Viruses and cancer

Viruses and Cancer

Robert Miller MD
www.aboutcancer.com

Viruses are responsible for 20% of
malignant conditions in humans,
including some of the most common
cancers worldwide, and are especially
common in immunosuppressed patients.

The identification of viruses associated with cancers
may provide prognostic information or alternative
treatments. Moreover, vaccines are now available for
two classes of viruses that are associated with cancer:
hepatitis B virus and human papilloma viruses (HPV).

With new molecular approaches for virus discovery,
the number of cancers that can be linked to viruses
with certainty will grow in the next few years.

A virus is a small infectious agent that can replicate only inside the
living cells of an organism. Viruses can infect all types of organisms,
from animals and plants to bacteria and archaea.

About 5,000 viruses have been described in detail, although there are
millions of different types. Viruses are found in almost
every ecosystem on Earth and are the most abundant type of
biological entity.

Virus particles (known as virions) consist of two or three parts: i)
the genetic material made from either DNA or RNA, ii) a protein coat
that protects these genes; and in some cases iii)
an envelope of lipids that surrounds the protein coat when they are
outside a cell.

History of Virus

• Viruses initially isolated in 1898 as miniscule infectious
microbes that caused plant diseases
• In 1909 Karl Landsteiner implicated a virus as the
cause of polio
• By the early 1920-’s the viruses that caused cowpox
and herpes had been isolated and grown in culture
• Jenner had shown that inoculation with cow pox
prevent small pox

Mukherjee, Siddhartha
(2010-11-16). The Emperor of
All Maladies: A Biography of
Cancer.

Hippocrates (c. 460 BC – c.
Aelius Galenus or Claudius Galenus (AD
370 BC) was
129–c. 200/c. 216), better known as Galen
an ancient Greek physician of
was
the Age of Pericles (Classical
prominent Roman (of Greek ethnicity) physic
Greece), and is considered
ian, surgeon and philosopher. Arguably the
one of the most outstanding
most accomplished of all medical
figures in the history of
researchers of antiquity

It was in the time of Hippocrates, around 400 BC, that a word for cancer
first appeared in the medical literature: karkinos, from the Greek word for
―crab.‖ The tumor, with its clutch of swollen blood vessels around it,
reminded Hippocrates of a crab dug in the sand with its legs spread in a
circle.

Another Greek word would intersect with the history of cancer— onkos, a
word used occasionally to describe tumors, from which the discipline of
oncology would take its modern name. Onkos was the Greek term for a
mass or a load, or more commonly a burden; cancer was imagined as a
burden carried by the body.
The Greeks had no microscopes. They had never imagined an entity called
a cell, let alone seen one, and the idea that karkinos was the uncontrolled
growth of cells could not possibly have occurred to them. They were,
however, preoccupied with fluid mechanics. The human body, Hippocrates
proposed, was composed of four cardinal fluids called humors: blood, black
bile, yellow bile, and phlegm.

The physician Claudius Galen, a prolific writer and influential Greek doctor
who practiced among the Romans around AD 160, brought Hippocrates’
humoral theory to its apogee. For cancer, Galen reserved the most
malevolent and disquieting of the four humors: black bile. Cancer, Galenic
theory suggested, was the result of a systemic malignant state, an internal

History of Cancer Theories
• Peyton Rous (a chicken virologist) in 1910 transmitted a
chicken sarcoma from one chicken to another (even
highly filtered substances) so must be a virus, RSV
(Rous sarcoma virus)
• In the 1920’s somatic mutation hypothesis theory of
cancer (environmental toxins or radiation)
• In 1935 Richard Schope reported a papilloma virus that
cause tumors in rabbits
• In the mid 1940’s discovered leukemia virus in mice
and cats
• In 1958 Denis Burkitt found an aggressive lymphoma in
Africa that appeared to spread by infection (later found
to be EBV or Epstein-Barr virus)
• In 1959 Howard Temin showed that the RSV could alter
the infected cells DNA and so it could write genetic
information backwards a so called retrovirus

Howard Temin

Temin's description of how tumor viruses act on the genetic material of the cell
through reverse transcription was revolutionary.

This upset the widely held belief at the time of a popularized version of the
"Central Dogma" of molecular biology posited by Crick who had claimed that
information flows exclusively from DNA to RNA to protein.

