Morphologic Spectrum of Undetermined Causes of Hemoptysis- A Pathologist’s Role
Nidhya GANESAN, Umamaheswari GURUSAMY
Department of Pathology, PSG Institute of Medical Sciences and Research, TAMILNADU, INDIA
Keywords: Hemoptysis, Immunologic, Diffuse alveolar hemorrhage, Capillaritis
Hemoptysis is the expectoration of blood or blood-streaked sputum from the tracheobronchial tree. The etiology may derive from
nonneoplastic conditions such as infections, chronic pulmonary diseases, and vasculitis or neoplastic causes. Sometimes a definitive cause
for hemoptysis cannot be found after ample diagnostic workup. The role of biopsy in such cases is to help the clinician in arriving at the
final diagnosis. Diffuse alveolar hemorrhage is the main histopathological finding in hemoptysis and it appears with diffuse chest infiltrates
Material and Method: A retrospective study of 2 years duration was conducted to identify the morphological spectrum of diseases presenting
with hemoptysis. A total of 243 lung biopsies obtained by various methods were retrieved in this study period and 20 cases with hemoptysis of
undetermined etiology were detected.
Results: Based on imaging and histopathology findings, the etiological causes of hemoptysis were divided into hemoptysis with and without
capillaritis or due to tumor/tumor-like lesions and due to miscellaneous conditions. The most common etiology was vasculitis followed by
Conclusion: Histopathology helps to detect the etiology, particularly in cases of hemoptysis due to non-immunologic causes. In immunologic
cases, histopathological findings may support the diagnosis in correlation with the clinical/imaging features.
Hemoptysis is the expectoration of blood from the
pulmonary parenchyma or the tracheobronchial tree below
the level of the glottis. The expectoration of blood can
vary from a small amount of blood-streaking sputum to
massive bleeding with life-threatening consequences. The
clinical diagnostic algorithm should aim to differentiate
and identify the etiology of hemoptysis, since massive
hemoptysis may result in a fatal outcome 1,2
The common causes of hemoptysis include pulmonary
tuberculosis (TB), malignancy, bronchiectasis, chronic
bronchitis, pneumonia, and fungal infections. The other
rare causes are vasculitis due to collagen vascular diseases
and hereditary hemorrhagic telangiectasia, essential cryoglobulinemia,
Behcet’s disease, acute lung transplantation
rejection, drug-induced (e.g., chemotherapeutic agents,
propylthiouracil), idiopathic pulmonary hemosiderosis,
and toxin or inhalation injury 3.
About 30% of cases attending respiratory clinics and
presenting with hemoptysis pose a problem in clinical
diagnosis, and the histopathology plays a vital role in
diagnosing these conditions. The condition can be localized
or diffuse depending upon the underlying etiology 4. Intra
alveolar hemorrhage, fibrin deposition, and hemosiderinladen
macrophages associated with or without capillaritis
are the common findings observed in cases of diffuse
alveolar hemorrhage (DAH) 5. Radiologically, DAH
shows patchy/ diffuse bilateral areas of lung consolidation
mainly involving the lower lobes and perihilar regions 6.
A literature search revealed only a few reports on using
histopathological interpretation in diagnosing unknown
causes of hemoptysis. This is vital to diagnose and treat
the condition earlier, as it prevents disease progression,
and constituted the reason for conducting the current
study. This study aims to identify the various uncommon
aetiologies of hemoptysis based on histopathological
features and the pathologist’s approach in diagnosing this
All lung biopsies, including lobectomy specimens received
in the department of pathology, between Jan 2018 to Jan
2020 (2 years duration) were retrospectively reviewed.
