Cancer in the Tropics

Cancer in the Tropics

23  Cancer in the Tropics Wendy B. Bernstein KEY FEATURES • Malignancy in low- and middle-income countries is a growing global health concern. • Inf...

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23 

Cancer in the Tropics Wendy B. Bernstein

KEY FEATURES • Malignancy in low- and middle-income countries is a growing global health concern. • Infections are involved in the pathogenesis of at least 20% of malignancies in developing nations. These infections could be reduced with clean water, vaccination, or lifestyle modifications. • Incidence rates of cancer are higher in high-income nations, but low- and middle-income nations bear the burden of cancer mortality. • Currently, developing nations are passing through Omran’s early stages of epidemiological transition and entering the stage of degenerative and human-made diseases before sufficient economic growth occurs to establish a medical infrastructure. • Any progress made by controlling communicable causes of cancer is erased by cancers due to tobacco, obesity, and low plant-based diet. • Cancers occurring in low- and middle-income nations are prevalent globally (lung), rare in high-income countries (cervical), rare outside the tropics (penile and conjunctival), have uncommon histologies or location within an organ (squamous cell carcinoma of the bladder, distal gastric adenocarcinoma), or are geographically concentrated (Kaposi’s sarcoma and Burkitt’s lymphoma belts).

INTRODUCTION With a few notable exceptions, the majority of countries within the tropics are nations with medium and low human development indices (HDIs). Is cancer a priority if clean water is not available and infectious diseases are uncontrolled? Using data displayed in Fig. 23.1, GLOBOCAN reported that while the incidence of the 18.1 million cases of cancer expected to be reported in 2018 will be higher in developed nations, 70% of the 9.6 million deaths will occur in developing nations.1,2 With transition, communicable causes of death are replaced with non-communicable causes. People live long enough to develop cancer. Risky behaviors replace oncogenic infections, and undermanaged prevalent infections continue to contribute to cancer incidence and mortality. Economic transition is occurring faster in today’s developing world. The adoption of risky lifestyles is outpacing control of infections and creation of health care systems, leaving the developing world to bear the burden of cancer mortality for some time. This chapter focuses on the pathogenesis of oncogenic infections unique to the tropics. Rare cancers unique to this region and common cancers with unique histologies will be discussed, as will the impact of tobacco and obesity. Behavioral, genetic, and environmental risk factors are discussed with relevant cancers. For consistency, all epidemiology data are derived from GLOBOCAN 2018, except where otherwise noted, and are presented in Table 23.1. The quality of the data is highly dependent on cancer registries, which may or may not be available in developing nations.

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INFECTION AND MALIGNANCY Fig. 23.2 shows the global distribution of cancers attributable to infection. Worldwide, the rate is 15.4%, 9.2% in high HDI nations, and 23% and 25.3% in medium and low HDI nations, respectively. In developing countries, the peak incidence of cancer occurs in persons aged 40 to 45 years.3

Bacterial Infections Helicobacter pylori infects half the world’s population, making it the most common etiologic agent of infection-related malignancy, responsible for an estimated 5.5% of the world’s cancer. It is the primary cause of distal gastric carcinoma. Prevalence rates are highest in developing nations, where the infection is acquired before age five. Though most infected persons remain asymptomatic, gastric adenocarcinoma occurs in 1% to 3% and mucosal-associated lymphoid tumor (MALT) in 0.1%.4 The pathogenesis of gastric adenocarcinoma begins with the progression of H. pylori–induced superficial gastritis to atrophic gastritis, a process that can take up to 10 years.5 Consumption of salted, pickled, or nitrate-preserved foods, along with alcohol and tobacco, exacerbate the oxidative damage done by the bacteria, causing loss of mucous glands. Bacterial virulence factors (CagA) and host immune function influence progression to this critical first step. Persons who do not develop atrophic gastritis do not develop cancer. With repeated cycles of epithelial damage and repair, oncogenic mutations accumulate, and over another 10-year period,5 gastric atrophy progresses to intestinal metaplasia, low- then high-grade dysplasia, and ultimately invasive carcinoma. With early malignancy, symptoms are minimal unless a coincidental H. pylori–induced peptic ulcer bleeds. With progression, the patient may develop abdominal pain, food intolerances, early satiety, anemia, and weight loss. Diagnosis is generally made with endoscopic biopsy. The bulk of these cancers occurs in Asian men, and unlike gastric adenocarcinoma in developed nations, which occurs in the proximal stomach, H. pylori–induced gastric cancer develops in the body and antrum.4 Gastric MALT is a less common malignancy caused by H. pylori. The healthy stomach does not contain lymphoid tissue, but with H. pylori infection, lymphocytes infiltrate the lamina propria, where polyclonal proliferation gives way to clonal B-cell proliferation.4 Persons with gastric MALT experience dyspepsia, epigastric pain, or bleeding. As with gastric adenocarcinoma, diagnosis is made with endoscopic biopsy. Though eradication of H. pylori has been shown to eliminate the risk for MALT and cure early-stage disease, the data are not as strong for the prevention of gastric cancer. This is due in part to re-infection and uncertainty as to when in the natural history of infection eradication is most effective in blocking oncogenesis. Choi et al.6 showed that H. pylori–infected persons who received eradication therapy versus placebo after undergoing resection of early gastric carcinoma or high-risk adenoma had 50% reduction in the incidence of metachronous cancers at 5.9 years of follow-up. There was also a statistically significant change in the rates of improvement in gastric atrophy in antibiotic-treated versus placebo-treated participants. There were no differences in overall survival or incidence of metachronous adenomata suggesting that after eradication, some persons remain at risk for gastric cancer whether due to eradication failure, re-infection, or residual dysplastic tissue that is unaffected

