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CYTOJOURNAL QUIZ CASE
CytoJournal 2018,  15:26

Cytologic examination of ascitic fluid in a patient with pleural-based mass: A unique presentation of a rare tumor


Department of Pathology and Radiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

Date of Submission08-Mar-2018
Date of Acceptance28-May-2018
Date of Web Publication15-Oct-2018

Correspondence Address:
Debasis Gochhait
Department of Pathology and Radiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cytojournal.cytojournal_7_18

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How to cite this article:
Dehuri P, Gochhait D, Rangarajan V, Sathiah P, Siddaraju N, Govindarajalou R. Cytologic examination of ascitic fluid in a patient with pleural-based mass: A unique presentation of a rare tumor. CytoJournal 2018;15:26

How to cite this URL:
Dehuri P, Gochhait D, Rangarajan V, Sathiah P, Siddaraju N, Govindarajalou R. Cytologic examination of ascitic fluid in a patient with pleural-based mass: A unique presentation of a rare tumor. CytoJournal [serial online] 2018 [cited 2018 Nov 21];15:26. Available from: http://www.cytojournal.com/text.asp?2018/15/1/26/243360

Editorial/Peer Review Statement
To ensure the integrity and highest quality of CytoJournal publications, the review process of this manuscript was conducted under a double-blind model (authors are blinded for reviewers and vice versa) through automatic online system.




A 47-year-female presented with complaints of cough, hemoptysis, and loss of weight for 1 month. Axial contrast-enhanced computed tomography showed moderately enhancing homogeneous left pleural mass, with associated mild pleural effusion. Pleural fluid cytology was followed by pleural biopsy. After 2 months, she had new complaints of pain and swelling of abdomen. Imaging studies revealed only ascites. Ascitic fluid was sent for cytological examination. The fluid was slightly viscous and hemorrhagic.


 » Question Top


What is your interpretation of cytology of ascitic fluid?

  1. Metastatic adenocarcinoma
  2. Reactive mesothelial proliferation
  3. Malignant mesothelioma
  4. Papillary mesothelial hyperplasia



 » Answer Top


The correct cytopathologic interpretation is:

C. Malignant mesothelioma

The cytopathologic diagnosis of malignant mesothelioma has always been challenging owing to the overlapping morphologic features with its other differential diagnoses. However, careful attention to the cytologic details combined with immunohistochemical staining on cell block can be of immense value in situations where cytological analysis of fluid may be the only available option.

In the present case, the cytologic features of malignant mesothelioma which overlapped with its closest differential diagnosis of metastatic adenocarcinoma were as follows:

  1. Arrangement of cells in tubulopapillary and acinar pattern [Figure 1]a1 and [Figure 1]a2
  2. Cellular pleomorphism [Figure 1]a1 and [Figure 1]a2
  3. Nuclear hyperchromasia
  4. Presence of peripherally arranged large vacuoles.[Figure 1]d2.


The cytomorphologic features (in the present case) which generally favor a malignant mesothelioma over metastatic adenocarcinoma are as follows:
Figure 1: (a1 and a2) The pleural fluid smears were very cellular comprising of three-dimensional papillaroid and tubular clusters of malignant cells. The tumor cells showed moderate pleomorphism, clumped chromatin, and prominent nucleoli. In addition, numerous mitotic figures were also noted (Papanicolaou stain). (b) Pleural biopsy showed pleomorphic tumor cells arranged in tubulopapillary and glandular pattern along with fibrocollagenous tissue (hematoxylin and eosin stain). (c1 and c2) Immunohistochemistry showed nuclear positivity for WT1 and nuclear and cytoplasmic staining for Calretinin. (d1) Ascitic fluid smears were highly cellular with formation of cell balls having knobby contours. In higher magnification, features such as cell-in-cell engulfment, giant atypical mesothelial cells were seen. (Papanicolaou stain). (d2) Irregularly distributed variable sized cytoplasmic vacuoles were also seen (May Grunwald Giemsa stain). (e1 and e2) Immunohistochemical stain done on cell block from ascitic fluid sample showing positive staining for calretinin and CK5/6

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  1. Presence of large cell balls with knobby or berry-like contours containing nuclei overlapping with each other
  2. Presence of giant mesothelial cells [Figure 1]d1
  3. Presence of cell-in-cell engulfment [Figure 1]d1.


The reactive mesothelial proliferations form smaller, uniform, less complex groups compared to malignant mesothelial proliferations.


