|Year : 2018 | Volume
| Issue : 2 | Page : 190-195
Malignant mesothelioma: A histomorphological and immunohistochemical study of 24 cases from a tertiary care hospital in Southern India
Monalisa Hui1, Shantveer Gurulingappa Uppin1, Kakarla Bhaskar2, Narahari Narendra Kumar2, Gongati Kruparao Paramjyothi2
1 Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India
2 Department of Respiratory Medicine, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India
|Date of Web Publication||31-Dec-2018|
Dr. Shantveer Gurulingappa Uppin
Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
BACKGROUND: Malignant mesotheliomas are histologically heterogeneous neoplasms. Definite diagnosis requires a varied panel of immunohistochemical (IHC) markers to differentiate these from histological mimics. Only a few case series have been reported in the Indian literature where mesotheliomas have been analyzed on routine histology and IHC. AIM: To evaluate the histological features of malignant mesothelioma and to elucidate the best possible immunomarker combination useful in different scenarios. MATERIALS AND METHODS: A total of 24 cases of malignant mesotheliomas of different sites encountered over a 6-year period were retrospectively analyzed with regard to their histomorphology and IHC findings. RESULTS: The pleura was the most common site of involvement (16 cases) followed by peritoneum (5 cases) and pericardium (3 cases). Epithelioid mesothelioma was the most common histological type (15 cases, 62.5%) followed by sarcomatoid (5 cases, 20.84%), deciduoid (2 cases, 8.34%), and 1 case each of desmoplastic and biphasic mesothelioma. Among the mesothelial markers, WT1 was positive in 17 of 20 (85%) cases and calretinin was positive in 20 of 21 (95.23%) cases. D2-40 and CK5/6 were positive in all cases where they were studied. Adenocarcinoma markers TTF-1, napsin A, and CEA had very high negative predictive value in ruling out mesothelioma. CONCLUSION: The differential diagnosis of mesotheliomas varies with histological type and tumor location. Judicious use of various combinations of IHC markers in different situation has been highlighted in this article.
Keywords: Histological type, immunohistochemistry, mesothelioma
|How to cite this article:|
Hui M, Uppin SG, Bhaskar K, Kumar NN, Paramjyothi GK. Malignant mesothelioma: A histomorphological and immunohistochemical study of 24 cases from a tertiary care hospital in Southern India. Indian J Cancer 2018;55:190-5
|How to cite this URL:|
Hui M, Uppin SG, Bhaskar K, Kumar NN, Paramjyothi GK. Malignant mesothelioma: A histomorphological and immunohistochemical study of 24 cases from a tertiary care hospital in Southern India. Indian J Cancer [serial online] 2018 [cited 2019 Mar 25];55:190-5. Available from: http://www.indianjcancer.com/text.asp?2018/55/2/190/249211
| » Introduction|| |
Mesotheliomas are malignant neoplasms arising from the serosal lining of the body cavities. The most common sites of involvement are the pleura (60%–70%) followed by peritoneum (30%–35%), and pericardium (0.7%). Diagnosis requires a multimodal approach that includes clinical findings, imaging studies, and tissue sampling for routine histology and immunohistochemistry (IHC). IHC has emerged as the most valuable and readily available diagnostic modality for the routine evaluation of these tumors. There are not many case series in the Indian literature where mesotheliomas have been analyzed on routine histology and IHC. A comprehensive literature search for published Indian studies revealed a series of 15 cases of primary pleural mesotheliomas from South India in a 25-year study highlighting the clinicopathological features. Another study reported only three cases over a 10-year period. However, detailed study on the expression of various imunohistochemical markers has not been reported in Indian literature. The aim of this study was to evaluate the histological features of malignant mesothelioma (MM) with special emphasis on the best possible immunomarker combination that can accurately diagnose these tumors in different scenarios.
