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30

Benign Mesotheliomas, Mesothelial


Proliferations, and Their Possible
Association with Asbestos Exposure
Giovan Giacomo Giordano and Oscar Nappi

Over the past several years the spectrum of mesothelial pathology


has greatly increased (1). Nevertheless, benign mesotheliomas and
mesothelial proliferations represent a rather broad category, encompassing clearly dened lesions, aspecic reactive patterns, and proliferating lesions that cannot yet be specically dened. As any other
human tissue, mesothelial epithelium and submesothelial mesenchymal tissue react to injuries with reproducible patterns (24). In particular, benign epithelial lesions can express one or more of several
growth patterns, which can be divided into papillary, adenomatoid,
micro- or macrocystic, and solid or nodular (Table 30.1); malignant
epithelial mesotheliomas also exhibit a similar microarchitecture. The
range of benign submesothelial (mesenchymal) proliferations is much
more restricted and basically includes reactive brous and brosclerosing changes and the solitary brous tumor (formerly called benign
brous mesothelioma).
Several contributions concerning differential diagnostic criteria
between mesothelial reactive changes and malignant mesotheliomas
on small specimens (5,6) and cytologic material (7) have been published; immunohistochemically, a strong linear membrane reactivity
for EMA and a nuclear reactivity for p53 are considered suspicious for
malignancy, but to a lesser extent both can be found also in reactive
proliferations (8). The evaluation of anamnestic data and clinical presentation always have to be considered.

Malignant Mesothelioma In Situ


For mesothelial proliferations showing frankly atypical cytologic features without stromal invasion, the term malignant mesothelioma in situ
has been introduced; these changes are often found in proximity of invasive mesothelioma or, rarely, before its development, and have been
considered morphologic precursors (9). Considering the poor effectiveness of any treatment of invasive mesotheliomas, the recognition of
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Chapter 30 Benign Mesotheliomas and Mesothelial Proliferations

Table 30.1. Epithelial growth patterns of mesothelium as expressed


in benign proliferations
Epithelial growth pattern
Papillary
Adenomatoid
Solid-nodular
(Micro-macro) cystic

Benign mesothelial proliferations


R A, WDPM
R A, AT
R A, NHMH
R A, AT, PMM

RA, reactive aspecic; WDPM, well-differentiated papillary mesothelioma; AT, adenomatoid tumor; NHMH, nodular histiocytic/mesothelial hyperplasia; PMM, peritoneal
multicystic mesothelioma.

a stage 0 mesothelioma, on the basis of validated and universally


accepted criteria, should represent a critical step in the management of
this tumor. Unfortunately, in our experience, so far, reliable criteria for
this diagnosis have not been codied. Therefore, since mesothelial reactive proliferations often show several degrees of cellular atypia, a diagnosis of malignant mesothelioma in situ should be made with extreme
caution considering the radical surgical therapy following this diagnosis. At the present time we think that only if there is a history of asbestos
exposure without evidence of recognized recent inammatory pathology and a multifocal or rather extensive mesothelial surface cell proliferations with consistent nuclear atypias, a diagnosis of malignant
mesothelioma in situ should be suggested; otherwise, the term atypical
mesothelial hyperplasia should be used for these lesions (6) and a followup with periodic observations could be preferable. Nevertheless, it is
noteworthy that cases of supercial atypical mesothelial changes associated with inltrating mesothelioma have been reported having an
inmmunoreactivity for EMA and p53 similar to that of invasive
mesothelioma (8); these features could represent an additional support
for a diagnosis of malignant mesothelioma in situ.

Epithelial Benign Mesotheliomas and


Mesothelial Proliferation
Papillary Pattern
A papillary pattern is not uncommon in epithelial benign and malignant mesothelial proliferations. Papillary-like cell aggregates are found
also in cytologic samples from serosal effusions secondary to malignant
as well as benign mesothelial pathology.
Well-differentiated papillary mesothelioma is an entity characterized
by a papillary growth pattern.
Well-Differentiated Papillary Mesothelioma
Well-differentiated papillary mesothelioma (WDPM) is a rare and
intriguing tumor (1012). It is currently considered a low-grade malignant tumor, more so than a fully benign tumor, in light of the wide
spectrum of lesions that are morphologically similar but biologically
different, including benign proliferations and aggressive lesions that
merge with true malignant mesothelioma.

