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CLINICAL REVIEW
David W. Eisele, MD, Section Editor
NON-AIDS KAPOSI’S SARCOMA IN THE
HEAD AND NECK AREA
Anna Patrikidou, MD,1 Kostas Vahtsevanos, PhD,1 Martha Charalambidou, PhD,2
Rosalia-Maria Valeri, PhD,3 Persefoni Xirou, MD,4 Kostas Antoniades, PhD5
1
Department of Maxillofacial Surgical Oncology, Theagenio Cancer Hospital, Thessaloniki,
Greece. E-mail: [email protected]
2
Department of Radiation Oncology, Theagenio Cancer Hospital, Thessaloniki, Greece
3
Department of Cytopathology, Theagenio Cancer Hospital, Thessaloniki, Greece
4
Department of Histopathology, Theagenio Cancer Hospital, Thessaloniki, Greece
5
Department of Oral and Maxillofacial Surgery, General Hospital ‘‘G. Papanikolaou,’’
Thessaloniki, Greece
Accepted 9 June 2008
Published online 28 October 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20945
Abstract: Kaposi’s sarcoma is classified into 4 types: classic
(sporadic), African (endemic), iatrogenic (transplant recipients),
and epidemic (acquired immunodeficiency syndrome [AIDS]associated). This article aims to feature a comprehensive review
of non-AIDS Kaposi’s sarcoma, including literature review and
report of 3 cases. Case material was from our hospital’s archive.
Literature review was conducted via electronic and manual medical database searches. Biological aspects, diagnostic difficulties, investigation protocols, and management modalities are
C 2008 Wiley Periodicals, Inc. Head Neck 31:
V
discussed.
260–268, 2009
Keywords: Kaposi’s sarcoma; non-AIDS; HHV-8; head and
neck; transplant
Described in 1872 as idiopathic multiple pigmented sarcoma,1 Kaposi’s sarcoma is a rare
angioproliferative disease. Four clinical types are
recognized: classic (sporadic, mainly in elderly
patients of European, Jewish, and Mediterranean
Correspondence to: A. Patrikidou
C
V
2008 Wiley Periodicals, Inc.
260
Non-AIDS Kaposi’s Sarcoma
descent), African (endemic, mainly in Sub-Saharan
Africa), iatrogenic (immunosuppression-associated, principally renal transplant-associated), and
epidemic (acquired immunodeficiency syndrome
[AIDS]-associated). The last type is reported in
western countries to be between 1000 and 77,000
times more common than the non–human immunodeficiency virus (HIV)-associated.2,3
Type I Kaposi’s sarcoma (classic) typically
manifests as cutaneous lesions of the lower
extremities and trunk with a slow, indolent course
and a tendency to develop multifocally. Visceral
involvement occasionally occurs,4–6 although it is
more frequent in type II and of course type IV.7
Most frequent sites of involvement for visceral
Kaposi’s sarcoma include the lymph nodes, gastrointestinal (GI) tract, and lungs.6 Type II Kaposi’s sarcoma (African) can be distinguished in the
adult (cutaneous) variant and childhood (lymphadenopathic/visceral) variant.8,9 Type III Kaposi’s
sarcoma is mainly transplant-associated, but has
HEAD & NECK—DOI 10.1002/hed
February 2009
FIGURE 1. Type I Kaposi’s sarcoma of the submandibular duct orifices (left) and the hard palate (right). [Color figure can be viewed in
the online issue, which is available at www.interscience.wiley.com.]
been reported in the context of other immunosuppressive conditions/treatment.
In contrast to type IV Kaposi’s sarcoma, which
usually presents as a disseminated, fulminant
form, non-AIDS Kaposi’s sarcoma seldom affects
mucous membranes, and head and neck mucosal
involvement is even more rare.8,10–12
The international literature focuses heavily on
type I Kaposi’s sarcoma and its well-celebrated
association with HIV. In contrast, the other types
of Kaposi’s sarcoma lesion are underrepresented,
even more so for the head and neck cases. However, the growing number of successful organ
transplantations internationally translates to an
increase of non-AIDS Kaposi’s sarcoma cases.
