Human Papillomavirus Case File

Human Papillomavirus Case File

Eugene C.Toy, MD, Cynthia Debord, PHD, Audrey Wanger, PHD, Gilbert Castro, PHD, James D. Kettering, PHD, Donald Briscoe, MD

CASE 30

A 42-year-old woman presents to the physician’s office for a routine gynecologic exam. She is feeling well and has no specific complaints at this visit. While reviewing your records, you see that she has not come in for a Papanicolaou (Pap) smear in approximately 5 years. She admits that she has not come in because she has been feeling fine and didn’t think it was really necessary. She has a history of three pregnancies resulting in three full-term vaginal deliveries of healthy children. She was treated at the age of 22 for Chlamydia. She has never had an abnormal Pap smear. Her social history is notable for a one-pack per day smoking history for the past 25 years. She is divorced from her first husband and is sexually active with a live-in boyfriend for the past 3 years. She has had 7 sexual partners in her lifetime. Her examination today is normal. You perform a Pap smear as part of the examination. The report arrives 10 days later with the diagnosis “high-grade squamous intraepithelial lesion.”

◆ What is the most likely infectious etiology of this lesion?

◆ What specific virus types confer a high-risk of cervical neoplasia?

◆ Where on a cellular level does this organism tend to replicate in benign diseases? In malignancies?

ANSWERS TO CASE 30: HUMAN PAPILLOMAVIRUS

Summary: A 42-year-old woman has high-grade squamous intraepithelial neoplasia on a Pap smear.

◆ Most likely infectious etiology of this lesion: Human papillomavirus (HPV)-related infection.

◆ Specific virus types confer a high risk of cervical neoplasia: HPV types 16 and 18 are most commonly associated with anogenital neoplasias.

◆ Location of replication in benign diseases and malignancies: The site of replication in benign HPV infections occurs in the host neoplasm where the viral DNA remains extrachromosomal. However, in HPV-related malignancies the viral DNA is integrated into the host genome.

CLINICAL CORRELATION

Human papillomavirus (HPV) preferentially infects the squamous epithelium of skin and mucous membranes causing epithelial proliferation and the development of cutaneous warts and genital, oral, and conjunctival papillomas. Although most HPV infections are benign, and most warts or lesions regress spontaneously with time, some HPV viral types have been shown to be linked to cervical and anogenital carcinomas (Table 30-1). Major risk factors for infection and progression to carcinomas include: multiple sexual partners, smoking, and immunosuppression.

Table 30-1

CLINICAL SYNDROMES AND THEIR ASSOCIATED HPV TYPES

APPROACH TO SUSPECTED HPV INFECTION

Objectives

1. Know the characteristics of the HPV.
2. Know the mechanism of infection and strategies for prevention and treatment.

Definitions

Koilocytes: Enlarged keratinocytes with shrunken nuclei.

Poikilocytosis: Presence of perinuclear cytoplasmic vacuolization and nuclear enlargement of epithelial cells.

Papillomas: An epithelial neoplasm producing finger-like projections from the epithelial surface.

Condylomas: Epithelial neoplasm and hyperplasia of the skin, resulting in the formation of a large cauliflower-like mass.

DISCUSSION

Characteristics of HPV That Impact Transmission

HPV is a member of the Papillomaviridae family. Over 100 distinct types of HPV have been identified based on DNA sequence studies. It has circular, double-stranded DNA genome contained within a small, nonenveloped capsid. HPV has a predilection for infecting the squamous epithelium of skin and mucous membranes. HPV is transmitted from person to person by direct contact, sexual intercourse, or via delivery through an infected birth canal. As a nonenveloped virus, HPV is more environmentally resistant to acids, detergents, and desiccation, which allows for transmission via contaminated fomites.

HPV gains entry through breaks in the skin and replicates in the basal cell layer of the epithelium. HPV DNA is replicated, and the viral particles are assembled in the nucleus of epithelial cells with late viral gene expression occurring in the upper layers of differentiated keratinocytes. In benign lesions, such as common skin warts, the viral DNA remains extrachromosomal in the nucleus of the infected epithelial cell. However, more commonly in carcinomas or high-grade intraepithelial lesions viral DNA becomes integrated into the host genome. The viral genome encodes transforming genes, which have been shown to cause the inactivation of proteins that inhibit cellular growth, making infected cells more susceptible to mutation or other factors that may lead to the development of dysplasia and cancer.

HPV DNA, primarily types 16 and 18, has been shown to be present in more than 95 percent of cervical carcinoma specimens. Because of their high occurrence in cervical cancers, these HPV types are considered to be high-risk, whereas HPV types 6 and 11 are considered low-risk and many other HPV types are considered benign. Yet, because many HPV-related infections (even those with types 16 and 18) are benign with lesions that can regress spontaneously, the utility of characterizing specific HPV types in clinical specimens remains to be determined.

Diagnosis

HPV infection presents clinically with the growth of a variety of cutaneous warts and papillomas. Warts result from HPV replication stimulating excessive growth of the epidermal layers above the basal layer (Figure 30-1). The presence of koilocytotic squamous epithelial cells can be detected in a Pap smear. While the use of DNA probes and PCR can be used in diagnosis and in viral serotyping.