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23

Age standardized (World) incidence rates, all cancers, by sex Males 571.2

Australia/New Zealand North America Western Europe Northern Europe Southern Europe Central and Eastern Europe Polynesia Eastern Asia Southern Africa South America World Caribbean Micronesia Melanesia Western Asia South-Eastern Asia Central America Northern Africa Eastern Africa Middle Africa South-Central Asia Western Africa 800

A

Females 362.2 322.1 292.1 295.0 247.0 216.5 204.3 192.0 196.1 195.2 182.6 182.9 160.3 203.6 154.6 142.5 149.7 137.3 150.7 109.2 95.9 122.0

387.6 363.5 344.6 319.5 280.1 241.7 238.4 230.5 220.0 218.6 213.1 204.6 97.3 190.1 156.1 139.3 138.9 112.4 101.8 97.5 95.6

600

400

200

0

200

400

600

800

ASR (World) per 100 000

Age standardized (World) incidence and mortality rates, all cancers Incidence Australia/New Zealand North America Western Europe Northern Europe Southern Europe Central and Eastern Europe Polynesia Eastern Asia South America Southern Africa World Melanesia Caribbean Micronesia Western Asia South-Eastern Asia Central America Northern Africa Eastern Africa Western Africa Middle Africa South-Central Asia

Fig. 23.1  GLOBOCAN 2018: (A) Estimated age standardized incidence rates for men versus women for all malignancies except non-melanoma skin cancer by geographic region. (B) Estimated age standardized incidence and mortality rates for all malignancies except non-melanoma skin cancer by geographic region. (Reproduced with permission from Ferlay J, Ervik M, Lam F, et al. 2018. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available from: http://gco.iarc.fr/today/ data/factsheets/cancers/39-All-cancers-fact-sheet. pdf).

92.9 91.2 105.0 101.7 100.9 123.1 118.3 123.2 91.9 113.1 101.1 124.4 101.7 115.8 95.1 94.7 65.3 88.5 97.4 77.3 79.1 65.6

463.1 350.2 323.4 316.2 278.4 238.3 220.3 213.2 204.3 204.2 197.9 197.3 196.2 180.3 168.2 147.2 144.0 137.2 131.9 108.3 104.2 96.3 600

B

Mortality

400

200 0 200 ASR (World) per 100 000

400

600

TABLE 23.1  Features of the Most Common Cancers Worldwide and the Most Common Cancers Attributable to Infection Site

Infectious Agent*

Lung

None known

Attributable Fraction† _

Other Factors§ Tobacco

Geographic Hot Spots

Control

Notes¥

Global with variation

Avoid tobacco Screening

Most common cause of cancer and cancer mortality globally

Continued

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TABLE 23.1  Features of the Most Common Cancers Worldwide and the Most Common Cancers Attributable to Infection—cont’d Site

Infectious Agent*

Attributable Fraction†

Geographic Hot Spots

Control

Notes¥

Breast

None known

_

Genetic Hormonal PM lifestyle

Global with variation

Screening Lifestyle

Most common cancer in women globally

Prostate

None known

_

Race/ethnicity Genetics

Global with variation

Screening

Second most common cancer in men globally

Colorectal

None known

_

Genetics IBD Lifestyle

Global with variation

Screening Lifestyle

Third most common cancer globally

Stomach, non-cardia

H. pylori

89%

Pickled/salted foods Alcohol Tobacco

East Asia (China) Africa Pacific Islands

Clean water Eradication Vaccine in development

Fifth most common cancer globally

Liver

HBV

73.4%

Aflatoxin Alcohol Iron overload Genotype B2, C

China Africa

Vaccination Treat chronic infection

Sixth most common cause of cancer Fourth most commom cause of mortality

Liver

HCV

73.4%‡

Alcohol Genotype 1b and 3

Oceania North America Europe

Treat chronic infection

Cervix

High-risk HPV

100%

HIV Lifestyle Tobacco

Eastern, southern central Africa Central America Melanesia

Vaccination Screening HIV control

Fourth most common cancer in women

Penis

High-risk HPV

51%

Uncircumcised UV Tobacco

Uganda South America India Southeast Asia

Neonatal circumcision

Common in areas of high HPV prevalence

Conjunctiva

High risk HPV

NA

HIV UV

Equator

Education

Lymphoma, MALT Marginal zone

H. pylori HCV

49.1% 3.6%

_ Cryoglobulinemia

Areas of high HCV prevalence

Eradication of H. pylori Treat HCV

Lymphoma, DLBCL

HBV** HCV EBV

49.1% 3.6% 49.1%

_ Cryoglobulinemia Immune suppression

Areas of high HBV, HCV prevalence

Vaccination Treat HCV

Burkitt’s lymphoma

EBV

52%

P. falciparum HIV

Equatorial Africa, New Guinea, Brazil

Malaria control HIV control

Nasopharyngeal carcinoma, non-keratinizing squamous

EBV

95.5%

Pickled, salted foods Genetics

Southern China Southeast Asia North Africa

Education

Kaposi’s sarcoma

KSHV (HHV-8)