Moreover, recent elucidation of molecular mechanisms associated with the disease suggests that it
might appear in clinical and pathological settings
further to the ones traditionally described. The
aforementioned facts were the incentives behind
this clinical review article, which includes an
extensive review of the literature as well as case
presentation.
CASE REPORTS
Two type I and 1 type III head and neck Kaposi’s
sarcoma cases are presented here. The patients
were all men, aged between 55 and 78 years and of
Greek origin. The medical history of the patients
with type I Kaposi’s sarcoma was unrelated to the
lesions.
One of the type I cases featured oral Kaposi’s
sarcoma as a sole manifestation (primary oral
Kaposi’s sarcoma), unusual to the common multifocal presentation of this type. Furthermore, it
FIGURE 2. Type I (upper row) and type III (lower row) Kaposi’s sarcoma of the right hard palate. CT views, 1-mm sections. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
Non-AIDS Kaposi’s Sarcoma
HEAD & NECK—DOI 10.1002/hed
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261
FIGURE 3. Kaposi’s sarcoma. Hematoxylin-eosin (H&E) staining. Magnification: 3100 (left), 3200 (right). [Color figure can be viewed
in the online issue, which is available at www.interscience.wiley.com.]
featured an infrequent localization (bilateral red
nodules at submandibular duct orifices, approximately 1 cm diameter each), compared with the
most usual oral Kaposi’s sarcoma presentations in
the palate or gingivae (Figure 1).
The second type I case featured a large (>3 cm
diameter) hard palate lesion extending to the alveolar process, covered by ulcerated epithelium
(Figure 1). He had a history of synchronous cutaneous lesions (upper and lower extremities bilaterally, abdomen, back), some of which had been
irradiated.
The patient with type III Kaposi’s sarcoma featured a hard palate lesion (3 cm 3 2 cm) extending
to the soft palate junction. This was an initial presentation (primary oral Kaposi’s sarcoma), 21
months following renal allograft transplantation
and immunosuppressive treatment with cyclosporine and cortisone. He subsequently developed
multiple metachronous cutaneous lesions of the
lower extremities and abdomen.
All patients were HIV-1, HIV-2, hepatitis B virus (HBV) and hepatitis C virus (HCV) negative.
CT imaging of the head and neck area showed the
FIGURE 4. Kaposi’s sarcoma. Immunohistochemistry with antibodies to CD34 (right) and factor VII-related antigen (left). Magnification: 3100 (left), 3200 (right). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
262
Non-AIDS Kaposi’s Sarcoma
HEAD & NECK—DOI 10.1002/hed
February 2009
FIGURE 5. Kaposi’s sarcoma. Human herpesvirus-8 immunohistochemistry with anti-LNA-1 antibody. Magnification: 3100 (left), 3200
(right). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
degree of osteolytic destruction (Figure 2) and
excluded neck lymphadenopathy. CT of the chest
and abdomen was normal for all patients.
Incisional biopsy and fine-needle aspiration
biopsy (FNA) were obtained from all lesions. With
regard to histopathology, formalin-fixed, paraffinembedded 4-lm tissue sections were immunohistochemically stained using an automated
staining machine (Ventana Medical Systems).
Hematoxylin–eosin staining revealed characteristic
features of Kaposi’s sarcoma, namely an atypical
spindle-cell component and incomplete slit-like
vascular channels of variable size with extravasated red blood cells (Figure 3). Immunostaining
with a standard avidin–biotin–peroxidase technique for CD34 and factor VIII-related antigen
was strongly positive (Figure 4). HHV8 immunohistochemistry was performed with the LNA-1
antibody (clone 13B10; Novocastra). All cases
showed nuclear staining of variable intensity.
Both the stained spindle and endothelial cells
showed speckled dot-like nuclear pattern. The
percentage of positive cells varied from 50% to
80% (Figure 5).
For cytological analysis, the aspiration material was processed using the liquid-based cytology
technique (Thinprep: automated processing and
smearing of cells on a monolayer). When cellular,
smears revealed spindle or polygonal singly dispersed cells with bland, plump nuclei, as typically
described in the literature13 (Figure 6). Longitudinal nuclear grooves of the nuclear membranes
were not identified. More than 50% of cells were
positive for factor VIII and CD34.
