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© AME Medical Journal. All rights reserved. AME Med J 2020 | http://dx.doi.org/10.21037/amj-2019-mpe-07
Introduction
Pleural carcinosis is caused by the implantation of
malignant cells to the visceral and/or parietal pleura, and
the most common result is the development of malignant
pleural effusion (MPE). Metastasis to the pleura (carcinosis),
along with pleural effusion, is a late event in the course
of many malignancy. Almost all malignant tumors at an
advanced stage can affect the pleural cavity; however,
certain malignancies are more prone to involve the chest.
These are malignancies of colon, breast, kidney, stomach,
pancreas, prostate, soft tissues, and genital tracts. It has
been estimated that 15% of all kinds of cancer patients will
develop pleural effusion as a result of pleural metastasis
of the primary cancers (1). Patients with metastatic lung
cancers may present clinically with signs and symptoms
related to pleural involvement or may be initially
asymptomatic. Diagnosis is never simple and treatment is
unfortunately only symptomatic and palliative. Established
praxis for treatment of MPE is well known, based on
standardised guidelines (2,3). It is evident that all the
conventional thoracic treatments such as thoracocentesis,
Review Article
Pleural carcinosis caused by extrathoracic malignancies
Marcello Migliore1, Misel Milosevic2, Bojan Koledin2
1Thoracic Surgery, Department of Surgery and Medical Specialities, University of Catania, Catania, Italy; 2Institute for Lung Disease of Vojvodina,
Sremska Kamenica, AP Vojvodina, Serbia
Contributions: (I) Conception and design: M Migliore; (II) Administrative support: None; (III) Provision of study materials or patients: M Migliore;
(IV) Collection and assembly of data: M Migliore; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final
approval of manuscript: All authors.
Correspondence to: Marcello Migliore, MD, PhD. Professor Thoracic Surgery, Thoracic Surgery, Policlinic University Hospital, Via Santa Soa 78,
Catania, Italy. Email: mmiglior@unict.it.
Abstract: Most of malignant tumors at an advanced stage can affect the pleural cavity creating malignant
pleural effusion (MPE). Pleural carcinosis secondary to extrathoracic malignancies has not been extensively
reported, and different treatments have been described. Although 40% of all cases of MPE are due to lung
cancer, the second-most common is breast cancer (25%), lymphoma (10%), ovarian cancer (5%), and gastro-
intestinal cancers (5%). For approximately 5% to 10% of MPE, no primary tumor can be found (cancer of
unknown primary). Denite evidence of a MPE can be obtained by cytological or histological conrmation
of cancer cells. taken using Uniportal surgery increases diagnostic accuracy as large biopsies could be
taken and used to perform supplementary tests for more advanced management such as immunotherapy
or hormone receptor status for breast cancer. Conventional thoracic treatments such as thoracocentesis,
chest tube drainage, pleurodesis, video-assisted thoracic surgery (VATS) procedure have shown extremely
limited effect on quality of life and long-term survival which ranges between 4–12 months. New technology
procedures such as hyperthermic intrathoracic chemotherapy (HITHOC) or immunotherapy have shown
some potentiality. With an eye toward the future, the main aim of this article is to provide a summary of the
well-known treatments for pleural carcinosis caused by extrathoracic malignancies with the main intention to
contribute to clarify decisions making.
Keywords: Malignant pleural effusion (MPE); uniportal video-assisted thoracic surgery (VATS); extrathoracic
malignant effusion; Talc pleurodesis; hyperthermic intrathoracic chemotherapy (HITHOC); hyperthermic
chemotherapy
Received: 16 April 2020. Accepted: 10 July 2020.
doi: 10.21037/amj-2019-mpe-07
View this article at: http://dx.doi.org/10.21037/amj-2019-mpe-07
8
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© AME Medical Journal. All rights reserved. AME Med J 2020 | http://dx.doi.org/10.21037/amj-2019-mpe-07
chest tube drainage, pleurodesis, video-assisted thoracic
surgery (VATS) procedure have highly limited effect.
