Brief Scientific Reports
Intrapulmonary Localized Fibrous Tumor
Intraparenchymal So-Called Localized Fibrous Mesothelioma
SAMUEL A. YOUSEM, M.D. AND STUART D. FLYNN, M.D.
This report describes three cases of intrapulmonary fibromas
which are histologically identical to localized fibrous tumors of
pleura (localized fibrous mesothelioma). Morphologically
these tumors are characterized by a haphazard proliferation of
cytologically bland spindle cells separated by variable amounts
of wavy hyalinized collagen. Entrapped bronchiolar and alveolar epithelium is common. These spindle cells lack expression
of cytoplasmic keratin, S-100 protein, desmin, and epithelial
membrane antigen, but are strongly decorated for intracellular
vimentin. The clinical behavior, differential diagnosis, and histogenesis of these lesions are discussed. (Key words: Mesothelioma; Localized/solitary mesothelioma; Fibroma of lung and
pleura) Am J Clin Pathol 1988; 89: 365-369
PRIMARY TUMORS of the pleura have been divided
into diffuse and localized types. 1215,22 The most widely
recognized lesion of this group is the diffuse malignant
mesotheliomas, both fibrous and epithelial types, which
have a strong association with asbestos exposure. In
contrast, the localized fibrous neoplasms, historically
classified as solitary fibrous mesotheliomas of lung, have
a unique and different clinical presentation, histology,
and biologic behavior. 3 " 6 ' 8 ' 101619 " 21 These pedunculated
polypoid masses usually are attached to the visceral
pleura of asymptomatic individuals. In contrast to diffuse mesothelioma, there is no association with asbestos
exposure, although a minority of patients will present
with episodic hypoglycemia or pulmonary osteoarthropathy. 1314 ' 23 Fibromas of pleura are derived from the submesothelial areolar tissues, 3 ' 51218 and have a histologic
appearance similar to benign fibrous proliferations of
the pericardium, testis, and peritoneum.
While pathologists commonly associate mobile polypoid pleural tumors with fibromas of the serous mem-
Received March 27, 1987; received revised manuscript and accepted
for publication June 16, 1987.
Address reprint requests to Dr. Flynn: Department of Pathology,
Yale University School of Medicine, 310 Cedar Street, RM LI 12
Lauder Hall, New Haven, Connecticut 06510.
365
Department of Pathology, Presbyterian-University Hospital of
Pittsburgh, Pittsburgh, Pennsylvania, and Department of
Pathology, Yale University School of Medicine,
New Haven, Connecticut
branes, we have recently reviewed three cases of "localized mesotheliomas" occurring primarily in the pulmonary parenchyma. While presumably this could be a
consequence of endophytic growth, two tumors were
not in continuity with the visceral pleural surface. This
report describes the histologic features of these parenchymal masses which appear to represent fibromas of
lung.
Report of Three Cases
Case 1
A 71-year-old white man presented with a solitary coin lesion of the
right lung on routine chest radiographs. The patient had a long history
of cigarette smoking. Preoperative serum studies failed to show hypoglycemia and physical examination was unremarkable. At thoracotomy, a well-circumscribed, 3.5-cm diameter spherical nodule was resected from the right middle lobe (Fig. 1). The mass was distinct from
the visceral pleura by 2 mm. Cut section revealed a firm, white,
whorled mass with multiple foci of recent hemorrhage. At present, the
patient is free of disease, three months postsurgery.
Case 2
A 55-year-old Hispanic woman was found to have a left-sided, noncalcified coin lesion on chest radiographs obtained because of a
chronic cough. No history of cigarette smoking was offered, and the
patient lacked hypoglycemia on routine blood work. Physical examination was unremarkable. Bronchoscopy demonstrated an intact normal bronchial tree. At thoracotomy, a wedge resection of the lingula of
the left upper lobe revealed a distinct intraparenchymal 1.5-cm mass
within the lung proper unattached to the overlying visceral pleura. It
was well circumscribed, firm and white, and had a whorled appearance
YOUSEM AND FLYNN
366
'MMMmMMwmmMimmMwmmm
FIG. 1. Thefibromasof lung were well circumscribed whorled white
to gray masses which were usually separated from the adjacent visceral
pleura (gross photograph).
on cut section. The adjacent lung parenchyma appeared hemorrhagic.
