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CASE R EVIEW

Microinvasive Carcinoma of the Cervix

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

Abstract: Superficially invasive cervical carcinomas only infre-

quently metastasize to regional lymph nodes or recur. A category of

superficially invasive carcinoma termed microinvasive carcinoma

has been defined, based on clinicopathologic studies of large num-

bers of superficially invasive squamous cell carcinomas. A micro-

invasive 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 betreated conservatively by a cone biopsy with adequate free margins

or with a simple hysterectomy, while more deeply invasive carci-

nomas 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 amena-

ble to conservative treatment.

Key Words: cervix, microinvasion, microinvasive carcinoma,

microinvasive adenocarcinoma

( Pathology Case Reviews 2006;11: 121–129)

Cancer of the cervix is the second most common malig-nant tumor in women worldwide, with nearly 500,000

new cases in 2002.1 More than 80% of cases occur in lessdeveloped countries, where cervix cancer accounts for 15%of cancers in women compared with only 3.6% of femalecancers in the United States.1 In developed countries such asthe United States, the number of cases has steadily declined over the years due to the widespread use of cytologic screen-ing, which permits detection and eradication of cervicalcancer precursors, thereby preventing the development of invasive cervical cancer. Still, the American Cancer Society

estimates that 10,370 cases of cervical cancer will be diag-nosed in the United States in 2005 and 3710 women will dieof the disease.2

The stage at diagnosis is the most important prognosticfactor in cervical cancer. Except for the earliest stages, cervicalcancer staging is based on clinical findings. This permits com- parisons between patients treated surgically and those who aretreated by radiation and never have surgical pathologic staging.The staging system established by the International Federationof Gynecologists and Obstetricians (FIGO) is most widelyused,3 although cervical cancer can also be staged using the

TNM (tumor, nodes, metastases) system. The FIGO stagingsystem divides invasive tumors into 4 stages. Stage I tumors areconfined to the cervix, while tumors in stages II–IV extend beyond the cervix (Table 1). In North America, about 60% of patients are diagnosed in stage I, 25% in stage II, 10% in stageIII, and 5% in stage IV. An increasing percentage (about 15%overall but up to 40% in some recent reports) of women withstage I cervical cancer have small superficially invasive tumorsthat have a low risk of recurrence or metastasis. Pathologists and gynecologic oncologists have worked together to develop repro-ducible and widely accepted criteria that will identify a prog-nostically favorable category of patients with early cervicalcancer who can be treated conservatively. Superficial prognos-tically favorable cervical cancers are termed microinvasive cer-vical carcinomas. Most studies of microinvasive carcinoma of the cervix have dealt with squamous cell carcinoma. Microin-vasive adenocarcinoma can be identified using the same diag-nostic criteria as are used for microinvasive squamous cellcarcinoma. Too few studies of superficial adenocarcinomas have been conducted to know for certain whether microinvasiveadenocarcinoma is a clinically favorable category that can betreated conservatively, although the preliminary data are prom-ising. In this report, we discuss criteria for the diagnosis of microinvasive carcinoma, its pathologic features, and its clinicalsignificance.

CASE REPORTA 34-year-old, gravida 3, para 0 had an abnormal

Papanicolaou test. The cytologic diagnosis was a high-gradesquamous intraepithelial lesion (SIL). A colposcopic biopsyconfirmed the diagnosis of high-grade SIL and the patient had a LEEP excision several months after the initial abnormalcytology diagnosis. Microscopic evaluation showed high-grade SIL characterized by full-thickness replacement of thesurface epithelium by atypical squamous cells with enlarged,hyperchromatic nuclei and an increased nucleus to cytoplasmratio. There were frequent mitotic figures, including some inthe 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 Oncol-ogy, 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, SanFrancisco, CA 94143. E-mail: [email protected].

