CASE REVIEW

Microinvasive Carcinoma of the Cervix

Karuna Garg, MD,* Joseph T. Rabban, MD, MPH,* Lee-may Chen, MD, and Charles Zaloudek, MD*

Abstract: Supercially invasive cervical carcinomas only infrequently metastasize to regional lymph nodes or recur. A category of supercially invasive carcinoma termed microinvasive carcinoma has been dened, based on clinicopathologic studies of large numbers of supercially invasive squamous cell carcinomas. A microinvasive carcinoma is one that invades to a depth of 3 mm or less, does not invade lymphovascular spaces, and shows 7 mm or less of horizontal spread. Microinvasive squamous cell carcinoma has such a low risk of metastasis or recurrence, 1% or less, that it can be treated conservatively by a cone biopsy with adequate free margins or with a simple hysterectomy, while more deeply invasive carcinomas are often treated by more radical methods. The category of microinvasive carcinoma is widely accepted for squamous cell carcinomas. It is less accepted for adenocarcinomas because fewer cases have been studied, but the studies that have been reported thus far suggest that microinvasive adenocarcinoma may also be amenable to conservative treatment. Key Words: cervix, microinvasion, microinvasive carcinoma, microinvasive adenocarcinoma (Pathology Case Reviews 2006;11: 121129)

ancer of the cervix is the second most common malignant tumor in women worldwide, with nearly 500,000 new cases in 2002.1 More than 80% of cases occur in less developed countries, where cervix cancer accounts for 15% of cancers in women compared with only 3.6% of female cancers in the United States.1 In developed countries such as the United States, the number of cases has steadily declined over the years due to the widespread use of cytologic screening, which permits detection and eradication of cervical cancer precursors, thereby preventing the development of invasive cervical cancer. Still, the American Cancer Society estimates that 10,370 cases of cervical cancer will be diagnosed in the United States in 2005 and 3710 women will die of the disease.2

The stage at diagnosis is the most important prognostic factor in cervical cancer. Except for the earliest stages, cervical cancer staging is based on clinical ndings. This permits comparisons between patients treated surgically and those who are treated by radiation and never have surgical pathologic staging. The staging system established by the International Federation of Gynecologists and Obstetricians (FIGO) is most widely used,3 although cervical cancer can also be staged using the TNM (tumor, nodes, metastases) system. The FIGO staging system divides invasive tumors into 4 stages. Stage I tumors are conned to the cervix, while tumors in stages IIIV extend beyond the cervix (Table 1). In North America, about 60% of patients are diagnosed in stage I, 25% in stage II, 10% in stage III, and 5% in stage IV. An increasing percentage (about 15% overall but up to 40% in some recent reports) of women with stage I cervical cancer have small supercially invasive tumors that have a low risk of recurrence or metastasis. Pathologists and gynecologic oncologists have worked together to develop reproducible and widely accepted criteria that will identify a prognostically favorable category of patients with early cervical cancer who can be treated conservatively. Supercial prognostically favorable cervical cancers are termed microinvasive cervical carcinomas. Most studies of microinvasive carcinoma of the cervix have dealt with squamous cell carcinoma. Microinvasive adenocarcinoma can be identied using the same diagnostic criteria as are used for microinvasive squamous cell carcinoma. Too few studies of supercial adenocarcinomas have been conducted to know for certain whether microinvasive adenocarcinoma is a clinically favorable category that can be treated conservatively, although the preliminary data are promising. In this report, we discuss criteria for the diagnosis of microinvasive carcinoma, its pathologic features, and its clinical signicance.

CASE REPORT
A 34-year-old, gravida 3, para 0 had an abnormal Papanicolaou test. The cytologic diagnosis was a high-grade squamous intraepithelial lesion (SIL). A colposcopic biopsy conrmed the diagnosis of high-grade SIL and the patient had a LEEP excision several months after the initial abnormal cytology diagnosis. Microscopic evaluation showed highgrade SIL characterized by full-thickness replacement of the surface epithelium by atypical squamous cells with enlarged, hyperchromatic nuclei and an increased nucleus to cytoplasm ratio. There were frequent mitotic gures, including some in the upper third of the surface epithelium. The SIL extended into the endocervical glands (Fig. 1A). There was a single

From the *Department of Pathology and Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California. Reprints: Charles Zaloudek, MD, Department of Pathology, Box 0102, University of California, San Francisco, 505 Parnassus Ave., M563, San Francisco, CA 94143. E-mail: charles.zaloudek@ucsf.edu. Copyright 2006 by Lippincott Williams & Wilkins ISSN: 1082-9784/06/1103-0121 DOI: 10.1097/01.pcr.0000217874.66523.cb

