Case 1 -
Lindsay A. Schmidt, University of Michigan, Ann Arbor, MI
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Patient is a 12-year-old previously healthy girl who presented to her primary care physician with
fatigue and significant (approximately 25 pounds) unintentional weight loss over the previous 6 months.
Two weeks prior to presentation, she also developed a productive cough and vomiting. Her mother noticed
nail changes as well. She had no significant travel or infectious exposures. She had been treated for
pneumonia at age 4. She lives in a rural location, with exposure to hay in a barn. On physical exam, she
was found to have very faint bibasilar crackles as well as clubbing of her finger and toenails. Plain
chest x-ray was found to have diffuse reticulonodular pattern. Laboratory findings show a normal sweat
chloride test. She had mild restrictive findings on pulmonary function testing. Clinically, she was
suspected to have sarcoidosis, infection, or hypersensitivity pneumonia. A wedge biopsy was performed
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Sections demonstrate multiple round nodules within pulmonary parenchyma. These nodules have a central
hypocellular zone with abundant myxoid matrix surrounded by a cellular zone. Tumor cells compose with
cellular periphery and are embedded within the central matrix. The tumor cells are epithelioid with
prominent eosinophilic cytoplasm. Tumor nuclei are round to oval with open chromatin and one or two
small nucleoli. The tumor cells are bland, and mitotic figures are difficult to find. Rare tumor cells
have a single prominent intracytoplasmic vacuole. Tumor cells are also present within lymphatic spaces
in the pleura and are spreading along vascular structures. Tumor cells are positive for CD34, CD31, and
Factor VIII, which highlights intracytoplasmic vacuoles.
Dail and Liebow first described this unusual thoracic tumor in a case series in 1975  .
At that time, they surmised that the tumor was derived
from bronchioloalveolar cells with a high rate of vascular invasion, leading to the name intravascular
bronchiolo-alveolar tumor (IVBAT). Cases contained in the literature prior to this were reported under
several different names, including "chondrosarcomatosis" and "pulmonary deciduosis"  .
Subsequent immunohistochemical and ultrastructural studies
demonstrated that this neoplasm was derived from endothelial cells
Consequently Weiss and Enzinger recognized that this entity was the lung's
counterpart to epithelioid hemangioendothelioma (EHE)
seen in other organs  .
Pulmonary EHE is now recognized as a low-to-intermediate grade vascular
neoplasm by the 2004 WHO Classification of lung tumors  .
Pulmonary EHE is now known to have a marked predilection for females
EHE can have a wide age range, occurring in the adolescent
population as well as patients in their seventies, with a mean age at presentation of 40 years. There
are no known exposures that are risk factors for the development of EHE  . P
ulmonary EHE is incidentally discovered in asymptomatic patients in
about half of known cases  . In patients who do
present with symptoms, cough and chest pain are the most common; uncommon presenting signs and symptoms
include hemoptysis and digital clubbing  . Men are
more likely to be asymptomatic than women. There are reported cases of patients presenting with the
signs and symptoms of pulmonary Langerhans' cell histiocytosis with spontaneous pneumothorax 
and with acute pulmonary thromboembolic disease and
pulmonary hypertension  . Radiographic findings in
pulmonary EHE are diverse, with most patients presenting with multiple unilateral or bilateral nodules
mimicking widely metastatic carcinoma
Occasionally, these nodules can become
and tend to be very slow growing, with reports of nodules remaining stable for ten
to twenty years  . Pulmonary EHE is also known
to occasionally present with a pattern mimicking interstitial lung disease on chest imaging, including
bilateral parenchymal opacities, increased interstitial markings, ground glass opacities, and nonspecific
thickening of bronchovascular bundles
The classic histologic features of pulmonary EHE include round to oval shaped nodules which have a
central hypocellular zone surrounded by a cellular peripheral zone. The center of the nodule can become
calcified. The tumor classically involves and spreads along vascular structures and airways. Within the
alveolar spaces, tumor cells spread into adjacent alveoli through pores of Kohn. The cells are embedded
within a matrix that can be myxoid, hyaline, or chondroid. The cells themselves are epithelioid with
eosinophilic cytoplasm, occasionally containing a single intracytoplasmic lumen. Tumor nuclei are round
to oval with dispersed chromatin and small nucleoli. Variants have been reported with prominent
plasmacytoid morphology and numerous intracytoplasmic vacuoles mimicking signet ring cell carcinoma 
and rhabdoid features with abundant eosinophilic
cytoplasm displacing the nucleus  .
Immunohistochemistry can be very helpful in identifying EHE, with tumor cells marking with various
endothelial markers including CD31, CD34, and Factor VIII in the majority of cases. Ultrastructurally,
tumor cells have been shown to contain desmosomal intracellular junctions, microfilaments, pinocytotic
vesicles, large central vacuoles, and Wiebel-Palade bodies
Numerous variants of pulmonary EHE have been described, including anterior mediastinal lesions  .
Pleural involvement by EHE is well-described, with
a tumor rind extending into parenchyma along fissures and interlobular septae, grossly and
radiographically mimicking malignant mesothelioma
. Patients with pleural involvement tend to
be older and have a worse prognosis than those with pulmonary involvement only
Mean survival in patients with pulmonary EHE is between 5 and 10 years, although cases with long-term
stable disease and even spontaneous regression have been described
. Poor prognostic indicators
include male sex, symptomatic presentation (especially cough and hemoptysis), weight loss, anemia,
metastases to more than one site, nodal involvement, pleural effusion (especially hemorrhagic effusion),
and pleural involvement
Histologically, poor prognostic features include fibrous pleuritis, extrapleural proliferation of tumor,
and spindled cells  . There is no current
standard therapy available for pulmonary EHE. Wedge resection versus larger resection has shown no
survival difference  . Chemotherapeutic options
include alpha-interferon, steroids, azathioprine, and platinum-based chemotherapies, though none have
shown consistent survival advantages. Additional therapeutic options suggested in the literature include
lung transplantation  and vascular endothelial
growth factor (VEGF)
inhibitors  .
The differential diagnosis of pulmonary EHE includes metastatic lesions, including both metastatic
adenocarcinoma (especially in cases demonstrating prominent signet ring cell morphology) and metastatic
sarcomas (especially epithelioid angiosarcoma). Immunohistochemical staining strategies should be aimed
at demonstrating an endothelial phenotype (CD31, CD34, and Factor VIII). Keratin staining has been
reported in some cases and must be interpreted with caution. Differentiating EHE from angiosarcoma can
be difficult. Features that favor a diagnosis of angiosarcoma include marked nuclear atypia, increased
mitotic activity, and anastomosing vascular channel formation
. In the pleura, both EHE and angiosarcoma have a poor prognosis; however angiosarcoma
tends to behave worse than EHE in the pleura.
Pulmonary EHE is an unusual neoplasm which can have numerous diverse presentations, including nodules,
pleural disease, and interstitial changes. The differential diagnosis includes metastatic carcinoma,
angiosarcoma, and mesothelioma. An immunohistochemical panel including endothelial markers can be
helpful in distinguishing these entities.
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