Genital Warts (HPV Infection) Causes, Symptoms, Treatment

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Laryngeal Papillomatosis

Laryngeal squamous cell papillomas (LSCPs) are the most frustrating benign lesions in the head and neck region. Because of their clinical specificities, such as multiplicity, recurrence and the propensity to spread to adjacent areas, it has been suggested that LSCPs should be renamed recurrent respiratory papillomatosis (RRP) 34, 89, 91, 187 . Recurrent respiratory papillomatosis is aetiological-ly related to HPV 4, 212, 283, 289, 352 . HPV-6 and -11 are the most frequent genotypes associated with RRP (Fig. 1.4b) 4, 126, 212, 284, 289, 330 . Human papillomavirus transmission in children is associated with perinatal transmission from an infected mother to the child 34, 88, 217 . The mode of HPV infection in adults remains unclear. The reactivation of a latent infection acquired perinatally or a postpar-tum infection with orogenital contacts has been suggested 4, 188 . In contrast to RRP, a solitary keratinising squamous papilloma or papillary keratosis of adults appears not to be...

Schneiderian papillomas

The ectodermally derived ciliated respiratory mucosa that lines the nasal cavity and paranasal sinuses, so-called Schneiderian membrane, gives rise to three morphologically distinct types of papillomas. These are referred to individually as inverted, oncocytic, and exo-phytic papillomas or, collectively, as Schneiderian papillomas. As a group, the Schneiderian papillomas are uncommon, representing only 0.44.7 of all sinonasal tumours 1423 . lnverted papilloma (Schneiderian papilloma, inverted type) A papilloma derived from the Schneiderian membrane in which the epithelium invaginates into and proliferates in the underlying stroma. Inverting papilloma, Schneiderian papil-loma, papillomatosis Inverted papillomas are two to five times more common in males, and are found primarily in the 40-70 year age group. They are distinctly uncommon in children. Table 1.3 Distribution of Schneiderian papillomas Table 1.3 Distribution of Schneiderian papillomas

Squamous Cell Papilloma

Squamous cell papillomas are located in the nasal vestibule and are formed by keratinising stratified squamous epithelium of the skin surface 122 . They are exophytic and consist of a thickened layer of differentiated squa-mous epithelium, without evidence of atypia or mitoses, which is supported by arborescent stalks of fibrovascu-lar stroma. Varying degrees of keratinisation are present and either hyperkeratosis, parakeratosis or both may be seen. They are benign, rarely recur after simple excision. Its main differential diagnosis is the exophytic schneide-rian papilloma.

Vaccination Against Human Papillomavirus

Persistent infection with high-risk type HPV is a necessary cause of cervical cancer and therefore elimination of HPV infection will prevent this cancer (33,34). Furthermore, the majority of infections are cleared by the host's immune system suggesting the vaccination against this agent is feasible. Historically, vaccines have come to represent a highly cost-effective means to reduce the morbidity and mortality of infectious diseases. These facts have driven the rational development of preventative and therapeutic vaccination strategies based on the detailed understanding of the molecular biology of the HPV life cycle. Vaccination could be implemented to prevent infection (prophylactic) or eliminate infection (therapeutic), or optimally by combining both strategies in a preventive and therapeutic vaccine. The preventive vaccines typically elicit neutralizing antibody to interfere with HPV infection. The therapeutic vaccines would be likely to induce a virus-specific cellular immune...

Inflammation on Pap smear

Moderate or severe inflammation should be evaluated with a saline preparation, KOH preparation, and gonorrhea and Chlamydia tests. If the source of infection is found, treatment should be provided, and a repeat Pap smear should be done every 6 to 12 months. If no etiology is found, the Pap smear should be repeated in 6 months.

Management of the Abnormal Pap Smear

Atrophy with inflammation is common in post-menopausal women or in those with estrogen-deficiency states. Atrophy should be treated with vaginal estrogen for 4-6 weeks, then repeat Pap smear. 7. Hyperkeratosis and parakeratosis. Parakeratosis is defined as dense nuclei within a keratin layer. When no nuclei are present, the cells are designated hyperkeratotic. Parakeratosis and hyperkeratosis occur as a reaction to physical, chemical, or inflammatory trauma, and it may clinically appear as leukoplakia. Benign-appearing parakeratosis or hyperkeratosis requires only a repeat Pap test in 6 months. When this finding persists, colposcopy is indicated.

Schneiderian Papilloma Exophytic

Mucous Papillomas

Fig. 1.29 Inverted papilloma A Low magnification showing hyperplastic aggregates of well-demarcated squamous and respiratory epithelium extending throughout the stroma. Note the absence of mucoserous glands. B Papilloma composed partially of hyperplastic, ciliated respiratory epithelium. Note the epithelial transmigration of neutrophils and the delicate basement membrane. C HPV nuclear and cytoplasmic reactivity can be seen in some inverted papillomas, usually in the same nuclei which exhibit features of koilocytic atypia (right). D Inverted papilloma and carcinoma. Note the inverted papilloma on the left and the normal ciliated respiratory epithelium of the sinonasal track in the middle of the illustration. The carcinoma at the right shows both in-situ and invasive components. Fig. 1.30 Oncocytic Schneiderian papilloma. A Note the yellow-tan appearance and fine papillary excrescences in some of the fragments. Close inspection of the cut surface of the fragment in the top center part...

Conjunctival Papilloma

Papillomas are of viral origin (human papillomavirus) and may develop from the bulbar or palpebral conjunctiva. They are benign and do not turn malignant. As in the skin, conjunctival papillomas can occur as branchingpediculate tumors or as broad-based lesions on the surface of the conjunctiva (Fig. 4.22). Papillomas produce a permanent foreign-body sensation that is annoying to the patient, and the entire lesion should be surgically removed. Conjunctival papilloma. Conjunctival papilloma. Fig. 4.22 Broad-based papilloma originating from the surface of the palpebral conjunctiva. Fig. 4.22 Broad-based papilloma originating from the surface of the palpebral conjunctiva.

Genital HPV infection

Almost all strains of genital HPV are oncogenic, whether of high potential (e.g., HPV 16, 18, 31, 33, 34) or low potential (e.g., HPV 6, 11), eventually potentially causing invasive disease such as cervical intraepithelial neoplasia, cervical cancers, genital cutaneous and mucosal squamous cell carcinomas (e.g., Bowen's disease) including penile carcinomas. Cervical cancer is the second or third leading cause of cancer deaths in epidemio-logical studies of adult women 1, 3, 5 . Pap smears are cytological sampling of the cervical mucosa and has been able to detect many cases of invasive HPV and has sampling errors, false positives and false negatives Vaccination against HPV is now FDA approved in the United States with the introduction of the quadrivalent three-dose Gardasil , a vaccine against HPV 6, 11, 16 and 18, approved for prevention in women aged 9-26 years old . The target group for vaccination is young women who may acquire oncogenic strains of HPV through sexual intercourse....

Etiology Human Papillomaviruses

Causality requires a judgment based on scientific evidence from human and experimental studies, as strict causality studies are often not appropriate in humans. Evidence linking certain human papillomavirus (HPV) genotypes to cervical carcinoma is extensive and compelling. More than two decades of research has led to the fulfillment of criteria, as proposed by Hill, to establish a causal link between high risk HPV infection and cervical cancer (Table 1). HPV DNA was first isolated from biopsies of cervical cancer more than 30 years ago (1,2). HPV DNA is detected in 99.7 of cervical carcinomas worldwide. The evidence overwhelmingly demonstrates that persistent high risk HPV infection is a necessary but not sufficient cause of this cancer (3). Harald zur Hausen's group in 1985 first cloned the archetypal and most common high risk HPV genotype, HPV-16, from a cervical cancer (4). A decade later, HPV was officially recognized as a human carcinogen by the World Health Organization (5). HPV...

Sinonasal Papillomas

Sinonasal papillomas may be divided into squamous cell papillomas of the nasal vestibule and schneiderian pap-illomas of the nasal cavity and paranasal sinuses 121 . The first are covered by epithelium of the skin surface. The latter are lined by well-differentiated respiratory epithelium (referred to as the schneiderian membrane) and comprise three histopathological types exophytic, inverted and oncocytic. The histopathological features that clearly differentiate between the three types of sch-neiderian papillomas have been well documented 173 . Human papilloma virus (HPV) types 6 and 11 are involved in the pathogenesis of exophytic papillomas, but not in the other two variants of schneiderian papillomas 35, 89, 128 . All oncocytic papillomas examined have been HPV-negative 35, 128, 221 .