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TABLE 1. FIGO Staging of Cervical Carcinoma

Stage I Stage IA Cervical carcinoma conned to uterus Invasive carcinoma diagnosed only by microscopy. All macroscopically visible lesions, even with supercial invasion, are stage IB. Stromal invasion with a maximal depth of 5.0 mm and a horizontal spread of 7.0 mm or less. Vascular space involvement, venous or lymphatic, does not affect classication. Stromal invasion 3.0 mm or less in depth and 7.0 mm or less in horizontal spread Stromal invasion more than 3.0 mm and not more than 5.0 mm with a horizontal spread 7.0 mm or less Clinically visible lesion conned to the cervix or microscopic lesion greater than IA2 Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina Tumor extends to pelvic wall and/or involves lower third of vagina and/or causes hydronephrosis or nonfunctioning kidney Tumor invades mucosa of bladder or rectum and/or extends beyond true pelvis; distant metastasis

Stage IA1 Stage IA2 Stage IB Stage II Stage III

Stage IV

FIGO indicates Fdration Internationale de Gyncologie et dObsttrique.

focus of invasive squamous cell carcinoma in which small irregular nests and rounded buds of malignant cells inltrated inamed edematous stroma (Fig. 1B). The carcinoma cells varied from basaloid with scanty cytoplasm to medium-sized cells with eosinophilic keratinized cytoplasm and vesicular nuclei (Fig. 1C). A few keratin pearls were present in the nests. It was unclear whether the invasive carcinoma originated from the surface or the glands, so the depth of invasion, 1.6 mm, was measured from the basal lamina of the surface epithelium to the point of deepest invasion. The horizontal spread was only 1.0 mm, and there was no lymphovascular space invasion (LVSI). The margins of the LEEP excision were free of invasive carcinoma and of high-grade SIL. The diagnosis was microinvasive squamous cell carcinoma arising in a background of high-grade SIL. The patient underwent denitive therapy by cold knife conization of the cervix 2 months later, at which time no residual invasive carcinoma or SIL was identied. An acetowhite area was identied on the cervix at a follow-up examination 6 months later. A biopsy showed mild squamous atypia but no SIL or invasive carcinoma. She remains free of residual or recurrent disease 3 years later.

What Is Microinvasive Carcinoma?

A universally agreed-on denition of microinvasive carcinoma of the cervix has been elusive. There have been competing denitions over the years. For example, in the United States microinvasive carcinoma has been dened as a carcinoma showing supercial invasion to a depth of 1 mm or less,4 as one invasive to 3 mm or less,5,6 and as one invasive to 5 mm or less.79 Some denitions have excluded supercially invasive carcinomas with LVSI, while others have included them.7 In Europe, denitions involving measurements in more than 1 dimension have been favored. Burghardt and Holzer10 meticulously sectioned and measured small cervical carcinomas in 3 dimensions and determined that tumors with

a volume of less than 500 mm3 have little risk of lymph node metastasis or recurrence. Complicated tissue processing systems are difcult to apply in the standard pathology laboratory. Recognizing this, FIGO has included a measurement of tumor length in its denition of early invasive cervical cancer, along with measurement of the depth, as a practical method of accounting for tumor size. The problem of dening microinvasive carcinoma has been largely settled in the United States, as most clinicians determine treatment of their patients based on the denition of microinvasive carcinoma put forward by the Society of Gynecologic Oncologists (SGO). The SGO dened a microinvasive carcinoma as one that invades the stroma to a depth of no more than 3.0 mm and that does not invade lymphovascular spaces (Table 2). The FIGO classication of stage I cervical cancer (a cancer that is limited to the cervix) has evolved over the years, but the current classication includes a category that is similar, but not identical, to the SGO denition of microinvasive carcinoma (Table 1). In the FIGO staging system, cancers that invade to a depth of 5 mm or less and that have 7 mm or less of horizontal spread are staged as IA. The most recent modication of the FIGO staging system altered the denition of stage IA1. Formerly, this stage included tumors showing only early stromal invasion, which, from a practical point of view, meant invasion of 1 mm or less. The revised denition of stage IA1 includes all cancers that invade to a depth of 3 mm or less, the same maximum depth that the SGO uses to dene microinvasive carcinoma. The FIGO denition differs in that there is a limit on the maximum amount of horizontal spread allowed (7 mm) and there is no assessment of the presence or absence of LVSI. Thus, a cancer with LVSI can still meet FIGO criteria for stage IA1 but not meet the SGO criteria for microinvasive carcinoma. A less likely possibility is that a carcinoma with considerable horizontal spread could meet the SGO criteria for microinvasion but not fall into FIGO stage IA1. FIGO stage IA2 includes supercially invasive cancers that invade to a depth of 3.1 mm to 5.0 mm. Any tumor that is clinically visible is by denition FIGO stage IB. Microscopic tumors that invade to a depth of more than 5 mm or that have horizontal spread of greater than 7 mm are also staged as IB. Our practice is to include the depth of invasion, the length of horizontal spread, and a comment as to whether or not LVSI is present in the pathology report. We also state whether the margins are free of invasive carcinoma and SIL, and, if they are, we measure and report the distance from the edge of the neoplasia to the margin. We provide the FIGO stage, but we use the SGO denition with a slight modication to decide whether or not to call a supercially invasive carcinoma microinvasive. Our modication is to use the FIGO maximum length classication as an additional criterion for microinvasive carcinoma. If the depth of invasion is 3 mm or less, the horizontal spread is 7 mm or less, there is no LVSI and the margins are free our diagnosis is microinvasive carcinoma (Table 3).

