Hindawi Publishing Corporation
Pathology Research International
Volume 2012, Article ID 854146, 6 pages
False-Negative Results of EndoscopicBiopsy intheDiagnosis of
Gastrointestinal Kaposi’s Sarcoma inHIV-InfectedPatients
Naoyoshi Nagata,1KatsunoriSekine,1Toru Igari,2YoheiHamada,3
HirohisaYazaki,3Norio Ohmagari,4JunichiAkiyama,1Takuro Shimbo,5KatsujiTeruya,3
ShinichiOka,3and Naomi Uemura6
1Department of Gastroenterology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku,
Tokyo 162-8655, Japan
2Department of Clinical Pathology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
3AIDS Clinical Center (ACC), Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
4Department of Infectious Disease, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
5Department of Clinical Research and Informatics, International Clinical Research Center, Research Institute,
National Center for Global Health and Medicine, Tokyo, Japan
6Department of Gastroenterology and Hepatology, Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan
Correspondence should be addressed to Naoyoshi Nagata, nnagata email@example.com
Received 9 August 2012; Revised 29 October 2012; Accepted 29 October 2012
Academic Editor: Piero Tosi
Copyright © 2012 Naoyoshi Nagata et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Kaposi’s sarcoma (KS) is a rare endothelial neoplasm mainly involving the skin, but it is often associated with AIDS. Diagnosis
of gastrointestinal (GI) tract KS, a common site of visceral involvement in AIDS, is important, but endoscopic biopsy carries a
risk of false-negative results (FNRs) due to its submucosal appearance. This study sought to determine the rate and causes of FNR
for endoscopic biopsy of GI-KS lesions. Endoscopic biopsy samples of 116 GI-KS lesions were reviewed retrospectively. All GI-KS
lesions were confirmed to be resolved following KS therapy. FNRs were yielded for 41 of the lesions (35.3%). Among upper and
lower GI sites, the esophagus was the only site significantly associated with FNRs (P < 0.01). Small size (<10mm) and patches
found on endoscopy were significantly associated with FNRs (P < 0.05). Findings of submucosal tumor (SMT) with ulceration
were significantly associated with true-positive results (P < 0.05). In conclusion, FNRs were found in 35.3% of GI-KS lesions and
were especially related to the site of the esophagus and endoscopic early stage (small size or patch appearance). An SMT with
ulceration may be relatively easy to diagnose on endoscopic biopsy. Caution should be exercised when performing endoscopic
biopsy of these lesions in AIDS patients and evaluating the histological features.
Kaposi’s sarcoma (KS) is a cancer of the lymphatic and blood
vessels that mainly involves the skin [1–3]. It is a rare cancer
but has become more widely known as one of the AIDS-
has decreased dramatically since the introduction of highly
active antiretroviral therapy (HAART) [4–6], KS remains the
most common malignancy among patients with AIDS .
KS can also involve the oral cavity, lymph nodes, and
viscera [1–3, 8]. The diagnosis of visceral KS is important
because the need for treatment and choosing among the
various options depend upon the extent of disease [8–
10]. The gastrointestinal (GI) tract is a common site of
visceral involvement [11–15], and a definitive diagnosis of
GI-KS can be made by endoscopic tissue biopsy [8, 16, 17].
Histopathologically, GI-KS is characterized by spindle cells
that form vascular channels, which fill with blood cells
[17, 18]. Endoscopically, GI-KS has various macroscopic
presentations: patches, polypoid lesions, submucosal nod-
ules, bulky masses, and ulcerations [13, 17, 19–23]. For
submucosal nodules especially, endoscopic biopsy sampling
2 Pathology Research International
has been known to yield false-negative results (FNRs) [17,
23–25]. Some GI-KS lesions might be more difficult to
identify histologically depending on their location, size, or
with false-negative histological results remain unknown.
The purpose of this study was to determine the rate and
causes of FNR from endoscopic biopsies of GI-KS lesions.
