**4. Kaposi's sarcoma**

#### **4.1 Background**

KS (Kaposi's sarcoma) is an angioproliferative tumor described by the Hungarian pathologist Moritz Kaposi in 1872. It is caused by KSHV (Kaposi's sarcoma-associated herpes virus) or γ2-herpes virus. KSHV belongs to the genus Rhadinovirus and has a DNA sequence similar to other rhadinoviruses (Albrecht, et al., 1992). With the introduction of HAART in 1996, the incidence of AIDS-related cancers such as KS and NHL (non - Hodgkin's lymphoma) has decreased (Shiels, et al., 2008). During the 1980s and early 1990s, US population rates of KS increased 30 fold (Eltom, et al., 2002). There were no KS cases during 1975-1979, before the advent of AIDS. In an HIV cancer match study, 81% of KS cases matched to HIV registries during 1980-2007 (Shiels, et al., 2011). AIDS occurred in a higher proportion of patients with Kaposi's sarcoma in age groups of 0-29 and 30-59 years (Shiels, et al., 2011).

#### **4.2 Pathogenesis**

KS lesions show varying cell diversity. Lesions are flat, comprising of inflammatory cells (T, B cells and monocytes). Neovascularization develops prior to development of these lesions and contain spindle-shaped cells. This dermal stage progresses to the plaque stage, in which the lesions are more indurated, edematous, and red or violet in color. The lesion eventually reaches the nodular stage and is characterized by visible masses with dominant spindle cells and inflammatory cells. These spindle cells express lymphatic-specific markers (e.g., Podoplanin and lymphatic vessel hyaluronan receptor LYVE-1) as well as participate in the signaling process during lymphangiogenesis (Skobe, et al., 1999, Weninger, et al., 1999).

#### **4.3 Clinical features**

There are four types of KS: classic type, endemic African KS, KS in organ transplant recipients, and HIV-infection/AIDS associated KS (Trattner, et al., 1993). KS is the most common neoplasm (20-50%) found in HIV-infected individuals (mostly homosexual and bisexual men) (Scully, et al., 1991).Oral lesions are evident in 40% of KS (Greenspan and Greenspan, 1990).Red or purplish macules, papules or nodules appear most frequently on the hard palate (Greenspan and Greenspan, 1990). Unless infected or ulcerated, these lesions do not blanch on pressure (Greenspan and Greenspan, 1990). Laryngeal involvement is also evident in individuals with KS (Pantanowitz and Dezube, 2006). Primary symptoms are hoarseness, throat discomfort, urge to cough, aphonia, dysphagia, stridor, and complete airway obstruction.

#### **4.4 Treatment**

The extent and bulk of the disease determines the therapeutic alternative that needs to be considered. Individuals with fewer than five cutaneous lesions are kept on watch until rapid proliferation, widespread dissemination or KS-related symptoms become more apparent. Treatment with HAART or other anti-retroviral therapies are beneficial and have shown histologic regression of existing lesions (Eng and Cockerell, 2004). HAART therapy causes inhibition of HIV replication, diminishes the HIV-1 transactivating protein Tat, ameliorates the immune response against KSHV, and shows direct anti-angiogenic activity (Cattelan, et al., 1999, Pati, et al., 2002, Sgadari, et al., 2002). Radiotherapy is indicated for lesions on the face, hands and upper extremities, obstructive lymphadenopathy, periorbital edema, lesions on soles of the feet, anorectal or genital lesions, oral lesions and ulcerating cutaneous lesions. Radiotherapy shows merits in symptomatic disease where systemic treatment is not necessary and expensive chemotherapy can be avoided (Swift, 1996). If an active opportunistic infection is observed, chemotherapeutic agents should be considered. Systemic chemotherapeutic treatment is indicated in extensive KS of oral cavity, widespread skin involvement, pedal or scrotal edema, symptomatic visceral involvement and flare induced by immune reconstitution inflammatory syndrome (Osoba, et al., 2001). Individuals may suffer from neutropenia and thrombocytopenia and hence controlled therapy should be the choice of treatment. Only nodular and symptomatic lesions of oropharynx should be treated with radiation. Recombinant and non-recombinant alpha interferons can be used for treatment of epidemic KS (De Wit, et al., 1988).