100%

HIV Immune suppression

Equatorial Africa

Education HIV control

Adult T-cell leukemia and lymphoma

HTLV-1

100%

Not defined

South Japan, Caribbean, Melanesia, Africa, South America

Education

Bladder, squamous cell carcinoma

Schistosoma haematobium

1.6%

Tobacco Childhood infection

North Africa Egypt

Eradication

Other Factors§

Most common cancer in KS belt, regardless of HIV status

Tenth most common cause of cancer

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TABLE 23.1  Features of the Most Common Cancers Worldwide and the Most Common Cancers Attributable to Infection—cont’d Site Cholangiocarcinoma

Infectious Agent*

Attributable Fraction†

Opisthorchis viverrini Clonorchis sinensis

NA

Other Factors§ Alcohol Tobacco Hepatic steatosis HBV HIV H. pylori

Geographic Hot Spots Southeast Asia Thailand China Korea

Control

23 Notes¥

Eradication

*All infectious agents are Group I carcinogens per IARC. †Data from Ref 3: Attributable fraction is the fraction of new cases of a specific cancer due to an infectious agent. ‡HCV-induced liver cancer is not distinguished from HBV-induced liver cancer. **HBV-induced lymphoma is not described separately. §Lifestyle implies low fiber diet, inactivity, and/or obesity, and/or multiple sex partners with unprotected sex. ¥ For consistency, all data are from GLOBOCAN 2018. DLBCL, Diffuse large B-cell lymphoma; IBD, inflammatory bowel disease; NA, Not available; PM, post-menopausal.

Attributable fraction 5% 5–9% 10–19% 20–29% 30–39% 40% Fig. 23.2  GLOBOCAN2012: Worldwide fraction of malignancies attributable to infection. Attributable fractions ranged from <5% in the West to ≥40% in sub-Saharan Africa (Reprinted with permission from http://www. thelancet.com/journals/langlo/article/PIIS2214-109X(16)30143-7/fulltext).

by eradication. Research efforts are focused on biomarkers to identify such persons for enhanced surveillance. Preventive vaccine development is underway, but success has been limited. A randomized phase III study from China tested an oral vaccine with efficacy of 72% at 1 year and 55% and 56% at 2 and 3 years, respectively.7 Understanding transmission and providing cleaner water have led to a decline in the incidence of H. pylori infections and a decline in distal gastric cancer.

Viral Infections Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are well-known risk factors for hepatocellular carcinoma (HCC) and are recognized risk factors for non-Hodgkin’s lymphoma (NHL). Globally, HBV is the more relevant tropical infection where in endemic regions, maternal–child transmission is particularly important; 30% to 50% of children infected before age 6 tend to have chronic infections, increasing lifetime risk for hepatocellular cancer. The mechanism by which HBV and HCV are proposed to induce HCC are reviewed by others.8,9 Briefly, HBV integrates in the host genome at sites that are predictable based upon age

and HBV genotype. Genotypes B2 and C confer greater risk for HCC. Integration results in genetic instability. Expression of the hepatitis B X gene induces proliferation via activation of RAS and AKT signaling cascades and suppresses apoptosis via p53 sequestration and inhibition of death receptor and mitochondrial apoptotic pathways (see Fig. 23.3). The unregulated proliferation of increasingly dysplastic hepatocytes ultimately results in malignant transformation.8 HCV does not integrate, and therefore maintenance of chronic infection requires continuous hepatocyte replication maintained by viral proteins. Critical to oncogenesis is the induction of inflammation and angiogenesis, evasion of immune detection, inhibition of apoptosis, and sustained unregulated hepatocyte proliferation, all executed by HCV proteins. Genotypes 3 and especially 1b, along with host polymorphisms in cytokine and major histocompatibility complex genes, confer higher risk for development of HCC.9 In addition to alcohol, mycocystin, and iron overload, aflatoxin exposure is a particularly relevant risk factor for HCC in subSaharan Africa and Southeast Asia. Aflatoxin B1, the most toxic aflatoxin, is a metabolite of Aspergillus flavus and A. parasiticus, which infect grains and ground nuts stored in warm, damp locations.

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A

Receptor tyrosine kinase with ligand

Growth factor receptor and ligand

P

P +

Rb

P Rb P

E2F



Cell ready to divide?

P

RAS

P

PI3 K

P

RAF

P

AKT

P

MEK

P

mTOR

P

ERK

E2F G1

G0

Cell cycle arrest

p53

M G2

S

E2F

DNA damage?

DNA repair complete +



Back to cell cycle

Damaged DNA 2° Oxidative stress Nitrosative stress Inflammation Radiation UV

Angiogenesis

Apoptosis

B

Transcription

Growth

Via mitochondrial (bcl-2) and death receptor apoptotic pathways

Mutated receptor tyrosine kinase

1 HPV

3 Aflatoxin

5 S. haematobium 7 KSHV

2 HBV/HCV

4 Tobacco

6 PF + EBV

P



1 2 3 4 5 6

P

PI3 K

P *muRAF

P

AKT

P *muMEK

P

mTOR

Mutated or inactivated p53

G0 M

S

2

E2F P

G1

Regulated

P

4 5

P *muRAS E2F

Survival

Mutated growth factor receptor

Rb 1 HPV prevents RB from binding E2F

Proliferation

G2 No cell cycle arrest No DNA repair

ERK

E2F

Damaged DNA 2° Oxidative stress Nitrosative stress Inflammation Radiation UV

Transcription of damaged DNA

E2F

Mutations Angiogenesis 7

Cells with damaged DNA enter cell cycle

2

Growth

AID induced breaks Proliferation

Survival

Increase survival via inhibition of mitochondrial (bcl-2) and death receptor apoptotic pathways