Exophytic Papilloma

Exophytic papilloma, also known as everted or fun-giform papilloma, is a single, warty tumour measuring up to 1.5 cm in diameter, arising most frequently at the nasal septum and only very rarely in the lateral nasal walls or in paranasal sinuses 122 . Males are predominantly affected. Patients tend to be younger than with other types of schneiderian papilloma. Exophytic papillomas are almost always unilateral 54 . No side is preferred and bilaterality is exceptional. The tumour is composed of branching papillary structures, with papillae covered by stratified non-keratinising squamous epithelium, admixed with intermediate or transitional cells and with ciliated respiratory epithelium that contains interspersed mucin-secreting cells. Koilocytosis is not infrequently found in the squamous epithelium. Seromucinous glands are abundantly found when the underlying submucosa is removed. The two main differential diagnoses are inverted papilloma and oncocytic papilloma. Neither the...

Squamous Papilloma

Squamous papilloma is a hyperplastic proliferation of squamous epithelium and is a member of the family of mucocutaneous lesions that includes verrucous vulgaris and condyloma acuminatum. They are thought to be caused by the human papilloma-virus (HPV), a large and growing family of viruses with more than 90 subtypes. No single member of this family is constantly associated with oral papillomas. HPV types 1, 2, 4, 6, 7, 11, 13, 16, 32, 57, 72, and 73 have been identified in oral papillomas and the virus is found in approximately 13 of specimens of normal oral mucosa. The ability to find the virus and identify the subtype may be related to the experience, skill, and tools of the clinician. The virus infects basal keratinocytes, and the portal of entry is created by a breach in the epithelial barrier. It is believed that the virus attaches to cell surface integrins and is internalized by endocytosis of the integrin-virus complex. Viral proteins E6 and E7 disable cellular proteins p53...


Squamous papilloma can occur on the conjunctiva of young children as either a sessile vascular lesion or as a fleshy papilloma-tous mass (Fig. 8.9). It is believed to be induced by human papillomavirus. If a conjunctival papilloma is not responsive to topical corticos-teroids, then surgical excision and conjunctival cryotherapy is prudent. In recalcitrant or multiply recurrent cases, topical mitomycin C, 5 fluo-rouracil, or interferon can be employed. In recurrent cases, oral cimetidine can be of benefit 20 . Fig. 8.9. Conjunctival papilloma Fig. 8.9. Conjunctival papilloma

Inverted Papilloma

Inverted papilloma is the most common type of sch-neiderian papilloma. This lesion occurs almost exclusively in the lateral wall of the nasal cavity and in the paranasal sinuses, although on rare occasions it may also arise on the nasal septum 226 . Grossly, they frequently have a polypoid appearance, but they differ from nasal polyps of the common type by their histological features. Inverted papillomas are composed of invaginat-ing crypts, cords and nests covered by non-keratinising squamous epithelium, which alternates with columnar ciliated respiratory epithelium and with intermediate or transitional epithelium (Fig. 2.4a). This newly formed duct system is similar to the embryonic development of the nasal mucosa 240 . The multilayered epithelium typically contains mucous cells and mucin-filled micro- cysts. The invagination of the mucosa may result in the presence of apparently discontinuous cell masses lying deep to the epithelial surface, but the basement membrane is intact and...

Terminological Problems

Dysplasia is a widely used histological term directly transferred from the uterine cervix to oral and la-ryngeal pathology indicating the architectural disturbance of squamous epithelium accompanied by cytologic atypia it is divided into three groups mild, moderate and severe 381 . Dysplasia has been replaced in the last two decades with new invented classifications, such as keratosis 20, 78 , squamous intraepithelial neoplasia 79 , oral intraepithelial neoplasia 200 , laryngeal intraepithelial neoplasia 122 , etc. to list only the most frequently used terminologies. These classifications contain only additional synonyms for dyspla-sia. They do not enhance our understanding of classification problems, but introduce other confusing terms for clinicians to deal with 20 . The only classification not based on cervical dysplasia or the subsequently introduced cervical intraepithelial system, is the Ljubljana classification of laryngeal SILs. The Ljubljana classification recognises four...

Oral Cavity and Oropharynx

The significance of Candida albicans as a possible aetiological factor of oral leukoplakia (OL) remains disputable 24, 303 , as does the role of HPV in oral carcinogenesis. The involvement of HPV in the initiation and progression of oral neoplasia is still a matter of debate. Different studies have generated conflicting results concerning the prevalence of HPV, ranging from 0 to 90 45, 345, 386 . The discrepancy observed may be related to the varying sensitivity of the methodologies applied for HPV detection and the epidemiologic factors of the patient groups examined. A recent study on 59 oral SCCs showed that the occasional findings of HPV DNA (8.4 ) may be the result of incidental HPV colonisation of the oral mucosa rather than viral infection. In the same study, HPV DNA was detected in 6.6 in the control group of healthy people who matched the subjects with oral SCCs in various clinical parameters. HPVs, therefore, probably play a limited role in the aetiopathogenesis of the...

Replicative Senescence

Pre-senescent cells can be experimentally manipulated to bypass replicative senescence through ectopic expression of certain genes. Expression of hTERT, the catalytic subunit of telomerase is capable of bestowing some but not all primary cells with immortality (29,30). Another mechanism of bypassing this first proliferative barrier is through simultaneous abrogation of the P53 tumor suppressor and retinoblastoma (RB) pathways (28). Expression of viral oncoproteins, such as SV40 large T antigen (31) or human papillomavirus E6 and E7 oncoproteins (32), which bind to and inactivate p53 and RB (33), respectively, offer experimental methods of achieving this dual inactivation.

Differential Diagnosis

Differential diagnosis includes verrucous hyperplasia, well-differentiated SCC, papillary SCC, and squamous papilloma. Lack of atypia helps to rule out the conventional SCC and papillary SCC. The VC also lacks the well-formed, wide papillary fronds of a squamous cell papilloma.

Relevance Of Immunological Response To Orbital Tumors

The same reasoning can be applied to orbital malignant tumors arising later in life. A recent review65 has shown that malignant lymphoma is the most common malignant tumor of the orbit in the population over the age of 60 years, accounting for 24 of cases.65 Malignant lymphoma, particularly the diffuse large-cell lymphoma (DLCL) has been shown to depend from an aberrant hypermutation state whose nature and consequences appear to be very similar to those described elsewhere under the generic term of genomic instability, which can be in part, considered physiologic for lymphocytes belonging to the B-cell lineage.66 Finally, human papilloma virus has been reported in neoplas-tic and nonneoplastic conditions of the external eye,67 as well as its possible relationship with an increased expression of the p53 protein, with consequent prognostic implications, particularly in conjunctival squamous cell carcinoma (CSCC),68 thus demonstrating the potential of the application of molecular...

Squamous cell carcinoma

Nasal Squamous Cell Carcinoma

Reported risk factors have included exposure to nickel, chlorophenols, and textile dust, prior Thorotrast instillation, smoking, and a history or concurrence of sinonasal (Schneiderian) papilloma. Human papillomavirus (HPV) has been found in some cases, especially those associated with inverted Schneiderian papilloma 303 , but a definite etiologic role has not been clearly established. Formaldehyde, despite the results of animal experiments, has not been found to be a definite risk factor in humans 502,1443,1571,2205,2904 . Fig. 1.8 Schneiderian papilloma with keratinization is associated with an area of malignant transformation into a squamous cell carcinoma with severe cytologic atypia. Fig. 1.8 Schneiderian papilloma with keratinization is associated with an area of malignant transformation into a squamous cell carcinoma with severe cytologic atypia. Precursor lesions for sinonasal squa-mous cell carcinomas are considerably less well defined than for oral or laryn-geal carcinomas....

Introduction To Viral Kinetics And Outcome

Periods may be caused by chronic infections. For example, rabies virus may remain silent for 30-100 days after an animal bite before causing sudden disease demanding medical treatment. Other stealth viruses, such as HIV, hepatitis B and C, and papilloma viruses, may bring about a mild ailment initially that may gradually progress to a fatal disease. Patients with chronic infections may seroconvert and have detectable virus even in the presence of antibodies. Others may be persistently infected by a virus, yet never develop symptoms. These carriers may have low levels of virus, which could potentially be transmitted to other individuals despite being below the level of assay detection. An understanding of how the host responds to viral infection aids investigators and health care workers in identifying and treating infection.