Fig. 7. Kaposi's Sarcoma

## **5. Human Papilloma Virus (HPV) infections**

#### **5.1 Background**

86 Global View of HIV Infection

KS (Kaposi's sarcoma) is an angioproliferative tumor described by the Hungarian pathologist Moritz Kaposi in 1872. It is caused by KSHV (Kaposi's sarcoma-associated herpes virus) or γ2-herpes virus. KSHV belongs to the genus Rhadinovirus and has a DNA sequence similar to other rhadinoviruses (Albrecht, et al., 1992). With the introduction of HAART in 1996, the incidence of AIDS-related cancers such as KS and NHL (non - Hodgkin's lymphoma) has decreased (Shiels, et al., 2008). During the 1980s and early 1990s, US population rates of KS increased 30 fold (Eltom, et al., 2002). There were no KS cases during 1975-1979, before the advent of AIDS. In an HIV cancer match study, 81% of KS cases matched to HIV registries during 1980-2007 (Shiels, et al., 2011). AIDS occurred in a higher proportion of patients with Kaposi's sarcoma in age groups of 0-29 and 30-59 years (Shiels,

KS lesions show varying cell diversity. Lesions are flat, comprising of inflammatory cells (T, B cells and monocytes). Neovascularization develops prior to development of these lesions and contain spindle-shaped cells. This dermal stage progresses to the plaque stage, in which the lesions are more indurated, edematous, and red or violet in color. The lesion eventually reaches the nodular stage and is characterized by visible masses with dominant spindle cells and inflammatory cells. These spindle cells express lymphatic-specific markers (e.g., Podoplanin and lymphatic vessel hyaluronan receptor LYVE-1) as well as participate in the signaling process during lymphangiogenesis (Skobe, et al., 1999, Weninger, et al., 1999).

There are four types of KS: classic type, endemic African KS, KS in organ transplant recipients, and HIV-infection/AIDS associated KS (Trattner, et al., 1993). KS is the most common neoplasm (20-50%) found in HIV-infected individuals (mostly homosexual and bisexual men) (Scully, et al., 1991).Oral lesions are evident in 40% of KS (Greenspan and Greenspan, 1990).Red or purplish macules, papules or nodules appear most frequently on the hard palate (Greenspan and Greenspan, 1990). Unless infected or ulcerated, these lesions do not blanch on pressure (Greenspan and Greenspan, 1990). Laryngeal involvement is also evident in individuals with KS (Pantanowitz and Dezube, 2006). Primary symptoms are hoarseness, throat discomfort, urge to cough, aphonia, dysphagia, stridor, and complete

The extent and bulk of the disease determines the therapeutic alternative that needs to be considered. Individuals with fewer than five cutaneous lesions are kept on watch until rapid proliferation, widespread dissemination or KS-related symptoms become more apparent. Treatment with HAART or other anti-retroviral therapies are beneficial and have shown histologic regression of existing lesions (Eng and Cockerell, 2004). HAART therapy causes inhibition of HIV replication, diminishes the HIV-1 transactivating protein Tat, ameliorates the immune response against KSHV, and shows direct anti-angiogenic activity (Cattelan, et al., 1999, Pati, et al., 2002, Sgadari, et al., 2002). Radiotherapy is

**4. Kaposi's sarcoma** 

**4.1 Background** 

et al., 2011).

**4.2 Pathogenesis** 

**4.3 Clinical features** 

airway obstruction.

**4.4 Treatment** 

HPV is the leading cause of orpharyngeal carcinomas (D'Souza, et al., Rosenquist, 2005). HPV16 is a common cause for the majority of oropharyngeal carcinomas (Kreimer, et al., 2005) . HPV-positive individuals are most frequently Caucasian and belong to high socioeconomic status (Gillison, et al., 2008). HIV-infected individuals have two to four-fold increase in risk for developing HPV-related oral cancers (Gilbert, et al.). HPV has also been considered as one of the etiologic factors for OHL (oral hairy leukoplakia) (Fejerskov, et al., 1977), as shown by identification of HPV antigens and HPV DNA (Loning, et al., 1985). HPV-induced OL shows prevalence ranged from 17% to 68.6% (Shroyer, et al., 1993, Sugiyama, et al., 2003).

Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 89

Treatment of HPV infection can be achieved either by use of targeted therapy against the virus or immune-stimulating therapy. Most dysplastic tissue can be treated by ablative and excisional therapy. Use of radiochemotherapy in the form of radiation ± cisplatin or cetuximal has shown beneficial results in treatment of oropharyngeal carcinoma. The overall survival rate was 60 % in HPV-positive individuals and 73 % in HPV-negative individuals

This lesion is also known as 'red-band gingivitis' or 'HIV-associated gingivitis'. LGE is commonly seen in immune-compromised individuals and is considered to be a potential precursor for necrotizing ulcerative gingivitis (NUG)/ necrotizing ulcerative periodontitis (NUP). According to the recent classification of periodontal diseases (Armitage, 1999), LGE

There is an increased number of bacteria and *Candida* species in the gingival sulcus associated with LGE. The bacteria seen include those commonly observed in periodontal disease such as *Bacteriodes gingivalis, Bacteriodes intermedius, Actinomyces viscosus,* 

The lesions present themselves as 2-3 mm wide red band around the marginal gingival of