6



CHAPTER 23  Cancer in the Tropics

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Fig. 23.3  Regulatory pathways in health and malignancy. (A) Health: After ligand binding, receptor kinase pathways are activated via phosphorylation promoting cell growth, proliferation, survival, and angiogenesis. Before cells enter the cell cycle and while in the cell cycle, checkpoints identify damaged DNA. Cells exit the cycle for DNA repair. p53, the protein product of TP53, and RB protein, the product of the RB gene, are key in regulating cell cycle progression. If DNA cannot be repaired, apoptosis follows to prevent cells from accumulating oncogenic mutations. (B) Oncogenic infections cause a variety of perturbations in cell machinery that contribute to independent growth, the hallmark of malignancy. Constitutive activation of the pathways controlling growth, proliferation, angiogenesis, and survival can result from mutations in growth factor and tyrosine kinase receptors, mutations in pathway proteins, or increased signaling via viral protein through unmutated pathway proteins. Regardless of the mechanism, response to feedback inhibition is lost. Loss of RB or p53 function allows cells with damaged DNA to replicate, resulting in the accumulation of somatic mutations of increasingly oncogenic potential. Expression of certain genes like AID, along with uncontrolled proliferation, sets up chromosomal breaks and translocations that provide selective growth advantages. Mutations in the mitochondrial or death receptor apoptotic pathways prevent elimination of cells with damaged DNA. P is phosphorylation, muRAS, muRAF, and muMEK refers to mutated RAS, RAF, and MEK. The red asterisk means the pathway protein is wild type (not mutated), but constitutively active by enhanced signaling. Depending upon the malignancy, some signaling proteins may be muted and others unmutated leading to constitutive activation of the pathway. Heavy green arrows represent enhanced or constitutive expression. Solid red lines with flat ends represent feedback inhibition, dotted red lines indicate loss of feedback inhibition, and dashed green lines means loss of proper signaling.

When consumed, aflatoxin B1 induces a specific inactivating mutation, G249T, in TP53 (the tumor suppressor gene that codes for p53 protein) (see Fig. 23.3). In HBV-endemic areas, co-exposure to aflatoxin B1 promotes higher rates of HCC than would be expected from HBV alone.10 Persons with HCC generally present with advanced disease characterized by weight loss, jaundice, and abdominal pain. Less common are presentations due to paraneoplastic syndromes that may cause hypercalcemia, hypoglycemia, watery diarrhea, or erythrocytosis. Diagnosis is made with computed tomography (CT) or ultrasound-directed biopsy. Because of the limited options for treating HCC and the lack of access to screening in low-resource countries, emphasis is on prevention by HBV vaccination of neonates. A study in Taiwanese children has demonstrated the efficacy of this approach in reducing HCC,11 but unfortunately, only 10% of African nations are meeting this standard.3 For those with chronic HBV infection, nucleoside reverse transcriptase inhibitors, especially entecavir, have been shown to reduce, but not eliminate, the risk for HCC.11 HCVinduced HCC is increasing in Oceania, North America, and Western Europe because of the prevalence of baby boomers who used intravenous drugs. It is estimated the incidence will continue to rise until 2020.9 Although persons who achieve a sustained virologic response with interferon and ribavirin have lower risks of HCC than those who do not, the risk persists, likely due to a residual population of cells with irreversible genetic changes induced by HCV. Test-and-treat programs using direct-acting anti-virals are currently too costly for resource-limited nations.9 Chronic HCV and HBV infections confer a 1.8-fold and a 2- to 3-fold risk of lymphoma, respectively. Both viruses are lymphotropic and capable of replication within B cells, directly affecting cellular pathways similar to those observed in hepatocytes. Another proposed mechanism for lymphomagenesis is chronic antigenic stimulation of hepatitis-specific B cells, which increases the likelihood of a mutation that confers a selective growth advantage. T-cell immune dysregulation from chronic hepatitis contributes to poor immune surveillance of transforming cells.12 As with HCC, there are data to suggest that prevention and treatment strategies can reduce the risk of, as well as treat lymphomas. The ability of alpha-interferon and ribavirin to induce remission in HCV-induced marginal zone lymphoma is well documented.13 It has been shown that HCV-infected persons who sustain complete virologic responses to interferon therapy have lower rates of lymphoma in comparison to those with incomplete responses.14 In terms of HBV, a cohort study from Taiwan demonstrated an increased risk of NHL in regions of high HBV prevalence; it also showed the protective effects of universal HBV childhood vaccination in reducing rates of NHL in adolescents.15