Pathology of Microinvasive Carcinoma

Microinvasive carcinoma (when we use this term we refer to squamous cell carcinoma unless otherwise indicated)
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FIGURE 1. a, High-grade SIL involves the surface and extends into glands. A small focus of invasive squamous cell carcinoma is in the cervical stroma between 2 glands. The depth of invasion, 1.6 mm, was measured from the basal lamina of the surface epithelium to the maximum depth of stromal invasion. b, The microinvasive carcinoma grows as large irregular nests and small round buds of malignant cells. The stroma contains many chronic inflammatory cells. c, Some cells in the invasive nests are basaloid, with dark nuclei and scanty cytoplasm. Others are keratinized and have abundant eosinophilic cytoplasm, more open vesicular nuclei, and prominent nucleoli. The keratinized cells form several pearls. d, This microinvasive squamous cell carcinoma arises in a background of extensive highgrade SIL, involving the surface and filling many endocervical glands. e, Comparison of cellular morphology in high-grade SIL (left panel) and early stromal invasion (right panel). In the early stromal invasion, the tumor cells have larger vesicular nuclei, and the tumor cells have more cytoplasm. f, Early stromal invasion. Compared with the cells in the SIL from which they arise, the invasive carcinoma cells have more abundant eosinophilic (pink) cytoplasm and larger, more open nuclei. g, Microinvasive squamous cell carcinoma. Nests of keratinized cells with central pearls invade desmoplastic inflamed stroma. h, Lymphovascular space invasion. A rounded nest of carcinoma cells is within a lymphatic space. Note the flattened endothelial cells that line the space. A vein is present at bottom; it has a thicker wall due to the presence of smooth muscle cells.

usually arises from abnormal epithelium involved by a SIL. The SIL is generally high grade, but rare cases arise from low-grade SIL caused by a high-risk HPV type. Stromal invasion only rarely arises from a small focus of high-grade SIL. It is most likely to be found when there is extensive high-grade SIL involving the surface epithelium and extending into the underlying endocervical glands; the endocervical gland involvement is often extensive (Fig. 1D).11 Invasion can originate from the surface epithelium or from a gland
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involved by SIL. In early stromal invasion, the ndings range from 1 or more tiny buds of carcinoma cells that barely invade the adjacent stroma to larger tongues of malignant cells that invade up to 1 mm. Sometimes multiple small invasive foci are present. The earliest forms of microinvasion consist of small rounded or irregular ngers or nests of malignant cells that push just beyond the basement membrane into the stroma (Fig. 1E). Small foci of invasion can be difcult to identify as they may contain only 10 20 cells in

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TABLE 2. SGO Criteria for the Diagnosis of Microinvasive Carcinoma

Depth of invasion 3 mm or less No lymphovascular space invasion
SGO indicates Society of Gynecologic Oncologists.