Copyright © 2006 by Lippincott Williams & WilkinsISSN: 1082-9784/06/1103-0121DOI: 10.1097/01.pcr.0000217874.66523.cb

Pathology Case Reviews • Volume 11, Number 3, May/June 2006 121



focus of invasive squamous cell carcinoma in which smallirregular nests and rounded buds of malignant cells infiltrated inflamed edematous stroma (Fig. 1B). The carcinoma cellsvaried 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 thenests. It was unclear whether the invasive carcinoma origi-nated from the surface or the glands, so the depth of invasion,1.6 mm, was measured from the basal lamina of the surfaceepithelium to the point of deepest invasion. The horizontalspread was only 1.0 mm, and there was no lymphovascular space invasion (LVSI). The margins of the LEEP excisionwere free of invasive carcinoma and of high-grade SIL. Thediagnosis was microinvasive squamous cell carcinoma aris-ing in a background of high-grade SIL. The patient under-went definitive therapy by cold knife conization of the cervix2 months later, at which time no residual invasive carcinomaor SIL was identified. An acetowhite area was identified onthe cervix at a follow-up examination 6 months later. A biopsy showed mild squamous atypia but no SIL or invasivecarcinoma. She remains free of residual or recurrent disease3 years later.

What Is Microinvasive Carcinoma?A universally agreed-on definition of microinvasive

carcinoma of the cervix has been elusive. There have beencompeting definitions over the years. For example, in theUnited States microinvasive carcinoma has been defined as acarcinoma showing superficial invasion to a depth of 1 mm or less,4 as one invasive to 3 mm or less,5,6 and as one invasiveto 5 mm or less.7–9 Some definitions have excluded superfi-cially invasive carcinomas with LVSI, while others haveincluded them.7 In Europe, definitions involving measurementsin more than 1 dimension have been favored. Burghardt and Holzer 10 meticulously sectioned and measured small cervicalcarcinomas in 3 dimensions and determined that tumors with

a volume of less than 500 mm3 have little risk of lymph nodemetastasis or recurrence. Complicated tissue processing sys-tems are difficult to apply in the standard pathology labora-tory. Recognizing this, FIGO has included a measurement of tumor length in its definition of early invasive cervical can-cer, along with measurement of the depth, as a practical

method of accounting for tumor size.The problem of defining microinvasive carcinoma has

been largely settled in the United States, as most cliniciansdetermine treatment of their patients based on the definitionof microinvasive carcinoma put forward by the Society of Gynecologic Oncologists (SGO). The SGO defined a micro-invasive carcinoma as one that invades the stroma to a depthof no more than 3.0 mm and that does not invade lympho-vascular spaces (Table 2). The FIGO classification of stage Icervical cancer (a cancer that is limited to the cervix) hasevolved over the years, but the current classification includesa category that is similar, but not identical, to the SGOdefinition of microinvasive carcinoma (Table 1). In the FIGO

staging system, cancers that invade to a depth of 5 mm or lessand that have 7 mm or less of horizontal spread are staged asIA. The most recent modification of the FIGO staging systemaltered the definition of stage IA1. Formerly, this stageincluded tumors showing only “early stromal invasion,”which, from a practical point of view, meant invasion of 1mm or less. The revised definition of stage IA1 includes allcancers that invade to a depth of 3 mm or less, the samemaximum depth that the SGO uses to define microinvasivecarcinoma. The FIGO definition differs in that there is a limiton the maximum amount of horizontal spread allowed (7mm) and there is no assessment of the presence or absence of LVSI. Thus, a cancer with LVSI can still meet FIGO criteriafor stage IA1 but not meet the SGO criteria for microinvasive

carcinoma. A less likely possibility is that a carcinoma withconsiderable horizontal spread could meet the SGO criteriafor microinvasion but not fall into FIGO stage IA1. FIGOstage IA2 includes superficially invasive cancers that invadeto a depth of 3.1 mm to 5.0 mm. Any tumor that is clinicallyvisible is by definition FIGO stage IB. Microscopic tumorsthat invade to a depth of more than 5 mm or that havehorizontal spread of greater than 7 mm are also staged as IB.