Of the received 243 specimens, 20 cases had hemoptysis
with undetermined causes. The obtained specimens
were derived from various procedures and included 117
transbronchial lung biopsies (TBLB), 62 endo bronchial
lung biopsies (EBLB), 28 guided (Ultra sonogram /CT)
biopsies, 19 thoracoscopic/Video-assisted (VATS) biopsies,
and 17 lobectomies. The cases with a history of hemoptysis
associated with common causes such as tuberculosis (TB),
carcinoma, bronchitis, bronchiectasis, and interstitial
lung diseases (ILD) were excluded from the study. The
clinical data obtained were age, sex, presenting complaints,
clinical diagnosis/differential diagnosis, and significantly
associated co-morbidities. Laboratory investigations such
as autoimmune workup (ANCA, ANA, etc.), sputum
for culture & acid-fast bacilli (AFB), bronchoalveolar
lavage (BAL) for culture and cytology, and other relevant
information were collected. The findings of imaging
(high-resolution computerized tomography - HRCT) and
bronchoscopic findings were recorded if available (not
Ethical approval for this study was obtained from PSG
Institute of Medical Sciences & Research (Approval
number: 20/117, Date: 27.05.2020).
Out of 243 lung biopsies received, a total of 20 cases with
symptoms of hemoptysis due to undetermined etiology
were included in our study.
Based on imaging and histopathological findings, the
etiology of hemoptysis was divided into localized and
diffuse/bilateral pulmonary involvement (Table I).
Depending upon the histological findings, the causes of
hemoptysis were further divided into
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|Table I: Etiological classification based on imaging & histopathological findings.
- Hemoptysis with capillaritis (Table II)
- Hemoptysis without capillaritis (Table III)
- Unusual tumors and tumor-like lesions (Table IV)
- Miscellaneous uncommon causes
Miscellaneous uncommon causes are listed below:
Pulmonary Alveolar Microlithiasis (n=1)
HRCT of a 34-year-old male who presented with
hemoptysis showed bilateral ground-glass densities with
septal calcification -? Interstitial lung disease. TBLB
sections showed distended alveoli containing concentric
lamellated, calcific material with few hemosiderin-laden
Pulmonary Endometriosis (n=1)
A 43-year-old man with a history of cirrhosis secondary
to hepatitis ‘C’ had recurrent episodes of hemoptysis.
Bronchoscopy revealed a mucosal white patch in the left
lingular segment. The biopsied lesion showed lung tissue
intimately admixed with a focus of endometrial glands
and stroma. CD 10 immunostaining of the stroma, as
well as estrogen and progesterone receptor staining of
the glandular component, were both consistent with
endometriosis (Figure 1A-D).
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|Figure 1: Bronchial
endometriosis. A) Bronchial
mucosa with a focus of
endometrial glands and stroma
(H&E; x4). B) High power view
C) CD10 positive stromal cells
(IHC; x40). D) ER positive
epithelial & stromal cells
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|Figure 2: Granulomatosis
A) Capillaritis with fibrin
thrombi (H&E; x10).
cells, karyorrhectic debris
& parenchymal necrosis
(H&E; x40). C) Mediumsized
vessel wall with
and destruction (H&E;
x10). D) Verhoeff-Van
Gieson (VVG) stain
highlights the outline of a
vessel wall (VVG; x40).
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|Figure 3: Eosinophilic
polyangiitis. A-B) A
infiltrated by eosinophils
and histiocytes with
partial destruction of a
vessel wall (H&E; x10
& x20). C) (PAS stain;
x40). D) Intra-alveolar
hemorrhage (H&E; x10).
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|Figure 4: Hemosiderin-laden
macrophages A) (H&E; x40).
B) (Perl’s stain; x40).
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|Figure 5: Silicosis. A) Multiple,
patchy silicotic nodules (H&E;
x10). B) Perivascular nodular
collection of pigmented
crystals under polarized light)
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|Figure 6: Fungal infection.
A) Intravascular plugs of fungal
organisms (H&E; x4). B) Septate,
acute angle branching hyphal
fungal organisms consistent with
aspergillus with oxalate crystals (PAS; x10).