Different types of warts (flat, plantar, or common), genital condylomas, and laryngeal papillomas can develop depending on the infecting viral type and the site of infection. Laryngeal papillomas can occur in infants born to mothers with active HPV genital lesions. While rare, these papillomas often require repeated surgical removal. Anogenital warts occur on the squamous epithelium of the external genitalia and anorectum and are most commonly caused by HPV types 6 or 11, however, these lesions rarely undergo malignant transformation. HPV types 16 and 18 are responsible for most cases of cervical intraepithelial neoplasia and cancer. Cervical cancer usually develops after a progression of cellular changes from cellular atypia to low-grade intraepithelial lesion, high-grade intraepithelial lesion and subsequently to carcinoma. Although the mechanisms of host defenses against HPV are not well understood, the immune system, especially cellular immunity, are important in the control of HPV infections. HPV diseases occur more frequently and tend to be more severe in immunocompromised hosts.

Figure 30-1. Schematic representation of a papilloma wart. HPV is incorporated in the basal layer and affects the maturing cells (left) and results in the skin wart or papilloma (right).

Treatment and Prevention

Although many HPV infections are benign with the resulting warts or lesions regressing spontaneously with time, because of the strong association of HPV with cervical carcinomas and transmission via vaginal delivery, physical treatment and removal of lesions is often performed. Physical treatment of warts and other lesions involves local cellular destruction by means of cryotherapy, acid application or electrocautery. Alternatively, immune stimulant therapy is used to promote immunologic clearance of the abnormal cells using either the injection of interferon or topical applications of imiquimod. Cervical cancer usually develops after a progression of cellular changes from cellular atypia to low-grade intraepithelial lesion, high-grade intraepithelial lesion, and subsequently to carcinoma. The introduction of routine screening of women for cervical cancer with Pap smears has resulted in finding more abnormalities in earlier, more treatable stages, and a marked reduction in the death rate from cervical cancer. Most deaths from cervical cancer now occur in women who have not had adequate Pap smear screening. A new qaudrivalent HPV vaccine, Gardasil, was FDA approved in 2006. The vaccine is composed of major capsid proteins assembled into virus-like particles and provides protection against infection with HPV types 6, 11, 16, and 18, which together cause 70 percent of cervical cancers (HPV 16 & 18) and 90 percent of genital warts (HPV 6 & 11). Additionally, infection with HPV can be prevented by avoiding direct contact with infected skin lesions, and by safe sex practices.

COMPREHENSION QUESTIONS

[30.1] Which of the following types of cancers is HPV most commonly associated with?

A. Anogenital

B. Breast

C. Lung

D. Oral

E. Prostate

[30.2] HPV-related cervical intraepithelial neoplasia can be diagnosed by the presence of which of the following histologic features?

A. Central, basophilic intranuclear cellular inclusions

B. Cowdry type A intranuclear cellular inclusions

C. Enlarged multinucleated cells

D. Cytoplasmic vacuolization and nuclear enlargement of cells

E. Numerous atypical lymphocytes

[30.3] Which of the following viral families is known to be causally associated with tumor formation in healthy appearing human adults?

A. Flaviviruses

B. Papovaviruses

C. Paramyxoviruses

D. Polyoma viruses

Answers

[30.1] A. Of the types of cancers listed, HPV is most commonly associated with anogenital carcinomas, which includes cervical carcinomas.

[30.2] D. HPV produces characteristic cytoplasmic vacuolization and nuclear enlargement of squamous epithelial cells, referred to as koilocytosis; answers A, B, C, and E are incorrect: Both Cowdry type A intranuclear inclusions and enlarged multinucleated cells can be seen with herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections; central, basophilic intranuclear inclusion bodies are seen in CMV infections, whereas the presence of atypical lymphocytes is seen specifically in Epstein-Barr virus (EBV) infections.

[30.3] B. HPV is a member of the Papillomaviridae family and is causally associated with cervical cancer in otherwise healthy individuals; answers A, C, D, and E are incorrect: Hepatitis C virus is a member of the flaviviruses family and causes chronic hepatitis and in severe cases is a factor in liver cancer development; paramyxoviruses include agents such as respiratory syncytial virus and measles virus and are not associated with carcinomas; human polyoma viruses include BK and JC viruses, which have been associated with immunocompromised patients, and their role in formation of human tumors is still under investigation.

MICROBIOLOGY PEARLS ❖ HPV has a tropism for squamous epithelium of skin and mucous membranes. ❖ HPV types 16 and 18 are most commonly associated with cervical carcinomas. ❖ Treatment of HPV-related lesions include immunologic agents, cryotherapy, acid application, and electrocautery.

REFERENCES

Bosch FX, Lorincz A, Meijer CJ, et al. The causal relationship between human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244. 

Murray PR, Rosenthal KS, Pfaller MA. Medical Microbiology, 5th ed. St. Louis, MO: Mosby, 2005:523–4. 

Ryan JR, Ray CG. Sherris Medical Microbiology, 4th ed. New York: McGraw-Hill, 2004:617–20. 

National Institute of Allergy and Infectious Disease. Human papillomavirus. www.niaid.nih.gov/factsheets/stdhpv.htm 

National Cancer Institute. About HPV vaccines. www.cancer.gov/cancertopics/ hpv-vaccines

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