Temin showed that certain tumor viruses carried the enzymatic ability to
reverse the flow of information from RNA back to DNA using reverse
transcriptase. This phenomenon was also independently and simultaneously
discovered by David Baltimore, with whom Temin shared the Nobel
Prize. Both scientists completed their initial work with RNA-dependent DNA
polymerase with the Rous sarcoma virus.

Virus gets the DNA into the cell
Uses the cell to make copies of
and it migrates into the nucleus
it’s DNA in DNA replication

DNA makes RNA copies
RNA goes out into the cell
called transcription

New viruses can break out of the
RNA goes to ribosomes to make
Cell in the lytic cycle
proteins (new viruses) in translation

Retrovirus

RNA

Enzyme,
reverse
transcriptase

RNA and reverse transcriptase New DNA with high mutation rate

A retrovirus is an RNA virus that replicates in a host cell. First it
uses its own reverse transcriptase enzyme to produce DNA from
its RNA genome, reverse of the usual pattern,
thus retro (backwards). This new DNA is then incorporated into the
host's genome .

The cell then treats the viral DNA as part of its own instructions,
which it follows blindly, making the proteins required to assemble
new copies of the virus.

A special variant of retroviruses are endogenous
retroviruses which are integrated into the genome of the host and
inherited across generations. When retroviruses have integrated
their own genome into the germ line, their genome is passed on to a
following generation. These endogenous retroviruses (ERVs),
contrasted with exogenous ones, now make up 5-8% of the human
genome.
Most insertions have no known function and are often referred to as
"junk DNA". However, many endogenous retroviruses play important
roles in host biology. Because reverse transcription lacks the

The replication cycle of a retrovirus entails the insertion ('integration') of a
DNA copy of the viral genome into the nuclear genome of the host cell. Most
retroviruses infect somatic cells, but occasional infection of germline cells
(cells that produce eggs and sperm) can also occur.

Rarely, retroviral integration may occur in a germline cell that goes on to
develop into a viable organism. This organism will carry the inserted retroviral
genome as an integral part of its own genome - an 'endogenous' retrovirus
(ERV) that may be inherited by its offspring as a novel allele. Many ERVs
have persisted in the genome of their hosts for millions of years. However,
most of these have acquired inactivating mutations during host DNA
replication, and are no longer capable of producing virus.

The majority of ERVs that occur in vertebrate genomes are ancient,
inactivated by mutation, and have reached genetic fixation in their host
species. For these reasons, they are extremely unlikely to have negative
effects on their hosts except under unusual circumstances.

20% of Human DNA is retrovirus.
Are we already part virus?

Borg is a collective proper noun for a fictional alien race that appears as
recurring antagonists in various incarnations of Star Trek. The Borg are a
collection of species that have been turned into cybernetic organisms
functioning as drones of the Collective, or the hive.

Peyton Rous
(1879 - 1970)

As a pathologist he made his seminal observation,
that a malignant tumor growing on a domestic
chicken could be transferred to another fowl simply by
exposing the healthy bird to a cell-free filtrate, in
1911.
This finding, that cancer could be transmitted by a virus (now known as the
Rous sarcoma virus, or RSV, a retrovirus), was widely discredited by most
of the field's experts at that time.

Since he was a relative newcomer, it was several years before anyone even
tried to replicate his prescient results. Although clearly some influential
researchers were impressed enough to nominate him to the Nobel
Committee as early as 1926 (and in many subsequent years, until he finally
received the award, 40 years later—this may be a record for the time
between a discovery and a Nobel Prize). In 1966 he was awarded a Nobel
Prize in Physiology or Medicine for his work.

RVS
RSV possesses only four genes in its genome, finally pinpointed
RSV’s cancer-causing ability to a single gene in the virus. The
gene was called src (pronounced ―sarc‖), a diminutive of sarcoma.
It encoded a protein whose most prominent function was to modify
other proteins by attaching a small chemical, a phosphate group,
to these proteins.

These enzymes were called the ―kinases,‖ and they were soon
found to behave as molecular master switches within a cell.
Bishop and Varmus found a nearly identical version of viral src
lodged firmly in the normal cell’s genome. Viral src— the cancer-
causing gene— was cellular src on overdrive. precursor of a
cancer-causing gene— the ―proto-oncogene,‖ as Bishop and
Varmus called it— was a normal cellular gene.