TABLE 3. Criteria for Microinvasive Carcinoma Used at University of California, San Francisco
Depth of invasion 3 mm or less Horizontal spread 7 mm or less No lymphovascular space invasion Margins free of invasive carcinoma and high-grade SIL
SIL indicates squamous intraepithelial lesion.

rounded or irregular protrusions into the stroma. In one review, 4.8% of cases of high-grade SIL were reinterpreted as showing early stromal invasion,12 and in another study, 4.7% of women initially thought to have SIL proved to have invasion.13 As the invasive foci enlarge, they tend to develop irregular scalloped borders or form small round or irregular nests in the stroma that appear separated from the epithelium from which they originated. The cells in invasive foci can be basaloid, with hyperchromatic nuclei, inconspicuous nucleoli, and scanty cytoplasm, similar to high-grade SIL cells. More often, however, the malignant cells are somewhat different from high-grade SIL cells (Fig. 1E). They may be keratinized, with abundant eosinophilic cytoplasm and large vesicular nuclei that are more pleomorphic than SIL nuclei (Fig. 1F). The nuclei often contain prominent nucleoli. An abrupt change in tumor cell morphology from dark basaloid SIL cells to larger keratinized cells with eosinophilic cytoplasm (pink cells), vesicular nuclei, and prominent nucleoli is a reliable marker of invasion. The stroma is frequently edematous and inamed at sites of invasion (Fig. 1B). A desmoplastic stromal reaction is often present around nests of invasive carcinoma, but stromal desmoplasia is less conspicuous at sites of early stromal invasion than it is around more deeply invasive nests of malignant cells. Early stromal invasion is most likely to be found in the transformation zone (about 90%), and, in one study, invasion originated from the surface epithelium in about 50% of cases and from endocervical glands involved by SIL in the other 50%.14 As invasion progresses beyond its earliest stages, the tumor cells grow in a variety of patterns. Supercially invasive tumors exhibit the same invasive growth patterns that are seen in more advanced squamous cell carcinomas. Thus, the most common nding is that of irregular tongue-like inltrative nests of keratinized cells invading a desmoplastic, inamed stroma (Fig. 1G). Invasive cancers sometimes seem to spray into the stroma as irregularly distributed small nests or cords of tumor cells. An inltrative SIL-like pattern is occasionally noted. In this pattern, elongated or rounded nests of basaloid tumor cells grow in the stroma. These nests differ from crypts involved by high-grade SIL in that they lack

peripheral palisading of the neoplastic cells, the cells exhibit greater nuclear atypia and mitotic activity than is seen in SIL, some of the nests have a scalloped or ragged inltrative margin, and the nests may contain necrotic debris. The irregular periphery of nests of invasive malignant cells contrasts with the smooth contour of glands involved by SIL. Some cancers grow as sheets or interconnecting ridges or trabeculae of tumor cells greater than 1 mm in maximum dimension, a pattern that has been termed conuent growth. Fibrovascular cores within sheets of tumor cells suggest this pattern of invasion. A potential diagnostic pitfall in the diagnosis of microinvasive carcinoma is the misinterpretation of misplaced benign or dysplastic epithelium as invasive cancer. Conization, biopsy, and obstetric procedures occasionally introduce nests of benign or dysplastic squamous epithelium into the cervical stroma. With healing, these nests become surrounded by stroma, and may be misinterpreted as foci of microinvasive carcinoma. In contrast to microinvasive carcinoma, misplaced epithelial nests are composed of bland keratinized cells. There is no nuclear atypia or mitotic activity and no desmoplastic stromal response surrounds the nests of benign epithelium. Introduction of dysplastic epithelium into the stroma or even into lymphovascular spaces is possible after biopsy, although it is rare. Clues to the correct diagnosis include a history of recent biopsy, stromal hemorrhage or hemosiderosis, and a histiocytic or giant cell reaction in the stroma. Misplaced dysplastic cells lack the nuclear and cytoplasmic features of carcinoma cells, and other nests of invasive cells are not present in the area. The introduction of dysplastic cells into lymphovascular spaces by biopsy or injection of an anesthetic is rare, although it has been reported.15 Our policy is to diagnose LVSI by microinvasive carcinoma only when cancer cells are identied in the stroma, as well as in lymphovascular spaces. This prevents the overdiagnosis of an artifact as invasive carcinoma. Any time atypical cells are found in a vascular space, a thorough search for invasion is necessary, including processing of all tissue and evaluation of level sections as indicated. Misdiagnosis of microinvasive carcinoma can have serious implications, as it can result in incorrect treatment. Obviously, accurate measurement of the depth of invasion and the lateral extent is crucial. These measurements are best made with an ocular micrometer. A less accurate but still acceptable alternative, except in borderline cases, is to use a handheld magnifying micrometer. We do not advocate use of a ruler or a measuring scale of the type that is present on some microscope stages; these are not sufciently precise for accurate measurement, except of the most obvious cases. The depth of invasion is measured from the epithelial-stromal junction at the site of origin to the deepest point of invasion. If the carcinoma originates from the surface, the measurement is from the basement membrane of the surface epithelium overlying the invasive focus. When invasive carcinoma arises from an endocervical gland, the length of invasion is measured from the basement membrane of the gland to the point of maximal invasion. If the invasive carcinoma is not in continuity with the surface or the gland from which it origi 2006 Lippincott Williams & Wilkins