2.1. Subjects. Histopathology slides of endoscopic biopsy
samples of 116 consecutive, GI-KS lesions from 24 HIV-
infected patients who had not received anti-KS therapy
were retrospectively reviewed. All biopsies were performed
between 2002 and 2006 at the National Center for Global
Health and Medicine (NCGM), a 900-bed hospital located
for HIV/AIDS in Japan.
2.2. Ethics Statement. The institutional review board at
NCGM approved this study. All patients from whom clinical
samples were obtained during endoscopic biopsy provided
written informed consent prior to the procedure. Data
obtained from the patient medical records was anonymized
2.3. Clinical Factors. HIV infection route was determined by
the medical staff who interviewed each patient on the first
visit to our hospital. Routes of HIV infection were deter-
mined by medical staff who questioned each patient face to
face on the first visit to our hospital. Routes were classified
into six categories: homosexual, bisexual, heterosexual, drug
user, untreated blood products, and unknown. Patients who
sex with men (MSM).
CD4+cell counts were checked within 1 week of
endoscopy. HIV-RNA viral loads (VLs) determined by real-
time quantitative polymerase chain reaction (PCR) were
reviewed within 1 month of endoscopy. The minimum
detection level was 40 copies/mL of plasma. A positive result
for real-time HIV-RNA was defined as ≥40 copies/mL.
2.4. Diagnosis of GI-KS. Biopsy was performed using biopsy
forceps (FB-240U, FB230-K; Olympus Co., Tokyo, Japan).
All biopsies were performed by well-trained endoscopists
(experience of >1.000 colonoscopies).
A definitive diagnosis of GI-KS was defined as follows.
(1) Negative results confirmed from biopsy samples
for other GI diseases such as infection, inflamma-
tory bowel disease, hyperplastic polyp, fundic gland
polyp, inflammatory polyp, adenomatous polyp,
angioectasia, GI lymphoma, premalignant lesion,
esophageal cancer, gastric cancer, and colorectal
(2) Presence of proliferating spindle cells (Figure 1) with
vascular channel formations filled with blood cells
(Figure 1) seen on hematoxylin and eosin (HE)
Table 1: Baseline characteristics of GI-KS patients (N = 24).
Age, years (IQR)
Sex, male (%)
CD4 cell counts, cells/mL (IQR)
HIV viral load, copies/mL (IQR)
GI symptoms (%)
71 (15.5, 177.5)
115,000 (2,900, 145,000)
IQR: interquartile range; GI: gastrointestinal; MSM: men who have sex with
staining. Lesions with the absence of these findings
from biopsy samples were defined as FNR.
(3) Positive response to KS therapy (HAART or systemic
therapy of liposomal anthracycline); in particular,
for visible GI-KS lesions without typical pathological
findings from biopsy specimens, partial or complete
resolution confirmed on follow-up endoscopy fol-
lowing KS therapy.
2.5. Endoscopic Assessment of GI-KS. GI-KS was evaluated in
terms of site, size (≤10mm or >10mm), and macroscopic
findings on endoscopy. Site of GI involvement was classified
side colon (cecum, ascending colon, and transverse colon),
left-side colon (descending colon and sigmoid colon), and
rectum. Macroscopic findings were evaluated in the presence
of reddish mucosa with patches (Figure 2(a)), polypoid
lesion (Figure 2(b)), submucosal tumor (SMT), SMT with
ulceration (Figure 2(c)), and bulky mass (Figure 2(d)), as
previously reported [13, 17, 19–23]. Ulceration was defined
endoscopically as a distinct, visible crater >5mm in diameter
with a slough base.
2.6. Statistical Analysis. The descriptive patient character-
istics were summarized, and the absence rate of spindle
cells or vascular formations on pathology for the 116
samples was then analyzed to elucidate the FNR rate of
endoscopic biopsy. To determine the cause of FNRs, the
relationships between FNR and endoscopic findings (size,
site, macroscopic appearance) were evaluated using the χ2
test. Those factors that emerged as significant (P < 0.10)
on univariate analysis were included in a multiple exact
logistic regression model. A final model was then developed
by backward selection of factors showing values of P < 0.10
and odds ratios (ORs) and 95% confidence intervals (CIs)
Values of P < 0.10 were considered significant. All
statistical analyses were performed using Stata version 10
software (StataCorp LP, College Station, TX, USA).