| » Materials and Methods|| |
In all, 24 cases of mesotheliomas diagnosed at the Department of Pathology at Nizam's Institute of Medical Sciences over a period of 6 years from January 2010 to December 2016 were analyzed retrospectively. The demographic data, clinical features, and imaging findings were retrieved from medical records. Diagnosis of pleural mesothelioma was made on biopsies which included both thoraco-scopic (10 cases) and core needle plural (6 cases). All cases of pericardial mesotheliomas were diagnosed on biopsy specimen. In one of them, pericardectomy specimen submitted following initial biopsy diagnosis was also examined. Abdominal mesothelioma cases were diagnosed on biopsy specimens submitted following exploratory laparatomy. All the specimens were received and fixed in neutral buffered formalin, routinely processed for paraffin embedding. The hematoxylin and eosin (H and E)–stained sections along with IHC slides were reviewed in all the cases. The panel of IHC markers performed on each case varied depending on the site, histological subtype, and differential diagnosis considered.
IHC was done on formalin fixed paraffin embedded (FFPE) sections by polymer horse radish peroxidase (polyHRP) technique on fully automated immunostainer (Xmatrx ELITE; Biogenex). The sections were kept for fixation at 80°C for 15 min. Dewaxing was done in six changes in dewaxing solution (provided by Biogenex) for 3 min each. Antigen retrieval was done in citrate buffer (pH 6.0) and Tris buffer (pH 9.0) for cytoplasmic/membranous and nuclear markers, respectively, for 15–20 min. The sections were cooled to room temperature and rinsed in phosphate buffer saline thrice before immersion in 3% methanol H2O2 for 10 min to block endogenous peroxidase activity and power block for 10 min to inhibit binding to nonspecific sites. Sections were incubated with primary antibody for 60–90 min, then secondary antibody (super-enhancer) for 20 min, and polyHRP for 30 min. The slides were rinsed twice with phosphate-buffered saline before each step. The antigen–antibody complex was visualized using diaminobenzidine as chromogen for 7 min. Sections were counterstained with Mayer's hematoxylin for 5 min, dehydrated, and mounted in DPX. The various immunohistochemical (IHC) markers included are listed in [Table 1].
The pattern of IHC staining was taken into consideration while interpreting the results of the mesothelioma specific markers. For WT1, nuclear staining, calretinin both nuclear and cytoplasmic, D2-40 membranous, and CK5/6 cytoplasmic staining were considered positive. A cut-off of staining in at least 10% of tumor cells was taken as positive as per the guidelines laid down by the International Mesothelioma Interest Group and other published data.,
| » Results|| |
Age, gender, site, histological subtype. and IHC findings in all 24 cases of MMs are listed in [Table 2]. The age of the patients ranged from 17 to 88 years with a peak incidence in fourth to sixth decade. There was male preponderance with a M:F ratio of 1.7:1. The most common site was pleura (16 cases) followed by peritoneum (5 cases) and pericardium (3 cases). None of the cases had any history of childhood or occupational exposure to asbestos or any history of irradiation. The clinical presentation varied depending on the site of involvement. Patients with pleural mesotheliomas primarily presented with cough, shortness of breath, and chest pain. There was pleural effusion with multiple nodules or diffuse pleural thickening. All patients of pericardial mesotheliomas presented with chronic constrictive pericarditis, cardiac tamponade. and heart failure. Two of these cases were initially diagnosed as tuberculosis and were started on treatment with antitubercular drugs. The patients of peritoneal mesotheliomas presented with abdominal pain and ascites. One case on contrast enhanced computed tomography (CECT) showed adnexal mass with ascites suggestive of carcinoma ovary. But CA125 levels were within normal limits. There was another case which showed omental caking on CECT. However, tumor markers (CEA and CA125) were within normal limits.
|Table 2: Age, gender, site, histological subtype, and IHC findings in all cases of malignant mesotheliomas|
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Epithelioid mesothelioma was the commonest histological type (15 cases, 62.5%) followed by sarcomatoid (5 cases, 20.84%), deciduoid (2 cases, 8.34%). and 1 case each of desmoplastic and biphasic mesothelioma. While epithelioid mesotheliomas involved all three sites, the sarcomatoid, desmoplastic and biphasic subtypes were confined only to the pleura. All the three cases of pericardial mesotheliomas were of epithelioid subtype and both deciduoid mesotheliomas encountered involved the peritoneum.
