TIMELY REVIEWSection Editor: Zubair Baloch, M.D., Ph.D.
Cytological Diagnosis ofSarcoidosis Revisited:A State of the Art ReviewRavi Mehrotra, M.D., M.I.A.C.* and Vishal Dhingra, M.D.
Diagnosis of sarcoidosis has never been an easy task. This isprimarily because there is no single diagnostic test that canclinch the diagnosis. Demonstration of granulomas remains anessential criteria, but as granulomatous inflammation can beseen in host of conditions, it is necessary to exclude all possiblecauses, as well as to correlate with other findings, before arriv-ing at the diagnosis of sarcoidosis. Cytology has been usedeffectively since the last few decades in demonstration ofgranulomas in various organs. Recent developments in variousfields of cytodiagnosis of sarcoidosis including transesopha-geal ultrasound-guided fine-needle aspiration and endobron-chial ultrasonograpy-guided transbronchial needle aspirationhave revolutionized this field. These techniques are safe, mini-mally invasive, and give real-time information during aspira-tion. In comparision to the conventional methods, these alloweasier sampling and have better sensitivity. In addition tothese methods, a variety of ancillary techniques are also uti-lized and are reviewed here. Diagn. Cytopathol. 2011;39:541–548. ' 2010 Wiley-Liss, Inc.
Key Words: sarcoidosis; cytological diagnosis; transesophagealultrasound-guided fine-needle aspiration; transbronchial fine nee-dle aspiration
Sarcoidosis is a chronic, multisystem, granulomatous dis-
order, of unknown etiology, primarily affecting the lung
and lymphatic systems of the body.1 This disease is char-
acterized by the formation of noncaseating epitheliod cell
granulomas, usually accompanied by multinucleated giant
cells, as a result of disordered immune regulation in ge-
netically predisposed individuals exposed to certain envi-
ronmental agents. The initial clinical presentation of sar-
coidosis is variable, depending on the organ systems
involved. The diagnosis is established when clinicoradio-
logic findings are supported by cytological or histological
evidence of noncaseating epitheliod cell granulomas
and other causes of granulomas have been, definitively,
excluded.2
History
A common saying with regards to sarcoidosis is: ‘‘Moreis unknown about sarcoidosis than is known.’’
In 1877, Dr. Jonathan Hutchinson, a London surgeon-
dermatologist, first described the findings of a 50-year-old
man who had large purple skin plaques on the hands and
feet and similar skin lesions in a 64-year-old woman, on
her face and arms. The disease was then known as Hutch-
inson’s disease.
However, in 1889, Dr. Cesar Boeck, a Norwegian der-
matologist coined today’s name for the disease from the
Greek words ‘‘sark’’ and ‘‘oid,’’ meaning flesh-like,
named the process ‘‘multiple benign sarcoid of the skin.’’
He also showed that many patients also had sarcoid
lesions in the lymph nodes and lungs.
Dr. S. B. Wolbach, in 1911, described Asteroid bodies,
inclusion seen in sarcoid granulomas, in his article enti-
tled ‘‘A New Type of Cell Inclusion, not Parasitic, Asso-
ciated with Disseminated Granulomatous Lesions’’ as
star-shaped structures found within the cytoplasm of mul-
tinucleated giant cells.3
In 1958, scientists from all over the world met at the
Brompton Hospital in London for a conference about sar-
coidosis. Since then there has been a yearly international
sarcoidosis conference and a scientific journal for sarcoid-
osis. The history of sarcoidosis has been comprehensively
reviewed by Sharma.4
This article was presented, in part, at the ‘‘International conference onpathology of chest disorders: an integrated approach’’ organized by Pul-monary Pathology Society division of United States and Canadian Acad-emy of Pathology and Pulmonary Pathology Society of India at V.P.Patel Chest Institute, University of Delhi in Dec. 2008.
Division of Cytopathology, Department of Pathology, Moti Lal NehruMedical College, Allahabad, India
*Correspondence to: Ravi Mehrotra, M.D., M.I.A.C., Professor ofPathology, Moti Lal Nehru Medical College, 16/2, Lowther Road,Allahabad 211002, India. E-mail: [email protected]
Received 20 April 2010; Accepted 1 May 2010DOI 10.1002/dc.21455Published online 14 October 2010 in Wiley Online Library
(wileyonlinelibrary.com).
' 2010 WILEY-LISS, INC. Diagnostic Cytopathology, Vol 39, No 7 541
Epidemiology
Sarcoidosis occurs throughout the world but its incidence
varies widely in different countries and ethnic groups.
The disease is more prevalent in certain groups, such as
African Americans and Northern Europeans. The recorded
prevalence is *10 and 40/100,000 populations in the US
and Europe, respectively.5 In the United States, rates are
highest in the Southeast; it is *10 times higher in Ameri-
can blacks than in whites. On the other hand, the disease
is uncommon in Chinese and Southeast Asians.
