| Abstract|| |
Introduction: Malignant mesothelioma is an aggressive neoplasm arising from serosal lining and has a poor prognosis. Definite diagnosis requires confirmation through a biopsy; however, it is sometimes difficult on microscopic evaluation alone and requires the use of a wide panel of immunohistochemical markers. So, immunohistochemistry (IHC) is of paramount importance and must be routinely used for a definite diagnosis. Till date, very few studies on morphology and detailed IHC markers of mesothelioma have been reported from India. Aims: To analyze the histomorphological findings of malignant mesothelioma, study the utility and role of the various immunohistochemical markers. Material and Methods: A total of 76 cases of mesotheliomas diagnosed at a tertiary cancer center in Udaipur were analyzed retrospectively from January 2015 to January 2020. Comprehensive data were analyzed including demographic, clinical, radiological, histopathological features along with a wide panel of IHC markers. Results: Mesothelioma occurs over a wide age range from 40 to 70 years. It most commonly involved pleura in 68 cases (89.47%) with very few cases from the peritoneum. On computed tomography (CT) scan, nodular pleural or peritoneal thickening was present. On microscopy, the most common histopathological type was epithelioid mesothelioma (58 cases, 74.3%) followed by sarcomatous (9 cases, 12.8%), deciduoid (6 cases, 8.6%), and 3 cases of biphasic (4.3%). On IHC, WT1, mesothelin, and calretinin markers were positive in 85.91%, 80%, and 93.33% cases of mesothelioma, respectively. Other markers were helpful to rule out differential diagnosis in difficult scenarios. Conclusion: Therefore, the correlation of histopathology with clinico-radiological findings and judicious use of a panel of IHC markers is required for routine evaluation and definite diagnosis. IHC is also useful in situations with similar morphological spectrum in specific locations.
Keywords: Differential diagnosis, epithelioid type, histomorphological evaluation, IHC markers, mesothelioma, pleural involvement
|How to cite this article:|
Patel T, Aswal P. Malignant mesothelioma: A clinicopathological study of 76 cases with emphasis on immunohistochemical evaluation along with review of the literature. Indian J Pathol Microbiol 2021;64:655-63
|How to cite this URL:|
Patel T, Aswal P. Malignant mesothelioma: A clinicopathological study of 76 cases with emphasis on immunohistochemical evaluation along with review of the literature. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Dec 8];64:655-63. Available from: https://www.ijpmonline.org/text.asp?2021/64/4/655/328568
| Introduction|| |
Mesothelioma is a malignant tumor of the mesothelial lining of various organs. It is a rare tumor in the world and still rarer in India. The most common site is the pleural cavity for about 85% cases. Extrapleural sites are peritoneum, pericardium, tunica vaginalis, and other serosal layers., The earliest description of a possible chest wall (pleura) tumor was made in 1767 in which, Joseph Lieutaud, the founder of pathologic anatomy in France, found two cases of “pleural tumors” during his study of 3000 autopsy cases.
Recent data according to the Indian Council of Medical Research, National Cancer Registry Programme, suggest incidence rates in India accounting for 0.05–0.08 and 0.05–0.1 per 100,000 among men and women, respectively. The commonest cause of mesothelioma is linked to asbestos exposure in various literature with a long latency period ranging from 30 to 40 years. The incidence of mesothelioma is decreasing in developed countries due to reduced exposure in working and living areas, but in underdeveloped and developing countries it is increasing because of increased industrial and environmental exposure.