Fourteen months after surgery, she is free of recurrent pulmonary
disease.
Case 3
An 82-year-old white woman with a history of systemic hypertension presented with persistent cough and early morning sputum production. Mild, generalized fatigue and dyspnea on exertion were additional complaints. Chest radiographs revealed a 3.5-cm soft tissue
density in the posterior aspect of the right lung with hilar lymphadenopathy. A computerized tomographic (CT) scan showed a 2.5-cm
pulmonary nodule in the superior segment ofthe right lower lobe with
right hilar and subcarinal lymphadenopathy. A primary pulmonary
carcinoma with mediastinal metastases was suspected. Preoperative
physical examination revealed rhonchi and decreased breath sounds in
the right base. Routine blood work showed no evidence of hypoglycemia. At thoracotomy, a segmental resection of the right lower lobe
revealed an intraparenchymal 3.0-cm, well-circumscribed gray mass
with a bulging cut surface which abutted on the visceral pleura. Multiple mediastinal nodes were biopsied, but were unremarkable histologically. At eight months follow-up, the patient is alive and well without
recurrent disease.
Microscopic Findings
The histology of the three tumors was similar. The
mass lesions were composed of spindle cells arranged in
A.J.C.P. • March 1988
a variety of architectural patterns. The most common
was a haphazard, disorderly arrangement of short interdigitating fascicles consisting of loosely compact spindle
cells (Fig. 2). Cellularity varied with the elongate cells
sometimes closely apposed, but more commonly separated by lamellar deposits of wavy, coarse collagen
fibers. Where cellularity was reduced, the hyalinized
collagen fibers formed irregular whorls and had a cartwheel-like configuration. Still other areas had a loose
edematous or myxoid stroma which stained for acid
mucopolysaccharides with Alcian blue. In case 2, a hemangiopericytoma-like pattern was observed with the irregular fascicles arranged in a "tuft and weaved" pattern
around gaping staghorn-like vessels.
The spindle cells had oval-to-elongated and tapered
nuclei, diffuse fine chromatin, and scant bipolar cytoplasm (Fig. 3). The eosinophilic cytoplasm and plump
nuclei lay in close apposition to the ropy collagen, and
the nuclei appeared to be "stuck" eccentrically to the
collagenous lamellae. Cytologic atypia was absent and
mitoses were extremely inconspicuous (less than
V20HPF).
Necrosis was absent, although case 1 had abundant
recent hemorrhage within the tumor mass and iron and
calcium encrustation of adjacent pulmonary elastica.
Vascular and lymphatic invasion were not identified.
The most interesting changes occurred at the advancing margin. Two tumors had a broad pushing edge
which was lined on its parenchymal aspect by metaplastic type II pneumocytes and bronchiolar epithelium
(Fig. 4). As the tongues of fibroma infiltrated the parenchyma, slit-like and branching tubules (reflecting engulfed alveolar pneumocytes) were incorporated into
the fibrous tumor. In some areas, this entrapped epithelium divided the spindle proliferation into leaf-like
fronds, superficially resembling a fibroadenoma of
breast. Focally, particularly in case 3, the spindle cells
expanded the pulmonary interstitium and alveolar
septa, and the fibrous tissue appeared to fuse around
distorted air spaces as it irregularly infiltrated the pulmonary parenchyma.
Bronchioles, arteries, and veins were enveloped by the
neoplastic mesenchyme. Bronchiolar epithelium be-
FlG. 2 (upper, left). At low magnification, the tumors appeared distinct from the adjacent alveolar epithelium, with the neoplastic spindle cells
forming haphazard fascicles with variable amounts of hyalinized collagen. Hematoxylin and eosin (X60).
FlG. 3 (upper, right). The spindle cells had oval nuclei, inconspicuous bipolar eosinophilic cytoplasm and scant mitotic activity.
Ropy, wavy collagen separated the cellular component and formed a storiform pattern. Hematoxylin and eosin (X160).
FIG. 4 (lower, left). Alveolar epithelium formed irregular branching and slit-like inclusions within the mesenchymal tissue. Superficially a
resemblance to the leaf-like fronds of breast fibroadenomas was noted. The spindle cells used the pre-existing interstitial skeleton as a means of
infiltration. Hematoxylin and eosin (X40).
