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Pleura & peritoneum

Pleura mesothelial tumors

Mesothelioma versus adenocarcinoma

Authors: Jasmine Vickery, M.D., Aliya N. Husain, M.D.

Editorial Board Member: Jefree J. Schulte, M.D.

Last author update: 23 May 2022

Last staff update: 20 January 2023

Copyright: 2003-2024, PathologyOutlines.com, Inc.

PubMed Search: Pleura mesothelioma versus adenocarcinoma

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Table of Contents

Cite this page: Vickery J, Husain AN. Mesothelioma versus adenocarcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pleuramesovsadeno.html. Accessed May 4th, 2024.

Definition / general

Mesothelial proliferations are a spectrum of benign to malignant lesions of the lining of the serosal cavities
Adenocarcinoma is a malignant epithelial neoplasm with glandular differentiation

ICD coding

ICD-10:
- C45.9 - mesothelioma, unspecified
- C80.1 - malignant (primary) neoplasm, unspecified site

Epidemiology

Age and gender are unreliable distinguishing factors, as both tumors have a slight male predominance and peak incidence in patients over 65
History of asbestos exposure should not be taken into consideration by the pathologist when confirming or excluding mesothelioma; diagnosis should be made using morphology and immunohistochemical studies (Arch Pathol Lab Med 2009;133:1317)
Unlike adenocarcinoma, tobacco is not implicated in the causation of mesothelioma; however, tobacco (especially cigarette) smoke and asbestos can synergistically interact in the causation of lung cancer (Int J Environ Res Public Health 2019;17:258)
Etiologies and epidemiology for metastases are dependent on site of origin

Etiology

See epidemiology

Clinical features

Wide variety of symptoms can lead to a diagnosis of lung cancer and are not specific to a pathologic entity
Presenting symptoms include chest wall pain (unilateral or bilateral), pleurisy, cough and progressive dyspnea secondary to pleural effusion (Surg Pathol Clin 2020;13:73)
Both commonly present with insidious onset of chest pain or dyspnea
Other site specific symptoms may or may not be present in patients with metastatic carcinoma

Diagnosis

In the initial evaluation of patients with suspected malignant pleural mesothelioma, radiological imaging is essential
- Computed tomography (CT) of the chest is the primary imaging modality but magnetic resonance imaging (MRI) and positron emission tomography (PET) can provide additional information for surgical planning (Radiographics 2004;24:105)
- Further investigation of suspected malignant pleural mesothelioma includes thoracentesis of any existing pleural effusion with cytological examination and closed pleural biopsy
If there is not enough tissue to reliably distinguish mesothelioma and adenocarcinoma on closed pleural biopsy, surgical intervention via video assisted thoracoscopic, biopsy or open thoracotomy can be pursued (Eur Respir Rev 2016;25:472)
Concurrent bronchoscopy at the time of surgery can also be considered, as endobronchial lesions are typically not seen in mesothelioma and their presence argues against this diagnosis (Tuberc Respir Dis (Seoul) 2015;78:297)

Laboratory findings / pleural fluid measurements

High levels of hyaluronic acid (concentrations exceeding 100,000 ng/ml) are suggestive of mesothelioma (Respir Investig 2013;51:92)
Carcinoembryonic antigen elevation (CEA) in both serum and malignant pleural effusions has been associated with pulmonary adenocarcinoma (J Thorac Dis 2018;10:E340)
When malignant pleural effusions occur in either mesothelioma or adenocarcinoma, they are typically exudative effusions (Dtsch Arztebl Int 2019;116:377)

Radiology description

Mesothelioma
- Most often presents with unilateral disease
- Diffuse thick rind-like or nodular pleural thickening which may extend into the lung (Indian J Radiol Imaging 2013;23:313)
- May be associated with unilateral pleural effusion and ipsilateral lung volume loss
Adenocarcinoma of lung / metastatic carcinoma
- Lung primary: main finding is a lung mass / nodule which may extend to the pleura
- Metastatic adenocarcinoma: often multiple nodules in the lung or pleura
Pitfalls
- Both may have bilateral disease or mediastinal lymph node involvement
- Mesothelial diaphragmatic invasion with liver involvement can mimic a primary liver tumor

Radiology images

Images hosted on other servers:

Mesothelioma: CT
shows homogenously
enhancing
thickening

Pleural metastases in ovarian adenocarcinoma

Prognostic factors

75% of mesotheliomas are detected at stage III - IV at diagnosis
CT screening detected adenocarcinoma is usually at an earlier stage and has a better prognosis (J Natl Compr Canc Netw 2018;16:412)
Metastatic adenocarcinoma, is, by definition, high stage and has poor prognosis

Case reports

45 year old woman with pleural epithelioid mesothelioma and ALK translocation with response to targeted immunotherapy (Lung Cancer 2020;142:47)
61 year old man with pleural fluid asbestos bodies and lung adenocarcinoma (Rom J Morphol Embryol 2016;57:1171)
70 year old man with concurrent mesothelioma and lung adenocarcinoma (Respir Med Case Rep 2018;26:45)