Mesothelioma occurs over a wide age range, but the vast majority of tumors are seen in patients aged more than 60 years. Mesothelioma patients clinically present with insidious onset of symptoms with a presentation in the form of pleuritic chest pain, dyspnea, cough, fatigue, or weight loss.,
Mesothelioma is difficult to diagnose on microscopy alone. Histopathologist must develop an algorithmic approach with thorough knowledge of all microscopic variants and IHC markers, also utilizing clinical and radiological findings. Pathological diagnosis of mesothelioma continues to expand gradually as new antibodies are exercised for IHC use. This is mainly applied to differentiate well-differentiated epithelioid mesothelioma from reactive mesothelial proliferation, sarcomatoid, or desmoplastic mesothelioma from reactive pleural fibrosis, and epithelioid mesothelioma from metastatic or pseudomesotheliomatous carcinoma, usually adenocarcinoma. The selection of IHC markers to be included in the panel differs depending on the tumor site, microscopic type, and the differential diagnosis assessed in the given case.,
A combined first-line regimen using cisplatin and pemetrexed is considered the gold standard for malignant mesothelioma. Younger age, epithelioid type (versus sarcomatoid or biphasic) of mesothelioma and Tumour(T), Nodes(N), Metastases(M) staging are indicators of longer median survival and strongly influence the therapeutic strategy.
There are only very few case studies in Indian literature that described a detailed analysis of histomorphological features and IHC markers. The study aimed to highlight different variants of mesothelioma and emphasize the role of routine use of IHC markers for definite diagnosis and to differentiate its variants from histological mimickers.
| Materials and Methods|| |
It is a retrospective study of 76 cases of mesothelioma diagnosed at a tertiary cancer center in Udaipur during 5 years between January 2015 and January 2020. Patients diagnosed based on hematoxylin-eosin (HE) stained biopsy and subsequently confirmed on IHC were included in this study. Patients with inadequate biopsy specimens and inconclusive IHC findings were excluded from the study.
All the cases were retrospectively analyzed for their clinical history, radiological findings (CT scan), microscopic features, and IHC results. Key clinical parameters including gender, age, history of smoking, and exposure to asbestos were also noted. Histopathological findings including histological subtyping were reported according to the WHO classification of pleural tumors (4th edition, 2015).
The following wide panel of IHC markers was studied: Cytokeratin (CK) 5/6, calretinin, mesothelin, WT-1, CK7, CK19, epithelial membrane antigen (EMA), thyroid transcription factor-1 (TTF-1), carcinoembryonic antigen (CEA), GATA-3, PAX-8, P40, P63, CD56, synaptophysin, MOC-31, CA125, CA-19.9, CDX2, CK20, glypican-3, HepPar-1, vimentin, S100, CD34, smooth muscle antigen (SMA) [Table 1].
HE stain was done using Harris hematoxylin with a regressive staining method. After dewaxing, rehydrate sections through graded alcohol. Stain in hematoxylin followed by bluing, differentiation, and eosin stain. Dehydrate through alcohol followed by clearing and mounting.
IHC was carried out on formalin-fixed tissue on fully automated IHC stainer (Xmatrx ELITE, Biogenex). Sections with 3–4 μm thickness were picked up on slides coated with poly-L-lysine, followed by overnight incubation at 37°C. Dewaxing using xylene followed by rehydration. Antigen retrieval was done in sodium citrate buffer, pH 6.0 at 100° for 20 min. After pretreatment with phosphate buffer saline and 3% H2O2, sections were incubated with primary antibody for 60 min, secondary antibody for 30 min, and horse radish peroxidase for 30 min. Diaminobenzidine chromogen for 5 min, with Mayer's hematoxylin counterstain, was used. Slides were dehydrated followed by clearing and Dibutyl phthalate Polystyrene Xylene (DPX) mounting.
Reactivity can be a nuclear, cytoplasmic, membranous, or combined pattern. During interpretation of IHC results, the location of the target antigens and reactivity patterns was studied. WT1, TTF-1, CDX2, PAX8, p40, and p60 with nuclear staining; for calretinin and S100 both with nuclear and cytoplasmic staining, for D2-40 and mesothelin with membranous staining; and for CK5/6, CK7, CK19, CK20, and vimentin with cytoplasmic staining were acknowledged as positive. To consider immunostain as positive, a cutoff of staining of at least 10% of tumor cells was applied as per the guidelines by the International Mesothelioma Interest Group.