G.G. Giordano and O. Nappi

The large majority of the cases arise in the peritoneum of women 30


to 40 years of age. However, sporadic cases also have been described
in the peritoneum of male patients, as well as in the pericardium,
pleura, and tunica vaginalis (13).
Clinically, the usual presentation is pain and serous effusion. Macroscopically, the lesion generally exhibits a supercial, sometimes multifocal vegetative proliferation. Microscopically, a papillary proliferation
characterized by papillae with a brovascular stalk lined by bland,
single mesothelial cells, is present (Fig. 30.1); no mitosis is usually
detected; in some case, psammomas bodies have been described. Papillary proliferation is supercial but occasionally adenomatoid-like
microtubules in underlined stroma have been observed.
Immunohistochemically, proliferating cells are reactive for cytokeratin (CK) and mesothelial markers (calretinin, HMBE-1). Carcinoembryonic antigen (CEA) is always negative. Especially on small biopsies,
WDPMs have to be differentiated from aspecic reactive mesothelial
hyperplasia, epithelial malignant mesothelioma with a prominent
papillary pattern, and serous papillary carcinoma of the ovary and
peritoneum. Clinical presentation is important in differentiating
WDPM from reactive mesothelial hyperplasia that usually is not mass
forming and from malignant mesothelioma in which the cytomorphologic features are also signicant. Immunoreactivity for B72.3, Ber-Ep4,
CA19.9, and Leu-M1 and negativity for calretinin and HMBE-1 are
useful markers in differentiating WDPM, as well as malignant

Figure 30.1. Well-differentiated papillary mesothelioma of peritoneum. This


eld shows several papillary projections with a brovascular stalk lined by
bland, at, single mesothelial cells. In the underneath stroma, a proliferation
of duct-like structures is seen. Inset: a papillary structure with a broad stalk
seen at high power.

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Chapter 30 Benign Mesotheliomas and Mesothelial Proliferations

mesotheliomas, from papillary serous carcinoma of the peritoneum or


of the ovary; CEA immunoreactivity is also an excellent negative
marker for mesothelial neoplasias but is not always detected in papillary carcinoma (14,15).
Adenomatoid (Pseudoglandular, Tubular) Pattern
The adenomatoid pattern is also frequently expressed by proliferating
epithelial mesothelium as well as epithelial mesothelial tumors. Sometimes associated with a microcystic pattern, this pattern is typically represented by adenomatoid tumors. The so-called mesothelioma of the
atrioventricular node also shows a similar pattern but it does not have
a mesothelial origin.
Adenomatoid Tumor
Adenomatoid tumor (AT) is a benign mesothelial tumor with a dominant tubular pattern. This tumor usually arises from the mesothelium
of the paratesticular region (16), from the serosal surface of the uterus
wall (17) and, much less frequently, from that of the ovary, salpynx, and
broad ligament. Exceptionally, it can arise also from the pleura (18) and
pericardium (19). Macroscopically, AT is usually a small nodule, often
found incidentally if it is less than 1 cm. Microscopically, its growth
pattern is characterized by bland, at, epithelioid cells arranged in
tubules, gland-like structures, microcysts, or cords (Fig. 30.2). Not infrequently, a cytoplasmatic vacuolization is present with a signet ringlike
feature. A mesothelial origin of the AT has been denitively conrmed
by ultrastructural and immunohistochemical studies (20,21); this tumor
always is immunoreactive for CK/cocktail, EMA, and calretinin.

Figure 30.2. Adenomatoid tumor of rete testis. A proliferation of duct-like and


glandular-like structures in a brous stroma is shown.

G.G. Giordano and O. Nappi

Sometimes AT has to be histologically differentiated from adenocarcinomas, vascular tumors, and on rare occasions, from malignant
epithelial mesotheliomas with a dominant tubular/glandular pattern.
Appropriate immunohistochemical reactions, such as CEA and other
possible markers for specic adenocarcinomas as well as endothelial
markers, usually help to clarify the diagnosis in selected cases.
Rarely, cases of AT having an inltrating local pattern have been
reported, but the behavior of AT is usually indolent and benign.
Mesothelioma of the Atrioventricular Node
The so-called mesothelioma of the atrioventricular node is not a true
mesothelioma. This denition is a misnomer based on historical observations regarding the similarity of the proliferative cells with mesothelial cells and the lesions pattern with that of an adenomatoid tumor.
Today, it has been accepted that it arises from a congenital heterotopia
of endodermal tissue (2224). The large majority of these tumors has
been detected during autopsy (some sporadic cases have been reported
in transplanted hearts) and most of them, although inconspicuous,
range in size from a few millimeters to 1 to 2 cm and have been considered the cause of death in cardiac arrest or ventricular brillation (23).
Macroscopically, this tumor often exhibits micropolycystic features
in the area of the atrioventricular node. Microscopically, microcystic
spaces are lined by bland, at, mesothelioid cells that are immunoreactive for CK; positivity for CEA also has been reported.
Cystic/Microcystic Pattern
Although cases of AT with a dominant microcystic pattern have been
reported, the best example of a lesion characterized by this pattern is
the peritoneal multicystic mesothelioma.
Peritoneal Multicystic Mesothelioma
Peritoneal multicystic mesothelioma (PMM) arises almost exclusively
from the peritoneum (2,25); exceptional cases have been described in
the testis (26) and pleura (27). Like adenomatoid tumor, the histogenesis of PMM has also been controversial, the true mesothelial origin
having been conrmed only recently by ultrastructural and immunohistochemical studies. Cystic mesotheliomas, arising from serosal peritoneal membranes, can apparently involve the parenchyma of single
peritoneal and pelvic organs. The common clinical setting is the pelvic
peritoneum of young female patients; on the basis of the size of the
proliferation, it can be accidentally detected, present vague symptoms,
or show a palpable abdominal mass and pain; ascitis is rarely present.
It can be also multifocal with synchronous or metachronous proliferating lesions in several parts of the abdomen and pelvis. Macroscopically, one cyst (in this case, terms such as cystic mesothelioma and
mesothelial cyst seem more appropriate) or several cysts with thin
walls and variable size are present; cysts usually have a uid content
(2,25).