3.1. Baseline Characteristics. Characteristics of the 24
and the HIV infection route was MSM in all cases. Median
CD4+count was 71cells/mL and median HIV-RNA VL was
Pathology Research International3
Figure 1: Pathological features of GI-KS on HE staining. (a) Low-power view showing a distinct proliferative lesion within the submucosa
of the small bowel intestine. (b) High-power view showing spindle cell proliferation with vascular channel formations filled with blood cells.
Figure 2: Gastrointestinal Kaposi’s sarcoma on endoscopy. (a) Dark reddish patch lesion (arrow) in the esophagus. (b) Small (≤10mm) and
polypoid lesion in the duodenum. (c) Submucosal tumor-like lesion with ulceration in the stomach. (d) Bulky tumor mass surrounding the
anorectal area causing anorectal stenosis.
115,000 copies/mL. GI symptoms were noted in 8 patients
(33.3%) as follows: epigastric pain (n = 4), nausea or
vomiting (n = 3), hematemesis (n = 1), melena (n = 1),
hematochezia(n = 2),anddiarrhea(n = 2)(duplicatedata).
3.2. Macroscopic Appearance of GI-KS on Endoscopy. A total
of 113 GI-KS lesions were from 24 HIV-infected patients
(Table 2). “Patches” appearance was noted in 40 lesions
(34.5%)whichwerelocatedmainlyintheduodenum(n = 8,
20.0%) and right-side colon (n = 9, 22.5%). Only one lesion
“SMT” appearance was noted in 46 lesions (39.7%) located
mainly in the stomach (n = 18, 39.1%) and duodenum
(n = 14, 30.4%). “SMT with ulcer” appearance was noted in
4 Pathology Research International
Table 2: Macroscopic appearances of GI-KS on endoscopy according to the GI site (n = 116).
Patches (n = 40)
15 (37.5%)0 33 (71.7%)
4 (10.0%)0 18 (39.1%)
8 (20.0%)0 14 (30.4%)
25 (62.5%) 1 (100%)13 (28.3%)
5 (12.5%) 1 (100%)
Polypoid (n = 1) SMT (n = 46)SMT with ulcer (n = 26)
Bulky tumor (n = 3)
GI: gastrointestinal; SMT: submucosal tumor.
Table 3: Rate and causes of false-negative endoscopic biopsy results for GI-KS lesions on univariate analysis.
(n = 116)
Lesions with true-positive results
(n = 75)
Lesions with false-negative results
(n = 41)
Upper GI tract
Lower GI tract
SMT with ulcer
GI: gastrointestinal; SMT: submucosal tumor.
Table 4: Factors associated with false-negative endoscopic biopsy
results in GI-KS lesions on multivariate analysis (n = 116).
Esophageal site 7.26
Patches on endoscopy 3.30
GI: gastrointestinal; CI: confidential interval.
26 lesions (22.4%) located mainly in the stomach (n = 10,
38.5%) and duodenum (n = 9, 34.6%). “Bulky tumor”
appearance was noted in 3 lesions only in the rectum.
3.3. Diagnostic Yield of GI-KS on Endoscopic Biopsy. No
clinical complications of GI-KS lesions were seen. There
were no significant gastrointestinal bleeds or perforations,
either spontaneous or after endoscopic biopsy. Diagnostic
yield of GI-KS is shown in Table 3. Among the 116
lesions, 75 (64.7%) were histologically proven by endoscopic
histological results (FNR) that were confirmed to have
resolved following KS therapy.
Among the GI locations, the esophagus was significantly
(P < 0.01) associated with FNR. In regards to the size
of lesions, those <10mm in diameter were significantly
associated with FNR (P<
appearance, patches were significantly associated with FNR
(P < 0.01), while a finding of SMT with ulceration was
significantly associated with true positive results (P < 0.05).
On multivariate analysis, the esophageal site and a patch
pattern on endoscopy were independently associated with
FNR (Table 4).