FIG. 5 (lower, right). Polyclonal immunostains for vimentin decorated the spindle cells and failed to stain entrapped epithelium (lower)
while keratin stains formed a photographic negative, staining normal epithelial structures (upper). Immunoperoxidase (XI60).
Vol. 89 • No. 3
BRIEF SCIENTIFIC REPORTS
367
•7 :;
.
4
**'
-.Jf - -••'
4
-.- J*'
Cr.'
>
,
i
V
V.".
*
rV
.. " •
>
• i—
c•
• eO* • •
''jr. -. '
k
* IK
,«0
\4jfc.
^ . *^
V-
368
YOUSEM AND FLYNN
A.J.C.P. • March 1988
came flattened and attenuated, assuming a hobnail appearance. Occasional pools of inspissated mucus were
localized to the injured and obstructed bronchioles.
Pertinent negative findings included the absence of a
connection of the tumor mass to the visceral pleura in
cases 1 and 3. In case 2, the neoplasm extended to the
surface of the flattened mesothelium of the visceral
pleura. No evidence of smooth muscle or lipomatous
differentiation was seen in any tumor.
Periodic acid-Schiff (PAS) stain showed strong cytoplasmic staining of the spindle cells in two cases, but
intracellular neutral mucin was not identified after diastase predigestion. Cytoplasm was faintly eosinophilic,
but lacked striations with trichome stains, which highlighted the blue lamellar deposits of collagen. Reticulin
stains showed a variable amount of fibers surrounding
both single and clusters of spindle cells.
Immunoperoxidase studies with polyclonal antibodies to keratin and vimentin, using methods previously
described,1'24 were also performed in cases 2 and 3. Only
the entrapped pulmonary epithelium was decorated
with cytoplasmic keratin. The spindle cells of the tumor
lacked keratin positivity, but showed cytoplasmic staining with antibodies directed at vimentin (Fig. 5). Subpleural and interstitial mesenchymal cells showed similar staining properties. Polyclonal stains for S-100 protein, desmin, and epithelial membrane antigen failed to
decorate the neoplastic cells.
nign proliferation of subpleural mesenchyme based on
histologic features. Following this proposal, however,
Stout and co-workers21,22 suggested that these lesions
were solitary mesothelial proliferations, citing tissue
culture studies indicating fibroblastic and mesothelial
characteristics. This belief was further supported by ultrastructural studies indicating the formation of lumenlike spaces, blunt villous cytoplasmic projections, and
cilia, features suggestive of an epithelial derivation.11,17
Since then, however, more extensive electron microscopic studies revealed the features of fibroblasts—spindle cells with elongated cytoplasmic processes, prominent rough endoplasmic reticulum, and abundant cytoplasmic microfilaments.9,18 Glycogen was sporadically
present and basement membrane was absent. While
poorly formed cell junctions were observed, desmosomal attachments and tonofilaments were not identified.
Said and associates18 provided further support for a mesenchymal origin in that immunohistochemical studies
indicated the neoplastic cells lacked expression of cytoplasmic keratins of 45, 55, and 63 kD molecular weight.
This was in contrast to their positive findings in diffuse
malignant fibrous mesotheliomas and mesothelial cells
in culture. The immunoperoxidase studies performed
on two of our cases supported these data in that keratin
was absent and cytoplasmic vimentin was strongly expressed. Vimentin positivity in the absence of keratin
expression provides strong support for a mesenchymal
origin of these neoplasms.
Discussion
Solitary fibrous tumors of pleura were initially described as localized mesothelial proliferations.12 In 1931,
Klemperer and Rabin12 became the first to distinguish
the diffuse, rapidly fatal fibrous mesotheliomas from the
more indolent localized tumor which they regarded as a
fibrous tumor derived from the subpleural mesenchyme. Subsequent to this work, solitary fibrous tumors
of pleura achieved a classic clinical and pathologic description: a large pedunculated mass attached by a narrow pedicle to the visceral pleura, in an asymptomatic
individual who occasionally had hypoglycemia or pulmonary osteoarthropathy.3'5'101519 Despite this, even
early reports by Stout and co-workers21,22 and others3'5,6
indicated that a minority of localized fibrous tumors of
pleura were intrapulmonary lesions. Dalton and associates5 found that 7.5% of their 40 localized primary
tumors of pleura were pulmonary parenchymal masses.