| Results|| |
The age group of patients varies from 40 to 74 years. Of the 76 patients, 43 (56.5%) were male. The median age in men and women was 58.3 and 63.2 years, respectively. On the basis of clinical history, all patients were residents of a demographic area in southeastern Rajasthan where mining activities mainly of marble and granite quarrying are being carried out in extensive areas. Out of which 69 patients (90.78%) were workers in marble and granite quarries and gave history of average duration of exposure ranging between 10 and 18 years. A total of 70 patients (92.10%) had a history of chronic smoking. Most of the cases commonly involved the pleura (68 cases, 89.47%) with remaining cases from the peritoneum (8 cases, 10.52%). The most common complaint was an insidious onset of chest pain associated with dyspnea in 61 patients (80.26%), followed by dry cough and breathlessness in 35 patients (46%).Weight loss was seen in 30 patients (39.5%). Pleural effusion was present in 72 patients (95%). On CT scan, nodular/diffuse pleural/peritoneal thickening was present in 67 patients (88%). However, nine patients (12%) presented with negative findings on CT scan and later on thoracoscopy, pleural nodules were identified and biopsied.
All peritoneal mesothelioma cases had tumor markers (CA-125, CA-19.9, CEA) within normal limits. On microscopy, the most common histopathological type was epithelioid mesothelioma (58 cases, 76.31%), which includes solid (39 cases, 51.31%), tubulopapillary (13 cases, 17.10%), and other (06 cases, 7.9%) patterns. Other histopathological types were sarcomatoid (nine cases, 11.84%), deciduoid (six cases, 7.9%), and three cases of biphasic mesothelioma (3.94%).
On biopsy, epithelioid mesothelioma shows tumor cells arranged in tubular, papillary, and/or solid pattern. One case showed surface papillary projections with a deeper area showing invasion of stroma having a diffuse pattern. Deciduoid type shows large polygonal cells with round vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm. Biphasic mesothelioma shows admixture of epithelial and spindle cell component. Sarcomatoid type shows sheets of spindle cells with moderate atypia [Figure 1].
|Figure 1: Histopathological types: Epithelioid mesothelioma: (a-d) Tubular pattern. (10×; 20×, 20×; 40×). (e and f) Papillary and diffuse pattern (10×; 40×.). (g and h) Solid pattern. (20×; 40×). (i and j) Papillary pattern (20×; 40×). Deciduoid mesothelioma (k and l), showing large tumor cells with abundant eosinophilic cytoplasm. Few cells showing binucleation. (20×; 40×). Biphasic mesothelioma (m and n) consists of epithelial component admixed with spindle cell component (20×; 40×). Sarcomatoid mesothelioma (o and p) showing high cellularity, plump spindle cells with elongated nuclei and mitosis (10×; 40×)|
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On IHC WT1, mesothelin and calretinin markers were positive in 85.91% (61/71), 80% (52/65), and 93.33% (70/75) cases of mesothelioma, respectively. The sensitivity of calretinin is higher than WT-1 and mesothelin. CK-5/6 is positive in 83.3% (10/12) of the cases; however, this marker was studied in a lesser number of cases. All the epithelioid types of mesothelioma were 100% (58/58) positive for calretinin, 100% (10/10) positive for CK5/6, 89.28% (50/56) positive for mesothelin, and 92.85% (52/56) positive for WT-1. Both the deciduoid and biphasic types are 100% (6/6 and 2/2, respectively) positive for calretinin. Sarcomatoid types are 44.4% (4/9) positive for calretinin. All types of mesothelioma show high sensitivity for Cytokeratins (CKs) (CK7, CK19) (94.59%) but lack specificity, whereas EMA is positive in mesothelioma showing epithelioid component only (76.36%) [Table 2].