Salivary Type Adenomas

Oncocytic papilloma with atypical cells papillary stalks covered by columnar cells with frequent atypical nuclei and onco-cytic cytoplasm-forming microcysts Fig. 2.5. Oncocytic papilloma with atypical cells papillary stalks covered by columnar cells with frequent atypical nuclei and onco-cytic cytoplasm-forming microcysts

Cylindrical Cell Carcinoma

And polystratified masses of cells that give rise quite often to invaginations of the surface epithelium, which at low magnification may mimic inverted papilloma. The tumour cells are commonly cylindrical and have a tendency to form palisade arrangements perpendicular to the underlying basement membrane (Fig. 2.9b). The nuclei are atypical and show increased mitotic activity, as well as abnormal mitotic figures. The pattern of invasion is usually expansive, being characterised by pushing margins with focal infiltration of the stroma. The basement membrane remains in most cases conspicuous, despite stromal infiltration, which should not be regarded as carcinoma in situ. Foci of squamous metaplasia, with transition from cylindrical to squamous epithelium, are not uncommon and when extensive these tumours may be indistinguishable from squamous cell carcinoma. This resulted in denominations such as transitional cell carcinoma and non-keratinising squamous cell carcinoma, which may be...

Project Title Adhesion And Proliferation In Oral Cancer Progression

Summary Oral cancer is characterized by relentless growth and invasion, frequently resulting in distant metastasis. While significant progress has been made in defining the clinical and histopathological characteristics of cancer, the molecular mechanisms of tumor progression remain poorly understood. The major focus of the proposed Program Project is to further define the alterations that occur during the stepwise conversion of normal mucosa to oral dysplasia, and finally to invasive squamous cell carcinoma. The project comprises four interactive research laboratories at the University of California San Francisco. That have considerable experience in defining molecules related to tumor progression, including tumor marked analysis, growth factor and adhesion receptor function, signal transduction, and molecular genetics. Moreover, this group has already initiated approaches to the analysis of the complex issues related to the sequential processes characterizing tumor progression....

Low Grade Adenocarcinomas

Different histological patterns may be recognised papillary, glandular, mucinous, trabecular, cribriform and clear cell. The papillary pattern is characterised by complex papillary fronds lined by bland columnar cells that may occasionally mimic oncocytic (columnar) cell papilloma. Quite similar tumours also develop in the nasopharynx 267 . The glandular pattern may simulate adenoma nevertheless, the presence of closely packed glands, forming back-to-back arrangements, indicates the true malignant nature. Mucinous tumours have to be distinguished from mucoceles and from mucinous adenocarcinoma of intestinal or salivary type 20, 224 . The trabecular pattern may resemble acinic cell carcinoma 200 . The cribriform arrangements have to be distinguished from low-grade salivary duct carcinoma of salivary glands 62 . The clear cell type has to be separated from the salivary-type tumours with clear cells and

Project Title Animal Model Of Proliferative Verrucous Leukoplakia

Human papillomavirus (HPV) is the leading candidate for a role as a viral co-factor in oral cancer. In women, estrogen has been linked to multiple malignancies, including breast, cervical and uterine cancers, but, heretofore, estrogen has not been studied as a possible factor in oral cancer, despite the fact that well-recognized hyperplastic lesions of the oral cavity occur as a result of hormonal changes during pregnancy and puberty. We hypothesize that HPV and estrogen interact in the oral cavity to cause proliferative verrucous leukoplakia, an oral condition, seen predominantly in women, which is associated with a high prevalence of HPV infection and which ultimately eventuates in oral cancer. Interactions between HPV and estrogen in the pathogenesis of cervical cancer have been studied in a specific transgenic mouse model (K14-HPV16), in which a portion of the HPV16 genome is targeted to the progenitor compartment of the epithelium by means of the keratin 14 promoter....

Increasing the sensitivity of ISH

Has been successfully applied to immunohistochemistry and ISH (Adams, 1992 Aigner et al., 1999 Herbst et al., 1998 Niedobitek et al., 1997 Speel et al., 1998 Zaidi et al., 2000 Zehbe et al., 1997). TSA is based on the horseradish peroxidase-catalysed deposition of hapten-labelled tyramide molecules at the site of antibody or probe binding. In the case of ISH, peroxidase usually is brought to the site of hybridisation by employing a hapten-labelled probe, followed by binding of a peroxidase-labelled hapten-specific antibody (Speel et al., 1998). Since any of the reagents employed for probe detection may contribute to background labelling, use of probes directly labelled with peroxidase followed by TSA has been advocated (van de Corput et al., 1998). However, such probes are not widely available yet. Use of biotin-labelled probes and biotinylated tyramide can result in excessive background staining due to the presence of endogenous biotin in many tissues (Niedobitek and Herbst, 1991...

Rates Of Hpvdna Detection And Abnormal Cytology

Younger women have HPV rates up to six to eightfold than that of older women. Prevalence rates range from 12 to 56 in women under 21 years compared with 2-7 in women more than 35 years of age (4,5,16,17). Although, some countries have prevalence rates that begin to rise again after the age of 50 years, the rates do not reach to those of young women (18). Approximately, 50 of adolescents and young women acquire a cervical HPV infection within 5-7 years after initiating sexual intercourse with the highest risk factor being a recent new sexual partner (19). As previously discussed LSIL is the morphological manifestation of cervical HPV infections and high rates of LSIL would therefore be expected in this group. Rates of LSIL range from 2 to 14 (20-22) in adolescents whereas in older women (> 30 years) the rates range from 0.6 to 1 . However, it is important to emphasize that HPV detection in adolescents is most commonly associated with normal cytology. More than three-quarters of...

Cervical Cancer Screening

As discussed earlier, the high rates of HPV and abnormal cytology in adolescents began the movement to screen all sexually active women including young adolescents in the United States (9-11). The guidelines also proposed that once screening was initiated, if three consecutive annual Pap smears were normal, screening intervals could be extended to every 3 years except for high risk women who should be screened annually. All adolescent women who are sexually active are often considered high risk (9) because adolescents have the highest rates of STIs including Neisseria gonorrhoeae and C. trachomatis (3,47,48). The low sensitivity of a single smear fueled the recommendations for early and frequent screening (49). However, new data suggest that even if adolescents are not screened within 3 years after the onset of sexual activity the chances of any HPV progressing to carcinoma-in situ are extremely rare. Whereas, screening and discovering abnormal cytological smears create unnecessary...

Human Immunodeficiency Virus And Cervical Cancer

Human immunodeficiency virus (HIV) is a retrovirus belonging to the lentivirus family and is the causative agent of AIDS. Numerous studies have documented a high prevalence of HPV coinfection (19), with an increase in both latent and symptomatic HPV infection. HIV alters the natural history of HPV infection with decreased regression rates and more rapid progression to high-grade and invasive lesions, resulting in a more aggressive phenotype. High-grade lesions have been associated with both high- and low-risk HPV types, leading to speculation that HIV may increase the oncogenicity of the HR types, and possibly the activity of low-risk types also (20). However, whereas the development of AIDS-related malignancies, such as Kaposi's sarcomas and non-Hodgkin's lymphoma are attributable to immune deficiency, the relation between HIV and cervical cancer remains to be elucidated.

Adenomatoid Hamartoma

Respiratory epithelial adenomatoid hamartoma (or polypoid hamartomas) typically arises within the nasal cavity and paranasal sinuses (see also Chap. 2), but has also been reported in the nasopharynx 199 . Patients are adults with an age range of 24-81 years. The polypoid exophytic hamartomas are rubbery, tan to brown and can reach up to 6 cm in size. They are lined with ciliated respiratory epithelium with mucin-secreting goblet cells. The widely spaced glandular proliferations arise from invagination of the surface epithelium. A thick eosinophilic basement membrane surrounds the glands and surface epithelium. The ample stroma may be oe-dematous and well-vascularised or fibrous with varying amounts of lymphocytes and inflammatory cells (Fig. 6.4). Glandular acinar proliferations may be scant and large cysts may predominate when the fibrous stro-ma predominates 206 . Some nasopharyngeal hamar-tomas include a chondro-osseous component and cysts lined with squamous epithelium. Due to...

Artificial Dna Putting Together The Pieces

PCR and DNA probes have been of great value to the areas of molecular biology, medicine, and biotechnology. Using these tools, scientists can detect the DNA associated with HIV (the virus that causes AIDS), Lyme disease, chlamy-dia, tuberculosis, hepatitis, HPV (human papilloma virus), cystic fibrosis, muscular distrophy, and Huntington's disease.

Clinical Utility of Testing

This syndrome perform monthly self breast examinations and undergo annual clinical breast examinations beginning at age 18 to 20 years. Mammography should ensue at age 25 to 35 years and be conducted every 2 years until age 40, at which time they can follow general population guidelines for breast cancer screening. Annual pelvic examinations and Pap smears should begin in the teens. Surveillance for ovarian cancer is complicated by a lack of efficient screening tools that avoid unnecessary laparo-scopic surgeries, but nevertheless, annual abdominal and transvaginal ultrasound alone or in combination with CA-125 testing is recommended.18 Although these surveillance practices are recommended, there have been no published reports proving their efficacy. Additional studies are needed to determine the appropriate cancer screening modalities in individuals with Peutz-Jeghers syndrome.