All patients were treated with superficial field
radiotherapy with 60Co gamma rays. For the floor
of mouth lesions, a central 8- 3 8-cm field was
used, with a total administered dose of 38 Gy fractionated over 16 days in 12 fractions of 150 cGy.
Non-AIDS Kaposi’s Sarcoma
For the first hard palate lesion (type III), 2 fields
were used (frontal 7 3 4 cm and lateral 4 3 4 cm),
each receiving a total dose of 1260 cGy given in 7
fractions of 180 cGy over days. The second hard
palate lesion (type I) received an initial total
dose of 30 Gy in 15 fractions of 200 cGy over
24 days, and an additional course of 16 Gy in 8
fractions of 200 cGy over 9 days. Severe mucositis was observed in 1 patient and was managed
according to protocol. Treatment resulted in com-
FIGURE 6. Kaposi’s sarcoma of the maxilla. Fine-needle aspiration (FNA) biopsy, Papanicolaou stain (ThinPrep; magnification 3400). [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
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263
plete remission in all patients. The total administered doses were similar to previously reported,
typically curative due to the known radiosensitivity of the tumor.14
Patient follow-up was 2 to 38 months. All
patients were disease-free on last follow-up,
except for the patient with the renal transplant
who had suspicious areas on the right medial tibial surface, and remained on observation.
Non-AIDS Kaposi’s Sarcoma in the Head and Neck
Area. We reviewed the literature from both
before and after the onset of the AIDS epidemic,
when the incidence of head and neck Kaposi’s sarcoma significantly increased. Both limited (case
reports, series, review articles) and unlimited
searches were performed with a combination of
relevant MeSH terms (‘‘Kaposi’s sarcoma,’’ ‘‘oral,’’
‘‘head,’’ ‘‘neck,’’ ‘‘head and neck,’’ ‘‘transplant’’)
using the MEDLINE and EMBASE databases.
A limited number of review articles focus on
the incidence of Kaposi’s sarcoma in the head and
neck area outside the well-characterized occurrence in HIV-positive individuals.6,8,12,15–19 Most
reviews, however, mainly focus on the oral cavity
lesions rather than head and neck in general. All
non-AIDS Kaposi’s sarcoma cases involving the
head and neck area were documented, including
the nose, eyes, ears, and larynx. We identified 251
non-AIDS head and neck Kaposi’s sarcoma cases
including our 3 cases (reference list too extensive
to be fully cited). Patient age ranged from 22 to 80
years, with an average age of 55.9 years (SD,
16.15 years). The men-to-women ratio was 3.6:1,
significantly different to the reported 17:1 ratio
for type I Kaposi’s sarcoma in general.18 The sublocalization of the lesions within the head and
neck area is presented in Figure 7 (lesions in different head and neck sites in the same patient are
considered separately). In our review of the literature, the commonest sites of presentation (where
site was specified) were the palate (hard and soft)
and the oropharynx (including the tonsilar fossae), also being the commonest sites reported in
the literature. The increased incidence of auricular lesions noted in our review (11.6%) actually
reflects 2 large published series.17,20 The fact that
the ear did not feature, with comparable incidences, in previous reviews is probably because, as
mentioned earlier, they mostly focused on oral
cavity/mucosal involvement. Unusual sites of presentation included the salivary glands (0.7%),
scalp (1.1%), and buccal mucosa (1.1%). Overall,
23 patients (9.16%) had multiple head and neck
264
Non-AIDS Kaposi’s Sarcoma
Kaposi’s sarcoma lesions on presentation. There
were 53 cases (21.11%) of primary head and neck
Kaposi’s sarcoma, 31 of which (12.35%) were
located in the oral cavity (mainly initial presentation followed by lesions elsewhere, while some
cases were sole manifestation). It should be noted
that the figures on primary and multiple lesions
represent only documented cases, as cases with
missing data were not included in the estimation.