Treatment

Surgical management depends on stage and resectability of the tumor

Gross description

Diffuse pleurotropic growth pattern is most common in mesothelioma (J Carcinog 2008;7:3)
Peripheral adenocarcinoma encasing the lung, so called pseudomesotheliomatous growth, will usually have a component involving the lung parenchyma

Gross images

Images hosted on other servers:

Pseudomesotheliomatous
growth

Diffuse malignant pleural mesothelioma

Frozen section description

There are no distinctive features that distinguish mesothelioma and adenocarcinoma on frozen section

Microscopic (histologic) description

Epithelioid variant is the most common histological subtype of mesothelioma and its principal differential consideration is adenocarcinoma; they are difficult to differentiate histologically if adenocarcinoma does not produce obvious mucin
Morphologic features of mesothelioma (J Clin Pathol 2006;59:564):
- Round or cuboidal tumor cells, paracentric nuclei, small nucleoli, moderate to abundant amount of cytoplasm with low nuclear to cytoplasmic ratio
- Often deceptively bland cytologic features
Morphologic features of adenocarcinoma (J Clin Pathol 2006;59:564):
- Tend to have columnar morphology with more pleomorphism, eccentric nuclei, prominent nucleoli, nuclear molding, cellular crowding and variable amount of cytoplasm
- More likely to have high nuclear to cytopasmic ratio
Background myxoid stromal change favors a diagnosis of mesothelioma but is not a definitive feature
Pitfalls:
- Papillary formations or psammoma bodies can be seen in reactive and malignant mesothelial proliferations as well as adenocarcinoma
- Intracytoplasmic vacuoles can be seen in both entities

Microscopic (histologic) images

Contributed by Aliya N. Husain, M.D.

Mesothelioma invading lung

Nuclear WT1 immunostaining

Metastatic mesothelioma in lymph node

Calretinin+

Focal lymphocytic inflammation

Invasive mesothelioma

CK 5/6

Epithelioid mesothelioma with papillary features

D2-40

GATA3+

Adenocarcinoma invading pleura

Acinar and solid growth patterns

Positive for TTF1 and napsin A

Claudin 4+

ER+

CDX2 reactivity

PAX8+

GATA3+

Cytology description

Adenocarcinoma appears as a distinct population from background mesothelial cells, while mesothelioma appears as a uniform population
Adenocarcinoma is the likeliest lung cancer cell type to generate a malignant pleural effusion and it is also associated with the highest cytological yield (Ann Transl Med 2019;7:352)
In adenocarcinoma, the cells may line up to form a picket fence arrangement
Cytomorphology of mesothelial cells consists of sheets or individual cells with windows between the cells
In 1 study, the 3 features that were statistically significant to distinguish mesothelioma from adenocarcinoma were: a giant atypical mesothelial cell being indicative of mesothelioma, in contrast to increased nuclear pleomorphism and acinar structures being indicative of adenocarcinoma (Diagn Cytopathol 2009;37:4)
Cytoplasmic vacuoles in reactive mesothelial cells tend to be paranuclear without indentation of the nuclear membrane, unlike in adenocarcinoma
Cytoplasmic vacuoles of mesothelial cells contain hyaluronic acid, while those of adenocarcinoma contain epithelial mucin
Pitfalls: both entities can occur as cell balls with smooth or knobby contours

Cytology images

Contributed by Takashi Hori, C.T., Akira Yoshikawa, M.D., Anja C. Roden, M.D. and Andrey Bychkov, M.D., Ph.D.

Adenocarcinoma cluster of tumor cells

Adenocarcinoma gold mucin

Adenocarcinoma papillary cluster

Pleural fluid with mesothelioma, epithelioid type

Mesothelioma brush border

Mesothelioma glycogen granules

Mesothelioma pleural effusion

Images hosted on other servers:

Giant atypical mesothelial cells

Mesothelioma pleural fluid

Adenocarcinoma pleural fluid

Adenocarcinoma large malignant cells

Mesothelioma parakeratotic-like cell

Immunohistochemical stains (positive and negative stains)