Respiratory epithelial adenomatoid hamartoma

Respiratory Epithelial

Additional findings may include inflammatory sinonasal polyps, hyperplasia and or squamous metaplasia of the surface epithelium unrelated to the adeno-matoid proliferation, osseous metaplasia, rare association with inverted type Schneiderian papilloma, and rare association with a solitary fibrous tumour 2766 .

Mechanism of Infection

The pathogenesis of cervical cancer is initiated by HPV infection of the cervical epithelium during sexual intercourse. Virions penetrate the epithelium through microabrasions and invade the basal cells of stratified epithelia of the uterine cervical transformation zone, establishing their genomes as a stable, low copy number of viral episomes (50-100 genomes per cell) in an initial burst of replication (Fig. 3 see Color Fig. 3 (Color Plate 4, following p. 50). HPV life cycle. The pathogenesis of cervical cancer is initiated by HPV infection of the cervical epithelium during sexual intercourse. Virions penetrate the epithelium through microabrasions and invade the basal cells of stratified epithelia. Initiation of replication is facilitated by interaction of E1 with E2. Because the virus replicates using the host machinery, it must force the keratinocytes into S phase, despite signals for terminal differentiation of the squamous epithelium. This is achieved by three viral oncoproteins...

Prophylactic Vaccines

The ultimate expression of medical success is prevention of a disease, and subsequently, its total eradication. It was not until the last case of endemic smallpox occurred in Somalia in 1977, with eradication of the disease declared shortly thereafter that vaccination was recognized as the means to eliminate diseases from the planet. The first mass vaccination strategy to prevent a cancer was the hepatitis B vaccine. Although, it has taken 20 years to demonstrate impact on hepatoma rates, the success of this preventive vaccine is now clear. Because the etiology of cervical cancer is infectious in nature, interfering with HPV infection with a prophylactic vaccine should theoretically prevent development of the disease and potentially achieve total eradication of cervical cancer and other HPV-related cancers. However, prophylaxis does not benefit those with preexisting disease. This is a significant issue because of the considerable burden of HPV infection worldwide. Furthermore, purely...

Invasive Squamous Cell Carcinoma

Cancer, but the results are conflicting. HPV, mainly type 16, has been found in 3-85 of laryngeal cancers 213 . Moreover, HPV DNA has been detected in 12-25 of individuals with a clinically and histologically normal larynx 271, 313 . It appears, therefore, that HPV infection plays little role, if any, in laryngeal carcinogenesis 126, 177, 211, 213 .

Prognosis and predictive factors

Condyloma acuminatum often responds to simple excision or ablation by laser or cryosurgery but appears to carry a higher risk of recurrence than squamous papilloma. Unlike ano-genital condylo-ma, there is no documented risk of malignant transformation, regardless of the presence of high-risk HPV types.

Cyclooxygenase Activity And Expression

Protein kinase D (PKD) is a family of three isozymes, PKD1-3, that have in common with PKC a conserved DAG TPA binding-site. However, PKD is not activated by DAG TPA, and is instead activated downstream of PKC by phosphorylation at activation-loop residues serine 744 748. PKD is involved in the transmission of PKC-dependent cell proliferative and survival signals.46 Interestingly, cell survival signaling by PKD may involve suppression of the JNK signaling pathway through PKD-JNK complex formation.47 A comparison of the inhibitory effects of resveratrol against purified PKD-1 (formerly called PKC j) vs. the PKC isozymes analyzed in Reference 45 determined that the polyphenol is somewhat more potent against PKD-1, and markedly so with respect to the kinase autophosphorylation reaction.48 This suggested that resveratrol inhibition of PKC might be reinforced in cells by coordinate inhibition of the PKC effector PKD. A recent analysis of growth-suppressive effects of resveratrol in the...

Screening for cervical cancer

Regular Pap smears are recommended for all women who are or have been sexually active and who have a cervix. C. Pap smears should be performed at least every 1 to 3 years. Testing is usually discontinued after age 65 in women who have had regular normal screening tests. Women who have had a hysterectomy including removal of the cervix for reasons other than cervical cancer or its precursors do not require Pap testing.

Molecular Basis of Disease

UC tumorigenesis is a multistep process. Papillary UC are thought to arise from areas of urothelial hyperplasia or from urothelial papillomas. Although most papillary tumors are low-grade tumors that have little tendency to progress to invasive tumors, a small proportion are highgrade tumors that have significant potential to progress to invasive UC. Most invasive UC tend to arise through the following sequence of events normal urothelium to dys-plasia to CIS to invasive cancer. Chromosomal instability (CIN) is present in invasive UC and CIS. It is likely that genes that maintain genomic stability are inactivated early during invasive UC tumorigen-esis. CIN drives tumorigenesis and tumor progression by accelerating the mutation rate in tumor cells.13 The genes responsible for CIN in invasive UC are not known, and the role of TP53 inactivation in CIN has been a matter of debate. pTa tumors show no evidence of CIN but, as noted above, tend to be diploid or near-diploid tumors with...

Atypical squamous cells of undetermined significance ASCUS

ASCUS indicates cells with nuclear atypia, but not atypia caused by human papilloma virus (HPV). 2. With a conservative approach to ASCUS smears, the patient is asked to return every 6 months for a repeat Pap smear. The American College of Obstetricians and Gynecologists (ACOG) advises a colposcopic examination if a patient receives two or more ASCUS reports (repeat Pap smears being obtained every 6 months) or if the patient's compliance is uncertain with the original report.

Lowgrade squamous intraepithelial lesions LGSIL

LSIL includes human papilloma virus (HPV) and CIN 1 (or mild dysplasia). Koilocytotic atypia is indicative of HPV. 2. A significant number of LGSIL smears represent processes that will revert spontaneously to normal without therapy. Repeat Pap smears every 4 to 6 months is recommended, with colposcopy being indicated if there is persistence or progression. However, because some women will progress and because of the high rate of false-negative Pap smears, clinicians may perform colposcopy after the initial LGSIL report.

Management of glandular cell abnormalities

When a Pap smear is performed during menstruation, endometrial cells may be present. However, endometrial cells on a Pap smear performed during the second half of the menstrual cycle or in a post-menopausal patient may indicate the presence of polyps, hyperplasia, or endometrial adenocarcinoma. An endometrial biopsy should be considered in these women.

Epidemiology and Demographics

1995,Baggish and Miklos5 performed a meta-analysis of 15 studies with 450 patients in an attempt to more accurately characterize women with vulvar vestibulitis. The typical vulvar vestibulitis patient is white, nulliparous, well-educated, and young. The women have frequently seen multiple clinicians, and have sought treatment for 2 to 3 years before the diagnosis is made. Many are diagnosed with recurrent urinary tract infections, candidal infections, human papillomavirus (HPV), and allergies. An increased rate of prior sexual abuse in these patients has been reported, but is controversial.6,7

Nonmalignant Skin Disease

Viral warts occur in more than 50 of transplant recipients, usually in sun-exposure areas. The causative agent of warts is the Human Papilloma Virus (HPV) of which there are 18 different subtypes. Type 5 may predispose to squamous cell carcinoma of the skin. Warts and skin cancer often appear in the same patient. Genital warts (condyloma acuminata) result from sexual transmission of a Human Papilloma Virus (HPV). The lesions are often resistant to therapy with topical preparation. Further, the lesions may recur after surgical removal, fulguration, cryotherapy, or laser therapy. Both condylomata and cervical neoplasias occur with an increased incidence following transplantation and often appear together in the same patient.

Background Information Epidemiology

Vulval carcinoma occurs most frequently in elderly women, peaking in incidence in the sixth and seventh decades, but with 30 of cases arising in premenopausal women. There are approximately 900 new cases per year in the UK. The American Cancer Society estimates the incidence of vulval cancer in the USA will be 3800 new cases in 2002, with 800 deaths expected. Symptoms of vulval malignancy include a mass, pruritus, pain and discharge. Human papilloma virus (HPV) infection is believed to predispose to malignant transformation in the vulval epithelium. Women presenting with invasive squamous carcinoma often have a history of vulval intraepithelial neoplasia (VIN) with histological evidence of viral infection in the vulval epithelial cells. As with the relationship between cervical intraepithelial neoplasia and invasive cervical carcinoma, there is postulated to be a progression from low grade VIN (dysplasia) to high grade VlN (carcinoma In situ) with eventual development of invasive...