The prevalence of sarcoidosis is higher in women than
in men with an average incidence of 16.5/100,000 in men
and 19/100,000 in women. Sarcoidosis is rare before
adulthood and in the elderly. The disease usually presents
before 40 years of age, peaking in those aged 20–29.
There is a second smaller peak in women over age 50.6
Diagnosis
To establish a diagnosis of sarcoidosis it is necessary that
granulomata must be present in two or more organs—
with no agent known to cause a granulomatous response
being identified.7 A diligent search should be made for
other causes of granulomatous inflammation, including
mycobacteria, fungi, parasites, and foreign bodies.
Although sarcoid granulomas have no specific diagnos-
tic features, there are, however, certain characteristics that
point toward the diagnosis. A diagnostic algorithm that
would be helpful to arrive at cytological diagnosis of sar-
coidosis is proposed (Fig. 1). The sarcoid granuloma con-
sists of a compact (organized) collection of mononuclear
phagocytes (macrophages or epitheliod cells) typically
without necrosis (Figs. 2A, B and 3A–C).8 Usually giant
cells are found within the sarcoid granulomas and these are
usually surrounded by a peripheral mantle of lymphocytes.
A variety of inclusions may be present, such as Schau-
mann’s bodies, asteroid bodies (Figs. 2C, D and 3D), bire-
fringent crystals, and Hamazaki-Wesenberg bodies; how-
ever, these inclusions are nonspecific and not diagnostic of
sarcoidosis.9
Since sarcoidosis is known to resolve spontaneously in
more than 70% of patients, the need for cytological/tissue
diagnosis has been the subject of hot debate. The argu-
ments of the opponents of cytological/tissue diagnosis are
based on risk/benefit and cost/benefit considerations,
while those of its proponents are based on the individual
patient’s perspective.10
Cytology
Cytology can be of immense value in the diagnosis of
sarcoidosis. Cytological evaluation can be easily done in
patients with lung and lymph node involvement. As these
organs are involved in majority of the patients with sar-
coidosis and morphological evidence of granulomas is
essential for diagnosis, cytology has an unequivocal role
in diagnostic work up in patient of sarcoidosis. The im-
portant role of fine needle aspiration cytology (FNAC) in
diagnosis and its underutilization was highlighted by
Tambouret et al.11 FNAC when used in conjunction with
clinical findings, radiological and laboratory investiga-
tions, is a useful tool in the diagnosis of sarcoidosis. The
procedure is a simple, safe, cost-effective and can be eas-
ily performed in any out-patient setting, with turnaround
time much less than that of conventional histopathology.
However, in spite of these advantages, cytology is rou-
tinely utilized only in few centers to arrive at a diagnosis
of sarcoidosis.
Cytology is used primarily to demonstrate granulo-
mas(s) in various organs that are affected by sarcoidosis.
It is preferred to demonstrate granuloma in at least two
organs and it is important to exclude other causes of gran-
ulomatous inflammation. Therefore, a portion of the speci-
men should be submitted for fungal and mycobacterial
cultures. Smojver-Jezek et al. studied 116 patients with
mediastinal/hilar lymphadenopathy and 171 transbronchial
fine needle aspirations (TBFNA) were performed from
different lymph nodes.12 Adequate lymph node samples
were obtained in 157 of 171 (91.8%) TBFNA while 14 of
171 (8.2%) samples were inadequate. Cytological findings
consistent with sarcoidosis were present in 133 of 157
(84.7%) samples and in 79 of 88 (89.8%) of patients.
Multinucleated Langhan’s giant cells with epithelioid cells
Fig. 1. Proposed algorithm for the diagnosis of sarcoidosis.
MEHROTRA AND DHINGRA
542 Diagnostic Cytopathology, Vol 39, No 7
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and variable numbers of lymphocytes, with or without
minimal necrosis, as the elements of granuloma were
found in 104/157 (66.2%) of TBFNA samples and in 63/
88 (71.6%) of patients. Small groups or scattered epithe-
lioid cells with lymphocytes, without multinucleated giant
cells or necrosis were considered as findings consistent
with sarcoidosis in 29/157 (18.5%) of TBFNA samples
and 16/88 (18.2%) patients. In 63.6% of patients, TBFNA
cytology was the only morphological evidence of granu-
lomatous inflammatory disease.
Lungs and Hilar Lymph Nodes
Lungs are, by far, the most common organ involved, and
the chest radiograph is abnormal in over 95% of patients
with sarcoidosis.13 The most common abnormalities
encountered are lymph node enlargement and parenchy-
mal lung involvement with fine or coarse reticulations.14
The most characteristic finding is symmetrical bilateral
hilar lymph node enlargement. In fact, sarcoidosis is the
most common cause of bihilar lymphadenopathy in the
Western world.15
Approximately 50% of patients with sarcoidosis have
impaired lung function tests with a restrictive pattern.