International Mesothelioma Interest Group recommends the initial diagnostic immunohistochemical panel should include at least 2 mesothelial markers and 2 general epithelial markers
For other tumors in the differential diagnosis, on the basis of morphology, specific markers can be added (e.g. TTF1, PAX8, etc.)
Use more markers if results inconclusive
Best positive mesothelioma markers: calretinin, CK5 or CK5/6, WT1, D2-40
Best positive carcinoma markers: claudin 4, MOC31, BerEP4, CEA and BG8 (Lewis antigen blood group)
Best positive lung adenocarcinoma markers: TTF1 and napsin (Arch Pathol Lab Med 2013;137:647)
Metastatic adenocarcinoma (Arch Pathol Lab Med 2009;133:1317)
- PAX8 is very useful for renal cell carcinoma; about 85 - 100% of renal cell carcinomas are positive; mesotheliomas are mostly negative
- Claudin 4 is positive in almost all lung adenocarcinomas, 90% of renal cell carcinomas, 98% of papillary serous carcinomas, 100% of gastric, pancreatic, colonic and biliary adenocarcinomas; mesotheliomas are always negative
- CDX2 is positive in 90 - 100% of colon, 80% of small intestine and 70% of gastric carcinomas and negative in mesothelioma
- PSA is often positive in metastatic prostatic adenocarcinoma and is always negative in mesothelioma
- Estrogen receptor is positive in 60 - 93% in serous and breast carcinomas and negative or has a very low positive rate (0 - 8%) in mesothelioma
- GATA3 is frequently positive in breast and urothelial carcinomas; however, 33 - 50% of epithelioid mesotheliomas also express GATA3
Strong diffuse staining for GATA3 favors a diagnosis of sarcomatoid / desmoplastic mesothelioma over metastatic sarcomatoid carcinoma of the lung (Am J Surg Pathol 2017;41:1221)

IHC stain	Mesothelioma	Adenocarcinoma	Staining pattern in positive cells
Calretinin	Positive	Negative	Nuclear and cytoplasmic
D2-40 (podoplanin)	Positive	Negative	Membranous
WT1	Positive	Negative	Nuclear
Cytokeratin 5 / 6	Positive	Negative	Cytoplasmic
Claudin 4	Negative	Positive	Membranous
MOC31	Negative	Positive	Membranous
TTF1	Negative	Positive	Nuclear
Napsin A	Negative	Positive	Granular cytoplasmic
B72.3	Negative	Positive	Membranous, cytoplasmic or both
BG8	Negative	Positive	Cytoplasmic
CEA (monoclonal)	Negative	Positive	Cytoplasmic with membrane enhancement
BerEP4	Negative	Positive	Membranous
BAP1	Loss in 60% of epithelioid MM	Retained	Nuclear

Special stains

With the advent of specific histochemical markers, these are now mostly historical and not useful in everyday practice
PAS after pretreatment with diastase or Alcian blue after hyaluronidase, positivity indicates neutral mucin which favors adenocarcinoma (Alcian blue without hyalurinadase is not helpful) (J Surg Oncol 1987;35:30)
Mucicarmine should not be used as it sometimes cross reacts with hyaluronic acid
Histochemical methods are most useful in epithelioid mesotheliomas and not useful in nonepithelioid mesotheliomas

Electron microscopy description

EM features	Mesothelioma	Adenocarcinoma
Apical microvilli	Long and thin, no glycocalyx	Shorter and have microvilli
Perinuclear tonofilament bundles	Present	Absent
Basal lamina	Present	Absent
Long desmosomes	Present	Absent

Helpful in distinguishing mesothelioma from adenocarcinoma in well differentiated tumors
Not helpful in distinguishing benign / reactive from malignant mesothelial proliferations
Reference: Ultrastruct Pathol 2006;30:3

Molecular / cytogenetics description

Most mesotheliomas (> 80%) harbor somatic alterations of the CDKN2A locus, 60% harbor somatic mutations and exonic deletions of the BAP1 gene and 30 - 50% show inactivation of NF2 (Transl Lung Cancer Res 2017;6:270)
Several driver gene alterations are known in lung adenocarcinomas including EGFR, KRAS and ALK

Additional references

Int J Clin Exp Pathol 2010;3:367, Galateau-Sallé: Macroscopic Features of Mesotheliomas, 1st Edition, 2006

Board review style question #1

Given the morphology of the above neoplasm involving the pleura, what would be the most useful initial panel of stains for diagnosis?

TTF1, BAP1, MOC31, CEA
TTF1, MOC31, p16, GATA3
WT1, calretinin, claudin 4, MOC31
WT1, D240, ER, CDX2

Board review style answer #1

C. WT1, calretinin, claudin 4, MOC31 is the only answer choice that has 2 mesothelioma markers (WT1, calretinin) and 2 adenocarcinoma markers (claudin 4, MOC31). BAP1 is lost in the majority of epithelioid mesotheliomas and is indicative of malignancy but is not a sensitive initial diagnostic marker. GATA3 and p16 are not specific to mesothelioma. ER and CDX2 are specific to certain metastatic adenocarcinomas but not other adenocarcinomas.

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Board review style question #2

Molecular alterations of which of the following genes is least likely to be occur in pleural mesothelioma?

ALK
BAP1
CDKN2A
NF2

Board review style answer #2

A. ALK. Genetic alterations in NF2, CDKN2A and BAP1 are commonly associated with epithelioid mesothelioma of the pleura. ALK-EML4 translocations are seen in 3 - 7% of lung adenocarcinomas. ALK alterations rarely occur in a subset of peritoneal mesotheliomas. Rare case reports of pleural mesothelioma with ALK translocations have now recently been described and although very uncommon are important to recognize because they may impact treatment options. (JCO Precis Oncol 2019;3:PO.19.00048, Transl Lung Cancer Res 2018;7:537)

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