0.05). As for macroscopic
Endoscopy is clearly a valuable diagnostic method for
Pathology Research International5
that FNR were yielded in 41 of the 116 lesions (35.3%)
in this study. Previous studies on GI-KS patients have also
reported a relatively low diagnostic yield for endoscopic
biopsy [17, 23–25]. Friedman et al.  found a diagnostic
Saltz et al.  reported a diagnostic yield of 15% and thus a
potential false-negative rate of 85%. Moreover, in a study of
non-AIDS patients by Kolios et al. , biopsies resulted in
a definitive diagnosis in 5 of 26 patients (19.2%). However,
it is important to keep in mind that the lesions that led to
the FNRs in these studies might have included non-KS GI
diseases. In the present study, we defined GI-KS as biopsy
specimens negative for other GI diseases and with a positive
response to KS therapy, such as shrinkage or disappearance
Various clinical factors can contribute to FNR on biopsy.
Submucosal location or tumor growth is considered to
account for the poor diagnostic yield of standard forceps
biopsies [17, 23]. Moreover, it has been suggested that the
size of biopsy forceps used was 5mm in the upper GI tract
or 8mm in the lower GI tract . We also used forceps
similar in size in the present study. We hypothesized that in
the analysis of endoscopic biopsy of GI-KS, FNR varies with
site in the GI tract, lesion size, and macroscopic appearance.
Secondly, with regard to the GI site, we found the
esophagus to be the only site associated with FNR on
both univariate and multivariate analyses. In this study, we
assessed the site by dividing the GI into 7 parts. Because
it is difficult to differentiate the ascending colon from the
cecum and the descending colon from the sigmoid colon
on endoscopy, we divided the colon into the right-side and
left-side colon. No other study has divided the GI tract into
small segments and investigated the diagnostic yield in such
detail as in the present study. The yield of endoscopic biopsy
in the upper GI tract has been estimated as 13%, which is
low compared with 36% on sigmoidoscopy . It is not
clear if the low diagnostic rate for the esophagus contributed
to the result. The most likely explanation is that lesions
in the esophagus had almost a patchy appearance, but the
number of lesions at this site was relatively small (n = 4).
Further prospective studies with a larger number of patients
Thirdly, in terms of the endoscopic appearance of GI-
KS, small lesions (<10mm) and patches were found to be
significantly associated with FNR on univariate analysis.
Because such characteristics could be confounding factors,
we performed multivariate analysis and found that patches
were correlated with FNR as an independent factor. We
suggested that these lesions contain only a small amount of
tumor tissue, which made such biopsy specimens too small
to be diagnostically useful. On the other hand, the finding
of “SMT with ulceration” was significantly associated with
true-positive results, and these lesions were easily diagnosed
by biopsy. This result may be attributable to the ulcerous
appearance of the tumor, which makes it easy to obtain
samples from the submucosal layer [26, 27].
Fourth, we found that endoscopic biopsy is a safe
diagnostic method for GI-KS even in the presence of an
ulcerative or bulky tumor. A previous report  also
highlighted the importance of biopsy for distinguishing
associated with bleeding complications, which are consistent
with the present results.
Endoscopists and clinicians should become familiar with
the diagnostic yield of GI-KS varies depending on the mor-
evaluate lesions associated with FNR. Because KS-related
GI lesions indicate visceral involvement, the indications
for and selection of HAART and systemic chemotherapy
need to be considered [8–10]. GI-KS often starts out as
small patches in the early stage, and KS should not be
ruled out just because the biopsy result is negative. It was
recently reported that immunohistochemistry for human
herpesvirus-8 (HHV8), CD31, CD34, and D2-40 is useful
for differentiating KS from other gastrointestinal tumors
of similar appearance . When hematoxylin and eosin
staining does not show characteristic proliferating spindle
cells with vascular channel formations filled with blood cells,
the application of such immunohistochemical analysis may
reduce the frequency of FNR.
Endoscopic biopsy is essential for diagnosing GI-KS and
it is a safe method. While FNR were found in 35.3% of
lesions, FNRs differed according to a lesion site, size, and
macroscopic appearance. On endoscopic biopsy, FNR was
and site of esophagus, whereas SMT with ulceration is
relatively easy to diagnose. Caution should be exercised
when performing endoscopic biopsy of these lesions in AIDS
patients and evaluating the histological features.