It is of note that laryngeal Kaposi’s sarcoma
lesions seem to be almost always associated with
classical skin lesions, and that the majority of
head and neck cases were reported to be associated with simultaneous skin involvement of other
regions in 84%.17
With regard to type III Kaposi’s sarcoma
lesions, these occur mainly in patients with renal
transplant21–24 but also in patients with other
transplants (eg, cardiothoracic, liver transplant),
as well as after immunomodulatory treatment for
other conditions (eg, Hodgkin’s disease).6,22 Kaposi’s sarcoma lesions in these patients are reported
to be of a higher incidence compared with the
general population, the difference ranging from
150 to 200 times,9,22 to even a 500- to 1000-fold
increase,25,26 with large racial ethnic variation. It
is actually estimated to be the fourth most common posttransplant malignancy (4%).27 Interestingly, it presents in the same ethnic groups as
types I and II Kaposi’s sarcoma; however, the
men-to-women ratio is 3:1 in contrast to the
reported 17:1 ratio in type I Kaposi’s sarcoma.18
The average time for Kaposi’s sarcoma development following transplantation is 21 months.18
Disease course and aggressiveness depends on
the degree of immunosuppression, and frequently
regresses following modification or discontinuation of immunosuppression.8,9 Alternatively,
radiotherapy may be carefully used for lesions of
FIGURE 7. Kaposi’s sarcoma in the head and neck area: lesion
distribution. KS, Kaposi’s sarcoma; ns, nonspecified. [Color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
HEAD & NECK—DOI 10.1002/hed
February 2009
the oral cavity or the skin.9 We identified 20
reports (including our own) of type III Kaposi’s
sarcoma,12,22,23,28–36 including 1 incidence of oral
Kaposi’s sarcoma with concurrent tuberculosis.34
The average age of the patients was 48.4 years
(SD, 13.75). The men-to-women ratio was 2:1. Sixteen of 20 cases (80%) were primary lesions, and
in 5 cases (25%) there were multiple head and
neck lesions on presentation. As with our case, cyclosporine and costicosteroid combination is
reported to have stronger association with development of Kaposi’s sarcoma lesions7 compared
with azathioprine and prednisolone (0.87% of
patients with renal transplant under cyclosporin
treatment).24,37 This is possibly due to the inhibitory effect of cyclosporin on T-helper cells.30 This
also indicates the reason for the biological similarity between cyclosporin-related type III Kaposi’s
sarcoma and AIDS-Kaposi’s sarcoma, reflecting on
both tumor aggressiveness and similar intracytoplasmic abnormalities.30
Another interesting feature is that in previous
decades (prior to the 1980s) Kaposi’s sarcoma
was found to be associated with numerous conditions of abnormal immune response (immunodeficiencies, hypogammaglobulinemia, multiple
myeloma, lymphoblastic leukemia, lymphangioma,
chronic lymphocytic leukemia, autoimmune hemolytic anemia).38 A percentage of these cases,
however, might represent undiagnosed HIV cases.
It is worth noting that the small number of
reported cases might be the result of inaccurate
histopathological diagnosis. It could also be the
result of little interest in the recording of the head
and neck cases, especially for patients with type
III Kaposi’s sarcoma.
DISCUSSION
The lesion is associated with a rhadinovirus, the human herpesvirus 8 (HHV8; previously termed Kaposi’s sarcoma associated herpesvirus, KSHV), identified in 1994.39,40 The complete
HHV-8 genome sequence shows that it has sequence similarities to other gammaherpesviruses
including herpesvirus saimiri (HVS), murine gammaherpesvirus 68 (MHV68), and Epstein–Barr virus (HHV-4). The approximately 165-kb genome
contains over 80 open reading frames arranged in
a long unique region flanked by multiple 801-bp
terminal repeat units of high G1C content. The
long unique region contains blocks of conserved
genes found in most herpesviruses, interspersed
Pathogenesis.
Non-AIDS Kaposi’s Sarcoma
with blocks of nonhomologous genes that are specific for HHV-8 and related viruses.