Project Title Hpv And Mrps In Oral Cancer Pathogenesis

Summary The molecular pathogenesis of oral cancer remains poorly understood. A substantial proportion of oral dysplasias and cancers, but not all, are associated with human papillomavirus (HPV) infection. A better understanding of the mechanisms underlying HPV+ and HPV-oral disease incidence and progression is needed to develop new approaches to this highly lethal disease. The focus of this project is on the role of two novel cellular proteins, macrophage inhibitory factor-related protein (MRP)-8 and MRP14 in the pathogenesis of oral cancer. MRP8 and MRP14 are members of the factor-related protein (MRP)-8 and MRP14 in the pathogenesis of oral cancer. MRP8 and MRP14 are members of the S-100 calcium binding protein family. They have been shown to have multiple intracellular and extracellular functions in white blood cells, but their biology in normal and neoplastic oral epithelium has not yet been studied. MRP8 and MRP14 may regulate intracellular calcium levels and play a role in...

Project Title Hpv Genetic Instability Oral Cancer

Summary (Provided by Applicant) Frequent infection with human papillomavirus (HPV) in the oral cavity has been noted in HIV immunocompromised children and adults. HIV-infected individuals are more susceptible to infection with multiple HPV subtypes, including types 16 and 18. These high risk HPVs that are closely associated with development of malignant oral cancer the viral DNA is frequently found in oral cancer cells and tissue. Moreover, transfection of normal human oral keratinocyte (NHOK) cells with cloned high risk HPV genome immortalizes these cells, which can convert to fully transformed cells when exposed to chemical carcinogens. Since (1) the same chemical carcinogens cannot transform NHOK cells and (2) the loss of genomic integrity is the hallmark of neoplastic cells, high risk HPV must play a critical role in the malignant transformation of NHOK cells by disrupting cells' ability to maintain genomic integrity. Genomic integrity is maintained by constant repair of DNA...

Absorption Metabolism and Excretion

Natural interferons produced by human leukocytes, recombinant interferons produced in bacteria, and recombinant interferons conjugated to monomethoxy polyethylene glycol (PEG pegylated interferons) are available in the United States. The various preparations may be administered subcutaneously, intramuscularly, intravenously, or intralesionally (e.g., into genital warts). Natural or recombinant interferons typically achieve peak plasma levels within 4 to 8 hours of subcutaneous

Choroid Plexus Tumors

Neoplasms of the choroid plexus account for approximately 3 of brain tumors in children and are much more common during the first year of life. The majority of these tumors originate in the lateral ventricles (specifically the trigone), but they can occur in the fourth, and rarely the third, ventricle as well. Choroid plexus papillomas are slow-growing tumors and complete resection, possible in the majority of patients, is generally curative. The choroid plexus carcinoma is an anaplastic choroid plexus neoplasm and constitutes approximately 15 of choroid plexus neoplasms. This histology is much more invasive than the papilloma and has propensity for sub-arachnoid metastasis. Long-term survival following complete resection has been well documented but survival following incomplete resection, in spite of the use of either radiation, chemotherapy or both, is infrequent. The role of chemotherapy as an adjuvant therapy is unclear, although several series have documented the utility of...

Histologic Type of Metastases and Immunohistochemical Features

Metastatic cystic tonsillar crypt carcinoma, resembling a branchial cleft cyst. Inset high power view of non-keratinising carcinoma, human papilloma virus type 16 positive Fig. 9.13. Metastatic cystic tonsillar crypt carcinoma, resembling a branchial cleft cyst. Inset high power view of non-keratinising carcinoma, human papilloma virus type 16 positive

Sexually Transmissible Infections

Papilloma External warts Patient may apply podofilox 0.5 solution or gel 2 times a day for 3 days, followed by 4 days of no therapy, for a total of up to 4 cycles, or imiquimod 5 cream at bedtime 3 times a week for up to 16 weeks. Cryotherapy with liquid nitrogen or cryoprobe, repeat every1-2 weeks or podophyllin, repeat weekly or TCA 80-90 , repeat weekly if necessary or surgical removal. Vaginal warts cryotherapy with liquid nitrogen, or TCA 80-90 , or podophyllin 10-25

Tumourassociated antigens

DNA viruses, such as adenoviruses and papovaviruses (e.g. polyoma and SV40), induce cellular transformation in rodents. Other viruses have been implicated in human cancers. Epstein-Barr virus, for example, has been implicated with nasopharyngeal carcinoma, P-cell lymphomas and Hodgkin's lymphoma. Human papilloma virus is linked to most cervical cancers.

Development of the Angiogenic Phenotype in Tumors

Although angiogenesis is essential to both tumor progression and the development of metastases, many of the molecules and mechanisms that are involved in the angiogenic process still have not been elucidated. Recently, in vivo models of carcinogenesis have helped to define better the temporal relationship between development of the angiogenic pheno-type and tumor progression. Three models have been successful in investigating this relationship and involve overexpression of either the SV40 T antigen oncogene under control of the insulin gene promoter in RIP-Tag transgenic mice which develop pancreatic islet cell cancers, the bovine papillomavirus genome in BPV1.69 transgenic mice which develop dermal fibrosarcomas, or the human papillomavirus-16 oncogene under control of the

Of the Surface Epithelium

Metaplastic epithelium, without goblet cells. There is a strong association between HPV and conjunctival papillomas. HPV type 6 11 is the most common HPV type in conjunctival papilloma. The sensitivity of koilocy-tosis as an indicator of HPV in conjunctival papilloma is low 105 . Papillomas are more extensively discussed in Chap. 1.

Gynecologic Procedures

Similar to the general population, routine gynecologic care is an important part of health care maintenance for stable female transplant recipients. Some problems encountered are similar, but some are distinct from the general population. Mucocutaneous herpes infections from herpes simplex virus type 1 or 2 and condylomata acuminata from human papilloma virus are relatively common. Occasionally, extensive disease may warrant systemic antiviral therapy. Surgical resection is occasionally necessary, and this can be undertaken without jeopardy to patient or graft survival. The incidence of cervical dysplasia and or neoplasia is increased among immunosuppressed women, and some authors have suggested an etiologic relationship between the effects of immunosuppression and growth of the human papilloma virus.4 As with other histopathology, an abnormal Papanicolaou smear should be managed aggressively. We recommend a cervical cone biopsy for definitive diagnosis. When indicated hysterectomy...

Multiplex Polymerase Chain Reaction

In a few short years, the polymerase chain reaction (PCR) has had a major impact on how clinical laboratories diagnose infectious diseases. PCR has been used for the diagnosis of infections caused by several noncultivatable viruses including human papillomavirus (HPV), parvovirus B19, and BK JC papovaviruses. Arguably, the greatest impact of PCR has been in the field of retro virology, where it has been used to detect infections in seronegative

Is patient in significant respiratory distress Is there significant respiratory difficulty or increased work of

Is patient hoarse Listen to voice or cry. Lesions that cause significant dysphonia (severe hoarseness) can cause sudden, complete airway obstruction (eg, laryngeal papillomas, exudative infections, aspirated foreign bodies). Recurrent Respiratory Papilloma. Viral lesion with predilection for vocal folds often presents with hoarseness preceding stridor. Can cause sudden, complete airway obstruction. Vascular Ring or Sling. Congenital malformation of major vessels (eg, double aortic arch), causing extrinsic compression of trachea.

Perspectives For The Future

The molecular cell biology of cancer provides avenues for new therapies, but prevention remains crucial and preferable to therapy. Avoidance of obvious carcinogens, in particular cigarette smoke, can significantly reduce the incidence of lung cancer and perhaps other kinds as well. Beyond minimizing exposure to carcinogens such as smoke or sunlight, certain specific approaches are now feasible. New knowledge of the involvement of human papillomavirus 16 in most cases of cervical cancer holds promise for developing a cancer vaccine that will prevent viral action. Antibodies against cell surface markers that distinguish cancer cells are a source of great hope, especially after successes with the clinical use of monoclonal antibodies against human EGF receptor 2 (Her2), a protein involved in some cases of human breast cancer. Further steps must involve medicine and science. Understanding the cell biology of cancer is a critical first step toward prevention and cure, but the next steps...

