, DNA analysis, and proteomic studies may enhance the diagnostic accuracy and further treatment strategies.
The sensitivity and specificity of FNA in differentiating malignant from benign lesions vary from 54% to 98% and 88% to 99%, respectively,, in various studies. This study depicted a similar overall cytological diagnostic accuracy for differentiating malignant from benign tumors (90%), with a sensitivity of 73.34% and specificity of 95.56%.
As established by most studies, FNAC can determine neoplastic nature of lesions in most cases. However, the exact categorization and subtyping may be difficult due to shared cytological features, cell of origin, and tumor heterogeneity. Thus, many cases may have to be grouped under suspicious and indeterminate category, with numerous differential diagnoses varying from non-neoplastic to benign to malignant tumors. Precision of FNA salivary gland tumor subtyping is lower and ranges from 62% to 80%. In this study, six cases were categorized as suspicious or atypical providing multiple differential diagnoses, four cases were false negative for malignancy, two cases of false positive for malignancy, and five cases were subtyped incorrectly.
The most common benign and malignant lesions in the current analysis were pleomorphic adenoma and mucoepidermoid carcinoma, respectively, which is similar to that observed by Panchal and Shah and Rajat et al. Pleomorphic adenomas commonly exhibit a metachromatic fibrillary and frayed stroma which make their diagnosis simple. However, some cases may have hyaline globules, high cellularity, and squamous metaplasia which can result in overinterpretation as adenoid cystic carcinoma or mucoepidermoid carcinoma as seen in three of our cases.
As depicted in the current analysis, one case of pleomorphic adenoma and one case of onocytoma were falsely interpreted as malignant due to high cellularity and reactive changes seen in the cells. Our findings are similar to that of Cohen et al. and Hajdu and Melamed. Mucoepidermoid carcinoma, although the most common malignant tumor of major salivary glands, poses a diagnostic challenge in cytopathology. The false-negative interpretation is due to various reasons including paucicellularity, cystic fluid diluting tumor cells, presence of inflammatory cells, and degenerated epithelial cells in the aspirates. Misinterpretations are common as the bland-looking intermediate cells are mistaken as benign salivary gland cells and the scattered mucinous tumor cells are mistaken for histiocytes or mucus-containing macrophages. This erroneous interpretation occurred in two of our cases where mucoepidermoid carcinoma was diagnosed as pleomorphic adenoma and retention cyst.
Adenoid cystic carcinoma on cytology shows variable cellularity with small monotonous looking basaloid tumor cells and acellular homogeneous nonfibrillary extracellular matrix which takes different shapes from branching tubules, cylinders, to spheres. A distinctive feature of adenoid cystic carcinoma is its sharp interface between the matrix and tumor cells. Hyaline globules are not very specific for adenoid cystic carcinoma and can occur in basal cell adenoma, polymorphous low-grade adenocarcinoma, basal cell adenocarcinoma, epithelial myoepithelial carcinoma, and even basaloid squamous cell carcinoma. In this study, two cases were falsely interpreted as pleomorphic adenoma on cytology, but review of the smears showed that there was a distinct interface between the tumor cells and matrix which was initially missed. Similar observations were noted by Lee et al. and Kapadia et al.
Previous to the Milan classification, there were various classifications proposed to improve the clinical significance of salivary aspirates. Milleret al. used a five-tier system to classify salivary lesions as myxoid-hyaline, basaloid, oncocytoid, lymphoid, and squamoid lesions. Tessy et al. classified lesions as inflammatory, benign, malignant, and others. Griffith et al. used a four-category system – benign, Neoplasm of uncertain malignant potential (NUMP), suspicious for malignancy, and positive for malignancy. Rossi et al. classified salivary gland FNA specimens into six categories – unsatisfactory, non-neoplastic, neoplasm, atypical, suspicious, and malignant. Most of these classifications were proposed to circumvent the diagnostic pitfalls due to overlapping cytological features by assigning the aspirates into broad diagnostic categories and to also provide the probabilistic information and risk stratification. However, these classifications were complex and unmanageable, and thus did not stand the test of time.
The current analysis demonstrates that FNAC is a safe and reliable diagnostic tool for presurgical evaluation and management of salivary gland pathology. Furthermore, use of the Milan System for Reporting Salivary Gland Cytopathology can increase the overall effectiveness and communication with clinicians and between institutions, thus improving the overall patient care.
| Conclusion|| |
The Milan system of reporting salivary gland cytopathology is a risk stratification system having a great potential of escalating clinical communication, guide treatment and provide counselling for the patients and thus improving the overall care. However, further studies may be required to confirm its competence.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Griffith CC, Pai RK, Schneider F, Duvvuri U, Ferris RL, Johnson JT, et al
. Salivary gland tumor fine-needle aspiration cytology: A proposal for a risk stratification classification. Am J Clin Pathol 2015;143:839-53.
Liu CC, Jethwa AR, Khariwala SS, Johnson J, Shin JJ. Sensitivity, specificity, and posttest probability of parotid fine needle aspiration: A systematic review and meta-analysis. Otolaryngol Head Neck Surg 2016;154:9-23.
Schmidt RL, Narra KK, Witt BL, Factor RE. Diagnostic accuracy studies of fine-needle aspiration show wide variation in reporting of study population characteristics: implications for external validity. Arch Pathol Lab Med. 2014; 138 (1):88–97.