Denis Parsons Burkitt
1911 - 1993

During World War II, Burkitt served with the Royal Army Medical Corps in
England and later in Kenya and Somaliland. After the war Burkitt decided his
future lay in medical service in the developing world and he moved to
Uganda. He eventually settled in Kampala and remained there until 1964.

Burkitt 'made two major contributions to medical science related to his
experience in Africa. The first was the description, distribution, and
ultimately, the etiology of a pediatric cancer that bears his name Burkitt's
lymphoma

His second major contribution came when, on his return to Britain, Burkitt
compared the pattern of diseases in African hospitals with Western diseases.
He concluded that many Western diseases which were rare in Africa were
the result of diet and lifestyle. He wrote a book Don't Forget Fibre in your
Diet, which was an international best-seller.

Henry Kaplan
1918-1984

Stanford Medical
Linear
Accelerator in
1955 and also in
the 1975 lab to
research cancer
viruses

Henry Kaplan
He is credited with
finding that leukemias
and cancers of the
lymph system in mice
were caused by a
latent virus activated
when radiation or
chemicals suppressed
the function of the
animal's normal
immune system in
1959

Cancer Theories
• By the 1960,s cancer was considered infectious, the
NCI has a large Special Virus Cancer Program and
Rous got the 1966 Nobel Prize
• 1970’s efforts to prove that retro viruses caused most
cancers failed (a few years later HIV)
• cancer-causing gene— the ―proto-oncogene,‖ as
Bishop and Varmus called it— was a normal cellular
gene. Mutations induced by chemicals or X-rays
caused cancer not by ―inserting‖ foreign genes into
cells, but by activating such endogenous proto-
oncogenes.

Genetics and Cancer
Cancer, in short, was not merely genetic in its origin; it
was genetic in its entirety. Abnormal genes governed
all aspects of cancer’s behavior. Cascades of aberrant
signals, originating in mutant genes, fanned out within
the cancer cell, promoting survival, accelerating growth,
enabling mobility, recruiting blood vessels, enhancing
nourishment, drawing oxygen— sustaining cancer’s
life.

These gene cascades, notably, were perversions of
signaling pathways used by the body under normal
circumstances.

Mukherjee, Siddhartha (2010-11-16). The Emperor of
All Maladies: A Biography of Cancer (pp. 387-388).

Oncovirus
An oncovirus is a virus that can cause cancer. This term originated from
studies of acutely transforming retroviruses in the 1950–60s. It now refers to
any virus with a DNA or RNA genome causing cancer and is synonymous
with "tumor virus" or "cancer virus". The vast majority of human and animal
viruses do not cause cancer, probably because of long-standing coevolution
between the virus and its host.

Worldwide, the WHO International Agency for Research on Cancer
estimated that in 2002 17.8% of human cancers were caused by infection,
with 11.9% being caused by one of seven different viruses. The importance
of this is that these cancers might be easily prevented through vaccination
(e.g., papillomavirus vaccines), diagnosed with simple blood tests, and
treated with less-toxic antiviral compounds.

A direct oncogenic viral mechanism involves either insertion of additional
viral oncogenic genes into the host cell or to enhance already existing
oncogenic genes in the genome.

Indirect viral oncogenicity involves chronic nonspecific inflammation
occurring over decades of infection, as is the case for HCV-induced liver
cancer.

Cancer Viruses: Classes
There are two classes of cancer viruses: DNA and RNA viruses.
Several viruses have been linked to certain types of cancer in
humans. These viruses have varying ways of reproduction and
represent several different virus families.

DNA Viruses
The Epstein-Barr virus has been linked to Burkitt's lymphoma.
The hepatitis B virus has been linked to liver cancer in people with
chronic infections.
Human papilloma viruses have been linked to cervical cancer.
Human herpes virus-8 has been linked to the development of Kaposi
sarcoma.

RNA Viruses
Human T lymphotrophic virus type 1 (HTLV-I), a retrovirus, has been
linked to T-cell leukemia.
The hepatitis C virus has been linked to liver cancer in people with
chronic infections.