The cases I and II are of epithelioid pleural mesothelioma, in which IHC markers were applied to rule out the possibility of carcinoma [Figure 2] and [Figure 3]. Case III of peritoneal mesothelioma was differentiated from metastatic serous carcinoma using IHC markers [Figure 4]. Case IV showing a papillary pattern of pleural mesothelioma with positive nuclear WT1 [Figure 5]. Case V of deciduoid subtype and case VI of sarcomatoid mesothelioma showing CT scan, thoracoscopic, and IHC findings [Figure 6].
|Figure 2: Case I: (a) Contrast-enhanced CT chest showing right-sided pleural mesothelioma. (b-d) Mesothelin, calretinin and CK-7 showing positivity in tumor cells. (e) CEA negative in tumor cells. (f) CK19 positive in tumor cells. (g and h) Synaptophysin and CDX-2 negative in tumor cells. (i) Ki-67 showing positivity in tumor cells (about 10-15%). (j-l) CA-125, TTF-1 and PAX-8: negative in tumor cells|
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|Figure 3: Case II: (a) CT scan showing nodular, circumferential pleural thickening and calcified pleural plaques. (b) HE stained section shows neoplastic mesothelial cells invading underlying stroma. (c and d) WT-1 and EMA showing positivity in tumor cells. (e) Ki-67 stain on showing a high proliferative index. (f and g) CD56 and synaptophysin showing aberrant focal expression. (h and i) MOC-31 and p63: Negative in tumor cells|
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|Figure 4: Case III: (a) CT scan showing diffuse peritoneal mesothelioma. (b) HE stained section shows neoplastic epithelioid mesothelial cells embedded in a fibrous stroma. (c and d) Mesothelin and calretinin showing positivity in tumor cells. (e) CK7: Positive in tumor cells. (f ) CK20: Negative in tumor cells. (g) Ki67: About 20% positivity in tumor cells. (h-l) CEA, desmin, DNcocktail, GATA3, TTF1: Negative in tumor cells|
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|Figure 5: Case IV: (a) CT scan showing extensive pleural thickening in the right chest without free fluid. (b and c) HE stained sections show malignant mesothelial cells arranged in a papillary pattern. (10×, B), (40×, C). (d) WT-1: Nuclear positivity in tumor cells. (e) Mesothelin: Negative in tumor cells (f) CK7: Strong positivity in tumor cells. (g) p40: Negative in tumor cells (h) Ki-67: Showing a high proliferative index in tumor cells. (i) TTF-1: Negative in tumor cells|
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|Figure 6: Case V: (a) Contrast-enhanced CT (CECT) scan in mediastinal window shows pleural based circumferential nodular enhancing soft tissue thickening in left hemithorax. (b) Multiple nodules over costal pleura on thoracoscopy. (c) Deciduoid Mesothelioma, HE; 10×. (d) D2-40 Positive in Tumor cells. Case VI: (e) CECT scan in mediastinal window shows circumferential pleural thickening. (f) Thoracoscopic biopsy from pleural nodule. (g) Sarcomatoid mesothelioma with necrosis, HE, 10×. (h) WT1 positive. (i) Ki-67 showing high index in tumor cells|
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| Discussion|| |
Mesothelioma is a rare aggressive tumor showing diverse morphological spectrum. On extensive search, Indian literature shows only few case series and original articles on mesothelioma. A study of 24 cases was done in South India describing histopathological and IHC findings. Another study comprises of 15 cases spanning over 25 years from South India was also published. A smaller study with three cases over 10 years duration was reported. So to the best of our knowledge, this is the largest case study from India describing the clinicopathological features and detailed immunohistochemical review.