On histology, epithelioid mesotheliomas showed various architectural patterns ranging from tubulo-papillary to acinar and diffuse pattern with tubulo-papillary pattern being the commonest [Figure 1]. The histomorphological features in these had a close resemblance to carcinoma. and hence IHC was done to confirm the diagnosis. One case of pericardial mesothelioma on histology showed diffuse infiltration by cords of polygonal cells simulating Indian file pattern of arrangement, a pattern seen in infiltrating lobular carcinoma of breast. In addition, there were signet ring cells with intracytoplasmic vacuoles. The positivity for mesothelial markers on IHC ruled out a possibility of metastatic carcinoma in this case as well [Figure 2]. The sarcomatoid mesotheliomas showed sheets and fascicles of pleomorphic spindle cells with mitosis and necrosis. IHC helped to rule out mesenchymal tumors in these cases [Figure 3]. The deciduoid mesotheliomas comprised sheets of large, round to polygonal cells with abundant glassy eosinophilic cytoplasm and round vesicular nuclei with prominent nucleoli [Figure 4]. The biphasic subtype had a combination of epithelioid and sarcomatoid subtypes. The desmoplastic mesothelioma showed scattered spindle cells in a dense collagenous stroma.
|Figure 1: Epithelioid mesothelioma. (a) CECT thorax shows loss of lung volume on the left side with thickened nodular pleura. (b and c) Polygonal cells infiltrating fibroadipose tissue (H and E; ×100 and ×400). ((d-g) WT1, calretinin, D2-40, and CK5/6 showing positivity in the tumor cells (polyHRP; ×400). (h-j) Tumor cells negative for TTF1, napsin, and CEA (polyHRP; ×400)|
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|Figure 2: Pericardial mesothelioma. (a) CECT chest showing thickened pericardium. (b and c) Tumor cells infiltrating fibrocollagenous and fibroadipose tissue are arranged in nests and cords (H and E; ×40 and ×100). (d) Cells show pleomorphic vesicular nuclei and moderate amount of eosinophilic cytoplasm (H and E; ×400)|
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|Figure 3: Sarcomatoid mesothelioma. (a) Spindle cells arranged in interlacing fascicles (H and E; ×100). (b and c) Tumor cells positive for D2-40 and calretinin (polyHRP; ×100)|
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|Figure 4: Deciduoid mesothelioma. (a) CECT abdomen shows multiple peritoneal nodules. (b) Fragments of tissue removed at laporatomy. (c and d) Polygonal cells show glassy eosinophilic cytoplasm and round vesicular nuclei with prominent nucleoli (H and E; ×400). (e-j) Tumor cells positive for WT1, calretenin, D2-40, CK 5/6, Pan CK, CK7 (polyHRP; e, f 400 × and g-j ×100). (k and l) Tumor cells negative for ER and CDX2 (polyHRP; ×100)|
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The results of the IHC markers in various histological subtypes are listed in [Table 3] and [Table 4]. Among the mesothelial markers, WT1 was positive in 17 of 20 (85%) cases and calretinin was positive in 20 of 21 (95.23%) cases. All the four cases negative for the above mesothelioma markers were of sarcomatoid subtype. D2-40 and CK5/6 were positive in all the cases where they were studied. Apart from these, the non-specific markers such as Pancytokeratin and Cytokeratin 7 were studied in few cases. Pancytokeratin was positive in five out of six mesotheliomas (epihelioid 2, sarcomatoid 2, and biphasic 1). One case that was negative was sarcomatoid subtype. CK7 was positive in all four cases where it was studied (epithelioid 3, deciduoid 1). All the adenocarcinoma markers studied were negative in mesotheliomas except for one case of epithelioid mesothelioma which was unusually positivite for TTF-1. This case in addition was positive for all four mesothelioma markers, that is, WT1, calretinin, D2-40, and CK5/6 and was negative for other adenocarcinoma markers napsin, A and CEA. Hence, it was finally categorized as mesothelioma. Another case of epithelioid mesothelioma showed positivity for CEA but was negative for TTF1 and positive for WT1 and calretinin. Smooth muscle actin (SMA), S100, CD34, Bcl2, CD31, CD21, CD117, and ALK were negative in cases of sarcomatoid mesothelioma wherever done. Negative staining for ER and CDX2 excluded metastatic carcinoma in cases of peritoneal MM. The sensitivity of calretinin was higher than WT1 (95.24% vs 85%). Although D2-40 and CK5/6 were 100% sensitive, the number of cases studied with these markers was less. All the adenocarcinoma markers had a very high negative predictive value in ruling out mesothelioma.