Sarcoidosis constitutes 2% of interstitial lung disease.16
Various modalities can used to confirm the presence of
granulomas in lung/hilar tissue.
Bronchoalveolar Lavage (BAL)
In patients with sarcoidosis, cytological findings in BAL
include normal or mildly elevated total cell predominance
of lymphocytes, usually normal percentage of eosinophils
and neutrophils, as well as an absence of plasma cells and
foamy alveolar macrophages.17 Bronchoalveolar lavage
(BAL) with examination of lymphocyte populations
(CD4/CD8 ratio) is sometimes used as a complementary
Fig. 2. (A) Cytology smear showing cluster of epithelioid cell along with lymphocytes, forming granulomas (MGG, 3400). (B) Higher power showingepithelioid cells granuloma (MGG, 31000). (C) Smear showing an asteroid body within a giant cell (MGG, 31000). (D) Cell Block showing an aster-oid body (H&E, 3400). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
CYTOLOGICAL DIAGNOSIS OF SARCOIDOSIS
Diagnostic Cytopathology, Vol 39, No 7 543
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test for the diagnosis of sarcoidosis. In one study, a lym-
phocyte CD4/CD8 ratio of greater than 3.5 had a sensitiv-
ity of 53%, specificity of 94%, a positive predictive value
of 76%, and a negative predictive value of 85% for the
diagnosis of sarcoidosis.18 Ozdemir et al. reported on 50
patients of sarcoidosis and showed that the BAL fluid
concentration of an apoptotic molecule, CD95 (Fas), was
significantly higher in patients with chronic sarcoidosis
compared with those with spontaneous remission.19
Another study by Heron et al. evaluated the utility of the
integrin CD103, expressed on CD4+ T lymphocytes in the
BAL fluid, in the diagnosis of sarcoidosis in 56 patients.
These authors have shown that the combined use of the
CD103+CD4+/CD4+ ratio (<0.2) with either the BAL
CD4+/CD8+ ratio (>3) or the relative BAL/peripheral
blood CD4+/CD8+ ratio (>2) could discriminate sarcoido-
sis from other interstitial lung diseases with a sensitivity
of 66% and a specificity of 89%.20
Transbronchial Fine Needle Aspiration (TBFNA)
In the 1950s Brouet and Euler introduced transbronchial
needle aspiration through a rigid bronchoscope.21 But it
was Wang et al., in 1978, who used transbronchial needle
aspiration with fibreoptic bronchoscopy, thereby avoiding
more invasive surgical procedures, such as mediastino-
scopy.22–24 The method was used for sampling of intralumi-
nal lesions. In the last two decades its primary indication
has been to obtain material from mediastinal and/or hilar
nodes in staging of lung carcinomas and differential diagno-
sis of reactive lymphadenopathy including sarcoidosis.25,26
Pisircriler et al. diagnosed intrathoracic sarcoidosis by
visualizing epithelioid cell granulomas in 441 patients,
based on cytologic examinations of transbronchial aspira-
tion specimens from mediastinal lymph nodes.27 The
results were confirmed histologically using transbronchial
lung biopsy (TBLB) or thoracoscopy. The sensitivity of
cytology was 92%. In another study, Tambouret et al. an-
Fig. 3. (A) Histopathology section showing epthelioid cell granulomas (H&E 340). (B) Higher power showing epithelioid cells granuloma (H&E.3100). (C) Histopathology section showing granulomas (H&E, 3400). (D) Histopathology section showing granulomas with asteroid body (arrow)(H&E, 31000). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
MEHROTRA AND DHINGRA
544 Diagnostic Cytopathology, Vol 39, No 7
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alyzed the use of FNAC in the clinical examination of 32
patients with noncaseating granulomas, detected in all and
proven by histology in half of the patients.11
Smojver-Jezek found the sensitivity of TBFNA cytology
in sarcoidosis presenting as mediastinal/hilar lymphadenopa-
thy to be 78.7% and specificity 92.3%. The positive predic-
tive value for sarcoidosis was 97.8% and negative predictive
value was 60%. Overall diagnostic accuracy of TBFNA
cytology in the diagnosis of mediastinal/hilar sarcoidosis
was 86.2%.12
The diagnostic yield of TBFNA in the diagnosis of
mediastinal/hilar sarcoidosis is dependent on the needle
gauge, the brochoscopist’s skill and the number of nodes
sampled. Whenever possible, sampling of more than one
nodal region is advised to increase diagnostic yield. Triso-
lini et al. showed cytologic TBFNA yielded more material
than that of histologic samples in both the patient-based
(79% versus 30%) and the procedure-based analyses
(70% versus 22.5%), a finding that contrasts with reports
from other investigators.26 Though diagnostic yields in
TBNA are similar to those of transbronchial lung biopsy
(TBLB),28 the major advantage is that there is lesser mor-
bidity and lower chances of potential complications like
pneumothorax and bleeding with TBLB.