Nearly all adults acquire a human papillomavirus (HPV) infection shortly after becoming sexually active. Of the 40 serotypes that infect mucosal epithelium, at least 15 are considered high risk, seven of which are responsible for most HPV-associated cancers, HPV-16, HPV-18, HPV-45, HPV-33, HPV-31, HPV-52, and HPV-58. In addition to nearly all cervical cancers, high-risk HPVs are a necessary, but not sufficient factor in anal, vaginal, vulvar, penile, head and neck,3 and conjunctival cancers.16 Cervical, penile, and conjunctival carcinomas are the malignancies most relevant to the tropics. Although HPV infects the deep basal epithelium where it is isolated from circulating immune cells, an immune response usually develops, clearing the majority of infections before becoming a risk for malignancy. If infection persists, squamous intraepithelial neoplasia grade 1 (SIN1) progresses to increasingly dysplastic SIN2 and SIN3, where spontaneous regressions are unlikely. Inflammation from persistent HPV infection, co-morbid infections, trauma, or smoking promotes epithelial proliferation, secretion of proangiogenic factors, and resistance to apoptosis. Oxidative and nitrosative stress lead to double-strand breaks in host and HPV episomal DNA, inducing linearization and virus integration. Linearization occurs in the region of early genes, E1 and E2 causing loss of E2’s structural integrity and subsequent loss of expression of the E2 protein (pE2). pE2 normally functions to suppress expression of E6 and E7 genes. With loss of pE2, E6 and E7 protein expression increase, binding and inactivating p53 and Rb respectively (see Fig. 23.3). Loss of cell cycle regulation follows, allowing cells with damaged DNA to replicate, resulting in an accumulation of somatic mutations that contribute to malignant transformation.17 This process generally takes between 10 and 15 years, though more rapid progression has been reported.18 In developing nations, HIV is an important co-factor in high-risk HPV infections. The cell-mediated immune defect supports persistent infection. HIV tat protein in conjunction with tumor necrosis factor alpha and interferon gamma (IFN-γ) induces disruption of the tight junctions between epithelial cells, enhancing HPV access to the basal layer. HIV tat protein enhances transcription of E6 and E7, supporting oncogenesis before linearization, offering an explanation for why HPV-related cancers in any site among HIV-infected persons progress more quickly.19,20 Nearly 90% of cervical cancer cases occur in the developing world. Women with localized disease may be entirely asymptomatic or report metrorrhagia. As disease advances, dyspareunia, pelvic pain, and bleeding develop. Screening with Papanicolaou smear and treatment of pre-invasive lesions have been shown in the developed world to reduce the incidence of and death from invasive malignancy. Screening and treatment strategies for resource-limited settings are available,21 but given their limitations, the World Health Organization (WHO) recommends HPV vaccination for pre-teen girls and rapid HPV testing in older women.

23

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Penile cancer, with annual incidence rates of less than 1% in developed nations, accounts for up to 10% of cancers in equatorial nations with high cervical cancer prevalence. Risk factors in addition to HPV include HIV, tobacco, ultraviolet (UV) exposure, and poor hygiene among uncircumcised men. Due to embarrassment and fear, there is delay and under-reporting of symptoms. Pruritis and burning around a phimotic foreskin, with or without a purulent discharge, are common in early disease. With progression comes fistula formation and urinary retention. Bleeding and pain are less common. Treatment options are limited, so emphasis is on prevention. Neonatal circumcision abolishes risk and is favored over HPV vaccination.22 Squamous cell carcinoma (SCC) of the conjunctiva, a rare malignancy, was originally described in fair-skinned older men living in tropical regions. With the HIV epidemic, the disease appeared outside the usual demographic, and findings of high-risk HPV infection in pre-malignant and malignant lesions were reported. The malignancy usually presents in the nasal conjunctiva as a gray-white gelatinous mass with surrounding injection from feeder vessels (Fig. 23.4). It can be confused with benign neoplasms of the nasal conjunctiva, pinguecula, or pterygium, which also occur in persons with UV exposure and dry eyes. Patients with either neoplasm can experience blurry vision or a foreign body sensation, necessitating biopsy for diagnosis. Though questions about the pathogenesis remain, there appears to be a relationship between high-risk HPV, the mutagenic effects of UV, and HIVinduced immune suppression that are permissive for the development of carcinoma.16 Kaposi’s sarcoma herpesvirus (KSHV), or HHV-8, is a gammaherpesvirus with geographically distinct prevalence rates, more than 50% in equatorial Africa, within the Kaposi’s sarcoma belt (Fig. 23.5A), about 20% in the Mediterranean, and less than 10% A

in Asia and the West. KSHV is transmitted horizontally via saliva, sexual intercourse, and transfusion; vertical transmission is rare. Saliva is considered the most important mode of transmission in African heterosexuals, with pre-mastication by an infected adult being the primary means of childhood infection.23 The mechanisms by which KSHV induces malignant transformation are complex. The virus targets endothelial cells, B

Fig. 23.4  Squamous cell carcinoma of the conjunctiva. A gelatinous mass with surrounding feeder blood vessels in the nasal conjunctiva. (With permission from Mata E, Conesa E, Castro M, et al. Conjunctival squamous cell carcinoma: paradoxical response to interferon eyedrops. Archivos de la Sociedad Espanola de Oftalmologia 2014; 89(7):293–6.)

B

The Gambia

Kampala

Fig. 23.5  The Kaposi’s sarcoma, Burkitt’s lymphoma, and malaria belts of equatorial Africa. (A) Kaposi’s sarcoma belt. Red, seroprevalence rates >40%; purple, 30%–40%; green, 10–20%; and yellow <10%. (B) Burkitt’s lymphoma and malaria belt. Gray shading represents the Burkitt’s lymphoma belt and black hashmarks represent the malaria belt or areas of malaria holoendemnicity. (Panel A, From Mesri EA, Cesarman E, Boshoff C. Kaposi’s sarcoma and its associated herpes virus. Nat Rev Cancer 2010;10(10):707–9. Panel B, From https:// figshare.com/articles/_The_Burkitt_lymphoma_belt_overlaps_the_regions_of_Africa_in_which_malaria_ is_holoendemic_/1158451.)