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|Figure 7: Myelolipoma. A) Bronchial mucosa with squamous metaplasia and a fairly circumscribed lesion composed of adipocytes
admixed with hematopoietic elements (H&E; x4). B) High power view (H&E; x10). C) Myeloperoxidase stain (IHC; x10).
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|Figure 8: Endobronchial
A) Showing admixture of
squamous and glandular elements
(H&E; x4). B) High power view (H&E; x10).
Pulmonary Intravascular Haemangioma (n=1)
HRCT of an elderly male showed multiple small nodules
in both the lungs and a lobulated enhancing soft tissue
lesion attached to the anterior wall of the right atrium-?
Malignancy. TBLB sections showed lung parenchyma
with medium to large-sized vessels containing an
intraluminal, adherent lesion of tubular vascular spaces
lined by endothelial cells. CD31 & CD34 immunostaining
highlighted the endothelial cells. Since the right atrial
mass could not be biopsied, the clinical/imaging findings
were correlated and the final HPE diagnosis made was
intravascular capillary haemangioma/?fragmented from
Haemoptysis is considered to be a serious medical condition
and has a broad differential diagnosis. All cases with
microscopic evidence of hemorrhage do not present with
hemoptysis clinically. Similarly, all patients who presented
with hemoptysis will not show alveolar hemorrhage
Haemoptysis with Capillaritis (Granulomatosis with
Polyangiitis & Eosinophilic Granulomatosis with
Pulmonary vasculitis is characterized by inflammation of
the small and medium-sized vessel wall, causing pulmonary
hemorrhage. Imaging studies show multiple lung cavitary
nodules/masses, which may mimic metastasis. Also in
some conditions, the lung infiltrates are transitory making
the diagnosis a challenging one 7.
Schnabel et al. stated that histopathological findings may
vary depending upon the type of biopsy. They found out that
the yield of guided lung biopsy is high when compared to
TBLB since gross lesions are easily visible. Similarly, most of
our cases had undergone guided biopsies and were adequate
Travis et al. suggested that capillaritis is a morphologic
marker of DAH in their study. They concluded that
capillaritis and necrotizing granulomatous inflammation
with mixed inflammatory cell infiltrate were
pathognomonic features of GPA. Parenchymal necrosis,
extravasated fibrin, and scattered multinucleate giant cells
in a biopsy could suggest the diagnosis of a GPA even in the
absence of granuloma. The destruction of the vessel wall
can be highlighted by VVG elastic stains. However, correct
sampling is essential for the maximum yield 9,10.
The diagnosis of EGPA can be made if the biopsy shows
granulomatous vasculitis with extravasated eosinophils and
evidence of eosinophilic pneumonia 11. Correspondingly,
three cases in our series showed capillaritis and the
remaining two were diagnosed based on relevant clinical
and imaging findings.
Haemoptysis without Capillaritis
Fungal Infection: Alveolar hemorrhage resulting from
fungal infection is infrequent. The possible pathogenesis
of hemoptysis in fungal infection could be 1) due to
chronic inflammation as the granulation tissue lining the
cavity is rich in capillaries, 2) these new vessels are rather
fragile and can rupture easily, and 3) erosion of the blood
vessels adjacent to the cavity 12. The presence of calcium
oxalate crystals in a patient with a cavitary lesion will raise
suspicion of a fungal infection and the pathologist should
search for the same in the adjacent area 13. Likewise, our
cases also had similar histology which would have led to
Silicosis: An autopsy case study by Kyeong et al. revealed that
unlike silicosis which affects mainly the lung parenchyma,
silico - tuberculosis also affects the pulmonary vasculature
causing hemoptysis 14. Our cases did not have evidence
of tuberculosis. Streak-type hemoptysis seen in our cases
could be explained by the destruction of small-sized blood
vessels by fibrosis and chronic inflammation 15.