HHV8 deoxyribonucleic acid sequences were
found in approximately 95% of Kaposi’s sarcoma
lesions and more than 50% of peripheral blood
cells in both patients with AIDS and non-AIDS
Kaposi’s sarcoma, not related to age, sex, race,
and geographic distribution.41,42 In contrast, it
was rarely detected in normal skin biopsies of
such patients and completely absent from control
tissues of healthy individuals. HHV8 seroprevalence is indeed a predictive marker for Kaposi’s
sarcoma development.3,7,43 HHV8 encodes homologues of human cellular proteins involved in cell
cycle regulation, cell proliferation, apoptosis,
angiogenesis, and immune regulation. Most of the
spindle and endothelial cells are latently infected,
with a small subpopulation supporting lytic viral
growth.7 With regard to genotype, the classical
Mediterranean samples are reported to be prototype A strains, whereas in Africa the B and C
strain subgroups are predominant.44
Pathogenesis of Kaposi’s sarcoma is now recognized to be multifactorial. Kaposi’s sarcoma initiation involves activation of CD81 T cells and
expression of Th1 inflammatory cytokines such as
interferon-gamma (IFN-g), interleukin 1b (IL1b), and tumor necrosis factor-a (TNF-a). These
promote reactivation of HHV8 and activation of
endothelial cells to acquire the spindle-shaped
phenotype and produce angiogenic factors such as
basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Kaposi’s
sarcoma progression is associated with the longterm expression of HHV8 latency genes such as
latent nuclear antigen (LANA), viral cyclin D
(v-cyc D; ORF 72), viral flice inhibitory protein (vFLIP; open reading frame [ORF] K13), kaposin
(ORF K12), and the deregulated expression of
oncogenes or oncosuppressor genes (c-myc, Bcl-2,
p53). This latter ‘‘molecular piracy’’ may help the
virus to evade immune responses, prevent cell
cycle shutdown, and interrupt activation of apoptotic pathways. In addition, the HIV-1 Tat protein acts as a progression factor for AIDS-Kaposi’s
sarcoma by stimulating Kaposi’s sarcoma growth,
angiogenesis, and migration/invasion, the latter
by upregulation of matrix metalloproteinases
expression.3,7 Therefore, it might be that Kaposi’s
sarcoma lesions progress from an early-stage polyclonal reactive-inflammatory-angiogenic hyperplastic process to a monoclonal true sarcoma in
later stages. Furthermore, there is evidence that
a milieu of immunosuppression (such as occurring
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in HIV-affected individuals and patients with
transplant) supports HHV8-induced Kaposi’s sarcoma progression, and is hence associated with
more aggressive forms of the disease.7
Histopathology. For all Kaposi’s sarcoma types, 3
phenotypic stages (patch, plaque, nodular) are
recognized, with corresponding progressive histopathology characterized by perivascular and interstitial spindle cell proliferation, angiogenesis,
inflammatory cell infiltrate, and edema.7,45 The
precise lineage relationship of Kaposi’s sarcoma is
still uncertain. Endothelial cells of vascular or
lymphatic origin are considered the cells of origin.
However, the spindle-cell compartment is heterogeneous, and despite the fact that Kaposi’s sarcoma-derived spindle cell lines have been found to
produce collagenases and exhibit invasive potential in vitro, they failed to produce malignant
tumors in immunodeficient mice, highlighting the
controversy on the definition of Kaposi’s sarcoma
as a true neoplasm versus a reactive process/
hyperplasia, at least at its early stages. This is further enhanced by the fact that Kaposi’s sarcoma
lesions can simultaneously appear at different sites with symmetrical or dermatome
distribution and can regress spontaneously or
following therapy.3,7,45
Cytopathology. Diagnosis by aspiration cytology
is possible, and the aspirate may reveal composite
rafts or tangles and singly dispersed individual
cells. The cells are spindle or polygonal with
bland, plump nuclei without hyperchromatism,
sometimes with characteristic longitudinal nuclear grooves or infoldings of the nuclear membrane. Diagnostic intracytoplasmic bodies that
represent altered ingested red cells might be identified. Mitoses are few. Hemosiderin granules may
be found in accompanying macrophages.
If found, these spindle cells indicate proliferated endothelial cells which can be confirmed by
immunocytochemistry, eg, for factor VIII or cluster of differentiation antigen 34 (CD34).