 » Further Work up Top


The tumor cells were also positive for WT1, Calretinin [Figure 1]c1 and [Figure 1]c2 p53 and Cytokeratin 5/6 and stained negatively for PAX 8, BerEP4, Desmin, CEA, and TTF 1. With the biopsy diagnosis of malignant mesothelioma [Figure 1]b, neoadjuvant chemotherapy was planned for the patient. Other metastatic work-ups (including bone scan) were negative. There was no lymphadenopathy. Post three cycles of chemotherapy, pleurectomy, and decortication were done. The pleurectomy specimen comprised of multiple small bits and flap-like grayish brown tissue. The histopathological sections showed residual tumor cells (around 40%) with similar morphology as seen in the small biopsy along with areas of necrosis (post-neoadjuvant chemotherapy-induced changes). The patient was discharged after postoperative care, and she improved symptomatically over a period of 2 months. However, this improvement in symptoms was interrupted by new complaints of pain, discomfort, and swelling in the abdomen. On clinical evaluation, there was ascites which was tapped and sent for cytological examination. There was no evidence of any detectable mass lesion in ultrasonographic (USG) studies of abdomen and pelvis. With similar morphologic and immunohistochemical profile (which was performed on cell block [Figure 1]e1 and [Figure 1]e2) came a diagnosis of malignant mesothelioma involving both pleural and peritoneal cavities. No further radiological workup (other than USG) was possible as the patient did not survive for long after the presentation with ascites. The patient was a homemaker and did not have any history of exposure to asbestos in her life which is also an odd finding in our case.


 » Additional Quiz Questions Top


  1. Which virus has been implicated in the pathogenesis of malignant mesotheliomas?


    1. HTLV
    2. HPV
    3. SV40
    4. EBV.


  2. Which histologic subtype of mesothelioma is supposed to have grave prognosis?


    1. Epithelioid
    2. Sarcomatoid
    3. Mixed.


  3. Which subtype of asbestos fiber has the maximum propensity to cause mesothelioma?


    1. Serpentine
    2. Crocidolite
    3. Chrysotile
    4. Amosite.



 » Answers to Additional Quiz Questions Top


  1. SV40 is an oncogenic DNA virus. It induces DNA strand breaks in human mesothelial cells. The viral large T-antigen (Tag) inactivates the function of the tumor suppressor genes p53 and RB and induces chromosomal aberrations. The small t-antigen (tag) may contribute to transformation by binding to the protein phosphatase PP2A. The viral genomic sequences have been frequently detected in mesotheliomas, bone sarcomas, brain tumors, and few Non-Hodgkin's lymphomas
  2. Sarcomatoid pattern of mesothelioma is listed in the adverse prognostic factors of malignant mesothelioma
  3. Amphibole asbestos has the maximum propensity to cause mesotheliomas. There are two distinct subtypes, namely amosite and crocidolite. Crocidolite is more potent than amosite (5:1) in this association.



 » Brief Review of the Topic Top


Malignant mesotheliomas are rare tumors accounting for <1% of all cancer deaths in the world.[1] Mesothelioma involving the serosal sacs is known however mesothelioma involving more than one serosal cavity has rarely been reported.[2] The present case is an extremely rare report of pleural and peritoneal malignant mesothelioma which could be synchronous primary or metastatic.

Historically known to be a tumor induced by exposure to asbestos, the peak age of incidence is sixth to seventh decade;[3] however, our patient did not have any such history. The International Mesothelioma Interest Group panel recommends that a cytologic suspicion of malignant mesothelioma should be followed by biopsy confirmation that must be supported by appropriate clinical and radiologic findings.[4] There are many histopathological subtypes of mesothelioma such as the epithelioid (tubulopapillary, micropapillary trabecular, acinar, solid, clear cell, signet ring cell, small cell, rhabdoid, and pleomorphic), sarcomatoid or biphasic. Depending on the histological subtype, the cytology of the mesothelioma may be varied ranging from bland to very pleomorphic tumor cells.[4] Our case is the tubulopapillary subtype which closely mimics lung adenocarcinoma morphologically. In the pleural cavity, it has to be differentiated from involvement by lung adenocarcinoma which is the most common cause of pleural infiltration/mass with effusion. The epithelial cells can be differentiated from mesothelioma cells with the help of immunohistochemical markers (EMA, CEA-monoclonal, Ber-EP4, TTF1, Napsin A for epithelial origin while calretinin, CK 5/6, WT1, and D2-40 for mesothelial origin). Although EMA staining can be seen in both adenocarcinomas and mesotheliomas, the pattern of staining is different. While it is membranous in epithelial cells, the staining is cytoplasmic in mesothelioma. Morphologically high cellularity, large cell balls (50 cells) with berry-like pattern, complex papillary pattern with cellular stratification, cytologic atypia, very prominent nucleoli, and frequent mitotic figures including atypical ones differentiates mesothelioma from reactive mesothelial cells.[4] Other features such as intercellular windows, with lighter dense cytoplasm edges, and low nuclear to cytoplasmic ratios with the presence of macronucleoli are also mentioned.[5] However, these features have considerable overlap with reactive mesothelial cells. Hence, histopathology is a compulsory requisite for the definite diagnosis along with a panel of immunohistochemical markers.[6] Recent diagnostic markers such as a combination of BAP1 (BRCA-associated protein) immunohistochemistry and p16 FISH have been advocated by some authors. According to a study by Hida et al. the detection of loss of nuclear staining of BAP1 by IHC combined with the homozygous deletion of p16 detected by in situ hybridization offer a high sensitivity of 92.5% in the differentiation of benign versus malignant mesothelial cell proliferations.[7]