Our practice is to include the depth of invasion, thelength of horizontal spread, and a comment as to whether or not LVSI is present in the pathology report. We also statewhether 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 FIGOstage, but we use the SGO definition with a slight modifica-tion to decide whether or not to call a superficially invasivecarcinoma microinvasive. Our modification is to use theFIGO maximum length classification as an additional crite-rion for microinvasive carcinoma. If the depth of invasion is3 mm or less, the horizontal spread is 7 mm or less, there isno LVSI and the margins are free our diagnosis is microin-vasive carcinoma (Table 3).

Pathology of Microinvasive CarcinomaMicroinvasive carcinoma (when we use this term we

refer to squamous cell carcinoma unless otherwise indicated)

TABLE 1. FIGO Staging of Cervical Carcinoma

Stage I Cervical carcinoma confined to uterus

Stage IA Invasive carcinoma diagnosed only by microscopy. Allmacroscopically visible lesions, even with superficialinvasion, are stage IB. Stromal invasion with a maximaldepth of 5.0 mm and a horizontal spread of 7.0 mm or

less. Vascular space involvement, venous or lymphatic,does not affect classification.

Stage IA1 Stromal invasion 3.0 mm or less in depth and 7.0 mm or lessin horizontal spread

Stage IA2 Stromal invasion more than 3.0 mm and not more than 5.0mm with a horizontal spread 7.0 mm or less

Stage IB Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2

Stage II Cervical carcinoma invades beyond uterus but not to pelvicwall or to lower third of vagina

Stage III Tumor extends to pelvic wall and/or involves lower third of vagina and/or causes hydronephrosis or nonfunctioningkidney

Stage IV Tumor invades mucosa of bladder or rectum and/or extends beyond true pelvis; distant metastasis

FIGO indicates Fédération Internationale de Gynécologie et d’Obstétrique.

Garg et al Pathology Case Reviews • Volume 11, Number 3, May/June 2006

© 2006 Lippincott Williams & Wilkins122



usually arises from abnormal epithelium involved by a SIL.The SIL is generally high grade, but rare cases arise fromlow-grade SIL caused by a high-risk HPV type. Stromalinvasion only rarely arises from a small focus of high-gradeSIL. It is most likely to be found when there is extensivehigh-grade SIL involving the surface epithelium and extend-ing into the underlying endocervical glands; the endocervicalgland involvement is often extensive (Fig. 1D).11 Invasioncan originate from the surface epithelium or from a gland

involved by SIL. In early stromal invasion, the findings rangefrom 1 or more tiny buds of carcinoma cells that barelyinvade the adjacent stroma to larger tongues of malignantcells that invade up to 1 mm. Sometimes multiple smallinvasive foci are present. The earliest forms of microinvasionconsist of small rounded or irregular fingers or nests of malignant cells that push just beyond the basement membraneinto the stroma (Fig. 1E). Small foci of invasion can bedifficult to identify as they may contain only 10–20 cells in

FIGURE 1. a, High-grade SIL in-volves the surface and extends intoglands. A small focus of invasivesquamous cell carcinoma is in thecervical stroma between 2 glands.The depth of invasion, 1.6 mm,was measured from the basal lam-ina of the surface epithelium to themaximum depth of stromal inva-sion. b, The microinvasive carci-noma grows as large irregular nestsand small round buds of malignantcells. The stroma contains manychronic inflammatory cells. c,Some cells in the invasive nests arebasaloid, with dark nuclei andscanty cytoplasm. Others are kera-tinized and have abundant eosino-

philic cytoplasm, more open vesic-ular nuclei, and prominent nucleoli.The keratinized cells form several“pearls.” d, This microinvasivesquamous cell carcinoma arises in abackground of extensive high-grade SIL, involving the surfaceand filling many endocervicalglands. e, Comparison of cellular morphology in high-grade SIL (leftpanel) and early stromal invasion(right panel). In the early stromalinvasion, the tumor cells havelarger vesicular nuclei, and the tu-mor cells have more cytoplasm.

f, Early stromal invasion. Comparedwith the cells in the SIL from whichthey arise, the invasive carcinomacells have more abundant eosino-philic (“pink”) cytoplasm andlarger, more open nuclei. g, Micro-invasive squamous cell carcinoma.Nests of keratinized cells with cen-tral pearls invade desmoplastic in-

flamed stroma. h, Lymphovascular space invasion. A rounded nest of carcinoma cells is within a lym-phatic space. Note the flattenedendothelial cells that line the

space. A vein is present at bottom;it has a thicker wall due to thepresence of smooth muscle cells.