Tumours of the nasal cavity and paranasal sinuses Introduction

Frontal Sinus Malignancy

Bone changes can give an indication of the aggressiveness of a tumour 2038 . In general, slowly growing lesions, such as Schneiderian papillomas, appear to push bone as they slowly remodel the osseous structure. More aggressive lesions, such as squamous cell carcinoma, can aggressively destroy bony walls leaving only a few remaining fragments 2425 . Occasionally, however, malignant lesions can cause bowing rather than infiltrating destruction of bone 2424 . The integrity of the thin plates of bone in the ethmoid sinus as well as the bony walls of the sphenoid sinus and the bony nasal septum also suggests that malignancy is unlikely. Tumour location plays a significant role in differential diagnosis. Tumours in the region of the cribriform plate and upper nasal cavity suggest diagnoses such as olfactory neuroblastoma or meningioma. Inverted Schneiderian papilloma occurs predominantly along the lateral wall of

Malignant soft tissue tumours

Malignant Neoplasm Definition

Epithelial Invagination Into the tumour can be prominent, simulating an inverted papilloma. Spindle cells are arranged in compact fascicles, intersected by various amounts of delicate thin to dense keloid-like collagen. The cell bundles are arranged at acute angles to one another, occasionally giving rise to a herringbone or chevron pattern, while in most areas there is a more subtle fasciculation. A prominent storiform pattern is not seen. There is a marked variability in the cellu-larity within and between tumours. The cells are fusiform with a centrally placed hyperchromatic, needle-like nucleus surrounded by tapering cytoplasm which is often indistinct, creating a syncytial appearance to the fascicles. Most sinonasal tract fibrosarcomas are low grade. Nuclear pleomorphism is usually slight to moderate, but occasionally prominent. Mitotic figures are found in variable numbers. Haemorrhage and necrosis can be found in the poorly differentiated forms, with areas of myxoid...

Survey of Recombinant Viral Vaccines Currently under Development 6211 Herpes viruses

On a global basis, cervical carcinoma is the second commonest female cancer (after breast cancer). There is a strong body of evidence to support the link between the presence of high-risk human papillomavirus (HPV) strains such as HPV-16 and -18 and cervical cancer (Phillips & Vousden 1998) and an effective anti-HPV vaccine would have an enormous impact worldwide. In 2006, the FDA approved the first preventative HPV vaccine, Gardasil (Merck & Co.), while the similar GlaxoSmithKline HPV vaccine, Cervarix, is expected to be licensed in 2007. Both of these vaccines are recombinant virus-like particles (VLPs) composed of the major capsid protein, L1. L1 contains the major immunodominant neutralisation epitopes of the virus and induces high levels of protective neutralising antibodies. These protect girls and women against the two commonest HPV strains (HPV-16 and -18) implicated in cervical cancer, while Gardasil also targets HPV-6 and -11 which cause most cases of genital warts...

Conditions with excessive numbers of warts

In most patients, immunosurveillance and innate immunity contain HPV infection. Excessive numbers of warts are seen in a variety of genetic and acquired conditions (Tab. 4), and may be associated with an increased local risk of cutaneous oncogenesis. Malignant diseases caused by HPV infection

Potential Applications

In his 1988 review, Tenover stated that the goal of DNA probe technology was to eliminate the need for routine viral, bacterial, and fungal cultures (Tenover, 1988). Although this goal could eventually be reached, the principal advantage of molecular diagnostic methods in current clinical virology laboratories is in the detection of nonculturable agents such as human papilloma virus, human parvovirus, astroviruses, caliciviruses, hepatitis B virus, and hepatitis C virus. Molecular methods are also valuable for detecting viruses that are difficult to culture, including enteric adenoviruses, some coxsackie A viruses, and hantavirus. Indeed, PCR methods played a significant role in confirming the presence of hantavirus in the fatal respiratory disease outbreak in the Four Corners region of the southwestern United States (Centers for Disease Control, 1993), and rapid sequencing methods helped establish that the suspect agent was a new hantavirus. Molecular diversity studies helped...

Exogenous Sphingolipids To Prevent Cancer In Vivo

Sencar mice were treated with dimethylbenz- a -anthracene to induce skin cancer. Topical application of sphingosine, methylsphingosine, and N-acetylsphingosine did not inhibit the development of papillomas, and at high doses, the formation of papillomas was even enhanced.48,49 This was also seen in a follow-up study measuring the efficacy of sphingosine, N-methylsphingosine, and N-acetylsphin-gosine again, the sphingolipids did not change papilloma incidence,50 but both N-methylsphingosine and N-acetylsphingosine increased cancer-free survival. Furthermore, weekly application of sphingosine and N-acetylsphingosine for 10 weeks after treatment with phorbol esters suppressed tumor progression.50

Example of Cervical Cancer Screening

The Pap test, the standard screening test for cervical cancer, has never been studied in an RCT. A large body of consistent observational data, however, supports its effectiveness in reducing mortality from cervical cancer. Both incidence and mortality from cervical cancer have sharply decreased in a number of large populations following the introduction of well-run screening programs.23-26 Reductions in cervical cancer incidence and mortality were proportional to the intensity of screening.22,27 Case-control studies have found that the risk of developing invasive cervical cancer is 3 to 10 times greater in women who have not been screened.28-32 Risk also increases with longer duration following the last normal Pap test, or similarly, with decreasing frequency of screening.33,34 Screening every 2 to 3 years, however, has not been found to increase significantly the risk of finding invasive cervical cancer above the risk expected with annual screening.34,35 The precise sensitivity and...

June Halper Mscn Anp Faan

General healthcare should include regular general checkups by your primary care physician, with assessments appropriate for your age and current symptoms and concerns. Assessment of current symptoms and problems, blood pressure assessment, Pap smears, prostate examination, and tests and examinations appropriate for the person's age are indicated. Table 12.1 summarizes the National Multiple Sclerosis Society's preventive care recommendations for adults with MS.

Nonenzymatic Signal Amplification

Hpv Testing With Well Plates

High or low risk for oncogenic potential. Full-length probes negate the potential for false negatives because SNPs do not inhibit hybridization. The hybrid consists of the viral DNA with the RNA probe. An antibody specific to the DNA RNA hybrid that is attached to the microtiter plate well wall captures this hybrid. Following washing steps, only the hybrid is retained. Another DNA RNA-specific antibody that is conjugated to alkaline phosphatase detects the captured hybrid following addition of a chemiluminescence substrate. A luminometer measures the light produced from the reaction. An advantage to this particular system is that thin prep and autocyte specimens obtained during routine pelvic examination can be used later to identify infectious agents in specimens determined by cytopathologists to be suspicious or indeterminate (29-31). For example, many Pap smears are not clearly normal or dysplastic neoplastic, but are designated ASCUS (atypical squamous cells of unknown...

Prevention and Treatment

Figure 25.18 Genital Warts on the Penis, a Manifestation of Human Papillomavirus Infection Figure 25.18 Genital Warts on the Penis, a Manifestation of Human Papillomavirus Infection Papillomavirus STDs Genital Warts and Cervical Cancer Sexually transmitted human papillomaviruses (HPV) are among the most common of the sexually transmitted disease agents, infecting an estimated 40 million Americans. Although they cannot be cultivated in the laboratory, their presence in human tissues can be studied by using nucleic acid probes. Some of them are responsible for papillomas, warty growths, of the external and internal gentalia others cause non-warty lesions of mucosal surfaces such as the uterine cervix and are a major factor in the development of cervical cancer. Invasive cervical cancer strikes about 12,500 Americans each year and kills more than 4,500 of them. nucleic acid probes, pp. 225,236

Graft Chamber Mice Skin

Continuous human cell line, contains Adl2-SV40. h Papilloma cell lines, contain activated c-rasHa. ' Phenotype dependent on high v-rasHa expression. In addition to histological characterization, graft tumors can be analyzed using a series of markers that are associated with malignant progression of epidermal tumors. Tumors generated from oncogene-transduced grafted mouse keratinocytes have a similar pattern of marker expression as chemically induced mouse skin tumors.98 Specific polyclonal antibodies have been developed which allow in situ localization of protein markers.99 Keratins 1 and 10 are expressed in normal epidermis and well-differentiated papillomas, whereas keratin 13 is expressed during premalignant progression, often in cells that have lost expression of keratins 1 and 10.100 Keratin 8 is expressed only in highly dysplastic papillomas and in squamous carcinomas.100101 Additionally, the 6 34 integrin is a useful marker for the basal compartment which expands during the...

Review The Concepts

Loss of p53 function occurs in the majority of human tumors. Name two ways in which loss of p53 function contributes to a malignant phenotype. Explain the mechanism by which the following agents cause loss of p53 function (a) human papillomavirus and (b) benzo(a)pyrene.

Immunological Response To Cancer

Orbital Tumor

Tumor-specific antigens (TSAs) These substances are unique to cancer cells and cannot be found in their normal counterparts. Shared TSAs found on related tumors from separate individuals include oncoviral antigens expressed on the surfaces of infected cells. Oncogenic viruses found in humans include Epstein-Barr virus (EBV) in Burkitt's lymphoma and nasopharyngeal carcinoma, human T-cell lymphotrophic virus 1 (HTLV-I) in adult T-cell leukemia, human papilloma virus in cervical cancer, hepatitis B virus (HBV) in primary hepatoma, and human herpes virus 8 in Ka-posi sarcoma.