Asbestos (crocidolite variety) is considered the main risk factor. Other rare etiologic factors are radiation exposure, talc, erionite, or mica exposure. However, there are also a few reported cases of mesothelioma with no known source of asbestos exposure. Asbestos is a risk factor in only 50% of patients of peritoneal mesothelioma., Usually, the first investigation is chest X-ray showing pleural effusion. CT scan many times cannot differentiate mesothelioma from metastatic pleural malignancy. A Positron Emission Tomography (PET)-CT scan can differentiate benign from malignant disease, so it is utilized for diagnosis, staging, and biopsy guidance.,
Confirmation by biopsy and IHC is vital for definite diagnosis of mesothelioma. The most common mesothelioma subtype in the present study was an epithelioid type, constituting 52 cases (74.28%) comparable with studies by Hui et al., Sezer et al., Adel et al., Soomro et al., and other studies., The present study certifies that calretinin, WT1, and CK5/6 markers showed more sensitivity and specificity similar to other studies. Most studies also consider TTF-1 and CEA as most useful negative markers, comparable with the present study [Table 3].,,,,,,,
Selection of IHC panel markers depends on site of involvement, subtype, and differential diagnosis needed to be excluded. One study suggested a combination of four markers to rule out pulmonary adenocarcinoma, which includes calretinin and CK5/6 (or WT1) as mesothelial markers with MOC-31 and Ber-EP4 (or CEA) as epithelial markers. In a case of peritoneal epithelioid mesothelioma, the differential diagnosis would be serous papillary carcinoma of ovary and peritoneum. WT1 marker stains both mesothelioma and ovarian serous carcinoma, so their use is not advocated in the differential diagnosis. One study suggested calretinin and/or D2-40 as best positive mesothelial markers with MOC-31 and Ber-EP4 as best negative markers to exclude ovarian serous carcinoma., Few studies suggested that CK5/6 and D2-40 IHC markers are expressed by many cases of ovarian carcinoma., Serous carcinoma of the ovary and serous carcinoma of the peritoneum, both share identical phenotypic traits, which limits the role of IHC in their separation. In the present study WT1, calretinin, and mesothelin markers were utilized to rule out an extra pleural origin.
Clear cell variant of mesothelioma shows calretinin and CK5/6 unlike clear cell renal cell carcinoma (RCC)., Deciduoid variant of mesothelioma may be confused with ectopic decidual reaction, hepatocellular carcinoma (HCC), and adrenocortical carcinoma (ACC). Hep-Par1 and inhibin markers are expressed by HCC and ACC, respectively, but show negative results in mesothelioma. Only rare cases of mesothelioma showing solid pattern may require exclusion of SCC. WT1 and calretinin or mesothelin should be used as positive markers combined with p63 and MOC-31 to rule out SCC. CK5/6 marker is not used in this scenario, because it stains positive for both mesothelioma and SCC. p40 staining has high sensitivity and specificity compared to p63 and CK5/6, for differentiating SCC from mesothelioma.
Sarcomatoid mesothelioma shows a limited expression of mesothelial markers, with calretinin in 39–70% cases, CK5/6 in 0–29% cases, and Pan-CK in >70% cases., If initial CK is negative, then a secondary panel should include vimentin, desmin, S-100, CD34, FLI-1, STAT6, myoglobin and SOX10.,,, Differentiation between sarcomatoid carcinoma and sarcomatoid mesothelioma is difficult because both express Pan-CK with 90% sensitivity. Lineage-specific IHC markers TTF-1, napsin A, and p63/p40 favors sarcomatoid carcinoma. However, recent studies reported GATA3 marker 100% sensitive and 85% specific for sarcomatoid mesothelioma and MUC4 marker as 72% sensitive and 100% specific for sarcomatoid pulmonary carcinoma.
Desmoplastic mesothelioma must show at least 50% of desmoplastic pattern. Presence of chest wall fat/muscle invasion or tumor necrosis favors desmoplastic mesothelioma over the reactive stromal lesion., Solitary fibrous tumors are distinguished by positivity for CD34 and BCL-2, but negative for calretinin and Human Bone Marrow Endothelial cell marker-1 (HBME-1). Biphasic mesothelioma should comprise at least 10% of both components. Metastatic sarcomatoid carcinoma and metastatic melanoma can be differentiated by lineage-specific markers. Biphasic synovial sarcoma carries (X; 18) translocation and negative for mesothelial markers.