Pathology Case Reviews • Volume 11, Number 3, May/June 2006 Microinvasive Carcinoma

© 2006 Lippincott Williams & Wilkins 123



rounded or irregular protrusions into the stroma. In onereview, 4.8% of cases of high-grade SIL were reinterpreted asshowing early stromal invasion,12 and in another study, 4.7%of women initially thought to have SIL proved to haveinvasion.13

As the invasive foci enlarge, they tend to developirregular scalloped borders or form small round or irregular nests in the stroma that appear separated from the epitheliumfrom which they originated. The cells in invasive foci can be basaloid, with hyperchromatic nuclei, inconspicuous nucle-oli, and scanty cytoplasm, similar to high-grade SIL cells.More often, however, the malignant cells are somewhatdifferent from high-grade SIL cells (Fig. 1E). They may bekeratinized, with abundant eosinophilic cytoplasm and largevesicular nuclei that are more pleomorphic than SIL nuclei

(Fig. 1F). The nuclei often contain prominent nucleoli. Anabrupt change in tumor cell morphology from dark basaloid SIL cells to larger keratinized cells with eosinophilic cytoplasm (“pink cells”), vesicular nuclei, and prominent nucleoliis a reliable marker of invasion. The stroma is frequentlyedematous and inflamed at sites of invasion (Fig. 1B). Adesmoplastic stromal reaction is often present around nests of invasive carcinoma, but stromal desmoplasia is less conspic-uous at sites of early stromal invasion than it is around moredeeply invasive nests of malignant cells. Early stromal inva-sion is most likely to be found in the transformation zone(about 90%), and, in one study, invasion originated from thesurface epithelium in about 50% of cases and from endocer-

vical glands involved by SIL in the other 50%.14

As invasion progresses beyond its earliest stages, thetumor cells grow in a variety of patterns. Superficially inva-sive tumors exhibit the same invasive growth patterns that areseen in more advanced squamous cell carcinomas. Thus, themost common finding is that of irregular tongue-like infiltra-tive nests of keratinized cells invading a desmoplastic, in-flamed stroma (Fig. 1G). Invasive cancers sometimes seem to“spray” into the stroma as irregularly distributed small nestsor cords of tumor cells. An infiltrative “SIL-like” pattern isoccasionally noted. In this pattern, elongated or rounded nestsof 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 exhibitgreater nuclear atypia and mitotic activity than is seen in SIL,some of the nests have a scalloped or ragged infiltrativemargin, and the nests may contain necrotic debris. Theirregular periphery of nests of invasive malignant cells con-trasts 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 maximumdimension, a pattern that has been termed confluent growth.Fibrovascular cores within sheets of tumor cells suggest this pattern of invasion.

A potential diagnostic pitfall in the diagnosis of micro-invasive carcinoma is the misinterpretation of misplaced benign or dysplastic epithelium as invasive cancer. Coniza-tion, biopsy, and obstetric procedures occasionally introducenests of benign or dysplastic squamous epithelium into thecervical stroma. With healing, these nests become surrounded by stroma, and may be misinterpreted as foci of microinva-sive carcinoma. In contrast to microinvasive carcinoma, mis-

placed epithelial nests are composed of bland keratinized cells. There is no nuclear atypia or mitotic activity and nodesmoplastic stromal response surrounds the nests of benignepithelium. Introduction of dysplastic epithelium into the stromaor even into lymphovascular spaces is possible after biopsy,although it is rare. Clues to the correct diagnosis include ahistory of recent biopsy, stromal hemorrhage or hemosider-osis, and a histiocytic or giant cell reaction in the stroma.Misplaced dysplastic cells lack the nuclear and cytoplasmicfeatures of carcinoma cells, and other nests of invasive cellsare not present in the area. The introduction of dysplasticcells into lymphovascular spaces by biopsy or injection of ananesthetic is rare, although it has been reported.15 Our policy

is to diagnose LVSI by microinvasive carcinoma only whencancer cells are identified in the stroma, as well as in lymphovascular spaces. This prevents the overdiagnosis of anartifact as invasive carcinoma. Any time atypical cells arefound in a vascular space, a thorough search for invasion isnecessary, including processing of all tissue and evaluation of level sections as indicated.