Human Cancer Viruses
Virus % of Cancer Types
Cancer
Hepatitis (HBV and 4.9% Hepatocellular
HCV)
Human T-lymphotropic .03% Adult T cell leukemia
(HTLV)
Human Papillomavirus 5.2% Cervix, Anus, Vulva,
(HPV) Vagina, Oropharynx
Kaposi sarcoma associated 0.9% Kaposi sarcoma,
herpesvirus (HHV-8) multicentic
Castleman, primary
effusion lymphoma
Merkel cell polyomavirus NA Merkel cell

Epstein-Barr (EBV) NA Burkitt, nasopharynx

Hepatitis and Hepatoma
HCC can develop in patients with chronic Hepatitis B even in the absence
of cirrhosis. However, 70 to 90 percent of patients with HBV who develop
HCC will have cirrhosis

Hepatitis C accounts for at least one-third of the cases of HCC in the United
States. An important clinical observation is that HCC in patients with HCV
occurs almost exclusively in patients with advanced stages of hepatic
fibrosis or cirrhosis.

Attempts to prevent HCC should focus on preventing infection with HBV
and HCV, treating patients with viral hepatitis who are candidates for
treatment, and attempting to prevent the development of cirrhosis in
patients with liver disease.

Hepatoma

HCC is related to chronic DNA changes related to Hep
B infection

Currently available hepatitis B vaccines are extremely safe and have an
efficacy of >90 percent and are effective against all HBV serotypes and
genotypes. Thus, HBV infection can potentially be eradicated through global
vaccination.

Surveillance for hepatocellular carcinoma (HCC) is recommended for many

Age-standardized death rates
from Liver cancer by country
(per 100,000 inhabitants)

Virus % of Cancer Cancer Types
Hepatitis (HBV and HCV) 4.9% Hepatocellular

(HTLV)
Human 5.2% Cervix, Anus,
Papillomavirus (HPV) Vulva, Vagina,
Oropharynx
Castleman, primary
effusion lymphoma


Most Common STD
2003-2004 National Health and Nutrition Examination Survey
(NHANES) indicate 24 percent of female adolescents aged 14 to 19
years had laboratory evidence of at least one of the following
sexually transmitted diseases (STD):

Human papillomavirus (HPV, 18 percent)
Chlamydia trachomatis (4 percent)
Trichomonas vaginalis (3 percent)
Herpes simplex virus type 2 (HSV-2, 2 percent)
Neisseria gonorrhoeae

Among girls who reported ever having had sex, 40 percent had
laboratory evidence of one of the four STD, predominantly HPV (30
percent) and chlamydia (7 percent).

HPV Infections
Human papillomavirus (HPV) is the most commonly diagnosed
sexually transmitted infection in the United States.

The HPV genome encodes DNA sequences for six early (E) proteins
associated with viral gene regulation and cell transformation.

The two most important HPV proteins in the pathogenesis of
malignant disease are E6 and E7. At the molecular level, the ability
of E6 and E7 proteins to transform cells relates in part to their
interaction with two intracellular proteins, p53 and retinoblastoma
(Rb),

Following E6 binding of p53, is degraded in the presence of E6-
associated protein. This allows unchecked cellular cycling, and has
an anti-apoptotic effect. The HPV E7 protein disrupts cell cycling
leading to an increase in cellular p16 protein expression

Human Papillomavirus (HPV) infection of
epithelial cells.

HPVs infect basal cells of squamous epithelia through sites of mechanical trauma.
Infections with high-risk HPVs can lead to dysplasia and carcinoma in situ and to
invasive squamous cell carcinoma. Progression is a rare and slow process and
many lesions regress spontaneously.

HPV Cancers
Cancers Percent
Cervix > 99%
Anus 84%
Vagina 70%
Penis 47%
Vulva 44%
Oropharynx 36%
Oral Cavity 24%
JCO May 2011;29:1785

HPV Cancers 2004-2008
Cancer All Cases HPV Caused
Cervix 11,967 11,500
Vulva 3,136 1,600
Vagina 729 500
Penis 1,046 400
Anus (female) 2,900 2,700
Anus (male) 1,678 1,600
Oropharynx (female) 2,370 1,500

Oropharynx (male) 9,356 5,900

It has been estimated that at least 50 percent of sexually active
women (and men) are exposed to HPV once in their lifetime.
However, many experts believe that virtually all sexually active
adults have been infected by HPV for the following reasons:

Most HPV infections are transient, and can come and go between
measures of HPV
There are more than 40 HPV types that infect the entire lower
genital tract, including the vagina

Most HPV infections, including carcinogenic HPV genotypes,
typically resolve within 6 to 12 months. However, women with
persistent carcinogenic HPV infections are at risk of developing
precancerous lesions, although not all persistent infections
progress.