Despite this acknowledgment in the literature, this finding is not widely recognized and the three cases reported
herein focus primarily on their histologic and immunohistochemical presentation.
Although earlier investigators felt these neoplasms
were derived from the pleural mesothelium, Klemperer
and Rabin12 proposed that this tumor represented a be-
Because of their histologic similarity to the exophytic
pedunculated masses extending from the visceral pleura
into the thoracic cavity, we believe the lesions described
in this report represent analogous tumors of lung. Why
these tumors involved the lung as opposed to growing
into the thoracic cavity is controversial. One of our three
tumors abutted on the pleural surface of the major fissure of the left lung. It may be postulated that mechanical pressures in the tight confines of the major fissure
precipitated slow intrapulmonary growth. This endophytic proliferation would be facilitated if centered on
the loose connective tissue of an interlobular septum. In
the remaining two cases, no obvious attachment to the
pleura was observed. Two explanations for the location
in lung could be invoked: First, the subpleural mesenchyme is in direct continuity with the connective tissues
of the interlobular septa and ectopic nests of mesothelial
cells can occasionally be identified at this site. Intrapulmonary fibromas could arise from this septal mesenchyme or invaginations of the visceral pleura. A second
consideration is that these tumors originate de novo
from the fibroblasts of the pulmonary parenchyma.
These cells have similar ultrastuctural and immunohistochemical features to the subpleural connective tissue
elements,2 and a similar proliferation is characteristi-
Vol. 89 • No. 3
BRIEF SCIENTIFIC REPORTS
cally found as one component of pulmonary hamartomas. In fact, early reports of fibroadenomas of lung may
represent this spindle cell tumor with entrapped alveolar
epithelium.5,612 If no connection to the pleural surface is
seen, we designate these lesions as fibromas of lung,
recognizing their histologic unity with solitary/localized
fibromas ("mesothelioma") of the pleura.
The major histologic features of fibroma of the lung
and pleura have been previously described. Nonetheless,
it is worthwhile emphasizing several differential diagnostic features. In its parenchymal location, alveolar
pneumocytes and small bronchioles may become entrapped within the spindle cell proliferation. These cells
retain their benign cytologic appearance, and such cases
should not be mistaken as carcinosarcomas or adenocarcinomas with a metaplastic spindle cell component. If
an associated mesenchymal component is seen {e.g.,
adipose tissue or cartilage), the process is best considered
a pulmonary hamartoma providing cytologic features
remain bland.
In solitary pedunculated fibrous tumors of the pleura,
there are poorly defined criteria for malignant or aggressive behavior. Necrosis, cellular pleomorphism, and
high mitotic rate portend a more ominous prognosis in
polypoid tumors, although their absence does not imply
benign behavior.3'510'1619 In an excellent review by Briselli and co-workers,3 large-size (greater than 8 cm),
gross hemorrhage and necrosis, and rich vascularity
were also harbingers of an aggressive course. Clinical
hypoglycemia and pulmonary osteoarthropathy should
also suggest malignant behavior.1323 While the above
features can be applied to the exophytic fibroma of
pleura, it is unclear whether they can be utilized in the
lung neoplasms.
The major differential diagnostic considerations
would include malignant fibrous histiocytoma (MFH)
and pulmonary fibrosarcoma. MFHs usually are large
tumors with extensive necrosis and vascular invasion.
Their storiform growth pattern, pleomorphic malignant
giant cells, cytologic atypia, and abundant mitoses allow
easy discrimination. Fibrosarcomas in lung, as described
by Guccion and Rosen,7 have a prominent herringbone
growth pattern, frequent necrosis, and mitoses of greater
than 5/i0 HPF. fields. Abundant collagen deposits are
also rarely seen in these sarcomas. Finally, the ambiguous group of tumors classified as plasma cell granulomas, or fibrous histiocytomas of lung usually have a
dramatic chronic inflammatory cell infiltrate rich in
plasma cells and contain cytologically bland histiocytes
and xanthomatous cells.