Endoscopic Ultrasonograpy-GuidedFine-Needle Aspiration
Cytological diagnosis of sarcoidosis got a fillip with
development of linear echoendoscopes. It is now possible
to do transesophageal ultrasound-guided fine-needle aspira-
tion (EUS-FNA) and endobronchial ultrasonograpy-guided
transbronchial needle aspiration (EBUS-TBNA). These
methods are safe, minimally invasive, and give real-time
information for aspirations.29
The combination of EUS along with simultaneous
FNAC in mediastinal lymphadenopathy is well established
in diagnosis and staging of carcinoma lung,2–8 however,
cases of sarcoidosis using EUS-FNA and EBUS-TBNA
are relatively less well recognized. Mishra et al. recently
reported seven cases of sarcoidosis in 108 EUS-guided
mediastinal FNA procedures.30 Williams et al. diagnosed
sarcoidosis in five men by aspirating granulomatous mate-
rial from bulky posterior nodes. The patients represented
a subgroup from series of 120 patients undergoing EUS-
FNA of mediastinal lymph nodes.31 All of the patients
showed a clinical response to steroid treatment. Lohela et
al. diagnosed granulomatous inflammation using ultra-
sound-guided FNA cytology of lymph nodes.32 The
results were consistent with sarcoidosis in 88% of the
patients, and the diagnosis could be confirmed on histol-
ogy and clinical follow-up.
In a study conducted on 19 patients of suspected sar-
coidosis, using EUS-FNA with a linear echoendoscope
and a 22-gauge Hancke-Vilman needle, Fritscher et al.,
reported the overall diagnostic accuracy and sensitivity of
EUS-FNA in the diagnosis of sarcoidosis as 94 and
100%, respectively.33
Several studies have showed diagnostic yield of real-
time EBUS-TBNA to be 85–93%.34–36 Garwood et al.
demonstrated that the yield of EBUS-TBNA exceeded
80% at five passes, with no further increase in yield even
after seven passes.34
The usefulness of EBUS-TBNA in patients with suspi-
cion of sarcoidosis has been demonstrated by studies by
Wong et al. and Oki et al.35,36 EBUS-TBNA was diagnos-
tic in 85–91.8% of patients with a final diagnosis of sar-
coidosis. The negative predictive value (NPVs) found in
these studies were 11 and 12.5%, respectively. Advantage
of EBUS-TBNA over EUS-FNA is its greater ability to
access different hilar lymph nodes and nodes situated an-
terolateral to the trachea, which are more commonly
involved in sarcoidosis. Besides this, BAL and TBLB can
also be done along with bronchsocopy done for EBUS
TBNA.
In a recent study, von Bartheld et al., demonstrated that
cell-block analysis added to conventional cytological eval-
uation of EUS aspirates results in a high yield in detect-
ing granulomas in patients with suspected sarcoidosis and
reduces the false-negative rate substantially.37
Biopsy
Transbronchial lung biopsy (TBLB) is one of the pre-
ferred diagnostic methods for pulmonary sarcoidosis. Its
diagnostic accuracy is reported to be about 70% (range
40–90).38,39 It is recommended that four to five lung biop-
sies be performed to maximize the diagnostic yield.
TBLB is more likely to be diagnostic in patients with
parenchymal disease on chest radiograph (radiographic
stage II or III) than in those with a normal lung paren-
chyma (radiographic stage 0 or I).38
Endobronchial biopsy has a diagnostic yield of 40–60%
for sarcoidosis. Furthermore, endobronchial biopsy can be
performed with the TBLB procedure and has been shown
to increase the diagnostic yield for sarcoidosis above that
by using TBLB alone.40
Mediastinoscopy
Mediastinoscopy used to be the ‘‘gold standard’’ for mak-
ing the diagnosis of pulmonary sarcoidosis, but it is more
invasive and costly, as well as having a greater morbidity
than TBLB or TBNA. Therefore, mediastinoscopy should
be reserved for patients with negative TBNA findings.41,42
Head and Neck
In the head and neck region, salivary glands and lymph
nodes are often involved, in patients with sarcoidosis.
These sites can be easily accessed, for cytology, by con-
ventional FNAC, as they present with palpable mass(es).