Typically, no treatment is needed for this condition. Although LGE is listed under 'Lesions of fungal origin', it is not typically treated with anti-fungal medications. Mechanical removal of plaque and calculus helps reduce inflammation and excessive bleeding. Chlorhexidine gluconate (0.12%) mouth rinses can be used twice daily. If the lesion persists,

NUG is a painful condition of the gingiva characterized by ulcerations, bleeding, and foul breath. It is also called Vincent's infection, Vincent's angina, or trench mouth. When the infection spreads to the alveolar bone, it is called NUP. Prevalence of NUP in HIV-infected individuals has been reported by various researchers. Its prevalence with HIV was reported in 1994 as 6% (Glick, et al., 1994). Over a period of a decade, the incidence of HIV in NUP patients increased to 69.6% (Shangase, et al., 2004). Recent reports suggest 43% of patients with NUP were HIV-seropositive (Phiri, et al.). Studies have shown that HIV-infected individuals with NUP are 20.8% more likely to have a CD4+ count lower than 200 (Glick, et

systemic antibiotics (metronidazole) may be prescribed to reduce the bacterial load.

**6.2 Necrotizing Ulcerative Gingivitis and Periodontitis (NUG and NUP)** 

**5.4 Treatment** 

(Lill, et al.).

**6.1.1 Background** 

**6.1.2 Pathogenesis** 

**6.1.3 Clinical features** 

**6.1.4 Treatmen** 

**6.2.1 Background** 

al., 1994).

**6. Periodontal lesions associated with HIV** 

is classified under 'Gingival diseases of fungal origin.'

*Fusobacterium nucleatum,* and *Aggregatibacter actinomycetemcomitans*.

the teeth. These lesions are not typically painful, but bleed readily.

**6.1 Linear Gingival Erythema (LGE)** 

#### **5.2 Pathogenesis**

HPV is mainly infectious through expression of oncogenes such as E6/E7 (Al-Bakkal, et al., 1999), which cause phosphorylation of CHK2, leading to caspase activation (Al-Bakkal, et al., 1999, Moody and Laimins, 2009, Tominaga, et al., 1999). The intrinsic apoptotic pathway of caspase activation plays an important role in HPV replication (Moody, et al., 2007). HPV proteins flourish and regulate amplification primarily by caspase activation, leading to immortalization of the suprabasal layer of epithelium, specifically the keratinocytes (Sakai, et al., 1996).

### **5.3 Clinical features**

HPV induced oral and pharyngeal cancers are most evident in younger females (<40 years). OSCC (oral squamous cell carcinoma) normally occur on the buccal mucosa (2-10%), lip (4- 40%), alveolar ridge (2-18%) retromolar trigonous (2-6%), hard palate (3-6%), floor of mouth (25%), ventral two third of tongue (50%), alveolar ridge (2-18%), floor of mouth (25%) and oropharynx (25%). Squamous cell carcinoma of the oropharynx most commonly originates in the tonsils and tongue base (the two most common sites), pharyngeal walls, and soft palate.

Fig. 8. Human Papilloma Virus Lesions

### **5.4 Treatment**

88 Global View of HIV Infection

HPV is mainly infectious through expression of oncogenes such as E6/E7 (Al-Bakkal, et al., 1999), which cause phosphorylation of CHK2, leading to caspase activation (Al-Bakkal, et al., 1999, Moody and Laimins, 2009, Tominaga, et al., 1999). The intrinsic apoptotic pathway of caspase activation plays an important role in HPV replication (Moody, et al., 2007). HPV proteins flourish and regulate amplification primarily by caspase activation, leading to immortalization of the suprabasal layer of epithelium, specifically the keratinocytes (Sakai,

HPV induced oral and pharyngeal cancers are most evident in younger females (<40 years). OSCC (oral squamous cell carcinoma) normally occur on the buccal mucosa (2-10%), lip (4- 40%), alveolar ridge (2-18%) retromolar trigonous (2-6%), hard palate (3-6%), floor of mouth (25%), ventral two third of tongue (50%), alveolar ridge (2-18%), floor of mouth (25%) and oropharynx (25%). Squamous cell carcinoma of the oropharynx most commonly originates in the tonsils and tongue base (the two most common sites), pharyngeal walls, and soft

**5.2 Pathogenesis** 

et al., 1996).

palate.

**5.3 Clinical features** 

Fig. 8. Human Papilloma Virus Lesions

Treatment of HPV infection can be achieved either by use of targeted therapy against the virus or immune-stimulating therapy. Most dysplastic tissue can be treated by ablative and excisional therapy. Use of radiochemotherapy in the form of radiation ± cisplatin or cetuximal has shown beneficial results in treatment of oropharyngeal carcinoma. The overall survival rate was 60 % in HPV-positive individuals and 73 % in HPV-negative individuals (Lill, et al.).