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185

23

A

C

B

D

Fig. 23.6  Kaposi’s sarcoma. (A) Classic. (B) Immune suppression associated. (C) HIV associated or epidemic. (D) Endemic. (With permission from Hengge UR, Ruzicka T, Tyring SK, et al. Update on Kaposi’s sarcoma and other HHV8 associated diseases. Part 1: epidemiology, environmental predispositions, clinical manifestations, and therapy. Lancet Infect Dis 2002;2(5):281–92.)

lymphocytes, epithelial cells, and macrophages through G-coupled protein receptors and persists as an episome attached to host DNA, never integrating. Latency genes modulate host signaling pathways to promote target cell proliferation, inhibit cell cycle checkpoints, tumor suppressor genes, and apoptosis, and support an inflammatory environment (see Fig. 23.3). Virus-infected cells evade immune detection through down-regulation of TLR-4 and IFN production.23 HIV tat protein contributes to proliferation of KSHV-infected cells, and the associated cell-mediated immune defect prevents their clearance.24 KSHV is a necessary, but not sufficient, factor in the development of Kaposi’s sarcoma (KS), primary effusion lymphoma, and multicentric Castleman’s disease. KS, a multifocal tumor of lymphatic endothelial origin,23 is the most common KSHV-related malignancy and the most relevant to the tropics. Of the four epidemiologic subtypes, classic, transplant associated, endemic, and epidemic or AIDS associated, the latter two are most pertinent to this discussion. There are two forms of endemic KS, cutaneous and lymphadenopathic, with the latter being an aggressive, often lethal, disease more common in children. Otherwise, the clinical manifestations of endemic and epidemic KS are similar and range from indolent cutaneous lesions of cosmetic concern to limb- or life-threatening disease with visceral involvement (Fig. 23.6). HIV co-infection

confers a 50-fold increase in the risk of developing KS,25 and because HIV transmission in sub-Saharan Africa is primarily heterosexual, epidemic KS occurs in nearly equal proportions in men and women. Combination antiretroviral therapy has reduced the incidence of epidemic KS by 70% to 90% in resource-rich settings, and preliminary data support similar effectiveness in sub-Saharan Africa. Challenges persist in addressing the numbers of HIV-KSHV co-infected persons and the problem of incident KS in persons with preserved CD4+ T-cell counts.26 Treatment for life- or limbthreatening endemic or epidemic KS may require chemotherapy. Nasopharyngeal carcinoma, a rare head and neck cancer with a clonal Epstein–Barr virus (EBV) infection, is the leading cause of cancer in some parts of Asia and Africa. The malignancy develops in a stepwise fashion similar to cervical cancer, except EBV infection does not occur until epithelial cells have undergone pre-malignant changes. Genetic predispositions and local customs explain the narrow incidence of this malignancy. Consumption of salt-preserved foods is common in high-prevalence areas; preservation is incomplete, and foods undergo putrefaction, generating nitrosamines. Common genetic predispositions include decreased ability to metabolize nitrosamines, inability to present EBV proteins to the immune system, and polymorphisms in the polymeric immunoglobulin receptor (PIGR) that facilitate EBV entry into the nasal

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epithelium.27 Patients may present with nasal discharge, bleeding, or serous otitis media secondary to obstruction. Cranial nerve (CN) palsies, especially in CN V, VI, and XII, develop with tumor extension. Because of the rich lymphatic supply to the nasopharynx, more than half of patients present with adenopathy. The retropharyngeal nodes are the most commonly involved but due to location can only be assessed with imaging. As disease advances, cervical adenopathy in all levels may develop. Diagnosis is made via biopsy after CT localization of tumor. Human T-cell leukemia virus (HTLV-1) is estimated to infect between 5 and 10 million people, with areas of high prevalence adjacent to areas of low prevalence within the same country (also see Chapter 38.9). The virus is transmitted via intercourse, blood products, organ transplant, and to children through extended breastfeeding. The virus targets CCR4 expressing CD4+ T cells and is responsible for adult T-cell leukemia and lymphoma (ATLL). The virus, spread by cell-to-cell contact, randomly integrates. Malignant transformation results from the action of HTLV-1 gene products such as tax protein on apoptotic and T-cell proliferation pathways. The lifetime risk for ATLL in infected persons is 2% to 5% with malignancy presenting 20 to 30 years after infection. Response to chemotherapy is poor, though better outcomes have been reported using mogamulizumab (anti-CCR4) in Japanese patients.28 There is no vaccine, so public health efforts are directed at identifying and educating HTLV-1 carriers about transmission. The efficacy of such measures has been demonstrated in Japan, but not in developing nations.29