CYTOLOGICAL DIAGNOSIS OF SARCOIDOSIS
Diagnostic Cytopathology, Vol 39, No 7 545
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Mondal et al., in 1993, diagnosed sarcoidosis in 18 cases
presenting with palpable lymphadenitis in the head and
neck region.43 Salivary gland enlargement, is well known
in sarcoidosis. Aggarwal et al. reported sarcoidosis in two
presenting with bilateral parotid gland enlargement and
one with bilateral submandibular gland enlargement, by
FNAC.44 Smears showed noncaseating epithelioid cell
granulomas with or without giant cells and salivary gland
acini with varying degrees of degenerative changes. After
excluding other granulomatous lesions, sarcoidosis was
suggested and was subsequently proved in all three cases.
Asteroid bodies have been reported, in both lymph node
and parotid smears, however these are uncommonly
found.45 The authors group have diagnosed four such
cases on FNAC of the head and neck region with the
diagnosis being supported by angiotensin-converting
enzyme levels and confirmation by histology (Unpub-
lished Observation). FNAC, therefore, may be considered
a useful diagnostic modality in cases of sarcoidosis pre-
senting primarily with head and neck involvement.
Ancillary Techniques
Elevated serum angiotensin-converting enzyme level, are
seen in 50–60% patients. Serum angiotensin-converting
enzyme (SACE) is produced in the epithelioid cell of the
sarcoid granuloma and its levels reflect the total granuloma
burden in sarcoidosis.46,47 Although an elevated SACE was
initially thought to be diagnostic of sarcoidosis it is neither
sensitive nor specific diagnostic marker of sarcoidosis and
does not reliably correlate with disease activity or its prog-
nosis.48 Elevated levels of lysozyme are also seen in the
two-thirds of patients of sarcoidosis.49 They are derived
from the macrophage and correlate with SACE levels.
Biochemical abnormalities that have been described in
patients of sarcoidosis are hypercalcaemia, hypercalciuria,
hyperuricaemia, elevated serum aminotransferase, alanine
aminotransferase, and alkaline phosphatase.
Pulmonary function tests in typically show restrictive
pattern with impaired findings in more than half of
patients of sarcoidosis. Diffusing capacity of the lung for
carbon monoxide (DLCO) and the vital capacity test are
sensitive parameters to assess the pulmonary function.
Bilateral hilar adenopathy on chest radiograph suggests
the diagnosis of sarcoidosis, especially if the patient has
no fever, night sweats, or weight loss.10,15 Findings on
chest high-resolution computed tomography (HRCT) may
be more specific for the diagnosis of sarcoidosis than the
chest radiograph, although inadequate for the diagnosis to
be made without histologic confirmation.50 Gallium-67
(67Ga) scans show characteristic uptake, Panda/lambda sign
in patients with sarcoid lesions are positive; however, it has
been observed that transferrin receptor rapidly downregu-
lates after few months of systemic corticosteroid therapy,
possibly leading to a false-negative gallium scan.51 The
18F-fluorodeoxyglucose (FDG)-PET can also be of value
for evaluating systemic inflammatory activity,52 and is more
sensitive than gallium scanning.53,54 More recently, Kaira et
al., demonstrated that combination of L-[3-18F]-a-methyl-
tyrosine (18F-FMT) with conventional FDG-PET is more
useful in discriminating sarcoidosis from malignancy.55
To demonstrate cardiac involvement of sarcoidosis
recent studies have shown cardiac MRI to be a useful
diagnostic tool. In 10 patients with clinically diagnosed
cardiac sarcoidosis, Tadamura et al. have demonstrated
that delayed enhancement in cardiac MRI is useful for the
early detection of cardiac involvement having a sensitivity
of 100%, and was more specific and sensitive than echo-
cardiography, thallium and gallium scintigraphy.56
Use of genetic testing, though seems to hold promise
for the future, is yet to achieve clinical relevance. In a
recent study by Grunewald and Eklund showed that, in
patients with Lofgren’s syndrome, *99% of the human
leukocyte antigen (HLA) DRB1_0301/DQB1_0201-posi-
tive patients showed a spontaneous remission, whereas
only 55% of the HLA-DRB1_0301/DQB1_0201-negative
patients had a spontaneous remission.57
Kveim-Stilzbachs test is a diagnostic test of historical
importance. Splenic suspension from a spleen involved
with sarcoidosis is inoculated intradermally.58 However,
as the sensitivity and specificity vary depending upon the
spleen that is used and the suspension is not approved
Food and Drug Administration, this test is not considered
as a standard diagnostic test for sarcoidosis and is rarely
performed nowadays.50
Pitfalls of Cytological Assessmentof Sarcoid Granulomas
Tuberculosis may also present as noncaseating granulo-
mas. As it is primarily a pulmonary disease, it may present
as a diagnostic dilemma, especially in those parts of the
world where it has high prevalence. To make this distinc-
tion a suspicious clinical history of tuberculosis (pyrexia,
night sweats, recent travel to endemic areas, no previous
BCG vaccination) coupled blood, sputum or urine tests for
AFB, culture, PCR, and good response to anti-tuberculous
drugs would therapy supports the diagnosis of tuberculo-
sis. This is depicted in a tabular form to help distinguish
between granulomas of these two diseases (Table I).