Mechanical decompression and creation of adhesions in
case of pleurodesis result in a 4 to 12 months length of life,
and some improve of QOL, according to most published
data.
This article provides a summary of the well-known
treatments for pleural carcinosis caused by extrathoracic
malignancies with the main intention to contribute to
clarify decisions making for this common clinical problem.
Incidence
The incidence of MPE with pleural carcinosis in Europe
is approximately 375,000 to 400,000 new patients/year,
and has been found at autopsy in 15% of patients with
malignant tumors and in 42–77% of exudative pleural
effusion. Although 40% of all cases of MPE are due to
lung cancer, the second-most common is breast cancer
(25%), lymphoma (10%), ovarian cancer (5%), and gastro-
intestinal cancers (5%). For approximately 5% to 10% of
MPE, no primary tumor can be found (cancer of unknown
primary). In our previous experience with 23 patients with
malignant disease and pleural effusion due to extrathoracic
disease 39.1% were due to breast cancer and 21.7% were
idiopathic (Table 1).
Pathophysiology
The parietal pleura has a more significant impact to
pleural fluid exchange than the visceral pleura, and this is
probably secondary to the closeness of the parietal pleura
to microvessels and lymphatics. The regular volume of
pleural uid is around 0.26 mL/kg body-weight. When in
the chest the balance between production and absorption
of the pleural fluid is compromised, pleural effusion is
unavoidable. Pleural carcinosis creates an irritation of the
pleura leading to increase development of interstitial pleural
uid as a consequence of augmented permeability.
Clinical symptoms
The extent of the effusion is the main responsible for the
symptoms and signs, progressive dyspnea, accompanied
or not by chest pain, and cough is a common symptom.
Nevertheless, symptoms of the underlying malignancy
are frequently associated, and the patent’s overall physical
condition is often reduced.
Diagnosis
The main question is if histopathological confirmation of
pleural carcinosis is mandatory in a patient with previous
cancer elsewhere. In the real life when MPE is suspected
a chest X-ray is the first diagnostic step, and patients
with pleural carcinosis usually have medium-large pleural
effusions. For some authors ultrasound (US) is not only
complementary to radiological investigations of the chest
but often provides better results, and therefore, should
be the first imaging examination method after chest
radiography in presumed pleural disease. Nevertheless,
recently, US has been demonstrated to be unreliable for
establishing this method as the rst diagnostic tool (4).
Computed tomography scan (CT) and magnetic
resonance offer more data in many patients with suspected
tumors of the chest. Moreover, MPE is not rare ndings on
the follow up HRCT in final stage of malignant diseases,
even yet in asymptomatic patients. In case of massive
effusion, thoracocentesis should performed to conrm the
presence of bloody MPE, and to permit the lung to expand
as it is important to evaluate the presence of a trapped lung
or lobe to individualize the treatment. Nevertheless, denite
evidence of a MPE can be obtained only by cytological or
histological verification of cancer cells. The accuracy of
cytological proof of cancer cells range, from 50% to 90%.
Diagnostic accuracy increases by a large biopsy taken using
uniportal video-assisted thoracic surgery (U-VATS) (5-7).
Moreover, the large biopsy can also be used to perform
supplementary tests for more advanced management such
as immunotherapy or hormone receptor status for breast
cancer.
Table 1 Clinical experience with 23 patients with extrathoracic cancers
Metastatic cancer Number (n=23)
Breast 9
Thymus 2
Malignant lymphoma 2
Bladder 2
Rhabdomyosarcoma 1
Kidney 1
Larynx 1
Idiopathic 5
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© AME Medical Journal. All rights reserved. AME Med J 2020 | http://dx.doi.org/10.21037/amj-2019-mpe-07
Prognosis
In general, patients with pleural carcinosis and MPE have
poor quality of life, prognosis is dismal, with a mean survival
of approximately 4–12 months survival rate of around 18%.