| » Discussion|| |
The highest incidence of MM has been reported from some countries in Europe, Australia. and New Zealand. According to the Indian Council of Medical Research, National Cancer Registry Programme. the incidence is much lower in India accounting for 0.05–0.08 per 100,000 among men and 0.05–0.1 among women. MMs are histologically heterogeneous tumors predominantly seen in males with a peak age incidence in the fifth to sixth decade. The most common etiology in cases of pleural and peritoneal mesotheliomas is linked to asbestos exposure with a long period of latency ranging from 30 to 40 years. Surprisingly, in our study none of the cases had history of any occupational exposure. The other etiological factors include simian virus 40 and history of prior irradiation. It has an insidious onset with clinical presentation ranging from pleuritic chest pain, dyspnea, cough, fatigue, and weight loss. All three cases of pericardial mesotheliomas presented with constrictive pericarditis. So MMs should be suspected in all cases of long-standing unexplained constrictive pericarditis. The peritoneal mesothelioma presents with vague symptoms such as abdominal pain, distention, anorexia, and weight loss and thus leads to advanced disease at presentation. Radiological features reveal diffuse irregular pleural thickening with massive pleural effusion. CECT is helpful in all suspected cases to delineate the extent of the lesion. Kawashima et al. in their series of 50 cases of MM found pleural thickening in 92% cases and thickening of the pleural surfaces of the interlobar fissures in 86% cases. They also noticed pleural effusion (74%), calcifications (20%), and chest wall invasion (18%). Positron emission tomography is effective in differentiating MM from a reactive process and is also useful for staging. Tumors which diffusely infiltrate the pleura pericardium or peritoneum mimic MM clinically and radiologically. Histology is the gold standard for diagnosis. An adequate biopsy should be interpreted in the background of appropriate clinical, radiologic, and surgical findings. There is morphological overlap between a reactive mesothelial proliferation and MM. Both can have papillary configuration with nuclear atypia and entrapment of cells within a fibrous stroma mimicking a neoplasm. In such cases, definite diagnosis requires the presence of stromal or fat invasion. All the cases in our study were large expansile masses with definite evidence of stromal and or fat invasion excluding the possibility of reactive mesothelial proliferation.
As epithelioid mesotheliomas display a variety of histological pattern, its distinction from adenocarcinomas involving the serosal cavities is difficult on light microscopy. There are no established guidelines for the use of specific antibody panels. A combination of two “positive” mesothelial and two “negative” carcinoma markers has been advocated by the International Mesothelioma Panel. The choice of IHC markers to be included in the panel varies depending on the location, histologic type, and the differential diagnosis considered in each case. The primary differential diagnosis for pleural epithelioid mesothelioma is metastatic lung adenocarcinoma. The use of epithelial markers in combination with the mesothelial markers is thus required for a definite diagnosis. In our experience, a panel of CEA, TTF1 and napsin A in combination with mesothelial markers (calretinin, CK5/6, D2-40, and WT-1) was useful to rule out pulmonary adenocarcinoma. One case which had unusual positivity for TTF1 was positive for all the four mesothelioma markers and negative for napsin A and CEA excluding the possibility of lung adenocarcinoma. Imaging studies in this case were also consistent with mesothelioma as the lesion was restricted to pleura with no evidence parenchymal involvement. Similar TTF1 positivity in MM has been reported by Richter G. et al. They further stated that TTF-1 positivity does not necessarily rules out MM.