Another pitfall may be finding noncaseous granulomas
in sarcoid reaction. These are morphologically identical to
the granulomas of sarcoidosis. Sarcoid reactions have
been reported in patients with various lymphomas, non-
small cell carcinoma of the lung, germ call neoplasm ei-
ther in lymph nodes draining the malignancy or in remote
lymph node stations.59 Interestingly, in the lung and other
organs, sarcoidosis or sarcoid reaction may sometimes
resemble a malignancy. These sarcoid-like granulomas
appear to represent a local T cell-mediated immune
MEHROTRA AND DHINGRA
546 Diagnostic Cytopathology, Vol 39, No 7
Diagnostic Cytopathology DOI 10.1002/dc
reaction,60 possibly due to the shedding of antigens or
other factors from the tumor tissue, but reportedly differ
from sarcoid granulomas since they additionally contain
B cells within the granulomas.61 The various confounding
factors have been recently reviewed by Cameron et al.62
Conclusion
As there is no single confirmatory diagnostic test for sar-
coidosis, its diagnosis has always remained a daunting
task for both physicians and pathologists. However, recent
developments in diagnostic modalities have gone a long
way to facilitate and ease this challenge. Newer techni-
ques to sample lesions, like EUS-FNA and EBUS-TBNA
for cytological analysis, hold lot of promise. These diag-
nostic procedures, being minimally invasive, are a lot
safer and have sensitivity comparable to the standard pro-
cedures such as TBLB and/or mediastinoscopy which are
routinely used to establish tissue diagnosis for sarcoidosis.
We therefore believe, in the light of data that has emerged
from various studies, that cytology aided by these novel
methods of aspirating material is an useful addition, if not
an alternative, in the diagnosis of this entity.
Acknowledgments
The authors gratefully acknowledge permission to use
Figs. 2C and D from Drs. Jorns/Knoepp from University of
Michigan, Ann Arbor, MI and Fig. 3D from Dr. Shyama
Jain of Maulana Azad Medical College, Delhi, India.
References
1. American Thoracic Society. Statement on sarcoidosis. Am J RespirCrit Care Med 1999;160:736–755.
2. Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOGstatement on sarcoidosis. American Thoracic Society/European Respi-ratory Society/World asssociation of sarcoidosis and other granuloma-tous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:149–173.
3. Wolbach SB. A new type of cell inclusion, not parasitic, associatedwith disseminated granulomatous lesions. J Med Res 1911;24:243–257.
4. Sharma OP. Available at: http://www.wasog.org/PDFs/sharma.pdf(Last accessed 15 Apr. 2010).
5. Braverman IM, Feedberg IM, Eisen AZ, et al. Fitzpatrick’s derma-tology in general medicine. 6th ed. New York: McGraw Hill; 2003.p 1777–1783.
6. Gordis L. Epidemiology of chronic lung diseases in children. Balti-more (MD): Johns Hopkins University Press; 1973. p 53–78.
7. Barnett BP, Sheth S, Ali SZ. Cytopathologic analysis of paratra-cheal masses: A study of 737 cases with clinicoradiologic correla-tion. Acta Cytol 2009;5:672–678.
8. Adams DO. The biology of the granuloma. Pathology of granulo-mas. New York: Raven; 1983. p 1–20.
9. Jorns J, Knoepp SM. Asteroid bodies in lymph node cytology:Infrequently seen and still mysterious. Diagn Cytopathol 2010. Jan4. [Epub ahead of print].
10. Reich JM, Brouns MC, Connor EA, et al. Mediastinoscopy inpatients with presumptive stage I sarcoidosis: A risk/benefit, cost/benefit analysis. Chest 1998;113:147–153.
11. Tambouret R, Geisinger K, Silverman J, et al. The clinical applica-tion of FNA in the diagnosis and management of sarcoidosis ActaCytol 1997;41:1620.
12. Smojver-Jezek S, Peros-Golubicic T, Tekavec-Trkanjec T, MazuranicI, Alilovic M. Transbronchial fine needle aspiration cytology in the di-agnosis of mediastinal/hilar sarcoidosis. Cytopathology 2007;18:3–7.
13. Joseph PL, Kazarooni EA, Gay SE. Pulmonary sarcoidosis. ClinChest Med 1997;18:755–785.
14. Elias JA, Tanoue LT. 1998. Textbook of pulmonary diseases.6th ed. Philadelphia: Lippincott-Raven. p 407–430.
15. Winterbauer RH, Betic N, Moores KD. A clinical interpretation ofbilateral hilar adenopathy. Ann Intern Med 1973;78:65–71.