The cytomorphological diagnosis has been stressed on by some authors[8] considering the fact that cytological samples may be the only available material for the diagnostic workup. Furthermore, the situation is extremely critical in cases of peritoneal mesothelioma in women[9] as they have radiologic as well as pathological features mimicking advanced serous adenocarcinomas of abdomen. Peritoneal adenocarcinomas are immunohistochemically positive for panCk and negative for calretinin while both being positive for WT1.[4] There are reports of synchronous occurrence of mesotheliomas with other adenocarcinomas,[10],[11] but literature review reveals only an occasional report of this tumor involving both pleural and peritoneal cavities.[2]


 » Summary Top


Body fluids may be the only available sample for diagnosis of tumors affecting the serous cavities. Hence, detailed cytologic examination carries utmost importance in spite of morphologic overlaps.

Peritoneal mesotheliomas need to be distinguished from advanced intra-abdominal serous adenocarcinomas especially in women with the help of immunohistochemical stains pancytokeratin and calretinin.

Dual site mesothelioma is a rare possibility which may be encountered.


 » Acknowledgments Top


We would like to acknowledge the Department of Medicine and Radiology for their contribution in the diagnosis of this case.


 » Competing Interests Statement by All Authors Top


The authors declare that they have no competing interests.


 » Authorship Statement by All Authors Top


All authors of this article declare that we qualify for authorship as defined by ICMJE.

Each author has participated sufficiently in work and takes public responsibility for appropriate portions of the content of this article.

PD has contributed in the interpretation of the case findings and drafting of the manuscript.

DG has contributed in the interpretation of the case findings, drafting of the manuscript, and interdepartmental coordination.

VR has been involved in design and coordination.

PS has contributed in clinical detailing of the case and drafting of the manuscript.

NS has contributed in interpretation of case findings and drafting of the manuscript.

RG has contributed the radiological details and has been involved in drafting of the manuscript.

Each author acknowledges that this final version was read and approved.


 » Ethics Statement by All Authors Top


As this is a quiz case without identifiers, our institution does not require approval from Institutional Review Board (or its equivalent).


 » List of Abbreviations (In Alphabetic Order) Top


  1. BAP 1- BRCA-associated protein 1
  2. CECT - contrast-enhanced computed tomography
  3. Pan CK - Pancytokeratin
  4. SV 40 – Simian virus 40
  5. USG - Ultrasonography.


 
 » References Top

1.
Hammar S, Douglas WH, Sonja K, Ronald FD. Neoplasms of the pleura. In: Tomashefski JF, Cagle PT, Farver CF, Fraire A, editors. Dail and Hammar's Pulmonary Pathology. Neoplastic Diseases of Lung. Vol. 2. New York: Springer; 2008. p. 558-600.  Back to cited text no. 1
    
2.
Del Gobbo A, Fiori S, Gaudioso G, Bonaparte E, Tabano S, Palleschi A, et al. Synchronous pleural and peritoneal malignant mesothelioma: A case report and review of literature. Int J Clin Exp Pathol 2014;7:2484-9.  Back to cited text no. 2
    
3.
Churg A, Roggli V, Galateau-Salle F. Tumours of the pleura: Mesothelial tumours. In: Travis WD, Brambilla E, Müller-Hermelink K, Harris CC, editors. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press, International Agency for Research on Cancer; 2004. p. 128-36.  Back to cited text no. 3
    
4.
Husain AN, Colby T, Ordonez N, Krausz T, Attanoos R, Beasley MB, et al. Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the international mesothelioma interest group. Arch Pathol Lab Med 2013;137:647-67.  Back to cited text no. 4
    
5.
Whitaker D. The cytology of malignant mesothelioma. Cytopathology 2000;11:139-51.  Back to cited text no. 5
    
6.
Trupiano JK, Geisinger KR, Willingham MC, Manders P, Zbieranski N, Case D, et al. Diffuse malignant mesothelioma of the peritoneum and pleura, analysis of markers. Mod Pathol 2004;17:476-81.  Back to cited text no. 6
    
7.
Hida T, Hamasaki M, Matsumoto S, Sato A, Tsujimura T, Kawahara K, et al. BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests. Pathol Int 2016;66:563-70.  Back to cited text no. 7
    
8.
Davidson B. The diagnostic and molecular characteristics of malignant mesothelioma and ovarian/peritoneal serous carcinoma. Cytopathology 2011;22:5-21.  Back to cited text no. 8
    
9.
Baker PM, Clement PB, Young RH. Malignant peritoneal mesothelioma in women: A study of 75 cases with emphasis on their morphologic spectrum and differential diagnosis. Am J Clin Pathol 2005;123:724-37.  Back to cited text no. 9
    
10.
Attanoos RL, Thomas DH, Gibbs AR. Synchronous diffuse malignant mesothelioma and carcinomas in asbestos-exposed individuals. Histopathology 2003;43:387-92.  Back to cited text no. 10
    
11.
Bianchi C, Bianchi T, Ramani L. Malignant mesothelioma of the pleura and other malignancies in the same patient. Tumori 2007;93:19-22.  Back to cited text no. 11
    


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