In the United States, the median age of cytologically-detected
precancerous lesions occurs approximately 10 years after the
median age of sexual debut

Explaining the rise in oropharyngeal HPV
infections since the 1980’s, changing
social norms

HPV Oropharynx Cancer
Epidemiologic studies have demonstrated that there has been a decrease in
the incidence of laryngeal, hypopharyngeal, and oral cavity cancers,
beginning in the late 1980s. This decline is believed to reflect the gradual
decrease in smoking, which is a primary risk factor for these cancers.

Despite the decrease in tobacco use, the incidence of oropharyngeal cancer
initially remained constant and then began to rise due to HPV related
cancers arising in the base of the tongue and the tonsillar region.
Furthermore, this association is primarily with HPV-16 suggested that
approximately 50 percent of oropharyngeal cancers were due to HPV, while
more recent studies suggest that HPV may account for much as 70 to 80
percent of these malignancies

The overall prevalence of HPV DNA in oral exfoliated cells was 6.9 percent,
and the prevalence of HPV16 was 1.0 percent. The prevalence of HPV
infection followed a bimodal distribution, with peaks at ages 30 to 34 and 60
to 64 years (7.3 and 11.4 percent, respectively). HPV prevalence was
approximately three-fold more common in men compared with women (10.1
versus 3.6 percent), consistent with the observed sex distribution for HPV
associated oropharyngeal cancer.

New Cancer Cases in the US
in 2013

Site Male Female

Tongue 9,900 3,690

Mouth 6,730 4,670

Pharynx 11,200 2,730

Oral (other) 1,790 670

Oropharynx (base of tongue or
tonsil)

Human Papillomavirus and Rising
Oropharyngeal Cancer Incidence in the
United States

JCO November 10, 2011 vol. 29 no. 32 4294-4301

Percent of Men Reporting Type of
Sexual Activity in the Past Year (2010)
100
Vaginal Intercourse
90
Fallatio
80 Cunnilingus

70

60

50

40

30

20

10

0
20 30 40 50 60 70

Man’s Age

Percent of Women Reporting Sexual
Activity in the Past Year (2010)
100
Vaginal Intercourse
90
Fallatio
80 Cunnilingus

70

60

50

40

30

20

10

0
20 30 40 50 60 70
Woman’s Age

HPV in Men
The rate of genital HPV infection among males is similar to that in
females. In any 12-month period, the probability that a sexually
active male will acquire a new genital HPV infection is 0.29 to
0.39, which is similar to estimates for females.

However, there are differences between the sexes in the immune
response to HPV. A larger proportion of females are HPV-
seropositive (17.9%, vs. 7.9% of males), and females have higher
titers of antibodies. The lower immune response to natural infection
in males may partially explain the higher prevalence of HPV
infections as compared with the prevalence among females, and the
constant prevalence and incidence of HPV infection across a wide
age range in males.

prophylactic vaccination of boys and men with quadrivalent HPV
vaccine may reduce the incidence of condylomata acuminata, as
observed within 3 years after the introduction of a vaccination
N Engl J Med 2011; 364:401-411

Pathology – The vast majority of HPV associated head and neck
cancers are squamous cell carcinomas. Immunohistochemistry
(IHC) for p16 is highly sensitive for HPV associated tumors

Epidemiologic factors – Patients with HPV positive oropharyngeal
cancer are approximately 10 years younger when compared to HPV
negative patients. Many of the patients seen with this entity are in
their late thirties or early forties.

Anatomic location – HPV associated tumors predominantly arise in
the base of the tongue or the tonsillar region,

Stage: more likely to present with a relatively early
stage (T1/T2) primary tumor, but relatively advanced disease in the
neck (N2/N3), often with a large cystic lymph node than is
sometimes mistaken for a cyst. Despite the biologic aggressiveness
of HPV positive cancer, these tumors appear to have a better
prognosis than head and neck cancers not associated with HPV with
a lower rate of distant metastases, significantly less likely to have a
second malignancy

Typical smoking related
oropharynx cancer, presented with
months of throat pain radiating into
ear


50 yo man, non-smoker presented with cystic neck nodes and occult
primary in the base of tongue


53 yo man with
large cystic
neck node and
occult primary
in base of
tongue

HPV Tonsil Cancer
63 yo non-smoker
man presents with
neck mass and small
lesion in tonsil

He was non-smoker

Bx = squamous
ISH = high risk HPV

IVA (T1N2b)