Misdiagnosis of microinvasive carcinoma can haveserious implications, as it can result in incorrect treatment.Obviously, accurate measurement of the depth of invasionand the lateral extent is crucial. These measurements are bestmade with an ocular micrometer. A less accurate but stillacceptable 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 somemicroscope stages; these are not sufficiently precise for ac-curate measurement, except of the most obvious cases. Thedepth 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 measure-ment is from the basement membrane of the surface epithe-lium overlying the invasive focus. When invasive carcinomaarises from an endocervical gland, the length of invasion ismeasured from the basement membrane of the gland to the point of maximal invasion. If the invasive carcinoma is not incontinuity with the surface or the gland from which it origi-

TABLE 2. SGO Criteria for the Diagnosis of MicroinvasiveCarcinoma

Depth of invasion 3 mm or less

No lymphovascular space invasion

SGO indicates Society of Gynecologic Oncologists.

TABLE 3. Criteria for Microinvasive Carcinoma Used atUniversity 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.





nated and the site of origin is not clear, the depth should bemeasured vertically from the basement membrane of thesurface epithelium to the point of deepest invasion, as wasdone in our case. If the surface is ulcerated, the measurementis 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 whenthere is only a single focus of invasion. The measurement ismore complicated in the 12% of cases in which 2 or more fociof invasive carcinoma are present.14 The proper method for measuring lateral extent in cases with multiple foci of inva-sion is not defined in staging manuals. We suspect that many pathologists measure from the lateral edge of one invasivefocus to the opposite lateral edge of the most distant focus of invasive carcinoma. Reich and Pickel16 suggest that if eachfocus of invasion is in continuity with the epithelium from

which it arose, the lateral extent of each focus should bemeasured and the values added to obtain a total lateral extent.On the other hand, if some foci of invasive carcinoma areentirely within the stroma and the site of origin cannot beclearly identified for each invasive focus, the pathologistshould measure the distance between the lateral edges of the2 most widely separated foci, even though invasive carci-noma may not fill the entire span.

In our laboratory, we consider an optimally processed cone biopsy to be one that has been received unfixed, per-mitting the pathologist to open the cone and pin it out. It isthen serially sectioned after fixation. The pathologist canmeasure horizontal spread on the microscopic slide (1 dimen-

sion) and can calculate lateral spread in a second dimension by counting the number of consecutive blocks involved byinvasive carcinoma and multiplying the number of positive blocks by the thickness of the tissue slices. This providesanother, albeit less accurate, measure of horizontal spread.We prefer not to fix unopened cone biopsies prior to process-ing them because sections prepared from such specimensoften have orientation problems. However, gynecologistssometimes submit unopened specimens in formalin, and theyare completely fixed by the time they arrive in the pathologylaboratory. 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 throughthe 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 nota superficially invasive carcinoma qualifies as microinvasivecarcinoma under the SGO definition. The presence of trueLVSI is of great clinical importance since even early stromalinvasion may be treated by radical hysterectomy with pelviclymph node dissection if LVSI is present. The greater the depthof invasion, the more likely the pathologist will identify LVSI.LVSI is diagnosed when the pathologist identifies nests or ballsof tumor cells within vascular spaces (Fig. 1H). The presence of

a layer of flattened endothelial cells helps the pathologist iden-tify lymphovascular spaces, but an endothelial lining is notalways visible, and, to complicate the problem, perivascular fibroblasts are easily confused with endothelial cells. It is usuallynot possible to determine whether a small vascular space is alymphatic or vascular channel; hence, the designation as a