On a differential diagnostic level, HHV8 positivity allows distinction of the early-stage lesions
from inflammatory dermatosis or angiodermatitis,47 and of the late-stage lesions from pyogenic
granuloma, spindle-cell hemangioendothelioma
(pseudo-Kaposi’s sarcoma, usually associated
with Klippel–Trenaunay syndrome), kaposiform
hemangioendothelioma,
hemangiopericytoma,
angiosarcoma, fibrosarcoma, bacillary angiomatosis, and other arteriovenous malformations.8,47,53
HHV8 immunohistochemistry offers the advantage of a fast, low-cost, and readily available diagnostic technique, particularly useful in ambiguous lesions where the characteristic histological
features of Kaposi’s sarcoma may not be well
developed. In these early-stage lesions it can aid
laboratory Kaposi’s sarcoma diagnosis, possibly in
combination with VEGFR-3 immunohistochemistry.54
HHV8 is also found in other AIDS-related conditions, such as multicentric Castleman’s disease
(MCD), a lymphoproliferative disorder, alone or
in the context of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal
gammopathy, and skin changes)48,49 and body
cavity-based lymphoma/primary effusion lymphoma, a condition of lymphomatous effusions in
cavities/serous membranes without mass formation, belonging to AIDS-NHL (non-Hodgkin’s
lymphoma).3,43,54,55 MCD has also been reported
in patients with non-AIDS receiving immunosuppressive treatment, also associated with HHV8
expression.37
Anti-HHV8 therapy can be used for both treatment and prophylaxis of Kaposi’s sarcoma, mainly
so in the HIV-positive patients who constitute a
high-risk group.7 The fact that HHV8 appears to
be transmitted via mucosal shedding50 may
explain both the increased transmission in homosexual men (oral exposure to infectious saliva),
and the increased percentage of oral cavity lesions
in AIDS-Kaposi’s sarcoma.
Kaposi’s sarcoma management
depends on the type, extent/dissemination of
lesions, and organs involved. Local treatment
modalities are surgical and laser excision, cryotherapy, radiotherapy, intralesional vinblastine or
vincristine injections, and topical application of
vinca alkaloids, bleomycin, or retinoids. Experimental local therapy includes injections of interferon-a (IFN-a), human chorionic gonadotrophin,
granulocyte macrophage colony stimulation factors, and recombinant interleukin-2. Systemic
Management.
HHV8
has been proposed as a differential diagnostic
marker for all Kaposi’s sarcoma types.46,47 HHV8
detection methods include HHV8 immunohistochemistry,47,48 polymerase chain reaction (PCR)
detection either nested,39,40,48,49 solution phase,43 or
real-time quantitative PCR,43,50,51 reverse transcriptase (RT)-PCR,52 PCR in situ hybridization,43,50 in situ RNA hybridization,50 or HHV8
serology.
HHV8 in the Diagnosis of Kaposi’s Sarcoma.
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Non-AIDS Kaposi’s Sarcoma
HEAD & NECK—DOI 10.1002/hed
February 2009
therapy includes highly active antiretroviral therapy (HAART) 6 IFN-a for minimal and/or indolent cutaneous disease and chemotherapy (paclitaxel, ABV [doxorubicin, bleomycin, vincristine],
vincristine 1 bleomycin, liposomal anthracyclines) for rapidly progressive/visceral disease.
Pathogenesis-based therapies include angiogenesis inhibitors, thalidomide, antisense oligonucleotides directed against angiogenic growth factors,
cellular protease inhibitors, HIV protease inhibitors, retinoic acids, and anti-HHV8 therapy.3,7,9,56
Especially for oral cavity Kaposi’s sarcoma,
radiotherapy is the consensus modality, with
reported complete remission of more than
85%.7,14 A fractionated regime of 1 to 5 Gy doses
to a total dose of 15 to 45 Gy is used to minimize
complications such as mucositis.7
CONCLUSION
Non-AIDS Kaposi’s sarcoma infrequently occurs
in the head and neck. HHV8 is useful as an
adjunct diagnostic tool in such cases. In addition
to the classic cases, Kaposi’s sarcoma seems to
have an increased incidence in transplant recipients, with head and neck cases representing a significant percentage, both as cutaneous and mucosal involvement.52 A closer collaboration between
transplant teams and maxillofacial surgeons/oral
pathologists would help toward early identification of these cases, as well as offer insight in the
biological characteristics of the disease in association with conditions of immune deficiency.
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