Therapeutically, we recommend complete excision in
all fibromas of the lung, usually by segmental resection
or lobectomy. This is a result of uncertainty in predict-
369
ing their biologic behavior. Furthermore, the spectrum
of cellularity in these lesions makes diagnosis by needle
aspiration or biopsy, or transbronchial biopsy a difficult
problem, and would make complete excision the prudent recommendation.
Acknowledgments. The authors thank K. Vest and Catherine
Haynes for excellent secretarial assistance.
References
1. Auclair PL, Langloss JM, Weiss SW, Corio RL. Sarcomas and
sarcomatoid neoplasms of the major salivary gland regions.
Cancer 1986;58:1305-1315.
2. Bolen JW, Hammar SP, McNutt MA. Reactive and neoplastic
serosal tissue. Am J Surg Pathol 1986;10:34-47.
3. Briselli M, Mark EJ, Dickerson GR. Solitary fibrous tumors of
pleura: Eight new cases and review of 360 cases in the literature.
Cancer 1981;47:2678-2689.
4. Clagett OT, McDonald JR, Schmidt HW. Localizedfibrousmesothelioma of the pleura. J Thorac Surg 1952;24:213-230.
5. Dalton WT, Zolliker AS, McCaughey WTE, Jacques J, Kannerstein M. Localized primary tumors of the pleura. Cancer
1979;44:1465-1475.
6. Foster EA, Ackerman LV. Localized mesotheliomas of the pleura.
Am J Clin Pathol 1960;34:349-365.
7. Guccion JG, Rosen SH. Bronchopulmonary leiomyosarcoma and
fibrosarcoma. Cancer 1972;30:836-847.
8. Heaney JP, Overton RC, DeBakey ME. Benign localized pleural
mesothelioma. J Thorac Surg 1957;34:533-560.
9. Hernandez FJ, Fernandez BB. Localizedfibroustumors of pleura:
A light and electron microscopic study. Cancer 1974;34:16671674.
10. Janssen JP, Wagenaar SS, Van Den Bosch JMM, Vanderschueren
RGJRA, Planteydt HT. Benign localized mesothelioma of the
pleura. Histopathology 1985;9:309-313.
11. Kawai T, Mikata A, Torikata C, Yakumaru K., Kageyama K,
Shimasato Y. Solitary (localized) pleural mesothelioma. Am J
Surg Pathol 1978;2:365-375.
12. Klemperer P, Rabin CB. Primary neoplasms of the pleura. Arch
Pathol 1931;11:385-412.
13. Maier HC, Barr D. Intrathoracic tumors associated with hypoglycemia. J Thorac Cardiovasc Surg 1962;44:321-329.
14. Mandal AK, Rozer MA, Salem FA, Oparah SS. Localized benign
mesothelioma of the pleura associated with a hypoglycemic
episode. Arch Intern Med 1983;143:1608-1610.
15. McCaughey WTE. Primary tumors of pleura. J Pathol Bact
1959;76:517-529.
16. Okike N, Bernatz PE, Woolner LB. Localized mesothelioma of
the pleura. J Thorac Cardiovasc Surg 1978;75:363-372.
17. Osamura RY. Ultrastructure of localizedfibrousmesothelioma of
the pleura. Cancer 1977;39:139-142.
18. Said JW, Nash G, Banks-Schlegel S, Sassoon AF, Shintaku IP.
Localized fibrous mesothelioma: An immunohistochemical
and electron microscopic study. Human Pathol 1984; 15:440443.
19. Scharifker D, Kaneko M. Localized fibrous "mesothelioma" of
pleura (submesothelial fibroma). Cancer 1979;43:627-635.
20. Shabanah FR, Sayegh SF. Solitary (localized) pleural mesothelioma. Chest 1971;60:558-563.
21. Stout AP, Himadi GM. Solitary (localized) mesothelioma of the
pleura. Ann Surg 1951;133:50-64.
22. Stout AP, Murray MR. Localized pleural mesothelioma. Arch
Pathol 1942;34:951-964.
23. Touyz R, Plitt M, Rumbak M. Hypoglycemia associated with a
lung mass. Chest 1986;89:289-290.
24. Yousem SA, Hochholzer L. Alveolar adenoma. Human Pathol
1986;17:1066-1071.