lymphovascular space. Red blood cells are occasionally iden-tified in the spaces and suggest that the channel is a blood capillary or a small vein. Pathologists occasionally use im-munohistochemical stains for endothelial markers to try toconfirm the vascular nature of spaces that contain tumor cells, but we do not advocate this. Immunohistochemical stainingdelays the diagnosis and is expensive. The main problem,however, is that we find that it is frequently unsuccessful. Thefocus in question may no longer be present on a deeper section prepared for immunohistochemistry, the endothelialcells may be too attenuated to stain convincingly or they mayhave been eroded. We make every effort to determinewhether vascular invasion is present on routine H&E-stained

sections and rarely resort to the use of immunohistochemicalstains for this purpose. LVSI can be difficult to identify withcertainty because it is easily confused with a more commonfinding, artifactual tissue retraction around nests of invasivetumor cells. This problem is not unique to the cervix; itoccurs in other anatomic sites as well and is a particular problem in breast pathology. To avoid errors, we concentrateour search for LVSI at the periphery of the tumor, wheretissue retraction artifacts are less frequent. Multiple nests of tumor cells surrounded by clear spaces likely represent tissueretraction artifacts since permeation of multiple lymphovas-cular spaces is unlikely in a superficially invasive carcinoma.

A diagnosis of microinvasive carcinoma is appropriateonly when the entire tumor can be evaluated. Thus, microin-

vasive 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 specimenmight reveal more deeply invasive carcinoma in adjacenttissues.9 In addition to making a definitive diagnosis of microinvasive carcinoma, it is important for the pathologist tomake an accurate determination of the status of the excisionmargins in a patient with microinvasive carcinoma. The pathologist should measure the distance from the edge of thecarcinoma 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 arepeat cone or a hysterectomy is necessary. Inadequate mar-gins increase the risk of recurrence and eventual metastasis.

Clinical FeaturesMicroinvasive 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 averagewoman with overt invasive carcinoma.17 Patients with micro-invasive carcinoma are usually asymptomatic, and the carci-noma is typically discovered during workup for an abnormalPapanicolaou test. Subtle cytologic features suggest the pos-sibility of microinvasion in a minority of cases.18,19 These





include increased or keratinized cytoplasm, increased nuclear atypia and pleomorphism, and conspicuous nucleoli in theatypical cells. An occasional patient presents with abnormal bleeding or a discharge.17 Generally, no abnormality is clin-ically visible on the cervix, and most patients are thought tohave SIL until invasion is discovered in a biopsy.19 Colpos-

copists sometimes suspect microinvasion if there is a suffi-ciently abnormal vascular pattern, but accurate colposcopicdetection requires considerable skill and appears to be pos-sible only when the depth of invasion exceeds 1 mm. 20,21

Prognostic factors in early cervical carcinoma includethe depth of stromal invasion, the presence or absence of LVSI, the volume or lateral extent of the tumor, and the statusof the excision margins. Analysis of these factors has led tothe delineation of a category of patients who have minimalrisk of lymph node metastasis or recurrence and who can betreated conservatively.

The depth of stromal invasion is a major factor indetermining the outcome of patients with early cervical can-

cer. Lymph node metastasis is the single most important predictor of long-term outcome in patients with early cervicalcancer, 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 nodemetastasis is only about 1%.22–25 When the depth of invasionis 3 mm or less, the risk of lymph node metastasis issufficiently low that routine pelvic lymph node dissection isnot necessary.22,26–28 The risk of recurrence in such patientsis less than 1%.22,29–31 Nevertheless, the finding of onlyminimal stromal invasion is not an absolute guarantee that

lymph node metastasis will not occur, and rare patients withinvasion of 1 mm or less develop widespread metastases.32

The risk of lymph node metastasis is 6%–8% in patientswhose tumors invade to a depth of 3 to 5 mm.22,23,27,33 Such patients have a 3%–6% risk of recurrence after treat-ment33,34; they are often treated by radical surgery withlymph node dissection.35 More conservative therapy is pos-sible in selected patients, such as those with no evidence of LVSI or confluent growth.36 Tumors that invade 3–5 mm arenot included in the category of microinvasive carcinoma,although they fall into FIGO stage IA2. When reviewingclinical studies of superficially invasive cervical cancers, it isimportant to carefully evaluate what authors deem to be a

recurrence. For example, in one large study, 1 patient wasreported 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 vaginalvault, the invasive carcinoma was adjacent to high-gradeSIL.17 Thus, these “recurrences” might well have been sec-ond primary foci, rather than true recurrences.