Effect of HPV-Associated p16INK4AExpression on Response
to Radiotherapy in Squamous Cell Carcinoma of the Head and
Neck

Local Control

JCO April 20, 2009 vol. 27 no. 12 1992-1998

Overall Survival

JCO April 20, 2009 vol. 27 no. 12 1992-1998

The cure rate is better for HPV oropharynx
cancers than for smoking related cancers

SURVIVAL

Non-smokers

smokers

Years
JCO June 10, 2012 vol. 30 no. 17 2102-2111

Chemoradiation

HPV +

HPV -

JCO September 20, 2010 vol. 28 no. 27 4142-4148

Quick Response to Radiation
combined with chemotherapy, Tonsil
cancer gone by 2 ½ weeks

Chemoradiation for Tonsil
Cancer

Cure Rates for Advanced Head and
Neck Cancer with Chemo-Radiation

Cisplatin

Erbitux (cetuximab)

Failure-free survival among patients with cancer of oropharynx, hypo
pharynx, or larynx; IJROBP 2011:81;915

RTOG 1016 Protocol Information

Phase III Trial of Radiotherapy Plus Cetuximab
Versus Chemoradiotherapy in HPV-Associated
Oropharynx Cancer

Primary Objective:
To determine whether substitution of cisplatin with cetuximab will result in
comparable 5-year overall survival
Patient Population:
Squamous cell carcinoma of the oropharynx (tonsil, base of tongue, soft
palate, or Oropharyngeal walls); stage T1-2, N2a-3, or T3-4 any N;
patient tumor must be p16 positive

HPV related cancers now cause 60 to 70%
of oropharynx cancers in the US (esp. HPV
16) These patients have a superior
response to therapy and better outcome.

Testing can be done for HPV by ISH or p16
by IHC. Ongoing trials will determine
whether to use this information to modify
therapy

Gardasil

Recommend HPV immunization of females, as advised by multiple
expert panels . Routine immunization should be offered to girls 11
to 12 years of age, but can be administered as early as nine years.
Catch-up vaccination should be offered for females aged 13 to 26
years who have not been previously vaccinated.

Recommend the use of quadrivalent HPV vaccine in males, as
advised by expert panels. Routine immunization should be offered
to boys aged 11 to 12, but can be administered as early as nine
years of age. Catch-up vaccination should be offered for males
between the ages of 13 to 21 who have not been previously
vaccinated. For MSM, catch-up vaccination should be offered up to
age 26.



(HTLV)
Kaposi sarcoma 0.9% Kaposi sarcoma,
associated herpesvirus multicentic
(HHV-8) Castleman, primary
effusion lymphoma


Kaposi Sarcoma
Kaposi sarcoma (KS)
It was originally described by Moritz Kaposi an Hungarian dermatologist
practicing at the University of Vienna in 1872.

It became more widely known as one of the AIDS-defining illnesses in the
1980s. The viral cause for this cancer was discovered in 1994, it is a
tumor caused by Human herpesvirus 8 (HHV8), also known as Kaposi
sarcoma-associated herpesvirus (KSHV).

Although KS is now well-established to be caused by a viral infection,
there is widespread lack of awareness of this even among persons at risk
for KSHV/HHV-8 infection.

KS Lesions in AIDS

Tom Hanks in the movie Philadelphia

Kaposi Sarcoma
Kaposi sarcoma (KS) is a vascular tumor that is etiologically associated with
human herpesvirus 8 (HHV-8), which is also known as the KS-associated
herpesvirus (KSHV). Although KS has been reported among all risk groups
for HIV infection, it is most common in homosexual or bisexual men. AIDS-
related KS is much less common in heterosexual injection drug users,
transfusion recipients, women or children, and hemophiliacs

In patients with AIDS-related KS, the CD4 count appears to be the most
important factor associated with the development of KS.

HHV-8
KS was rare until the early 1980s when, with the onset of the HIV
epidemic, it was described in several homosexual men in North
America
The epidemiology of Kaposi's sarcoma (KS) suggested a link
between the development of disease and a transmissible agent.