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nated and the site of origin is not clear, the depth should be measured vertically from the basement membrane of the surface epithelium to the point of deepest invasion, as was done in our case. If the surface is ulcerated, the measurement is from the surface overlying the invasive carcinoma to the point of deepest invasion; in this setting, the depth of invasion is equivalent to the thickness of the tumor. The lateral extent is the horizontal distance between one lateral edge of the invasive carcinoma and the other. Measurement of the lateral extent is straightforward when there is only a single focus of invasion. The measurement is more complicated in the 12% of cases in which 2 or more foci of invasive carcinoma are present.14 The proper method for measuring lateral extent in cases with multiple foci of invasion is not dened in staging manuals. We suspect that many pathologists measure from the lateral edge of one invasive focus to the opposite lateral edge of the most distant focus of invasive carcinoma. Reich and Pickel16 suggest that if each focus of invasion is in continuity with the epithelium from which it arose, the lateral extent of each focus should be measured and the values added to obtain a total lateral extent. On the other hand, if some foci of invasive carcinoma are entirely within the stroma and the site of origin cannot be clearly identied for each invasive focus, the pathologist should measure the distance between the lateral edges of the 2 most widely separated foci, even though invasive carcinoma may not ll the entire span. In our laboratory, we consider an optimally processed cone biopsy to be one that has been received unxed, permitting the pathologist to open the cone and pin it out. It is then serially sectioned after xation. The pathologist can measure horizontal spread on the microscopic slide (1 dimension) and can calculate lateral spread in a second dimension by counting the number of consecutive blocks involved by invasive carcinoma and multiplying the number of positive blocks by the thickness of the tissue slices. This provides another, albeit less accurate, measure of horizontal spread. We prefer not to x unopened cone biopsies prior to processing them because sections prepared from such specimens often have orientation problems. However, gynecologists sometimes submit unopened specimens in formalin, and they are completely xed by the time they arrive in the pathology laboratory. Such specimens can be serially sectioned, thus providing the opportunity to count the number of consecutive blocks that contain invasive carcinoma and permitting the pathologist to roughly determine horizontal spread through the cone as well as more accurately measuring the length of the invasive carcinoma on a single slide. LVSI does not have a bearing on the FIGO stage, but its presence or absence is crucial in determining whether or not a supercially invasive carcinoma qualies as microinvasive carcinoma under the SGO denition. The presence of true LVSI is of great clinical importance since even early stromal invasion may be treated by radical hysterectomy with pelvic lymph node dissection if LVSI is present. The greater the depth of invasion, the more likely the pathologist will identify LVSI. LVSI is diagnosed when the pathologist identies nests or balls of tumor cells within vascular spaces (Fig. 1H). The presence of
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a layer of attened endothelial cells helps the pathologist identify lymphovascular spaces, but an endothelial lining is not always visible, and, to complicate the problem, perivascular broblasts are easily confused with endothelial cells. It is usually not possible to determine whether a small vascular space is a lymphatic or vascular channel; hence, the designation as a lymphovascular space. Red blood cells are occasionally identied in the spaces and suggest that the channel is a blood capillary or a small vein. Pathologists occasionally use immunohistochemical stains for endothelial markers to try to conrm the vascular nature of spaces that contain tumor cells, but we do not advocate this. Immunohistochemical staining delays the diagnosis and is expensive. The main problem, however, is that we nd that it is frequently unsuccessful. The focus in question may no longer be present on a deeper section prepared for immunohistochemistry, the endothelial cells may be too attenuated to stain convincingly or they may have been eroded. We make every effort to determine whether vascular invasion is present on routine H&E-stained sections and rarely resort to the use of immunohistochemical stains for this purpose. LVSI can be difcult to identify with certainty because it is easily confused with a more common nding, artifactual tissue retraction around nests of invasive tumor cells. This problem is not unique to the cervix; it occurs in other anatomic sites as well and is a particular problem in breast pathology. To avoid errors, we concentrate our search for LVSI at the periphery of the tumor, where tissue retraction artifacts are less frequent. Multiple nests of tumor cells surrounded by clear spaces likely represent tissue retraction artifacts since permeation of multiple lymphovascular spaces is unlikely in a supercially invasive carcinoma. A diagnosis of microinvasive carcinoma is appropriate only when the entire tumor can be evaluated. Thus, microinvasive carcinoma cannot be diagnosed in a punch biopsy, nor is the diagnosis appropriate when invasive carcinoma or high-grade SIL extends to the margin of a LEEP excision or cone. Study of a subsequent therapeutic resection specimen might reveal more deeply invasive carcinoma in adjacent tissues.9 In addition to making a denitive diagnosis of microinvasive carcinoma, it is important for the pathologist to make an accurate determination of the status of the excision margins in a patient with microinvasive carcinoma. The pathologist should measure the distance from the edge of the carcinoma to the margins of the cone and provide similar information about the high-grade SIL that is also likely to be present. This information helps the surgeon decide whether the conization might be complete treatment or whether a repeat cone or a hysterectomy is necessary. Inadequate margins increase the risk of recurrence and eventual metastasis.