The significance of LVSI in microinvasive carcinoma has been a controversial issue. In general, the frequency of LVSIincreases with increasing tumor depth and size.37 LVSI is found inup to 10% of carcinomas with less than 1 mm of stromal invasionand 10%–30% of tumors that invade 1–3 mm.9,23,30,31 Someauthors 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 nodemetastasis 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 norisk of metastasis or recurrence if the tumor volume was lessthan 500 mm3 but later found that 5.6% of women with stageIA2 carcinoma developed recurrences. Tumor volume isdifficult to measure, and some have used horizontal length asan alternative. In general, tumor volume and tumor length are proportional to the depth of invasion,39 such that tumors thatare more deeply invasive also exhibit greater horizontalgrowth. The frequency with which residual carcinoma is

found in postconization hysterectomy specimens increasesfrom 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 deter-mining the most appropriate therapy for a patient with earlyinvasive carcinoma. Women whose cone margins are positivefor microinvasive carcinoma or SIL are more likely to haveresidual tumor in a subsequent hysterectomy specimen, and thedepth of stromal invasion in the hysterectomy may be deeper than that present in the cone.9,17,29,40,41 If the cone margins arefree of carcinoma, a postconization endocervical curettageonly 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 containatypical squamous epithelium, and residual carcinoma isfound in a significant percentage (15% or more) of cases.17,41

Positive cone margins therefore preclude a diagnosis of microinvasive carcinoma and indicate that either a repeatconization or radical surgery with lymph node dissection isnecessary.

Treatment of women with early invasive carcinoma isindividualized. In general, however, the standard treatment of a woman with microinvasive carcinoma is simple abdominalor vaginal hysterectomy. Preservation of fertility has becomeincreasingly important as more women delay child bearing,and more conservative options have been introduced in recentyears. Conization is now used as a fertility-sparing treatmentof selected patients with microinvasive carcinoma.42–44 Loopconization is sometimes used to treat microinvasive carci-noma, but tissue specimens obtained with the loop procedurecan be fragmented, precluding accurate measurement of thedepth and lateral extent of the carcinoma or evaluation of themargins.45 Nevertheless, the results obtained by cold knifecone and loop conization can be equivalent.46 The risk of recurrence is only about 1% for adequately treated womenwith microinvasive carcinoma.





Women with early carcinomas that do not meet criteriafor microinvasive carcinoma (FIGO stage IA1 carcinomaswith LVSI and FIGO stage IA2 carcinomas) have generally been treated surgically by radical hysterectomy with lymphnode dissection. Younger women who wish to conserve their fertility are sometimes treated by cone biopsy (with negative

margins) or radical vaginal trachelectomy with pelvic lymph-adenectomy. The risk of lymph node metastasis and recur-rence 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 therapyin younger women, such as conization with or without lymphnode dissection.37

Microinvasive AdenocarcinomaThe clinicopathologic features of stage 1A adenocarci-

noma of the cervix are not yet well established. In particular,while pathologists can recognize it, microinvasive adenocar-cinoma as defined by SGO criteria is not a recognized

clinicopathologic condition among gynecologic oncologists.It accounts for about 12% of microinvasive cancers,37 and some studies suggest that it may have a favorable prognosis,similar to that of microinvasive squamous cell carcino-ma.47,48 The patient age is similar to that of patients withmicroinvasive squamous cell carcinoma, and most patientsare diagnosed during evaluation for an abnormal Papanico-laou test.49,50 In the largest reported series, 77 patients withtumors invasive to 5 mm were studied.51 Pelvic lymph nodedissections were performed in 48 women, and all werenegative. No women with microinvasion (less than 3 mminvasion) or stage IA (less than 5 mm of invasion and lessthan 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 IBadenocarcinoma. A second patient, also with a stage IBcarcinoma (5-mm invasion, 10-mm length), developed squa-mous cell carcinoma in the vaginal vault 9 years after hys-terectomy. In another study, 21 of 200 women with early-stage adenocarcinoma of the cervix had stage IA1 tumors and negative cone-biopsy margins.49 None of 16 patients withlymph node dissections had metastases, and there were norecurrences. None of 21 Japanese women with adenocarci-nomas invasive to 3 mm or less had recurrences.52 Earlycancers can recur, but they are usually more advanced than