In case of discordant results, a panel of markers should be expanded and include additional markers for a definitive diagnosis. The role of mesothelial markers is limited in differentiating MM from squamous cell carcinoma as CK5/6, D2-40, and to a lesser extent calretinin are also positive in squamous cell carcinoma. Thus, WT1 is the most appropriate mesothelial marker when differential diagnosis includes squamous cell carcinoma.
The use of IHC is limited in sarcomatoid mesothelioma. Initial evaluation of a sarcomatoid tumor involving the pleura should include cytokeratins, calretinin, and D2-40 in the panel. Expression of other mesothelioma markers WT1 and CK5/6 is limited. In our experience, WT1 was negative in three of four cases and calretinin in one out of three cases studied. Strong and diffuse positivity for CK limits the differential diagnosis to sarcomatoid carcinoma and synovial sarcoma. Berg et al. in their study have shown that GATA3 had a sensitivity of 100% and a specificity of 85% in distinguishing sarcomatoid MM from sarcomatoid carcinoma. However, GATA3 was not included in our panel of IHC markers. The spindle cell component of a sarcomatoid carcinoma is difficult to differentiate from sarcomatoid mesothelioma in inadequately sampled small biopsies. The use of mesothelioma markers calretinin and D2-40 is recommended in such cases. Expression of CK is often variable or absent in sarcomatoid mesotheliomas. In this study, CK was negative in one out of three cases of sarcomatoid mesothelioma. Focal cytokeratin positivity may be seen in some sarcomas as well. So panel of IHC markers with sarcomatous differentiation should also be included. The MMs involving peritoneum mimic papillary peritoneal serous carcinoma or metastatic serous carcinoma of the ovary. IHC is an useful ancillary test for confirmation of diagnosis. WT1 and CK5/6 are commonly expressed in serous carcinomas and are not useful in distinguishing between epithelioid mesotheliomas and serous carcinomas. Thus, in cases of peritoneal mesotheliomas especially in females, the panel of mesothelial markers should include D2-40 and calretinin. Negative staining for ER helps confirm the diagnosis. Metastatic deposits to the peritoneum are also seen in other non-gynacological malignancies originating from stomach, pancreas, and colon. Therefore, IHC panels have to be adjusted accordingly. CK5/6 is not useful in this setting as it stains 38% pancreatic adenocarcinoma. The usefulness of calretinin as a single marker is also limited as it stains 10% of pancreatic adenocarcinoma. So if differential diagnosis includes metastatic non-gynecological malignancy, then a combination of D2-40 and WTI as mesothelial markers is useful.
Fibrous pleuritis closely resembles desmoplastic mesothelioma on morphology. IHC with desmin, EMA, and p53 are helpful in differentiating the two entities. The former is positive and the latter two are negative in the reactive mesothelial cells.
Till date, there is no single reliable antibody with absolute sensitivity or specificity. In this study, the sensitivity of various mesothelioma markers was comparable with other studies [Table 5]. Ordanez et al. reported high sensitivity for calretinin, cytokeratin 5/6, and WT1 for epithelioid mesothelioma and recommended the use of these antibodies as positive mesothelioma markers. The membranous staining pattern for D2-40 has also shown similar sensitivity. It also demonstrates high specificity in differentiating epithelioid MM from pulmonary adenocarcinoma. Chu et al. in their study found that the sensitivity of D2-40 is similar to that of calretinin, slightly higher than CK 5/6, and markedly superior to WT1.
|Table 5: Comparison of IHC results of different markers used in present with other studies|
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| » Conclusion|| |
The differential of mesotheliomas varies with histological type and tumor location. Definite diagnosis is difficult on histopathology alone and requires the use of a wide panel of IHC markers. In pleural epithelioid mesotheliomas, a combination of any two of mesothelial markers (calretenin, D2-40, WT1, and CK 5/6) in addition to two negative carcinoma markers especially TTF-1 and napsin will be useful to rule out lung adenocarcinoma. In sarcomatoid mesotheliomas, apart from mesothelial markers such as calretinin and D2-40, the panel should include CK and various mesenchymal markers. In peritoneal MM especially in females, the use of calretinin and D2-40 in combination with ER is helpful to rule out serous carcinomas. Judicious use of various combinations of IHC markers in different situation has been highlighted in this article.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]