Song IH, Song JS, Sung CO, Roh JL, Choi SH, Nam SY, et al
. Accuracy of core needle biopsy versus fine needle aspiration cytology for diagnosing salivary gland tumors. J Pathol Transl Med 2015;49:136-43.
Tyagi R, Dey P. Diagnostic problems of salivary gland tumors. Diagn Cytopathol 2015;43:495-509.
Wei S, Layfield LJ, Li Volsi VA, Montone KT, Baloch ZW. Reporting of fine needle aspiration (FNA) specimens of salivary gland lesions: A comprehensive review. Diagn Cytopathol 2017;45:820-7.
Ali S, Cibas E. The Bethesda System for Reporting Thyroid Cytopathology: Definitions, Criteria, and Explanatory Notes. 2nd
ed. New York: Springer; 2018.
Nayar R, Wilbur DC, editors. The Bethesda System for Reporting Cervical Cytology, ed. 3. Definitions, Criteria, and Explanatory Notes. New York, Springer; 2015.
Rossi ED, Faquin WC, Baloch Z, Barkan GA, Foschini MP, Pusztaszeri M, et al
. The Milan system for reporting salivary gland cytopathology: Analysis and suggestions from initial survey. Cancer Cytopathol 2017;125:757-66.
Ashraf A, Shaikh AS, Kamal F, Sarfraz R, Bukhari MH. Diagnostic reliability of FNAC for salivary gland swellings: A comparative study. Diagn Cytopathol 2010;38:499-504.
Contucci AM, Corina L, Sergi B, Fadda G, Paludetti G. Correlation between fine needle aspiration biopsy and histologic findings in parotid masses. Personal experience. Acta Otorhinolaryngol Ital 2003;23:314-8.
Daneshbod Y, Daneshbod K, Khademi B. Diagnostic difficulties in the interpretation of fine needle aspirate samples in salivary lesions: Diagnostic pitfalls revisited. Acta Cytol 2009;53:53-70.
Diacon AH, Schuurmans MM, Theron J, Louw M, Wright CA, Brundyn K,et al
. Utility of rapid on-site evaluation of transbronchial needle aspirates. Respiration 2005;72:182-8
Baram D, Garcia RB, Richman PS. Impact of rapid on-site cytologic evaluation during transbronchial needle aspiration. Chest 2005;128:869-75
Nanda KD, Mehta A, Nanda J. Fine-needle aspiration cytology: A reliable tool in the diagnosis of salivary gland lesions. J Oral Pathol Med 2012;41:106-12.
Howlett DC, Menezes LJ, Lewis K, Moody AB, Violaris N, Williams MD. Sonographically guided core biopsy of a parotid mass. Am J Roentgenol2007;188:223-7.
Supriya M, Denholm S, Palmer T. Seeding of tumor cells after fine needle aspiration cytology in benign parotid tumor: A case report and literature review. Laryngoscope 2008;118:263-5.
Zubair B, Andrew SF, Nora K, Bruce MW. The Milan System for Reporting Salivary Gland Cytopathology. In: William CF, Esther DR, editors. The Milan System for Reporting Salivary Gland Cytopathology. 1st
ed.. American Society of Cytopathology. Springer International Publishing AG; 2018. p. 2-4.
Rajendra Santosh AB, Bakki SR, Manthapuri S. A review of research on cytological approach in salivary gland masses. Indian J Dent Res 2018;29:93-106.
] [Full text]
Panchal U, Shah GH. A cytological and histological comparative study of salivary gland lesions at tertiary health care centre. Int J Biomed Adv Res 2015;6:470-4.
Rajat G, Deepika D, Dinesh K, Jyotsna S. Fine needle aspiration cytology (FNAC) of salivary gland lesions with histopathological correlation in a district hospital of Jammu region. Indian J Pathol Oncol 2016;3:32-7.
Cohen MB, Ljung BM, Boles R. Salivary gland tumors. Fineneedle aspiration vs frozen-section diagnosis. Arch Otolaryngol Head Neck Surg 1986;112:867-9.
Hajdu SI, Melamed MR. Limitations of aspiration cytology in the diagnosis of primary neoplasms. Acta Cytol 1984;28:337-45.
Kumar N, Kapila K, Verma K. Fine needle aspiration cytology of mucoepidermoid carcinoma. A diagnostic problem. Acta Cytol 1991;35:357-9.
Lee SS, Cho KJ, Jang JJ, Ham EK. Differential diagnosis of adenoid cystic carcinoma from pleomorphic adenoma of the salivary gland on fine needle aspiration cytology. Acta Cytol 1996;40:1246-52.
Kapadia SB, Dusenbery D, Dekker A. Fine needle aspiration of pleomorphic adenoma and adenoid cystic carcinoma of salivary gland origin. Acta Cytol 1997;41:487-92.
Miller TR. FNA of salivary gland: Problems and pitfalls. San Francisco: Director of Cytology, University of California; 2006.
Tessy PJ, Jayalekshmy PS, Cicy PJ, Usha P. Fine needle aspiration cytology of salivary gland lesions with histopathological correlation – A two year study. Int J Healthc Biomed Res 2015;3:91-9.
Rossi ED, Wong LQ, Bizzarro T, Petrone G, Mule A, Fadda G, et al
. The impact of FNAC in the management of salivary gland lesions: Institutional experiences leading to a risk-based classification scheme. Cancer Cytopathol 2016;124:388-96.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]