Clinical Features
Microinvasive carcinoma is most common in women 35 45 years of age, about 10 years older than the average patient with SIL and about 10 years younger than the average woman with overt invasive carcinoma.17 Patients with microinvasive carcinoma are usually asymptomatic, and the carcinoma is typically discovered during workup for an abnormal Papanicolaou test. Subtle cytologic features suggest the possibility of microinvasion in a minority of cases.18,19 These

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include increased or keratinized cytoplasm, increased nuclear atypia and pleomorphism, and conspicuous nucleoli in the atypical cells. An occasional patient presents with abnormal bleeding or a discharge.17 Generally, no abnormality is clinically visible on the cervix, and most patients are thought to have SIL until invasion is discovered in a biopsy.19 Colposcopists sometimes suspect microinvasion if there is a sufciently abnormal vascular pattern, but accurate colposcopic detection requires considerable skill and appears to be possible only when the depth of invasion exceeds 1 mm. 20,21 Prognostic factors in early cervical carcinoma include the depth of stromal invasion, the presence or absence of LVSI, the volume or lateral extent of the tumor, and the status of the excision margins. Analysis of these factors has led to the delineation of a category of patients who have minimal risk of lymph node metastasis or recurrence and who can be treated conservatively. The depth of stromal invasion is a major factor in determining the outcome of patients with early cervical cancer. Lymph node metastasis is the single most important predictor of long-term outcome in patients with early cervical cancer, and there is a clear relationship between the depth of stromal invasion and the presence of lymph node metastasis. Lymph node metastasis is exceptional when the depth of stromal invasion is 1 mm or less,4,12 and when the depth of stromal invasion is 3 mm or less the risk of lymph node metastasis is only about 1%.2225 When the depth of invasion is 3 mm or less, the risk of lymph node metastasis is sufciently low that routine pelvic lymph node dissection is not necessary.22,26 28 The risk of recurrence in such patients is less than 1%.22,29 31 Nevertheless, the nding of only minimal stromal invasion is not an absolute guarantee that lymph node metastasis will not occur, and rare patients with invasion of 1 mm or less develop widespread metastases.32 The risk of lymph node metastasis is 6% 8% in patients whose tumors invade to a depth of 3 to 5 mm.22,23,27,33 Such patients have a 3% 6% risk of recurrence after treatment33,34; they are often treated by radical surgery with lymph node dissection.35 More conservative therapy is possible in selected patients, such as those with no evidence of LVSI or conuent growth.36 Tumors that invade 35 mm are not included in the category of microinvasive carcinoma, although they fall into FIGO stage IA2. When reviewing clinical studies of supercially invasive cervical cancers, it is important to carefully evaluate what authors deem to be a recurrence. For example, in one large study, 1 patient was reported to have persistent carcinoma and 7 to have had recurrences. However, 2 recurrences were as high-grade SIL, and in 5 women with invasive recurrences in the vaginal vault, the invasive carcinoma was adjacent to high-grade SIL. 17 Thus, these recurrences might well have been second primary foci, rather than true recurrences. The signicance of LVSI in microinvasive carcinoma has been a controversial issue. In general, the frequency of LVSI increases with increasing tumor depth and size.37 LVSI is found in up to 10% of carcinomas with less than 1 mm of stromal invasion and 10%30% of tumors that invade 13 mm.9,23,30,31 Some authors have found LVSI to be a risk factor for lymph node

