Multifocal Stromal Invasion in Microinvasive Squamous Cell Carcinoma of the Cervix: How to Measure and Stage these Lesions

Approximately 12% of microinvasive squamous cell carcinomas (MSCC) of the cervix have more than one invasive focus when they first invade the cervical stroma (1). Subsequently these individual buds may coalesce to form a single focus of tumor. Various authors have suggested that lesions characterized by confluence of multiple foci have a worse prognosis than those with a single invasive focus (2), but others hold the opposite view (3). It is unclear how the lateral extent of lesions with multiple invasive foci should be measured to distinguish International Federation of Gynecology and Obstetrics (FIGO) stage Ia1 and Ia2 carcinomas from clinically occult stage Ib disease. In our laboratory we have seen this problem lead to descriptive histologic diagnoses such as “high-grade squamous intraepithelial lesion with multiple foci of microinvasion.” In clinical practice such diagnoses can lead to overtreatment or undertreatment. The 1995 FIGO criteria (4) for MSSC stipulate measurement of the lesion in two dimensions. The depth of invasion of stage Ia2 lesions must not exceed 5 mm and the second dimension, the horizontal spread, must not exceed 7 mm. Larger lesions are staged Ib. The depth of invasion is defined as the distance of the deepest focus of tumor from the epithelial-stromal junction of the adjacent dysplastic epithelium (surface or crypt). If the origin of the invasive focus cannot be seen, the depth of invasion is measured from the basal lamina of the surface epithelium to the deepest focus of invasion (4). The idea of adding a second dimension into the FIGO definition of MSCC was based on findings that a neoplasm that invades 4–5 mm can measure up to 22 mm in width (5,6). The width can be relevant to the prognosis (7–9). However, the FIGO definition provides no detail on how to measure horizontal spread. Measurement of the horizontal extent of a unifocal lesion is straightforward, but unclear if a lesion has multiple invasive foci, which can be located close together or far apart. For example, Singer and Monaghan (10) illustrate a lesion with two foci of MSCC 9 mm apart. Because of the different patterns that may occur with multiple invasive foci, it is necessary to define more precisely how to measure lateral tumor extension. We believe that three patterns of multiple invasive foci should be distinguished according to whether the invasive foci are contiguous with the epithelium from which they originate and whether the maximum horizontal spread can be measured in a single step serial section. In the type I pattern, multiple foci of microinvasion in one or more step-serial sections are contiguous with the surface epithelium (Fig. 1A). The greatest lateral spread of each individual invasive focus should be measured, and these measurements are added to determine the total horizontal spread. The normal tissue separating the different early invasive foci is not measured. In the type II pattern, the origin of the invasion cannot be seen in all of the early invasive foci, but the greatest lateral extension can be seen in one of the step-serial sections (Fig. 1B). In this situation, the breadth of the invasive focus is the distance between the two most lateral foci of invasion, including the normal tissue separating the early invasive foci. The type III pattern shows the same pattern as type II, but the maximum horizontal spread cannot be measured in a single step-serial section. In such lesions the width needs to be measured on all the step-serial sections involved, and the second dimension must be calculated by determining the distances between the sections (Fig. 1C).FIG. 1.: Methods of measuring lateral spread of microinvasive squamous cell carcinoma with multifocal stromal invasion. The dark gray, hatched areas represent noninvasive epithelium and the light gray areas the underlying stroma. The dark areas represent the early invasive foci. (A) (Type I): All invasive foci (1) are contiguous with the epithelium from which they originate. The lateral spread of the foci should be measured and added together to give the total horizontal spread. The intervening normal tissue is not included in the measurement. (B) (Type II): Invasive foci with (1) and without (2) continuity with the epithelium from which they arise are seen. In this case the lateral extension is defined as the maximum distance between the most lateral points of the tumor in the section. The intervening normal tissue is included in the measurement. (C) (Type III): The maximum horizontal spread cannot be measured in a single step-serial section. In such lesions the width is measured across all the step-serial sections involved, and the second dimension is calculated on the basis of the distances between the sections.With squamous cell cervical cancer, the risk of more distant spread, and thus the need for more aggressive treatment, increases with the extent of invasion. Women with larger tumors have a higher risk of lymph node metastases and recurrence than those with smaller tumors. Thus an increasing volume of invasive tumor is associated with an increasing risk of metastasis. Indeed, Burghardt et al. (11–13) suggested that the volume of invasive tumor is the most reliable prognostic factor in MSCC and that there is no risk of metastatic spread for tumors that are <500 mm3, provided that no vascular invasion is seen. Unfortunately, few groups have tested Burghardt's hypothesis (14). In step-serial sections of cone specimens with a unifocal invasive focus, tumor size can be measured in two dimensions in the one section that shows the largest area, and the third dimension can be calculated by counting the number of sections. This method can be applied to lesions with multiple invasive foci but is time consuming and impractical in a busy routine laboratory and is not consistent with the present FIGO rules for measurements in two dimensions. In summary, the growth pattern of stromal invasion should be considered when measuring the width of early invasive squamous cell carcinomas with multiple invasive foci. It is important to evaluate the entire lesion. Lesions with multiple invasive foci taken together measuring more than 7 mm in lateral extension should be classified as stage Ib. In these clinically occult carcinomas, measuring tumor extension in two dimensions should help plan treatment (15).