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Chapter 30 Benign Mesotheliomas and Mesothelial Proliferations

Figure 30.3. Peritoneal multicystic mesothelioma. Several cystic structures


internally lined by at mesothelioid cells are shown. Inset: mesothelioid cells
stained with cytokeratin (CK).

Microscopically, the internal cystic surface is lined by bland, at,


endothelioid cells (Fig. 30.3); immunoreactivity for cytokeratin/
cocktail, calretinin, or HMBE-1 is diagnostically present. A common,
sometimes difcult, differential diagnosis is with (multi)cystic lymphangiomas; nevertheless, immunoreactivity for endothelial markers
and immunonegativity for cytokeratin usually permit a correct
diagnosis.
Basically, PMM is a benign tumor, but radical surgery is mandatory
because of the possibility of recurrences; follow-up is needed also
because of multifocality. Cases of malignant cystic mesothelioma have
been reported, but in the majority of cases cytologic and clinical
features generally clarify the diagnosis. It is important to remember
that in the spectrum of mesothelial proliferations, cystic is not always
synonymous with benign (2,25).
Solid/Nodular Pattern
Within reactive hyperplastic changes of the mesothelium, a solid
pattern can be focally or extensively present. Moreover, there are some
peculiar clinical settings in which this pattern is characteristically
observed:
Inguinal or umbilical hernia sacs, following chronic injury or incarceration of mesothelium (Fig. 30.4): This feature, not infrequently
found in hernia sacs of children but also adults, has been dened as
nodular mesothelial hyperplasia and has sometimes led to a misdiagnosis of malignancy (28).

G.G. Giordano and O. Nappi

Figure 30.4. Nodular mesothelial hyperplasia in the inguinal hernia sac. A


nodular aggregation of mesothelioid cells in the stroma is seen.

Cardiac excrescences variously interpreted and called histiocytoid


hemangioma-like lesions (HHLL) (29) or mesothelial/monocytic
incidental cardiac excrescence (MICE) (30): These are characterized
by nests of round mesothelioid cells usually detected during cardiac
surgery; some authors have considered these lesions to be artifactually determined by aspirated mesothelial cells during cardiotomy
suction (31).
Nodular aggregates found in transbronchial biopsies: These can
represent a potential source of misdiagnosis, especially versus
neuroendocrine tumors (32).
The immunohistochemical evidence that many, if not most, of the
round mesothelioid cells present in these lesions are immunoreactive
for CD 68, a hystiocytic marker, and not for cytokeratin, which is positive only in other cells, has suggested that in most cases of the abovementioned pathologic ndings, a mixed proliferation of histiocytes and
mesothelial cells is present; alternatively, such evidence suggests that
the mesothelial cells are entrapped and not proliferating. Consequently,
a diagnosis of nodular histiocytic/mesothelial hyperplasia has been
suggested for all of them (33).