metastasis,6,38 while others have shown no such relationship.7 Small carcinomas have a low risk of lymph node metastasis, even in the presence of LVSI as compared with larger tumors. The preponderance of evidence suggests that the presence of LVSI indicates a slight increase in the risk of lymph node metastasis and recurrence, from about 1% to 2%3% in carcinomas that invade 3 mm or less. In the United States, if LVSI is found a carcinoma is excluded from the category of microinvasive carcinoma. Tumor volume correlates with the clinical behavior of early invasive carcinoma. Burghardt et al34 initially found no risk of metastasis or recurrence if the tumor volume was less than 500 mm3 but later found that 5.6% of women with stage IA2 carcinoma developed recurrences. Tumor volume is difcult to measure, and some have used horizontal length as an alternative. In general, tumor volume and tumor length are proportional to the depth of invasion,39 such that tumors that are more deeply invasive also exhibit greater horizontal growth. The frequency with which residual carcinoma is found in postconization hysterectomy specimens increases from 2% for cancers with less than 4 mm of horizontal spread to 27% for 4- to 8-mm horizontal tumor spread and 35% when the horizontal spread is greater than 8 mm. The status of the cone margins is important in determining the most appropriate therapy for a patient with early invasive carcinoma. Women whose cone margins are positive for microinvasive carcinoma or SIL are more likely to have residual tumor in a subsequent hysterectomy specimen, and the depth of stromal invasion in the hysterectomy may be deeper than that present in the cone.9,17,29,40,41 If the cone margins are free of carcinoma, a postconization endocervical curettage only rarely contains dysplastic epithelium, and only about 5% of women have residual carcinoma in a repeat conization or hysterectomy specimen. If the cone margins are positive, a postcone endocervical curettage is more likely to contain atypical squamous epithelium, and residual carcinoma is found in a signicant percentage (15% or more) of cases.17,41 Positive cone margins therefore preclude a diagnosis of microinvasive carcinoma and indicate that either a repeat conization or radical surgery with lymph node dissection is necessary. Treatment of women with early invasive carcinoma is individualized. In general, however, the standard treatment of a woman with microinvasive carcinoma is simple abdominal or vaginal hysterectomy. Preservation of fertility has become increasingly important as more women delay child bearing, and more conservative options have been introduced in recent years. Conization is now used as a fertility-sparing treatment of selected patients with microinvasive carcinoma.42 44 Loop conization is sometimes used to treat microinvasive carcinoma, but tissue specimens obtained with the loop procedure can be fragmented, precluding accurate measurement of the depth and lateral extent of the carcinoma or evaluation of the margins.45 Nevertheless, the results obtained by cold knife cone and loop conization can be equivalent.46 The risk of recurrence is only about 1% for adequately treated women with microinvasive carcinoma.
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Women with early carcinomas that do not meet criteria for microinvasive carcinoma (FIGO stage IA1 carcinomas with LVSI and FIGO stage IA2 carcinomas) have generally been treated surgically by radical hysterectomy with lymph node dissection. Younger women who wish to conserve their fertility are sometimes treated by cone biopsy (with negative margins) or radical vaginal trachelectomy with pelvic lymphadenectomy. The risk of lymph node metastasis and recurrence is low in this group of patients, although slightly higher than for microinvasive carcinoma (from about 3% up to a 7% risk of metastasis and about 3% risk of recurrence). 33,37 There appears to be a trend toward more conservative therapy in younger women, such as conization with or without lymph node dissection.37

Microinvasive Adenocarcinoma
The clinicopathologic features of stage 1A adenocarcinoma of the cervix are not yet well established. In particular, while pathologists can recognize it, microinvasive adenocarcinoma as dened by SGO criteria is not a recognized clinicopathologic condition among gynecologic oncologists. 37 It accounts for about 12% of microinvasive cancers, and some studies suggest that it may have a favorable prognosis, similar to that of microinvasive squamous cell carcinoma.47,48 The patient age is similar to that of patients with microinvasive squamous cell carcinoma, and most patients are diagnosed during evaluation for an abnormal Papanicolaou test.49,50 In the largest reported series, 77 patients with tumors invasive to 5 mm were studied.51 Pelvic lymph node dissections were performed in 48 women, and all were negative. No women with microinvasion (less than 3 mm invasion) or stage IA (less than 5 mm of invasion and less than 7 mm horizontal growth) had recurrences. Only 1 patient had recurrent adenocarcinoma; although her tumor invaded only 3.1 mm, it was 21 mm long, so it was a stage IB adenocarcinoma. A second patient, also with a stage IB carcinoma (5-mm invasion, 10-mm length), developed squamous cell carcinoma in the vaginal vault 9 years after hysterectomy. In another study, 21 of 200 women with earlystage adenocarcinoma of the cervix had stage IA1 tumors and negative cone-biopsy margins.49 None of 16 patients with lymph node dissections had metastases, and there were no recurrences. None of 21 Japanese women with adenocarcinomas invasive to 3 mm or less had recurrences.52 Early cancers can recur, but they are usually more advanced than