Parasitic Infections Endemic Burkitt’s lymphoma (eBL) is the most common childhood malignancy and accounts for 90% of lymphomas in the Burkitt’s lymphoma (BL) belt, (an area that extends from 10°N to 10°S of the equator) (Fig. 23.5B) where Plasmodium falciparum (Pf) is holoendemic.30 The syndemic relationship between EBV and Pf is established with early primary EBV infection in the setting of chronic malaria. Pf-infected red blood cells induce polyclonal B-cell proliferation through the parasite’s cysteine-rich interdomain region 1α. Latent EBV infections are reactivated, leading to increased viral burden and numbers of infected B cells. The parasite protein hemozoin binds to B cells, increasing expression of activation-induced cytidine deaminase (AID). AID induces mutations in TP53 and chromosomal breaks in highly transcribed areas of the B-cell genome, culminating in the hallmark c-myc translocations t(8;14)(q24;q32), t(2;8)(p12q24), or t(8;22)(q24;q11). Regardless of the specific translocation, the result is that the ordinarily tightly regulated c-myc gene, now under control of immunoglobulin enhancer elements, is constitutively expressed, driving cell growth and proliferation (see Fig. 23.3). Mutated TP53 permits accumulation of cells increasingly capable of independent growth, and EBV-induced immune defects suppress immune surveillance.30 Endemic BL typically presents with massive adenopathy in the jaw or orbit in HIV-negative children or young adults (Fig. 23.7). Epidemic BL presents with extranodal disease in HIV-positive adults with uncontrolled viral replication but preserved CD4+ T-cell counts. Clonal EBV expression is present in nearly all cases of eBL, but only in 40% of epidemic BL, where HIV is thought to replace EBV as the driver of B-cell proliferation.31 A logical approach to eBL is malaria control. A number of studies have been done, but, because rates of endemic BL started to fall before studies were completed, results are hard to interpret.30 Control of HIV replication theoretically would contribute to control of epidemic BL. Successful management of BL requires a medical infrastructure not available in endemic areas. Therapy must be tailored to patients’ health and access to care, resulting in 5-year event-free survivals of less than 60% in Africa compared with 84% to 92% in the West.31

Fig. 23.7  Burkitt’s lymphoma. A child with endemic Burkitt’s lymphoma with involvement of the jaw. (Courtesy, Dr. Juliana Otieno and Dr. Ann Moormann.)

Three genera of trematodes are potentially oncogenic, Schistosoma, Opisthorchis, and Clonorchis. The WHO estimates there are more than 200 million cases of schistosomiasis, most of which occur in low-resource nations without clean water. Schistosoma haematobium is associated with SCC of the bladder. There are weaker associations of S. japonicum with HCC and colorectal cancer, and S. mansoni with HCC.32 Circulating worms invade the venous plexus of the ureters and bladder, laying eggs that eventually pass into the bladder mucosa inciting inflammation and oxidative stress. Fibrosis follows, preventing complete emptying of the bladder. With bacterial colonization, urinary nitrosamines accumulate and along with oxidative stress cause mutations in K-ras, TP53, and bcl-2 allowing unregulated proliferation and survival of cells with DNA damage (see Fig. 23.3). Metaplasia progresses to dysplasia and ultimately invasive SCC.32 Malignant transformation requires several decades starting with childhood infection and after decades of chronicity, culminates in a diagnosis of cancer in the fifth decade, which is considerably younger than transitional cell patients in the developed world who present in the seventh decade. Painless hematuria and irritative voiding symptoms are common presentations for bladder cancer and chronic bladder schistosomiasis, whereas the presence of necroturia is more suggestive of malignancy.33 Diagnosis is confirmed by biopsy through cystoscopy. Although trematode control strategies have led to a dramatic decline in the prevalence of S. haematobium and incidence of SCC of the bladder, the overall incidence of bladder cancer remains steady. This unfortunate trend has been attributed to increased tobacco use,34 and an associated increase in transitional cell carcinoma of the bladder. An estimated 45 million people are infected with Clonorchis sinensis and Opisthorchis viverrini32 (see Chapter 128). Metacercariae, ingested after consumption of undercooked or inadequately preserved freshwater fish, excyst in the duodenum and ascend through the ampulla of Vater to biliary and pancreatic ducts to

CHAPTER 23  Cancer in the Tropics



induce cholangiocarcinoma (CCA). A number of mechanisms involving genetic and epigenetic changes are proposed. Parasitederived proteins induce chronic inflammation and oxidative DNA damage. Unregulated proliferation follows acquisition of activating mutations in oncogenes and inactivating mutations in tumor suppressor genes. Cytokines and chemokines induce angiogenesis to support neoplastic growth.35 Additional risk factors pertinent to the tropics include HIV, HBV, H. pylori, and alcohol and tobacco use. The rising rates of obesity-related hepatic steatosis are becoming increasingly relevant and are likely to abrogate the progress made by trematode eradication programs. Although CCA requires decades of chronic inflammation to develop, it is rarely diagnosed at a stage amenable to surgical cure. This is in part because symptoms of early disease such as nausea, anorexia, abdominal pain, and biliary obstruction are non-specific and associated with a variety of benign conditions, including chronic trematode infection. Most patients present with unresectable disease with malaise, abdominal pain, weight loss, jaundice, and ascites. Diagnosis is made with endoscopic retrograde cholangiopancreatography if available, but cytologic analysis of ascites may be just as useful and is more accessible, less expensive, and less invasive. Because there is no effective therapy for surgically unresectable disease, emphasis is on prevention and early detection through screening in high-risk populations. A finding of unexplained intrahepatic bile duct dilatation without obstruction on ultrasound or CT is associated with a healed trematode infection and should prompt screening.36 Screening methods vary, but tumor markers, CEA, and Ca19-9 levels, along with CT or magnetic resonance imaging are commonly employed.37

