CHAPTER 1
The histopathology of lower genital tract neoplasia

1.1 Introduction

Approximately 1 in 10 female cancers diagnosed worldwide are cancers of the cervix. Except in countries with effective screening programs the incidence has changed little. The discovery of cytologically detectable and anatomically confirmed premalignant phases has successfully shifted the presentation of cervical squamous tumors from the clinical to the preclinical stage; this being associated with dramatic falls in the prevalence of the disease when effective screening is undertaken.

1.2 Terminology

It is critical that the terminologies used for cytologic and histologic diagnosis are comparable so that they can be correlated with the colposcopic findings. In the last 15 years, our understanding of the molecular events associated with lower anogenital tract neoplasia has developed rapidly. In response to this knowledge, the terminology has changed with each new classification system providing a higher degree of sophistication. Gradually the terminology has become more uniform and a histologist's implications and a clinician's inferences have become more reliable. It is imperative that the nomenclature is uniform throughout the world for ease with statistics, although currently there still remain differences in terminologies between the USA and the rest of the world.

The concept of cervical cancer precursors

The concept of cervical cancer precursors dates back to 1886 when Williams noticed, next to invasive cancers, areas of epithelium that he recognized as non-invasive. The term “carcinoma in situ” (CIS) was introduced by Broders in 1932, and this term has been used from its introduction to the present day. Smith and Pemberton in 1934 reported a relationship between CIS and invasive cancer when they found that the changes described as CIS by Broders were present in a retrospective review of biopsies from patients who subsequently developed invasive cancer. This combination of histologic observations and retrospective clinical analysis led to the concept that invasive squamous cell carcinoma develops from precursor lesions that can be identified by the pathologist (Figure 1.1).

Figure 1.1 The concept of cervical cancer precursor progression and human  papillomavirus infection. CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus.

Carcinoma in situ

With the advent of exfoliative cytology it was recognized that not all cervical abnormalities had full-thickness atypical changes as described for CIS. The lesions, which were morphologically less complex than CIS but still contained many cytologic and histologic features of that entity, were recognized to form a broad histologic spectrum, ranging from minimal deviation changes, which closely resembled the normal epithelium, through epithelia with increasingly severe atypia and disorganization to the classical CIS. Reagan and coworkers in 1956 introduced the term “dysplasia” to designate those abnormalities with histologic and cytologic features that were intermediate between normal epithelium and CIS. Following this, Walters and Reagan in 1956 subclassified the dysplasia into three groups—mild, moderate, and severe—depending upon the degree to which full thickness of the epithelium was replaced by the atypical cells. The higher the histologic grade, the more likely the lesion was to progress to invasive cancer and the higher the risk of developing cancer.

Cervical cancer precursors

• Cervical cancer has precursor lesions which can be detected by cytology.
• These precursors can be classified as mild (cervical intraepithelial neoplasia 1/low-grade squamous intraepithelial lesion), moderate (cervical intraepithelial neoplasia 2/high-grade squamous intraepithelial lesion), or severe (cervical intraepithelial neoplasia 3/high-grade squamous intraepithelial lesion).

Terminology and management (Figure 1.2a)

When the terminology was originally proposed and generally accepted, the prevailing clinical management of patients with dysplasia and CIS was that patients with CIS required a hysterectomy to prevent the development of cancer. Women with a histologic diagnosis of dysplasia, whose clinical course was not well understood but could vary from remission to persistence and progression to CIS, were ignored, followed up, or treated by a variety of means, depending upon the clinician's understanding and acceptance of the natural history data. However, the distinction between dysplasia and CIS was frequently based upon poorly defined and arbitrary histologic distinctions. It gradually became clear that the enormous differences in approaches to treatment were the result of the unreliability of the diagnoses because of the high interobserver variability.

Figure 1.2 (a) Diagrammatic representation of the cytologic equivalents of  cervical intraepithelial disease. (b) Normal cervical epithelium. The epithelium is uniform in pattern and cytology. The cells mature progressively as they move toward the surface, the nuclei become pyknotic, and glycogenation occurs. (c) Human papillomavirus infection “alone” (low-grade squamous intraepithelial lesion). There is mild, full-thickness, cellular enlargement and hyperchromasia with karyopyknosis (1), binucleation (2), and a raisin-like nucleus with a surrounding halo (3). In the bottom three cell layers there is variable nuclear and cell size, irregular variable condensed chromatin aggregation, degenerative nucleoplasmic clearing, nucleolar increase, and some visible early koilocytes (4). These features at (4) are typical of regenerative or hyperplastic epithelial layers with some degenerative or poorly preserved features added in (e.g., nuclear clearing). They are not the features of neoplasia. ASCUS, atypical glandular cells of undetermined significance.

Biology and natural history

When patients with dysplasia were followed prospectively, it was noted that some cases regressed, some persisted, and some progressed to CIS. It also became clear that there was an inverse correlation of regression with histologic grade, and a direct correlation of progression with histologic grade. On the basis of these studies, a new term—“cervical intraepithelial neoplasia” (CIN) or squamous intraepithelial lesion (SIL)—was proposed. It was divided into grades 1, 2, and 3, in which CIN1/low-grade SIL (LSIL) corresponded to mild dysplasia, CIN2/high-grade SIL (HSIL) to moderate dysplasia, and CIN3/high-grade SIL(HSIL) corresponded to severe dysplasia and CIS. The concept of a continuum in the process of moving from normal epithelium through epithelial precursor lesions to invasive cancer was subsequently introduced, although this is now being challenged with many regarding CIN1/LSIL as no more than an expression of viral presence (human papillomavirus (HPV)) with minimal neoplastic potential.

The role of human papillomavirus

Over the last two decades through accumulated experimental, molecular, and clinical evidence it has become accepted that HPV is the etiologic agent in the majority of cervical and lower genital tract lesions. The realization has gradually emerged that, although the infections are ubiquitous in the young sexually active population, they are transient, often appearing and disappearing without cytologic abnormality. Persistent infection by high-risk HPV subtype is strongly associated with progression to high-grade lesions and invasion.

Nomenclature of human papillomavirus lesions

Subsequent to the recognition of HPV and its association with cervical dysplasia a plethora of terms such as flat condyloma, condyloma planum, condylomatous atypia, koilocytotic atypia, and warty atypia came into use. Many claimed that the new observation of the cyto-/histologic evidence of HPV infection need not and should not influence the microscopic grading of CIN. All low- and high-risk HPV types are thought to be associated with identical low-grade histology. Conversely, it is not possible to determine the HPV subtype merely by histologic and cytologic observation. The overdiagnosis of CIN1/LSIL in the presence of flat condylomatous HPV changes has also been stressed. The convention has developed to report biopsies as showing HPV atypia without changes of CIN/SIL or HPV atypia and CIN/SIL combined. In reality, there is little disagreement that most mild dysplasias, HPV and CIN1 or HPV alone, and indeed the majority of moderate dysplasias, or HPV and CIN2, either spontaneously regress or stay the same after prolonged follow-up, regardless of the histopathologic segregation.

Human papillomavirus and cervical cancer

• Human papillomavirus (HPV) is one of the main etiologic agents for cervical cancer.
• Both low- and high-risk HPV strains can give rise to low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia 1.
• Only high-risk HPV is responsible for disease progression.

Rationalization of histologic terminology

Low- and high-grade squamous intraepithelial lesions

The practical recognition of the limited reproducibility of cytologic and histologic assessments resulted in a new nomenclature: The Bethesda System (TBS) (National Cancer Institute Workshop, 1992). This...