Vitamin A And Cancer In Experimental Animals

As more animal studies were published and studies were broadened to include RA and synthetic retinoids, clearer patterns emerged in laboratory animals.21 Perhaps the earliest, most consistent effects of vitamin A and other retinoids were obtained with the initiation promotion model of skin carcinoma. Painting mice skin with a single dose of a carcinogen, such as DMBA, followed by one or more paintings with a promoter, such as croton oil or TPA, invariably produces many papillomas. Within 5 to 8 months, a few percent of the papillomas develop into carcinomas. Bollag22 showed that intraperitoneally dosing with high amounts of RA (100 mg kg > 300,000 nmol) reduced papilloma volume > 80 relative to controls. In a subsequent study, Bollag23 showed that oral dosing with RA (200 mg kg every 2 weeks) during promotion also reduced the incidence of carcinomas by 67 . These results presaged data, which consistently showed that retinol, retinyl palmitate, RA, and certain synthetic retinoids...

Adolescent Biological Vulnerability

Young age at first intercourse has long been associated with risk for invasive cancer. The risk of invasive cancer increases twofold in women who initiate sexual intercourse under the age of 18 years as compared with those initiating sexual intercourse after 19 years when controlling the number of lifetime sex partners (23). This finding suggests that there is a certain biological vulnerability of the cervix of young women to HPV infection. The adolescent cervix is structurally different from the cervix of adult women (6). It frequently has a mosaic appearance with different cellular components including relatively large areas of columnar and metaplastic squamous epithelium. Although, the adult cervix also contains these components, the predominant cell type in adults is the mature squamous cell. Both columnar and metaplastic squamous cells are vulnerable to HPV probably for a variety of reasons of which thinness of the epithelium may be one factor. Once sexual activity is initiated,...

Natural Histories Of Hpv Lsil And Hsil In Adolescents

For more than a decade, numerous studies have documented the transient nature of HPV infection in young women. Although, up to 50 of adolescents acquire HPV in adolescence approx 90 will clear the infection, (31-33) with 79-90 clearing it within 24 months. Certain HPV types, such as HPV 16, clear more slowly than other high- or low-risk types and new infections are constantly occurring. There is evidence that having multiple types of HPVs also slow clearance (34). Whether this reflects a global defect in the immune response or whether multiple HPV types act synergisti-cally is unclear. The remaining 5-20 of women with persistent infections are at risk for developing HSIL (31,35,36). Rates of regression among older women appear to be less frequent hence, detection of HPV in an older woman (defined as > 30 years) most likely reflects an already persistent infection and an increased risk for HSIL. Actual progression rates of SILs remain unknown because all studies are time-limited. Cox...

Immunosuppression And Cancer

Kaposi sarcoma (which is associated with human herpes virus type 8 (HHV-8)), non-Hodgkin's lymphoma of the Burkitt type (associated with another herpesvirus, the Epstein-Barr virus (EBV)), and conjunctival squamous cell carcinoma (associated with human papilloma virus (HPV)). In some studies, however, HIV AIDS has not been shown to lead to an increase in cervical cancer, which has a known association with HPV infection. This requires further study, as does the apparent lack of certain other cancers that might be expected to be increased in HIV AIDS.8 Within the first 5 years of immunosuppression, 40 of transplant recipients experience premalignant skin tumors such as actinic keratoses and Bowen's disease, as well as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).17 These tumors often have a more aggressive pattern of growth and atypical morphology.18 Sun exposure is a clear risk factor, and the presence of skin cancers or premalignant skin lesions may be a...

Viral Clearance Vs Oncogenic Progression

Although, epidemiological studies show that more than 80 of HPV infections are benign and cleared within 12-18 months (32), a fraction of infections persists and can Premalignant lesions of the cervix are characterized by abnormal cellular or epitheilial architecture in the areas surrounding the junction between the squamous and columnar epithelium (the transformation zone) of the uterine cervix. Nuclear enlargement, hyperchromasia, binucleation, presence of abnormal mitoses, high nuclear to cytoplasm ratios, cytoplasmic clearing (koilocytosis reflecting E4 expression), abnormal epithelial differentiation, increased mitotic activity, and irregular cellular orientation are all typical features of dysplasia. Low-grade SIL (LSILs, previously CIN Grade 1) reflect the pathological changes observed in the cervical epithelium with HPV replication (Fig. 4A see Color Plate 5, following p. 50) (35) and rarely progress to invasive cancer. At this stage, HPV DNA is still episomal. In women who...

Demographics and epidemiology

Warts are a very common illness worldwide. In the United States, children are the most likely targets of the common wart viruses. Warts follow acne and atopic dermatitis in frequency of diagnosis in pediatric dermatology clinics 12, 13 . It is thought that 10-20 of children will at sometime be infected with warts 1, 3, 14 . The peak incidence of disease varies from study to study with some studies showing a peak age grouping of 8-9 years and others pointing to a peak age range between 12 and 18 year olds 1, 14-16 . The incidence of plantar warts has doubled from its incidence in 1968, which was then found in 1.8-2.9 of primary and secondary school children, to currently 4.5 16 . Females and males are equally affected by HPV infections. The leading sites of HPV infection are the extremities, face and body. Hand warts are often transferred to other cutaneous sites including the lips, nose, and face, via autoinoculation. Autoinoculation is generally the route of disease extension or...

Anal squamous cell carcinoma

Epidemiological evidence has suggested that anal cancer may be associated with anal sexual activity. Male homosexual activity and HIV infection are strongly associated with the incidence of anal squa-mous carcinoma. Most specifically, human papillomavirus has been shown to be an important aetiological factor in anal, cervical, vulval, and penile squamous tumours. Ano-genital papillomavirus lesion condylomata

Hpv Biology 21 Structure

Fig. 1 (Color Plate 2, following p. 50). HPV genome organization. Schematic of the human papillomavirus 31 (HPV31) genome showing the arrangement of the major nonstructural and capsid genes along three frames. HPV31 mRNAs were investigated in CIN612 cells containing extrachromosomal HPV31. Four promoters were identified by primer extension, RNase protection, and nuclease 51 and ExoVII analyses (designated P77, P99, P742, and P3320 based on their respective nucleotide start sites). Adapted from reference 18. Fig. 1 (Color Plate 2, following p. 50). HPV genome organization. Schematic of the human papillomavirus 31 (HPV31) genome showing the arrangement of the major nonstructural and capsid genes along three frames. HPV31 mRNAs were investigated in CIN612 cells containing extrachromosomal HPV31. Four promoters were identified by primer extension, RNase protection, and nuclease 51 and ExoVII analyses (designated P77, P99, P742, and P3320 based on their respective nucleotide start sites)....

Chanchroid Causative Agent

Papillomavirus STDs Genital Warts and Cervical Cancer (Table 25.14) 1. Papillomavirus STDs are probably more prevalent than any other kind of STD HPVs are the main cause of abnormal Pap smears in young women.(Figure 25.19) 3. The causative agents, human papillomaviruses, are small DNA viruses that have not been cultivated in the laboratory.


16 of the worldwide incidence of cancer is due to infection. For developed countries, the proportion is 9 , and for developing countries, 21 . Human papillomavirus (HPV) of any type accounts for 82 of cervical cancers in developed countries and 91 in developing countries. The human papillomaviruses occur in 70 different types. The strongest evidence for carcinogeneity is for HPV types 16 and 18. 81 of cases of liver cancer are attributable to chronic infection with hepatitis B or hepatitis C.


Smoking and alcohol abuse are the greatest risk factors for the development of SCCs of the head and neck. Much attention has been paid to the possible role of viral infection, particularly the Epstein-Barr virus (EBV), and the human papillomavirus (HPV), in the pathogenesis of the head and neck carcinoma.

Viral oncogenesis

Approximately 15 of tumours worldwide can be attributed to viruses the majority of these are represented by hepatocellular and cervical carcinoma and are the sequelae of infection by two DNA viruses, the hepatitis B virus and the human papillomavirus respectively. Other viruses directly linked to human tumours include

Suggested Readings

Papilloma iso- or hyperdense, and T1 -isointense and JT2 SI Carcinoma heterogeneous invade parenchyma and cause edema Hydrocephalus Figure 15. Choroid plexus papilloma in the fourth ventricle. Noncommun-icating hydrocephalus with dilation of the temporal horns of the lateral ventricles. (transaxial T1-WI with contrast)

Previous conditions

Mucocutaneous candidiasis, oral hairy leukoplakia, hepatitis, pneumonia, sexually transmitted diseases, and tuberculosis should be sought. Past episodes of varicella-zoster, herpes simplex virus lesions, and opportunistic infections should be assessed. 2. Dates and results of earlier tuberculin skin tests should be obtained. Women should be are asked about dates and results of Pap smears. Previous immunizations and antiretroviral therapy should be documented.

