Immunohistochemical Diagnostic Approach in Neoplastic Pathology of Mesothelium

Keywords

Immunohistochemistry; Differential Diagnosis; Malignant Mesothelioma; Metastasis; Histological Variant

Editorial

Malignant mesothelioma (MM) is a highly aggressive tumor originating from the mesothelial cells lining the serosal cavities; therefore, the most common locations of this tumor include the pleura, followed by peritoneum, pericardium and tunica vaginalis testis [1].

According to the 2015 WHO classification, MM is classified in three major histopathologic patterns including epithelioid, sarcomatoid, and mixed (biphasic) [2]. In detail, about 70% of mesotheliomas are predominantly epithelioid, 25% biphasic and 5% sarcomatoid [2,3]. Within the category of epithelioid mesothelioma, a variety of growth patterns has been described including tubulopapillary, papillary, micropapillary, trabecular/glandular/acinar, solid, deciduoid and pleomorphic [4]; less commonly, MM cells may be clear, signet ring, small cells or rhabdoid. The sarcomatoid MM is the least frequent, but the most aggressive variant of mesothelioma [5]; histologically, it is composed of a proliferation of spindle-shaped cells arranged in a fascicular pattern of growth that may closely mimic other soft tissue tumours like fibrosarcoma or malignant fibrous histiocytoma. In addition, heterologous elements such as immature cartilage and bone tissue may be encountered in sarcomatoid MM [6]. Finally, a subset of MM, referred as “desmoplastic MM”, displays extensive stromal collagenization and “bland” histological appearance, difficult to distinguish from benign fibrous pleuritis [7]. Biphasic mesothelioma is histologically characterized by a combination of epithelioid cells and sarcomatoid cells in varying proportions. In this MM variant, the prognosis depends on the mixture of cells, being more favourable in cases containing more epithelial cells than sarcomatoid cells [2,4].

The diagnosis of pleural MM can be very challenging because it usually depends upon pathological assessment of small pleural bioptic fragments or cytological specimens; moreover, MM displays a wide variety of morphological features with a tendency to mimic other malignant neoplasms or benign/reactive conditions [2-5]. Indeed, the common challenge in mesothelial pathology is represented by the distinction between reactive mesothelial proliferations and MM, since morphological features between these two entities may overlap [8]. In fact, mesothelial cells can exhibit reactive changes as a consequence of several benign conditions that determine an injury such as chronic inflammation and infection, heart failure, cirrhosis, nephrotic syndrome, lung infarction and collagenopathies [8,9]. In all these conditions, in pleural effusions as well in serosal tissue fragments, a cellular increase associated with papillary/morular clusters or solid sheets can be observed. In comparison to normal mesothelium, the reactive cells exhibit an increased size with nuclear enlargement, prominent nucleoli and numerous mitotic figures [8,9]. In difficult cases, the morphological crucial characteristic helping to distinguish reactive mesothelial hyperplasia from MM is represented by the stromal tissue invasion [9,10]; however, when morphological features alone are insufficient for the distinction between malignant and benign mesothelial lesions, further analyses are mandatory. Another intriguing point is represented by the differential diagnosis between MM and other entities, such as metastatic carcinomas (lung, breast and gastrointestinal tract), sarcomas and lymphomas [10,11].

Taking into consideration the above mentioned heterogeneous morphologic appearance of MM, the diagnosis of this tumor may be not uncommonly very difficult to establish and it should be based not only on morphology, requiring appropriate immunohistochemical procedures [2,4,11].

Recently, practical strategies and recommendations for the MM diagnosis have been suggested and updated by expert pathologists in national consensus conferences [2,12,13]. However, there are still several controversies regarding the reliable immunohistochemical algorithm to apply in the differential diagnosis between MM and reactive mesothelial proliferations, MM and adenocarcinomas, MM and sarcomas with spindle cell components. The diagnostic immunohistochemical algorithm usually depends on the histologic MM subtype as well as on the MM location (pleural versus peritoneal). Accordingly, the recent guidelines on the diagnosis of MM, recommend that at least 2 mesothelial and 2 carcinoma markers should be always used in MM cases, utilizing either immunopositivity either negativity to achieve the final diagnosis [10-13]. Nevertheless, if the results are discordant, a next expanded algorithm has to be applied (Table 1) [11,13]. Once the neoplastic nature of the lesion has been confirmed, a further necessary step is represented by the correct identification of the MM subtype and its differentiation from other malignancies.

  

    
Positive Markers 
    
Negative Markers 
  
  

    
Pan-CK 
    
CK7 
  
  

    
CK 5/6 
    
CK20 
  
  

    
Calretinin 
    
MOC-31 
  
  

    
WT1 
    
BER-EP4 
  
  

    
D2-40 
    
TTF-1 
  
  

    
HBME-1 
    
Napsin-A 
  
  

    
EMA 
    
Claudin-4 
  
  

    
GLUT-1 
    
P40 
  
  

    
P-53 
    
P63 
  
  

    
IMP-3 
    
PAX-8 
  
  

    

    
CDX2 
  
  

    

    
BAP1 
  
  

    

    
Desmin 
  

Table 1: Most useful positive and negative immunostains in mesothelial
pathology.