FIGO stage IA1. For example, 2 of 36 patients with adenocarcinomas invasive to 3 mm or less had recurrences, but both had tumors that were greater than 7 mm in length, which would be staged as IB1 adenocarcinomas.53 A 62-year-old woman with a supercial adenocarcinoma invasive to 2.5 mm and a length of 4.0 mm was found to have bilateral pelvic lymph node metastases, indicating that even stage IA1 adenocarcinomas occasionally metastasize or recur.54,55 In a review of the literature on 436 patients with supercially invasive cervical adenocarcinomas (maximum depth of stromal invasion 5 mm), none of 126 had parametrial and none of 155 had adnexal involvement.50 Lymph node metastases were found in only 5 (2%) of the 219 patients who had lymph node dissections, and this gure was thought to be high due to incomplete reporting of data. There were 15 recurrences, and 6 patients died of tumor. Only 21 patients were treated by conization alone. Although only 7 had signicant follow-up, none had a recurrence. The data suggest that microinvasive adenocarcinoma of the cervix carries a similar prognosis to its squamous counterpart and that conservative therapy may be acceptable in selected patients. The diagnosis of early invasive adenocarcinoma can be challenging; it can be difcult to differentiate from adenocarcinoma in situ (ACIS), with which it is generally associated.48 Pathologic features suggestive of early invasion include the presence of ngers or trabeculae of atypical cells that have more abundant, eosinophilic cytoplasm than is seen in adjacent ACIS cells.56 Other small carcinomas grow as conuent glands or sheets of cells that push into the stroma. Some microinvasive carcinomas are easy to recognize as they grow in an inltrative pattern in which the malignant glands are surrounded by desmoplastic, inamed stroma (Fig. 2A) or they grow as conuent masses of glands. More subtle patterns of invasion can be difcult to recognize, and the diagnosis can be controversial.57 Some supercial adenocarcinomas grow as inltrative cribriform nests of tumor cells, others as invasive lobular aggregates of malignant glands (Fig. 2B), and still others as haphazardly arranged atypical glands. Stromal inammation or desmoplasia may or may not be present. Finally, occasional early adenocarcinomas grow in an exophytic papillary pattern. Like ACIS, microinvasive adenocarcinoma is frequently associated with a SIL, which is usually of high grade.58

FIGURE 2. a, Microinvasive adenocarcinoma. This very small adenocarcinoma arose at the squamocolumnar junction. The stroma around the malignant glands is desmoplastic and contains many lymphoid cells. b, Microinvasive adenocarcinoma. Lobules of malignant glands invade the superficial cervical stroma. 2006 Lippincott Williams & Wilkins

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The depth of invasion is measured from the basal lamina of the overlying surface squamous epithelium, if it is present. Otherwise, the measurement is from the surface to the deepest point of invasion. Papillary adenocarcinomas are measured from their surface to their deepest invasion into the stroma.

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CONCLUSION
The diagnosis of microinvasive carcinoma depends on the pathologist, since these cancers are too small to be seen by the clinician. Accurate diagnosis depends in part on optimum tissue processing to ensure that the entire tumor can be seen and measured. Key pieces of information that must be provided in the pathology report include the diagnosis (squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma), the grade, the depth of invasion, the maximum length of the tumor, the presence or absence of LVSI, and the status of the resection margins. An optimum denition of microinvasion is achieved by combining SGO and FIGO criteria: depth of invasion 3 mm or less, maximum length 7 mm or less, and no LVSI. Most microinvasive carcinomas are squamous cell carcinomas, but pathologists should recognize microinvasive adenocarcinoma as well and provide complete data in their reports since detailed pathologic information is required for optimum treatment planning. Microinvasive carcinoma can usually be treated conservatively, by conization or simple hysterectomy, with the expectation of a cure. REFERENCES
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