16. Baughman RP. Pulmonary sarcoidosis. Clin Chest Med 2004;25:521–530.
17. Costabel U, Guzman J, Drent M. Diagnostic approach to sarcoido-sis. Eur Respir Mon 2005;32:259–264.
18. Nagai S, Izumi T. Bronchoalveolar lavage, still useful in diagnosingsarcoidosis? Clin Chest Med 1997;18:787–797.
19. Ozdemir OK, Celik G, Dalva K, et al. High CD95 expression ofBAL lymphocytes predicts chronic course in patients with sarcoido-sis. Respirology 2007;12:869–873.
20. Heron M, Slieker WA, Zanen P, et al. Evaluation of CD103 as acellular marker for the diagnosis of pulmonary sarcoidosis. ClinImmunol 2008;126:338–344.
21. Euler HE, Strauch J, Witte S. Zur cytodiagnostik mediastinaler Gesch-wulste. Arch Ohr-Usw Heilk Hals-Usw Heilk 1955;167:376–383.
22. Wang KP, Terry P, Marsh B. Bronchoscopic needle aspirationbiopsy of paratracheal tumors. Am Rev Respir Dis 1978;118:17–21.
23. Wang KP, Terry PB. Transbronchial needle aspiration in the diag-nosis and staging of bronchogenic carcinoma. Am Rev Respir Dis1983;127:344–347.
24. Wang KP, Fuenning C, Johns CJ, Terry PB. Flexible transbronchialneedle aspiration for the diagnosis of sarcoidosis. Ann Otol RhinolLaryngol 1989;98:298–300.
25. Harrow EM, Oldenburg FA, Lingenfelter MS, Smith AM. Trans-bronchial needle aspiration in clinical practice. A five-year experi-ence. Chest 1989;96:1268–1272.
26. Trisolini R, Agli LL, Cancellieri A, et al. The value of flexibletransbronchial needle aspiration in the diagnosis of stage I sarcoido-sis. Chest 2003;124:2126–2130.
27. Pisircriler R, Atay Z, Lang W. Cytological diagnosis of intrathoracic epi-thelioid cellular inflammatory process. Pneumologie 1990;44:767–770.
28. Morales CF, Patefield AJ, Strollo PJ, Jr., Schenk DA. Flexible trans-bronchial needle aspiration in the diagnosis of sarcoidosis. Chest1994;106:709–711.
29. Annema JT, Rabe KF. State of the art lecture: EUS and EBUS inpulmonary medicine. Endoscopy 2006;38:S118–S122.
30. Mishra G, Sahai AV, Penman ID, et al. Endoscopic ultrasonographywith fine-needle aspiration: An accurate and simple diagnostic mo-dality for sarcoidosis. Endoscopy 1999;31:377–382.
31. Williams DB, Sahai AV, Aabakken L, et al. Endoscopic ultrasoundguided fine-needle aspiration biopsy: A large single center experi-ence. Gut 1999;44:720–726.
Table I. Differences Between Granulomas of Tuberculosisand Sarcoidosis
Criteria Sarcoidosis Tuberculosis
Epithelioid cell granuloma +++ +++Caseating cell necrosis, presentsas ‘‘dirty background’’
+ ++
Langhans’ giant cells � +++Histiocytic-type giant cells + ++Granulocytes + +++ZN stain for AFB � +++
Modified from table by Fritscher-Ravens et al.33
+, sometimes positive; ++, often positive; +++, strongly positive;�, usually negative.
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32. Lohela P, Tikkakoski L, Strengell L, et al. Ultrasound guided fine-needle aspiration cytology of non-palpable supraclavicular lymphnodes in sarcoidosis. Acta Radiol 1996;37:896–899.
33. Fritscher-Ravens A, Sriram PV, Topalidis T, et al. Diagnosing sar-coidosis using endosonography-guided fine-needle aspiration. Chest2000;118:928–935.
34. Garwood S, Judson MA, Silvestri G, et al. Endobronchial ultra-sound for the diagnosis of pulmonary sarcoidosis. Chest 2007;132:1298–1304.
35. Wong M, Yasufuku K, Nakajima T, et al. Endobronchial ultra-sound: New insight for the diagnosis of sarcoidosis. Eur Respir J2007;29:1182–1186.
36. Oki M, Saka H, Kitagawa C, et al. Real-time endobronchial ultra-sound-guided transbronchial needle aspiration is useful for diagnos-ing sarcoidosis. Respirology 2007;12:863–868.
37. von Bartheld MB, Veselic-Charvat M, Rabe KF, Annema JT. Endo-scopic ultrasound-guided fine-needle aspiration for the diagnosis ofsarcoidosis. Endoscopy 2010;42:213–217.
38. Gilman MJ, Wang KP. Transbronchial lung biopsy in sarcoidosis:An approach to determine the optimal number of biopsies. Am RevRespir Dis 1980;122:721–724.