Conflict of Interests
The authors declare that they have no conflict of interests.
This work was supported by a Grant from the National
Center for Global Health and Medicine (21-101).
The authors wish to thank Hisae Kawashiro, Clinical
Research Coordinator, for assistance with data collection.
 M. Braun, “Classics in Oncology. Idiopathic multiple pig-
mented sarcoma of the skin by Kaposi,” Ca-A Cancer Journal
for Clinicians, vol. 32, no. 6, pp. 340–347, 1982.
 V. Beral, D. Bull, S. Darby et al., “Risk of Kaposi’s sarcoma and
sexual practices associated with faecal contact in homosexual
or bisexual men with AIDS,” The Lancet, vol. 339, no. 8794,
pp. 632–635, 1992.
6 Pathology Research International Download full-text
 Y. Chang, E. Cesarman, M. S. Pessin et al., “Identification of
herpesvirus-like DNA sequences in AIDS-associated Kaposi’s
sarcoma,” Science, vol. 266, no. 5192, pp. 1865–1869, 1994.
 K. Buchacz, R. K. Baker, F. J. Palella et al., “AIDS-defining
opportunistic illnesses in US patients, 1994–2007: a cohort
study,” AIDS, vol. 24, no. 10, pp. 1549–1559, 2010.
 E. A. Engels, R. M. Pfeiffer, J. J. Goedert et al., “Trends in
cancer risk among people with AIDS in the United States
1980–2002,” AIDS, vol. 20, no. 12, pp. 1645–1654, 2006.
 R. J. Biggar and C. S. Rabkin, “The epidemiology of AIDS-
related neoplasms,” Hematology/Oncology Clinics of North
America, vol. 10, no. 5, pp. 997–1010, 1996.
 A. Mocroft, O. Kirk, N. Clumeck et al., “The changing pattern
of Kaposi sarcoma in patients with HIV, 1994–2003: the
EuroSIDA study,” Cancer, vol. 100, no. 12, pp. 2644–2654,
sarcoma: evaluation of potential new prognostic factors and
assessment of the AIDS Clinical Trial Group staging system
in the Haart era - The Italian Cooperative Group on AIDS
and tumors and the Italian cohort of patients na¨ ıve from
antiretrovirals,” Journal of Clinical Oncology, vol. 21, no. 15,
pp. 2876–2882, 2003.
 J. H. Gallafent, S. E. Buskin, P. B. De Turk, and D. M.
Aboulafia, “Profile of patients with Kaposi’s sarcoma in the
era of highly active antiretroviral therapy,” Journal of Clinical
Oncology, vol. 23, no. 6, pp. 1253–1260, 2005.
 J. Stebbing, A. Sanitt, M. Nelson, T. Powles, B. Gazzard, and
M. Bower, “A prognostic index for AIDS-associated Kaposi’s
sarcoma in the era of highly active antiretroviral therapy,” The
Lancet, vol. 367, no. 9521, pp. 1495–1502, 2006.
 B. J. Dezube, “Clinical presentation and natural history of
AIDS-related Kaposi’s sarcoma,” Hematology/Oncology Clinics
of North America, vol. 10, no. 5, pp. 1023–1029, 1996.
 P. Ngendahayo, T. Mets, G. Bugingo, and D. M. Parkin,
“Kaposi’s sarcoma in Rwanda: clinico-pathological and epi-
demiological features,” Bulletin du Cancer, vol. 76, no. 4, pp.
 J. B. Danzig, L. J. Brandt, J. F. Reinus, and R. S. Klein, “Gas-
trointestinal malignancy in patients with AIDS,” American
Journal of Gastroenterology, vol. 86, no. 6, pp. 715–718, 1991.
 L. Laine, J. Amerian, M. Rarick, M. Harb, and P. S. Gill, “The
response of symptomatic gastrointestinal Kaposi’s sarcoma to
chemotherapy: a prospective evaluation using an endoscopic
method of disease quantification,” American Journal of Gas-
troenterology, vol. 85, no. 8, pp. 959–961, 1990.