Differentiation between malignant mesothelioma and reactive mesothelial proliferation is crucial in small biopsy due to limited surrounding stromal tissue. Foci of frank stromal invasion favor malignancy. EMA and p53 seem to be preferentially expressed in mesothelioma, whereas desmin immunoreactivity is more common in the reactive mesothelium. Well-differentiated papillary mesothelioma shows surface papillary structures without stromal invasion but lacks submesothelial inflammation in contrast to reactive mesothelial hyperplasia. A benign adenomatoid tumor is a solitary, well-circumscribed, superficial nodule in contrast to multinodular pleural thickening of mesothelioma. Mesothelioma with a lobular pattern may resemble intrapleural thymoma which is ruled out by negative Tdt and CD1a. Vascular tumors, melanoma, and lymphoma may show pseudomesotheliomatous appearance, which can be ruled out by lineage-specific markers. On IHC, the positivity of large polygonal cells for cytokeratin in lymphohistiocytoid mesothelioma excludes lymphoepithelial carcinoma, lymphoma, or inflammatory pseudotumor.
However, recent publication data suggest a limited diagnostic value of older mesothelioma markers including p53, desmin, EMA, and GLUT-1. Novel IHC markers BAP1 (BRCA-associated protein), MTAP, 5-hmC (5-hydroxymethylcytosine), EZH2 (enhancer of zeste homolog 2) are more reliable in such a scenario. Nuclear BAP-1 loss is 100% specific for all mesothelioma including biphasic mesothelioma to rule out reactive mesothelial proliferation and to exclude metastasis from pulmonary, breast, gastric, peritoneal, ovarian, and other gynecologic serous carcinomas, however, limited role in excluding RCC and melanoma. Loss of cytoplasmic MTAP stain is 96-100% specific for mesothelioma including sarcomatoid type, which indicates deletion of CDKN2A (p16). Loss of 5-hmC nuclear staining and EZH2 overexpression on IHC is sensitive and specific for mesothelioma. HEG1 (heart development protein with EGF-like domains1) is a novel diagnostic and therapeutic mesothelial marker with higher sensitivity and specificity than WT1, calretinin, and D2-40. Claudin-4 is a relatively novel epithelial marker for mesothelioma. Few studies suggest that BAP-1 mutation is associated with favorable prognosis and longer survival. Novel marker programmed death-ligand 1 (PD-L1) with a positive expression on IHC is associated with poor prognosis. However, limited studies have been conducted for all these novel markers. So, multiple clinical trials and extensive studies at institutes need to be carried out before we apply them in a routine diagnostic panel.
In the present study, surprisingly all patients denied for any past exposure to asbestos. However, all patients were from the same demographic region of Southeastern Rajasthan (Vagad region), and 91% (69 patients) patients had a history of direct or indirect exposure to mining and quarrying industry of marble and granite. Mining and quarrying is a dust-releasing process and done extensively in this region of India. Asbestos is present in close association with marble in rocks and quarrying might lead to airborne asbestos fibers which may be implicated as a causative factor in this region. Therefore, further detailed studies need to be conducted to establish the role of airborne asbestos fibers or minerals other than the asbestos implicated in mesothelioma induction.
| Conclusion|| |
Mesothelioma is currently on a rise in the West, where asbestos was banned decades ago. Extensive studies need to be conducted to unravel the actual burden of mesothelioma cases in India and to ascertain the causative factors. It could rise to alarming levels in the next few decades in India if preventive and remedial measures are not implemented soon. Definite diagnosis based on histopathology and IHC plays a crucial role in the detection of confirmed cases and their appropriate management.
Judicious use of a panel of IHC markers is necessary to confirm the final diagnosis. On IHC, mesothelial markers, epithelial markers, and mesenchymal markers should be cautiously used to differentiate subtypes of mesothelioma from other carcinomas, sarcomas, reactive mesothelial proliferation, reactive pleural fibrosis, and other differential diagnoses. Use of novel mesothelial markers should be encouraged in future with diagnostic, prognostic, and predictive significance.
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Conflicts of interest
There are no conflicts of interest.
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Geetanjali Hospital Campus, NH-8 Bypass, Manvakhera - 313 002, Udaipur, Rajasthan
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]