39. Koonitz CH, Joyner LR, Nelson RA. Transbronchial lung biopsyvia the fiberoptic bronchoscope in sarcoidosis. Ann Intern Med1976;85:64–66.
40. Shorr AF, Torrington KG, Hnatiuk OW. Endobronchial biopsy forsarcoidosis: A prospective study. Chest 2001;120:109–114.
41. Gossot D, Toledo L, Fritsch S, Celerier M. Mediastinoscopy vsthoracoscopy for mediastinal biopsy. Results of a prospective non-randomized study. Chest 1996;110:1328–1331.
42. Porte H, Roumilhac D, Eraldi L, et al. The role of mediastinoscopyin the diagnosis of mediastinal lymphadenopathy. Eur J Cardio-thorac Surg 1998;13:196–199.
43. Mondal A, Das PK, Roychaudhuri BK. Cytological diagnosis of sar-coidosis of head and neck by fine needle aspiration biopsy. Indian JOtotoryngol Head Neck Surg 1993;2:78.
44. Aggarwal AP, Jayaram G, Mandal AK. Sarcoidosis diagnosed onfine-needle aspiration cytology of salivary glands: A report of threecases. Diagn Cytopathol 1989;5:289–292.
45. Lynch JP, III, Kazerooni EA, Gay SE. Pulmonary sarcoidosis. ClinChest Med 1997;18:755–785.
46. Lieberman J. Elevation of serum angiotensin-converting-enzyme(ACE) level in sarcoidosis. Am J Med 1975;59:365–372.
47. Callen JP, Hanno R. Serum angiotensin-converting enzyme levels inpatients with cutaneous sarcoidal granulomas. Arch Dermatol 1982;2:232–233.
48. English JC, Patel PJ, Greer KE. Sarcoidosis. J Am Acad Dermatol2001;44:725–743.
49. Pietinalho A, Ohmichi M, Lofroos AB, et al. The prognosis of pul-monary sarcoidosis in Finland and Hokkaido, Japan: A comparativefive-year study of biopsy-proven cases. Sarcoidosis Vasc DiffuseLung Dis 2000;17:158–166.
50. Judson MA. The diagnosis of sarcoidosis. Clin Chest Med 2008;29:415–427.
51. Kohn H, Klech H, Mostbeck A, Kummer F. 67Ga scanning forassessment of disease activity and therapy decisions in pulmonarysarcoidosis in comparison to chest radiography, serum ACE andblood T-lymphocytes. Eur J Nucl Med 1982;7:413–416.
52. Nguyen BD. F-18 FDG PET imaging of disseminated sarcoidosis.Clin Nucl Med 2007;32:53–54.
53. Nishiyama Y, Yamamoto Y, Fukunaga K, et al. Comparative evalu-ation of 18FFDG PET and 67Ga scintigraphy in patients with sar-coidosis. J Nucl Med 2006;47:1571–1576.
54. Futamatsu H, Suzuki J, Adachi S, et al. Utility of gallium-67 scin-tigraphy for evaluation of cardiac sarcoidosis with ventricular tachy-cardia. Int J Cardiovasc Imaging 2006;22:443–448.
55. Kaira K, Oriuchi N, Otani Y, et al. Diagnostic usefulness of fluo-rine-18-alphamethyltyrosine positron emission tomography in com-bination with 18Ffluorodeoxyglucose in sarcoidosis patients. Chest2007;131:1019–1027.
56. Tadamura E, Yamamuro M, Kubo S, et al. Effectiveness of delayedenhanced MRI for identification of cardiac sarcoidosis: Comparisonwith radionuclide imaging. AJR Am J Roentgenol 2005;185:110–115.
57. Grunewald J, Eklund A. Sex-specific manifestations of Lofgren’ssyndrome. Am J Respir Crit Care Med 2007;175:40–44.
58. Siltzbach LE. The Kveim test in sarcoidosis. A study of 750patients. JAMA 1961;178:476–482.
59. Steinfort DP, Irving LB. Sarcoidal reactions in regional lymphnodes of patients with non-small cell lung cancer: Incidence andimplications for minimally invasive staging with endobronchialultrasound. Lung Cancer 2009;66:305–308.
60. Kurata A, Terado Y, Schulz A, Fujioka Y, Franke FE. Inflammatorycells in the formation of tumor-related sarcoid reactions. HumPathol 2005;36:546–554.
61. Brincker H, Pedersen NT. Immunohistologic separation of B-cell-positive granulomas from B-cell-negative granulomas in paraffin-embedded tissues with special reference to tumor-related sarcoidreactions. APMIS 1991;99:282–290.
62. Cameron SE, Andrade RS, Pambuccian SE. Endobronchial ultra-sound-guided transbronchial needle aspiration cytology: A state ofthe art review. Cytopathology 2010;21:6–26.
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