Karnofsky performance status (KPS) represents the only
statistically signicant predictor of survival, and it is useful
in choosing the type of treatment/palliation in patients with
MPE. A limit of 40 or more KPS shown better outcomes
for patients planning pleurodesis (8). Prognosis is inuenced
by biological aggressivity of malignancy, histology of
the tumor, timely diagnosis, and the success of relatively
narrow field of therapeutic thoraco-surgical procedures.
In particular, the survival is longer in patients with breast
cancer compared with patients with stomach or ovarian
tumor.
Treatment
There is no doubt that the main objective of surgery
in patients with pleural carcinosis is palliation with the
intention to improve length and quality of life, and
decreasing the recurrence of the effusions. The rst step of
the treatment for patients with MPE is the fully evacuation
of the pleural effusion and, if the lung expands, pleurodesis.
Possible operative treatments options are summarized in
Table 2. Although at an initial stage minor pleural effusions
can be monitored, in case of progression with increasing
dyspnea, pleural effusion must be evacuated before a trapped
lung develops. Malignant diseases cause besides MPE also
paramalignant pleural effusion, which is categorized by the
absence of malignant cells. The distinction between those
two is of paramount importancy because they greatly differ
in prognosis and treatment (9).
Cytoreductive surgery has the main aim to reduce
tumor mass but it’s value in the management of pleural
carcinosis need confirmation. In presence of a chemo-
sensitive primary tumor (e.g., lung, breast, prostate cancer,
lymphoma), systemic chemotherapy may be used while
the effects of such therapy on pleural metastases is highly
questioned in case of synchronous or metachronous cancer.
Furthermore, radiotherapy may further improve survival.
Pleurodesis and permanent pleural catheters have been
showed in retrospective studies to improve quality of life
in patient with MPE. Nevertheless, there exist only one
prospective randomized trial comparing indwelling pleural
catheters to talc pleurodesis (10).
Thoracentesis
Thoracentesis is fundamental for two reasons. Firstly,
because it is useful to perform an accurate diagnosis in two-
thirds of patients with pleural carcinosis and malignant
effusion, and secondly because it alleviates dyspnea. Patients
with complete post thoracocentesis pulmonary expansion
are eligible for future pleurodesis.
Chest drain insertion
The insertion of a chest drain is suggested in case of fast
recurring pleural effusions following a thoracentesis, and
to give antineoplastic drugs (e.g., bleomycin) or talc for
pleurodesis. Recurrent MPE, usually after two complete
thoracentesis indicate the need for insertion of chest drain.
Chest tube insertion carries with its own risks. Because it is
a pathway for potential infection, patients with chest drain
require monitoring of inammatory parameters. In the case
of prolonged secretion, despite pleurodesis, a thoracic tube
with Heimlich valve may also represent a denite option for
palliation.
Indwelling pleural catheters
When the lung does not expand after a thoracentesis or
general conditions are poor, indwelling pleural catheters
can be used as an outpatient procedure (11). Several
authors have shown safety and effectiveness with a
success rate of 91%, and low complications. Moreover,
because it has been shown that the use of this type of
catheter achieves spontaneous pleurodesis in 26-58% of
patients, in many circumstances it is likely to eliminate
the catheter (12). In another case controlled and cohort
study it has been shown that median survival was
3.4 months and did not differ signicantly between breast
(n=39, 23%), lymphoma (n=12, 7%), or other extrathoracic
Table 2 Medical and surgical procedures
Thoracocentesis
Indwelling pleural catheter
Chest drain
VATS pleurodesis
Cytoreductive surgery P/D
HITHOC
HITHOC, hyperthermic intrathoracic chemotherapy.
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© AME Medical Journal. All rights reserved. AME Med J 2020 | http://dx.doi.org/10.21037/amj-2019-mpe-07
cancer (n=56, 34%). One or more complications such
as erroneous placement of tools or iatrogenic lesions
occurred in 19 patients (19%). Some authors performed
a randomized trial comparing the efficacy and safety of
indwelling tunneled pleural catheters and traditional
doxycycline pleurodesis showing a short hospital stay and
low recurrence rates for indwelling pleural drain (13).