In 1994, a novel gamma herpesvirus was subsequently identified in
KS biopsies. HHV-8 fits most closely into the family of human
gamma herpesviruses, which includes Epstein-Barr virus. Gamma
herpesviruses play an important role in cellular proliferation and the
development of malignancies

The exact mode(s) of transmission for HHV-8 remains unclear.
Saliva appears to be a source of infectious virus. It has been
proposed that saliva may be the main mode of HHV-8 transmission
in children and that it could be a source of mother-to-child
transmission. Other possible modes of transmission include sexual
transmission, blood transfusions, and solid organ transplantation

Neglected HIV with Advanced
KS in the Mouth


(HTLV)
Castleman, primary
effusion lymphoma
Merkel cell NA Merkel cell
polyomavirus

Friedrich Sigmund Merkel
(5 April 1845 – 28 May 1919)

was a leading
German anatomist a
nd histopathologist o
f the late 19th
century.

Merkel Cell
are oval receptor cells found in the skin that have synaptic contacts
with somatosensory afferents. They are associated with the sense of light
touch discrimination of shapes and textures. they contain dense core
granules, and thus may also have a neuroendocrine function.

Merkel Cell

Merkel Cell
Merkel cell carcinoma (MCC) of the skin is a rare, aggressive cutaneous
malignancy that predominantly affects elderly Caucasians and has a
propensity for local recurrence and regional lymph node metastases.

Merkel cell polyomavirus is a non-enveloped, double-stranded DNA virus
that may be causally linked to the development of MCC. The observation
that the integration of the virus into the tumor genome precedes the clonal
expansion of tumor cells supports a pathogenic role for this virus.

Reported prevalence rates for Merkel cell polyomavirus in tumors have found
the virus in around 80 percent of MCCs may be present in all MCC tumors

Merkel cell carcinoma -
polyomavirus

Merkel cell carcinoma - immunohistochemical stain for Merkel cell
polyomavirus A CM2B4 immunohistochemical stain reveals strong
immunoreactivity of Merkel tumor cells for an antibody targeting the Merkel
cell polyomavirus.

• Rare, aggressive tumor with local recurrence
rate of 25-30% and distant metastases in
35%
• 5 Year survival is 30 – 64%
• More common in older white men, with high
sun exposure and in immunosuppressed
• The Merkel Cell Polyomavirus (MCV)
identified in 2008 is found in 43 to 100% and
its role in the pathogenesis is under
investigation



(HTLV)
Castleman, primary
effusion lymphoma

Epstein-Barr (EBV) NA Burkitt,
nasopharynx

EBV Epstein-Barr virus

(EBV) is a widely disseminated herpesvirus, which is
spread by intimate contact between susceptible persons
and asymptomatic EBV shedders. The majority of primary
EBV infections throughout the world are subclinical and
unapparent. Antibodies to EBV have been demonstrated
in all population groups with a worldwide distribution;
approximately 90 to 95 percent of adults are EBV-
seropositive.

EBV is the primary agent of infectious
mononucleosis, persists asymptomatically for life in most
adults, and is associated with the development of B cell
lymphomas, T cell lymphomas, Hodgkin lymphoma and
nasopharyngeal carcinomas in certain patients.

Burkitt Lymphoma
Burkitt lymphoma (BL), which is characteristically localized in the jaw, is the
most common childhood malignancy in equatorial Africa. More than 95
percent of African children are infected with EBV by age three, whereas, in
affluent countries, primary infection is often delayed until adolescence

Malaria and EBV infection are considered cofactors in the genesis of
Burkitt lymphoma.

Hodgkins and Nasopharynx
Among HIV-infected patients, EBV infection has been associated with non-
Hodgkin lymphoma and, in children, smooth muscle tumors.

EBV genomic DNA was first reported in tissue specimens from patients
with Hodgkin lymphoma (HL) in 1987. The finding that the malignant cells in
HL, including the characteristic Reed-Sternberg cells, contain the EBV
genome in up to 50 percent of "Western" cases supports a pathogenic role
for EBV in this malignancy

Nasopharyngeal carcinoma is relatively rare in most populations. However,
it is one of the most common cancers in southern China. In contrast to
Burkitt lymphoma, the association of EBV with nasopharyngeal carcinoma
is highly consistent in both low- and high-incidence areas and EBV is
present in every anaplastic nasopharyngeal carcinoma cell

xenotropic murine leukemia virus
Xenotropic murine leukemia virus-related virus (XMRV) is a
gammaretrovirus that was first described in 2006. Initial reports linked the
virus to prostate cancer, and later to chronic fatigue syndrome (CFS), but
these were followed by a large number of studies in which no association
was found. It has not been established that XMRV can infect humans, nor
has it been demonstrated that XMRV is associated with or causes human
disease.

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