FIGO stage IA1. For example, 2 of 36 patients with adeno-

carcinomas invasive to 3 mm or less had recurrences, but both had tumors that were greater than 7 mm in length, whichwould be staged as IB1 adenocarcinomas.53 A 62-year-old

woman with a superficial adenocarcinoma invasive to 2.5 mmand a length of 4.0 mm was found to have bilateral pelvic

lymph node metastases, indicating that even stage IA1 ade-nocarcinomas occasionally metastasize or recur.54,55 In a

review of the literature on 436 patients with superficiallyinvasive cervical adenocarcinomas (maximum depth of stro-mal invasion 5 mm), none of 126 had parametrial and none of

155 had adnexal involvement.50 Lymph node metastaseswere found in only 5 (2%) of the 219 patients who had lymphnode dissections, and this figure 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 byconization alone. Although only 7 had significant follow-up,

none had a recurrence. The data suggest that microinvasiveadenocarcinoma of the cervix carries a similar prognosis to its

squamous counterpart and that conservative therapy may beacceptable in selected patients.

The diagnosis of early invasive adenocarcinoma can bechallenging; it can be difficult to differentiate from adeno-carcinoma in situ (ACIS), with which it is generally associ-

ated.48 Pathologic features suggestive of early invasion in-clude the presence of fingers or trabeculae of atypical cellsthat have more abundant, eosinophilic cytoplasm than is seen

in adjacent ACIS cells.56 Other small carcinomas grow asconfluent glands or sheets of cells that push into the stroma.Some microinvasive carcinomas are easy to recognize as they

grow in an infiltrative pattern in which the malignant glands

are surrounded by desmoplastic, inflamed stroma (Fig. 2A) or they grow as confluent masses of glands. More subtle patternsof invasion can be difficult to recognize, and the diagnosis

can be controversial.57 Some superficial adenocarcinomasgrow as infiltrative cribriform nests of tumor cells, others asinvasive lobular aggregates of malignant glands (Fig. 2B),and still others as haphazardly arranged atypical glands.

Stromal inflammation or desmoplasia may or may not be present. Finally, occasional early adenocarcinomas grow in anexophytic papillary pattern. Like ACIS, microinvasive adeno-carcinoma is frequently associated with a SIL, which is usually

of high grade.58

FIGURE 2. a, Microinvasive adeno-carcinoma. This very small adeno-carcinoma arose at the squamoco-lumnar junction. The stromaaround the malignant glands isdesmoplastic and contains manylymphoid cells. b, Microinvasiveadenocarcinoma. Lobules of malig-nant glands invade the superficialcervical stroma.





The depth of invasion is measured from the basallamina of the overlying surface squamous epithelium, if it is present. Otherwise, the measurement is from the surface tothe deepest point of invasion. Papillary adenocarcinomas aremeasured from their surface to their deepest invasion into thestroma.

CONCLUSIONThe 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 onoptimum 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 (squa-mous cell carcinoma, adenocarcinoma, adenosquamous car-cinoma), the grade, the depth of invasion, the maximumlength of the tumor, the presence or absence of LVSI, and thestatus of the resection margins. An optimum definition of microinvasion is achieved by combining SGO and FIGO

criteria: depth of invasion 3 mm or less, maximum length 7mm or less, and no LVSI. Most microinvasive carcinomas aresquamous cell carcinomas, but pathologists should recognizemicroinvasive adenocarcinoma as well and provide completedata in their reports since detailed pathologic information isrequired for optimum treatment planning. Microinvasive car-cinoma can usually be treated conservatively, by conizationor simple hysterectomy, with the expectation of a cure.

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