VATS talc pleurodesis
Although minimally invasive surgery can be performed with
1, 2 or 3 ports, since 20 years we prefer uniportal VATS
(14,15) which can be performed under local anesthesia
and sedation or under general anesthesia using single or
double lumen tube (5,16). Pleural biopsy, drainage of simple
or complex effusion and lung decortication can be easily
performed before talc pleurodesis/poudrage. Success ranges
between 85% and 93%, depending on the local findings
and the primary tumor. In our previous experience with
extrathoracic pleural malignant effusion we performed
uniportal talc pleurodesis as a spray powder in 51 patients
with a success rate at 30 days of 90% (46 out 51 patients).
Chest tubes were removed at 5±2 days (range, 2–9 days) and
hospital stay was 6±2 days (range, 2–10 days). Morbidity
was present in 12 (22%) patients (atrial fibrillation and
hyperpyrexia) (5) (Table 2). Among patients with MPE
and no previous pleurodesis, the TIME2 Randomized
Controlled Trial showed no signicant difference between
IPCs and talc pleurodesis at relieving patient-reported
dyspnea (17).
Debulking surgery
Pleurectomy and decortications are the main surgical steps
of debulking surgery which have been used mainly for
mesothelioma surgery. This type of surgery is associated
with high complication rates such as bleeding or empyema
(25%) and mortality rates which range, from 10% to
19% (18,19). When numerous pleurodeses have failed,
pleurectomy could be a possible option for highly selected
symptomatic patients with better prognosis (e.g., breast
cancer). Although EBM proofs for such intervention for
pleural effusion do not exist, at the moment pleurectomy
is not an alternative to pleurodesis or the insertion of an
indwelling pleural catheter. British Thoracic Society (BTS),
the European Society of Thoracic Surgeons (ESTS) and the
European Respiratory Society (ERS) do not recommend
pleurectomy as an alternative to pleurodesis or indwelling
pleural catheter in recurrent malignant effusions (2,20).
Hyperthermic intrathoracic chemotherapy
(HITHOC)
The use of HITHOC has the main goal to sterilized
the chest by injecting a chemotherapeutic agent into the
cavity which leads to increased exposure of tumor cells
to the agent itself. Hyperthermia improvs the efficacy
of chemotherapy. Ried et al. have shown under ex vivo
hyperthermic conditions, that cisplatin penetrates into
human lung tissue with a median penetration depth of
approximately 3–4 mm (21). Other authors (22) performed
VATS biopsy and HITHOC in 54 patients with MPE with
74.1% 1-year survival rate (23).
Cytoreductive surgery and HITHOC
In the chest, pleurectomy/decortications combined
with HITHOC has been used for pleural mesothelioma
and secondary tumors such as thymoma with pleural
involvement (24-27). HITHOC has already been performed
in individual patients with pleural carcinosis detected
intraoperatively during elective lung cancer resection and
resulted in improved survival (28-31). To date, cytoreductive
surgery and hyperthermic perfusion is not recommended
as treatment for patients with secondary pleural carcinosis,
unlike peritoneal carcinosis. This is because no curative
approach exists, as tumor growth is usually advanced and
generalized. The significance of this combination therapy
for pleural carcinosis might be demonstrated in the future.
Nevertheless, it is interesting to remember that already
in 1972, the concept of immune system activation in the
scenery of thoracic cancers was introduced by investigators
who noted enhanced survival in patients with empyema
after resections for lung cancer (32).
Pleural carcinosis secondary to metastatic
breast cancer
A review showed that 119 out 660 patients with breast
cancer developed thoracic metastases, which was also the
initial site of tumour recurrence. Metastases were most often
intrathoracic or intra-extra thoracic. In general the median
survival after diagnosis of MPE is less than and a solitary
thoracic metastasis which was 42 months (33). A randomized
study was performed in patients with breast cancer with
MPE. Patients underwent to VATS abrasion or bedside
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talc slurry (5 g). Pleurodesis was not signicantly different,
but hospital stay was shorter in the surgical group (5.5 vs.
7.5 days, P<0.05), and complication rate and mortality were
also better (16% vs. 26% and 0% vs. 9.5%) (34).