Viral Vaccines

Studies with influenza A and paramyxovirus indicated that immunoprophylaxis requires the generation of an immune response to viral proteins that will protect individuals on exposure to the infecting virus. The proteins inducing such a response are termed 'protective antigens' and, in the main, are represented by surface-located glycoproteins in enveloped viruses and capsid proteins in non-enveloped viruses (Epstein et al. 1993 Tao et al. 2000). Some non-structural proteins have also been found to be protective, such as the NS1 protein of dengue, T antigen of SV40 and Tat and Nef of HIV-1. Currently (2006), 16 viruses are covered by licensed vaccines in the United States. These protect against adenovirus, hepatitis A and B, influenza A and B, Japanese encephalitis virus, measles, mumps, papillomavirus, poliovirus, rabies, rotavirus, rubella, smallpox, varicella and yellow fever. infection is by antibody, with the assistance of MHC Class II-restricted CD4+ helper T-cells (TH). Most of...

P53 In Human Cancers

Are limited to narrow classes of tumors. Some mechanisms e.g human papilloma virus in cervical cancer, may be related to environmental access of the carcinogen, whereas others may reflect the specific differentiated tissue environment e.g. MDM2 amplification in sarcomas and brain tumors (3). Not all potential mechanisms for inactivation of the p53 pathways have been systematically investigated for the majority of tumors.


The role of human papillomavirus (HPV) infection in laryngeal carcinogenesis remains unsolved 2412 . The prevalence of HPV in laryngeal carcinoma varies significantly among various studies, ranging from 0 to 54.1 2517 . Although the overall prevalence of HPV infection found in 9 studies of precursor lesions 97,276,793,853,927,928,1522, 2065,2172 was 12.4 , HPV DNA was detected in a clinically and histologically normal larynx in 12-25 of individuals 1912,2172 . Thus, definite evidence of an etiologic role of HPV in precursor lesions, at least at present, is lacking, and HPV infection in precursor lesions may represent an incidental HPV colonization rather than true infection of the laryngeal mucosa.

P53 Polymorphism

Storey (9) implicated the proline argine polymorphism of the codon 72 of the tumor-suppressor gene p53 in the development of cervical cancer, with the observation that the p53 protein is more efficiently inactivated by the E6 oncoprotein of human papillomavirus in p53 arginine as compared with its proline isoform. These authors further noted that in the United Kingdom, individuals homozygous for the arginine allele were sevenfold more

Wnt Wingless Pathway

Wnt Wingless signaling pathway is involved in various pathological conditions including cancer. Wnt proteins' binding with their transmembrane receptors activate a canonical pathway, which is characterized by accumulation of p-catenin in the cytoplasm and in the nucleus. Activation of the receptors leads to the phosphorylation of the disheveled protein, through its association with AXIN1 and then prevents glycogen synthase kinase 3 from phosphorylating critical substrates, such as p-catenin. Thus, inhibiting its cytoplasm degradation. Excess p-catenin then goes to the nucleus to form an active transcriptional complex with T-cell factor, which activates transcription of target genes including c-myc and cyclin D1. Although, different components of the Wnt-signaling pathway are mutated in human cancer, only a few studies reported mutation of p-catenin and axin 1 in cervical cancer (23,24). However, a recent study (25) suggests that transformation of HPV-expressing human keratinocytes...

P16 and Ki67

The p16 protein plays a key role in controlling cell growth by inhibiting the cyclin-dependent kinase-4 and preventing phosphorylation of pRb, which maintains the Gj checkpoint. Several studies (33,34) have suggested that p16 is overexpressed in CIN and invasive adenocarcinoma as a result from HPV E7-mediated degradation of pRb through an ubiquitin-dependent mechanism. However, studies by methylation-specific polymerase chain reaction in situ showed that neoplastic cells with aberrantly methylated p16 were associated with the loss of p16 protein expression (35). Thus, suggesting that p16 hypermethylation can negate the seemingly protective role of p16 overexpression in response to HPV infection. p16 silencing by aberrant methylation is strongly associated with active tobacco use in squamous cell cervical cancer and highgrade dysplasia (36).


Every year approximately half a million women develop cervical cancer of whom 80 live in poor countries where population-based screening programs are virtually nonexistent. Although, 95 of the patients with precancerous lesions harbor HPV, only a small fraction of the cases eventually progress to invasive cancer. Therefore, HPV infection alone is considered insufficient for the malignant conversion, suggesting the role of other genetic changes in the development of cervical cancer.

Verrucous carcinoma

Vocal Cord Keratosis Histopathology

VC has been related to tobacco smoking. Human Papillomavirus (HPV) genotypes 16 and 18, and rarely 6 and 11, have been identified in some, but not all, VC 250,289,777,1233,1283 . The differential diagnosis of VC includes exophytic SCC, hybrid VC, papillary SCC, keratinizing squamous cell papillo-ma and verruca vulgaris. VC lacks cyto-logical atypia, this distinguishes it from exophytic SCC, hybrid VC and papillary SCC. The pushing margins of VC are smooth, in distinction to the irregular shaped invasive islands of SCC. Papillomas have thin, well-formed papillary fronds, with limited keratinization, as compared to the markedly keratinized papillae of VC. Verruca vulgaris of the larynx 722 characteristically contains layers of parakeratotic squamous cells with large keratohyaline granules, identical to their counterpart on the skin.

The pRb Pathway

The ability of a cancerous cell to break through senescence is governed by mutations affecting the pRb pathway, the p53 pathway, and the activation of Ras. As already discussed, pRb acts as the ultimate inhibitor of the G1 to S transition by binding and converting the E2F transcription factor into a repressor. Hyperphosphorylation of pRb, initially by cyclin D Cdk4 6 and then cyclin E Cdk2, dissociates pRb from E2F, allowing E2F-mediated transcription to occur. The importance of pRb in cancer is documented in hereditary retinoblastoma, which originally defined pRb as a tumor suppressor protein. In hereditary retinoblastoma, patients inherit one wild type and one mutant allele of RB1. The normal allele of RB1 is lost in a somatic cell, leading to the development of an RB1- - tumor. This loss of heterozygosity (LOH) defines the classic tumor suppressors.3 Although mutation of RB1 itself leads mainly to retinoblastoma and some osteosarco-mas, the importance of the pRb pathway to all...

The p53 Pathway

Mutations in the p53 pathway allow cancerous cells to avoid senescence by preventing cell-cycle arrest at the G1 to S and G2 to M transitions. TP53 is a canonical tumor suppressor gene and is subject to LOH in tumors. Germ-line mutation of p53 causes Li Fraumeni syndrome, an early-onset cancer syndrome, resulting in a broad spectrum of tumors, including cancers of the brain, breast, and blood.14 Additionally, Wilm's tumors often have germ-line mutations in TP53. Mutations in TP53 are found in more than 50 of all sporadic tumors, and, in some capacity, p53 appears to be dysregulated in every cancer. p53 functions as a tetrameric transcription factor, promoting the expression of cell-cycle arrest genes and proapo-ptotic genes in response to signals of DNA damage, aberrant growth signaling, heat shock, and other cellular stresses.7 Tumors commonly contain point mutants in the p53 DNA-binding domain, and mutations often result in the abnormal stabilization of p53. Additionally,...


In common with cervical carcinoma, invasive vaginal carcinoma is associated with vaginal intraepithelial neoplasia (VAIN), often induced by exposure to human papilloma virus. The rare clear cell carcinoma, which affects young women, is associated with maternal exposure to diethylstilboestrol.

Somatic genetics

There is some variation in the genetic profile of oral and oropharyngeal SCC that reflects the site-specific impact of various casual agents and differences in clinical presentation. The carcinogens in tobacco smoke, for example, increase the prevalence and spectrum of TP53 mutations 268 . Compared to carcinomas that arise in patients who smoke, carcinomas in patients who have never smoked harbour fewer p53 mutations, disproportionately involve women, typically arise from the oral tongue, and affect very young or very old patients 1351,2258 . For carcinomas of the oropharynx, oncogenic human papillomavirus (HPV), particularly the HPV-16 subtype, is an important causative agent More than 50 of oropharyngeal carcinomas harbour integrated HPV DNA 60,888,1999 . The E6 and E7 viral oncoproteins bind and inactivate the TP53 and retinoblastoma gene products respectively, disengaging two of the more critical pathways involved in cell cycle regulation 2788 . These HPV-positive oropharyngeal...