Unusual Tumors and Tumor-Like Lesions of the Lung
Primary Pulmonary Mesenchymal Tumors: Accounts for
less than 1% of all lung malignancy. These tumors show
lineage differentiation and can be diagnosed in the lung
with similar histological and immunological criteria as in
other sites (soft tissue) 16. Pulmonary hamartoma is the
most common benign mesenchymal tumor of the lung, and
is predominantly seen in older males. Geramizadeh et al.
and Ahmed et al. in their study stated that the occurrence
of hemoptysis in hamartoma is very rare and results from
giant or endobronchial tumors causing erosion of the
vessels 17,18. In contrast to their findings, our patient
was a middle-aged female with a small peripherally located
According to Hashimoto et al., it is important to identify
and differentiate metastatic mesenchymal tumors
correctly, since most mesenchymal tumors presented as
occult/unknown primary with pulmonary metastatic foci
19. Identically, one of our cases had metastatic LMS with
a known diagnosis of primary LMS of the thigh.
Mucoepidermoid Carcinoma (MEC): MEC is a rare
salivary gland type endobronchial tumor with mucous
secreting cells, squamous cells, and intermediate cells.
A definitive diagnosis requires bronchoscopy and
representative biopsy as this tumor exhibits morphological
heterogeneity. It can be misdiagnosed as primary nonsmall
cell lung carcinoma if the biopsy is inadequate 20,21. The diagnosis of this rare neoplasm was possible since
ours was a pneumonectomy specimen.
Myelolipoma: Pulmonary myelolipoma is distinctly
unusual and rarely presents with hemoptysis. Embolic
origin, reticuloendothelial cell metaplasia, and proliferation
of hematopoietic stem cells are possible mechanisms of
histogenesis. Tumour arising adjacent to the bronchial
cartilage may show bony trabeculae and this explains the
possible histogenesis of the metaplastic theory 22. Our
case also revealed a similar histology.
Miscellaneous Uncommon Causes
Pulmonary Endometriosis: Pulmonary endometriosis
is a rare form of extra pelvic endometriosis, occasionally
reported in men. Cases of male endometriosis have
typically been linked to increased circulating estrogen
levels. Peripheral conversion of androstenedione and
testosterone to the circulating estrogens was noted in men
with cirrhosis of the liver 23. Our patient had a history of
cirrhosis, possibly leading to an altered hormonal state that
interacted with a reactive/metaplastic process.
Pulmonary Alveolar Microlithiasis (PAM): PAM is a
rare autosomal recessive lung disease characterized by the
accumulation of concentrically laminated calcospherites
within the alveolar spaces. Lauta in his study stated that
there is a striking clinico-radiologic disparity in this
condition 24. Since our patient did not have other system
involvement, the possibility of PAM over secondary
calcification was favored by correlating the clinical and
Pulmonary Intravascular Haemangioma: The coexistence
of cardiac and pulmonary haemangioma is very
rare and very few reports of such an association have been
described so far. Imaging studies may help in diagnosing
cardiac haemangioma while histopathology is essential for
confirmation. Complete excision is the treatment of choice
in resectable cardiac haemangioma and solitary pulmonary
haemangioma 25. Since the general condition of the
patient was poor, resection was not possible in our case.
Fragmented emboli from a cardiac haemangioma could
also be considered as a differential.
In conclusion, in immunologic causes of hemoptysis,
histopathological findings may support the diagnosis in
correlation with the clinical/imaging features. However,
in cases of non-immunologic causes of hemoptysis, a
histopathologic examination is mandatory over clinical/
imaging studies. The cases presented here are incredibly
rare diseases with an uncommon presentation. The
diagnosis is often missed or delayed, due to a low index of
suspicion. Histopathological examination is imperative in
unexplained cases of hemoptysis as it plays a vital role in
The authors thank Dr. Anupama Moorthy (Prof & Head,
Dept. of Respiratory medicine) and Dr. Devanand (Prof
& Head, Dept. of Radiology) for their valuable discussions
CONFLICT of INTEREST
The authors declare no conflict of interest.
The authors declared that this study has received no
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