Pleural carcinosis secondary to hematologic
malignancies
Although all hematologic malignancies can present with
or develop pleural effusions, Hodgkin and non-Hodgkin
lymphomas present malignant carcinomatosis with a
frequency of 20% to 30%. A study on 833 patients with
pleural effusions of unknown etiology demonstrated that
pleural biopsy through medical thoracoscopy achieved
a definite diagnosis of B-cell NHL in 9 out of 10 (90%)
patients with MPE. The authors concluded that MT is a
useful method for diagnosing MPE induced by NHL. In
most cases, pleurodesis is necessary (35-37).
Pleural carcinosis secondary to ovarian cancer
Ovarian cancer is the 5th most common malignancy
which metastasis in pleura. From 2012–2018, according
to GLOBOCAN, mortality rate of ovarian cancer become
a higher with 0.1%, from 4.3–4.4%. Approximately 75%
of patients with ovarian cancer are diagnosed in advanced
stages (III–IV), which include spreading the tumor into the
pleural space. Cervical cancer they encompass 10% of all
new cases in 2018. Cervical cancer with an estimated over
500,000 cases and over 300,000 deaths in 2018 worldwide,
ranks as the fourth most frequently diagnosed cancer
and the fourth leading cause of cancer death in women.
Endometrial cancer is the most common cancer of the
female genitals. Hematogenous spreading are very rare, and
most common way of spreading is through pelvic and para-
aortic lymph nodes, pelvic viscera or adnexa. Incidence of
extra-pelvic, pulmonary metastasis is 2.3–4.6%.
Pleural carcinosis secondary to gastro-intestinal
cancers
Pleural carcinosis and MPE from gastrointestinal carcinoma
are not frequent, and involve about 5% of all MPE.
Advanced stage in colorectal cancer (CRC) is characterized
by distant metastasis usually in liver and lung. Pleural
manifestation is rare and reserved for end stage of mCRC
disease. Because the colon is drained by the portal system
metastatic disease is not expect in other organs without the
presence of the tumor in the liver. Rectal cancer, on the
other site, can be spread through the portal and systemic
venous system and can be present in pleural space in
majority of cases of mCRC. The presentation of CRC as
pleural effusion and isolated pleural metastasis without the
involvement of lung parenchyma is very rare. Theoretically
tumor cells can be spread via pulmonary circulation
and then involve parietal or visceral pleura. The data of
pulmonary metastasis of gastric cancer are very limited.
The most common way of spreading is hematogenous
(52.3%) followed by pleural (35.2%) and lymphangitic
(26.4%). Pancreatic cancer is also a possible cause of MPE,
but extremely rarely in the final stages. Checking the
amylase in the pleural effusion can conrm the etiology of
such effusion. Portal hypertension of every, even malignant
etiology, is a possible cause of pleural effusion. Mechanism
is well known and presented with movement of ascites uid
trough diaphragmatic defects. Bacterial superinfection with
enterobacteriaceae is most common complication in such
liquidothorax.
Pleural carcinosis secondary to renal carcinoma
MPE secondary to renal cell carcinoma is rare and
constitutes only about 1% to 2% of all MPEs. Moreover,
even though the lung is one of the most common sites of
metastasis of renal cell carcinoma the involvement of pleura
has been reported in about 12% of the autopsies of patients
with metastatic renal cell carcinoma. There are only few
case reports published to date that document the pleural
metastasis as initial presentation of renal cell carcinoma.
The presentation of renal cell carcinoma as pleural
effusion and isolated pleural metastasis without the
involvement of lung parenchyma is very rare (38,39).
Pleural carcinosis secondary to cancer of
unknown primary (CUP)
In some circumstances MPE is due to a CUP. We recall
that CUP could be dened as an mysterious cancer proved
histologically from a metastasis when after a thorough
diagnostic work-up no certain primary tumor is identied.
Patients with CUP develop usually fast metastases with a
poor response to chemotherapy and miserable survival (40).