TOBACCO The WHO estimates that of the 1 billion smokers worldwide, 80% live in low- and medium-income countries. Tobacco, the single most important risk factor for malignancy, particularly lung cancer, is responsible for 22% of cancer deaths.2 Other tobaccoassociated cancers include head and neck, esophagus, pancreas, liver, gastric, colon, cervix, renal, ureter, and bladder.38 The primary means by which smoking induces malignancy is via chemicalinduced inflammation and DNA damage, especially to genes like K-ras and TP53. In 2003, the World Health Assembly endorsed the WHO Framework Convention on Tobacco Control. As of 2015, 90% of the world’s countries had ratified the legally binding treaty. Participants committed to using evidence-based tobacco control measures such as MPOWER.39 A target was set for a 30% reduction in the 2010 smoking prevalence rates by 2025. In a 2015 report, however, only 21% of countries were on target for men and 49% for women. Prevalence rates remained lowest in the poorest nations, presenting an opportunity to prevent the epidemic from taking hold, but tobacco companies are systematically redirecting their advertising efforts to these nations.40

OBESITY By 2010, rates of obesity were so high in developed nations that epidemiologists added a fifth phase, age of obesity and inactivity,41 to Omran’s four stages of epidemiologic transition. In 2016, the International Association for Cancer Research (IARC) published an updated review of the malignancy and obesity literature and concluded there were sufficient data to link obesity with carcinoma of the esophagus, gastric cardia, colon-rectum, liver, gallbladder, pancreas, post-menopausal breast, uterus, kidney, and thyroid, as well multiple myeloma, and meningioma.42 In an attempt to understand the obesity-related cancer burden in diverse geographic areas, Arnold et al., using GLOBOCAN 2012 data, estimated that worldwide 3.6% of new cancers were related to obesity. In developing nations, 2% of

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cancers in women and 0.5% of cancers in men were linked, making obesity less of a risk factor than tobacco and oncogenic infections.43 Obesity, however, cannot be ignored in transitioning nations. Between 1975 and 2014, there was a sixfold increase in the number of obese persons globally. Recent obesity rates from China, South Africa, and the Middle East suggest that developing nations are reaching this fifth phase earlier in their transitions41 than did Western nations. There is considerable variability in the risk of obesity-induced cancers among ethnic groups.This is likely due to varying susceptibility to visceral adiposity and varying contributions from the homeostatic disruptions associated with obesity, sex hormone metabolism, insulin, and insulin-like growth factor signaling, adipokine-induced inflammation, immune dysfunction, and microbiome changes.44 Regardless of the mechanism, IARC data show that intentional weight loss has a beneficial effect on cancer risk, providing support for programs to avoid obesity for nations in transition.

Management Successful management of cancer requires timely and accurate diagnosis, staging, access to surgery, chemotherapy, radiation therapy, and palliative care. Only 26% of developing nations report adequate pathology services and 30% access to cancer treatment.2 These deficiencies translate to a delay in diagnosis, more advanced stage at diagnosis, poorer outcomes, and greater costs. Pathologists without access to advanced diagnostics and genetic testing will fail to identify malignancies with driver mutations that can be treated with targeted therapy. The inability to provide surgery for an early-stage cancer reduces chances for cure and adds to medical costs, as well as costs due to loss of productive life. It has been estimated that of the 15.2 million cases of cancer diagnosed in 2015, 80% required surgery, yet for nearly 75% of those patients, surgery was not available, safe, or affordable. Radiation therapy is estimated to be used at least once in about half of all cancer patients. Access is notoriously dependent on wealth and as such is not available in at least 30 African nations. Chemotherapy is similarly expensive and expertise dependent. Cost and production problems create shortages of life-saving medications. In many poor nations, 40% of essential cancer drugs are out of stock for a median of 30 days. A year’s worth of trastuzumab, a monoclonal antibody that reduces mortality by 50% in women with HER-2–amplified breast cancer, increases the cost of adjuvant therapy 100-fold. Palliative care emphasizes the management of physical, social, and spiritual distress due to cancer or its treatment. It has been shown to extend life and is recommended to supplement treatment for advanced cancer. Pain management is at the center of palliative care, but resource-limited countries rarely have the opioids needed for pain relief due to restrictions on use, lack of training, cost, and cultural attitudes.45 The impact of the burden of cancer in resource-limited nations cannot be overstated. Eliminating tobacco and eradicating oncogenic infections would reduce the risk for 22% and 25% of cancers, respectively.2 Understanding the mechanisms by which infections induce cancers reinforces the importance of prevention. Oncogenic infections cause cancers driven by mutations in TP53, K-ras, and blocked apoptotic pathways, which are especially difficult to treat, regardless of resources. Because of irreversible genetic changes induced by some infections, eradication may not eliminate the risk of malignancy. Ignoring the need for continued surveillance may be deadly. Though HIV does not cause malignancy directly, control of viral replication and preservation of immune function would reduce risk of KSHV, EBV, and HPV-related malignancies. Understanding the ethnic and geographic heterogeneity in susceptibility to specific cancers will allow for the creation of individualized programs to direct critical resources to prevent and treat relevant cancers. Prioritizing funding and partnerships with resource-rich centers, resource-stratified clinical practice guidelines, and WHO lists of

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essential medicines can be used to begin to realize the unmet needs across the management continuum. REFERENCES

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