 H. L. Ioachim, V. Adsay, F. R. Giancotti et al., “Kaposi’s
sarcoma of internal organs. A multiparameter study of 86
cases,” Cancer, vol. 75, no. 6, pp. 1376–1385, 1995.
 S. E. Krown, M. A. Testa, and J. Huang, “Aids-related Kaposi’s
sarcoma: prospective validation of the AIDS clinical trials
group staging classification,” Journal of Clinical Oncology, vol.
15, no. 9, pp. 3085–3092, 1997.
 S. L. Friedman, T. L. Wright, and D. F. Altman, “Gastroin-
testinal Kaposi’s sarcoma in patients with acquired immun-
odeficiency syndrome. Endoscopic and autopsy findings,”
Gastroenterology, vol. 89, no. 1, pp. 102–108, 1985.
 P. Kahl, R. Buettner, N. Friedrichs, S. Merkelbach-Bruse, J.
Wenzel, and L. Carl Heukamp, “Kaposi’s sarcoma of the
gastrointestinal tract: report of two cases and review of the
literature,” Pathology Research and Practice, vol. 203, no. 4, pp.
 N. Ahmed, R. S. Nelson, H. M. Goldstein, and J. G. Sinkovics,
“Kaposi’s sarcoma of the stomach and duodenum: endoscopic
and roentgenologic correlations,” Gastrointestinal Endoscopy,
vol. 21, no. 4, pp. 149–152, 1975.
 R. K. Rajan, S. Goodman, and M. H. Floch, “Gastroscopic
findings in Kaposi’s sarcoma,” Gastrointestinal Endoscopy, vol.
16, no. 2, pp. 104–106, 1969.
 H. S. Rose, E. J. Balthazar, and A. J. Megibow, “Alimentary
tract involvement in Kaposi sarcoma: radiographic and endo-
scopic findings in 25 homosexual men,” American Journal of
Roentgenology, vol. 139, no. 4, pp. 661–666, 1982.
 L. Weprin, R. Zollinger, K. Clausen, and F. B. Thomas,
“Kaposi’s sarcoma: endoscopic observations of gastric and
colon involvement,” Journal of Clinical Gastroenterology, vol.
4, no. 4, pp. 357–360, 1982.
 J. Sakagami, Y. Sogame, K. Kataoka et al., “Endoscopic
resection for the diagnosis of visceral Kaposi’s sarcoma,”
Journal of Gastroenterology, vol. 40, no. 1, pp. 98–103, 2005.
 R. K. Saltz, R. C. Kurtz, and C. J. Lightdale, “Kaposi’s sarcoma.
Gastrointestinal involvement correlation with skin findings
and immunologic function,” Digestive Diseases and Sciences,
vol. 29, no. 9, pp. 817–823, 1984.
 G. Kolios, A. Kaloterakis, A. Filiotou, A. Nakos, and
S. Hadziyannis, “Gastroscopic findings in Mediterranean
Kaposi’s sarcoma (non-AIDS),” Gastrointestinal Endoscopy,
vol. 42, no. 4, pp. 336–339, 1995.
 J. M. Buscaglia, S. Nagula, V. Jayaraman et al., “Diagnostic
yield and safety of jumbo biopsy forceps in patients with
subepithelial lesions of the upper and lower GI tract,”
 J. S. Ji, B. I. Lee, K. Y. Choi et al., “Diagnostic yield of
tissue sampling using a bite-on-bite technique for incidental
subepithelial lesions,” Korean Journal of Internal Medicine, vol.
24, no. 2, pp. 101–105, 2009.
 F. G. Rosado, D. M. Itani, C. M. Coffin et al., “Util-
ity of immunohistochemical staining with FLI1, D2-40,
CD31, and CD34 in the diagnosis of acquired immunod-
eficiency syndrome-related and non-acquired immunodefi-
ciency syndrome-related Kaposi sarcoma,” Archives of Pathol-
ogy & Laboratory Medicine, vol. 136, no. 3, pp. 301–304, 2012.