Immunotherapy
Although many efforts have been done to provide effective
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systemic and localized cytotoxic and immune-based
therapies, there is currently no effective treatment for
MPE, and according to the recent published data of the
PulMiCC trial, we could expect an increasing number of
MPE (41). Nevertheless, there is a contrast of opinions on
the role of immunotherapy in MPE. In fact, recently some
authors used immunohistochemical and transcriptional
methods to explore the predictive inuence of immune cells
and expression difference of associated immunomodulatory
particles in MPE. They found that the state of the immune
system in MPE permits to offer extra information on
prognosis (42). In contract other authors noted that the
attempt to treat MPE have shown a resistance to almost
all forms of drug treatment (43). The reason for the
development of drug resistance of MPE is probably at
the heart of the process that leads to the formation of
metastatic deposits on the pleura. This process involves
complex interplay establishing host-to-tumor signaling
through mechanisms that stimulate pleural inflammation,
tumor angiogenesis and vascular hyperpermeability (44).
Moreover, it seems that immunotherapy not only does
not lead to cure from MPE but appear to be in a complex
process where T-cell effectors are suppressed and killed, and
macrophages are reprogrammed to assist the development
of anger and invasiveness of the tumor phenotype (45).
It is evident that more data are necessary for the
development of immunotherapy directed to treat pleural
carcinosis, but it remains the fact that tailor immunotherapy
in tumor environments is desirable (46).
Conclusions and future perspective
Pleural carcinosis with symptomatic MPE is one of the
most common scenario in clinical practice for physicians
and surgeons. The correct decision making is mandatory
and differential diagnosis is imperative in order to
guarantee the best possible chance of success. Certainly,
the treatment of dyspnea using a thoracocentesis is the
primary treatment. Different procedures have been used to
prevent re accumulation of the effusion, between them talc
pleurodesis and indwelling pleural catheters are commonly
used depending on the general clinical condition and
the presence or not of a trapped lung. Uniportal VATS
is a good way to apply talc, and is recommended when
intraoperatively pleural carcinosis is detected and conrmed
at frozen section.
More aggressive surgical therapies such as VATS
pleurectomy has not been suggested by several guidelines.
Nevertheless, the “need to do something” for patients with
extrathoracic MPE lead many physicians and surgeons to
test new modalities, and recent studies have shown that
HITHOC alone or in combination with pleurectomy
decortication could achieve longer survival maintaining a
good quality of life. Despite of all existing controversy in
the context of efciency and effectiveness, HITHOC seems
to be at present the only “promising” method, but it needs
EBM proofs of effectiveness, reduction of side effects and
standardization.
In the future it is evident that treatment for pleural
carcinomatosis should be individualised, and therefore
based non only on the patient’s symptoms and quality of
life, but also according to the immunology of the primary
tumour and mood of the patient (47).
Acknowledgments
Funding: None.
Footnote
Provenance and Peer Review: This article was commissioned
by the Guest Editor (Dragan Subotic) for the series
“Malignant pleural effusion” published in AMJ Medical
Journal. The article was sent for external peer review
organized by the Guest Editor and the editorial ofce.
Conicts of Interest: All authors have completed the ICMJE
uniform disclosure form, available at: http://dx.doi.
org/10.21037/amj-2019-mpe-07. The series “Malignant
pleural effusion” was commissioned by the editorial ofce
without any funding or sponsorship. The authors have no
other conicts of interest to declare.
Ethical Statement: The authors are accountable for all
aspects of the work in ensuring that questions related
to the accuracy or integrity of any part of the work are
appropriately investigated and resolved.
Open Access Statement: This is an Open Access article
distributed in accordance with the Creative Commons
Attribution-NonCommercial-NoDerivs 4.0 International
License (CC BY-NC-ND 4.0), which permits the non-
commercial replication and distribution of the article with
the strict proviso that no changes or edits are made and the
original work is properly cited (including links to both the
formal publication through the relevant DOI and the license).
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See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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Cite this article as: Migliore M, Milosevic M, Koledin B.
Pleural carcinosis caused by extrathoracic malignancies. AME
Med J 2020.