Mesenchymal Benign Mesothelial Tumors and


Mesothelial Proliferations
Benign mesothelial lesions characterized by proliferations of mesenchymal tissue are basically represented by reactive submesothelial brosclerotic proliferations and the localized brous tumor. Submesothelial

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Chapter 30 Benign Mesotheliomas and Mesothelial Proliferations

brosclerotic proliferations are relatively common reactions of serosal


membranes to chronic injuries. Pleural plaques (PPs) and chronic brous
pleurisy, with the so-called brothorax at the extremity of the spectrum,
are the best clinically dened of them. Pleural plaques are rm, sometimes calcied lesions, present in the parietal pleura, microscopically
characterized by hypocellular collagen-rich mesenchymal proliferation
with a distinctive basket-weave pattern. They can present as single or
multiple lesions ranging from a few millimeters to several centimeters.
A relation with asbestos exposure is widely accepted and sufciently
documented; in selected cases, association with malignant mesothelioma has been described as well. Other pneumoconioses have been
reported to be associated with PP; in our experience, in spite of different
reported considerations, clinical presentation, number of lesions, and
microscopic morphology of these cases substantially overlap those that
are secondary to asbestos exposure.
Chronic Fibrous Pleurisy
Chronic brous pleurisy (CFP), especially in case of small biopsies, presents serious problems of differential diagnosis with sarcomatous
mesotheliomas if a consistent spindle cell proliferation is present, or
with desmoplastic malignant mesotheliomas (DMMs) if, as occurs
more frequently, the lesion is sclerotic and paucicellular (Fig. 30.5).

Figure 30.5. Fibrosing pleurisy (FP) (left) and desmoplastic malignant


mesothelioma (DMM) (right) are shown side by side. The two lesions are
impressively similar; DMM (upper right) shows some degree of nuclear atypia.
Cytokeratin is strongly expressed in DMM (lower right) but a focal and weak
positivity is also present in FP (lower left).

G.G. Giordano and O. Nappi

Reliable criteria of malignancy, in absence of frank sarcomatous overgrowths, are currently being considered (6): absence of a zonal effect
(consisting of a supercial high cellularity and deep paucicellularity,
usually present in chronic brotic reactions); invasion of surrounding
tissues (adipose tissue, skeletal muscle, lung parenchyma); the socalled bland necrosis, typical of DMM and consisting of circumscribed
areas in which necrosis is demonstrated by a poorly stained eosin; and
absence of an elongated capillary vessel perpendicular to the serosal
surface as an expression of the reactive granulation tissue usually
present in CFP.
Immunohistochemistry is usually of little help; it is remarkable that,
after an injury causing denudation of mesothelial layers, submesothelial
broblasts that normally expressed vimentin only acquire immunoreactivity for low molecular weight cytokeratin. For this reason, in the presence of mesenchymal mesothelial proliferations, the positivity for
cytokeratin should not be considered as diagnostic of desmoplastic
mesothelioma (2,6). Nevertheless, a clear immunonegativity, or a
weakly focal positivity for cytokeratin, favors the diagnosis of brosing
pleurisy, and the immunopositivity of brosclerosing proliferation inltrating lung parenchyma or striated muscle favors that of DMM.
Localized Fibrous Tumor of the Pleura
Localized brous tumor (LFT) of the pleura, although variously
named, has been thought for many decades to arise from surface
mesothelial cells and, therefore, to be a benign mesothelioma. Today, it
is considered a pleural localization of a potentially ubiquitous lesion of
mesenchymal origin (34). It can arise in the pleura of patients of both
sexes and of any age. In about 50% of cases, the tumor is asymptomatic
and incidentally found; otherwise, cough, pain, and dyspnea are
common symptoms. Typically, LFT is separated from the (generally
visceral) pleura by a peduncle, resulting in a polypoid mass, which
can also reach great size (up to 40 cm) and consistent weight. The cut
surface is rmly brous.
Microscopically, several features have been described: sclerosing,
myxoid, and hemangiopericytomatous. Typically LFT is immunoreactive for CD 34 (35); the positivity for this marker is needed to conrm the diagnosis (Fig. 30.6). Bcl-2 (36) and CD 99 (37), both positive
in the majority of cases, are considered useful to distinguish LFT from
sarcomatoid malignant mesothelioma, which is only sporadically
immunoreactive for them (37,38).
Some cases of LFT have a malignant behavior; histological criteria
for selecting them are similar to those of other mesenchymal neoplasias: an increase in cellularity, nuclear atypias, an inltrative pattern,
and a greater mitotic index (more than 4 high-power elds). Solitary
brous tumors have been described everywhere, including the pericardium (39), vaginalis testis (16) and the peritoneum (40).

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Chapter 30 Benign Mesotheliomas and Mesothelial Proliferations

Figure 30.6. Solitary brous tumor of the pleura. The diagnostic positivity for
CD 34 is shown.

Possible Relation of Benign Mesotheliomas and


Mesothelial Proliferations to Asbestos Exposure
To the best of our knowledge, excluding some sporadic and questionable reported cases, in none of the benign mesotheliomas described,
above does the asbestos exposure play a statistically signicant role;
the only mesothelial reactive change generally considered secondary
to asbestos exposure is the brosis macroscopically expressed by
pleural plaques (2).

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