Int J Gynecol Obster, 1991, 36: 5-12

International

Federation

of Gynecology

Microinvasive

and Obstetrics

cervix cancer

J.C. Schink and J.R. Lurain The Section

ofGynecologic

Oncology.

Department

Superior Street, Suite 420, Chicago, IL 60611

(Revised

and accepted

March

of Obstetrics and Gynecology,

Norrhwestern

University

Medical

School, 33.3 East

(USA)

4th. 1991)

Abstract

Introduction

Microinvasive cervix cancer (Stage Ia) is the earliest stage of squamous carcinoma, and has a 98% j-year survival. This article reviews risk factors, etiology, and diagnosis of this disease. The important prognostic factors for treatment planning are depth of invasion, lateral extent of invasive tumor, and lymphvascular space invasion. Conservative management is appropriate in selected cases with the goal of preserving fertility.

Cervical carcinoma is the leading cause of cancer death for women in third world countries. This cancer is the end point of a spectrum which ranges from mild dysplasia to invasive cervix cancer, with microinvasive cervical carcinoma representing the earliest malignant condition (Fig. 1). The International Federation of Gynecology and Obstetrics (FIGO) criteria for the diagnosis of microinvasive cervix cancer have evolved over the last two decades to more accurately reflect prognostic factors and treatment considerations. The current FIG0 definition of Stage Ia cervical cancer includes early stromal invasion (Stage Ial) which is virtually benign, and microinvasive carcinoma (Stage Ia2) which has significant risk of metastasis. This paper

Keywords: Microinvasive cervix cancer; Stage Ia cervix cancer; Early stromal invasion; Microcarcinoma; Human papilloma virus infection.

CIN

1

1

Mild

, Dysplasia

CIN

CIN

I

2

Moderate Dysplasia

Severe Dysplasia

I

3

Carcinoma in situ

Stage Ia Early Stromal Invasion

IStage Ib-IVb

Microinvasive carcinoma

Invasive cancer

I

I

Malignant

Premalignant

0

Years Fig. I.

The spectrum

of premalignant

0020-7292/91/%03.50 0 1991 International Federation Published and Printed in Ireland

and malignant

cervical

disease spans

IO-15

years in the typical

I 10-15 Years

patient.

Review Article

of Gynecology

and Obstetrics

6

Schink and Lurain

reviews the etiology, definition, diagnosis, prognostic factors, and treatment of stage Ia (microinvasive) cervix cancer. Etiology and risk factors

The concept of cervix cancer as a sexually transmitted disease (STD) was proposed in 1842 by Rigoni-Stern [9]. Recently, the search for an infectious agent has focused on the human papillomaviruses (HPV). DNA material from HPV types 16 or 18 can be found in 80 to 90% of cervix cancers [7]. HPV is a DNA virus with its viral genome divided into early and late reading genes. The early reading genes, Ei-E8, carry information for immortalization and transformation of a target cell. Malignant transformation is associated with integration of the E7 gene locus into the host cell’s DNA [1,15]. Squamous metaplasia of the cervical columnar epithelium may play a role in promoting integration or expression of this HPV gene locus in the transformed cell. Such an explanation would explain why women at highest risk for cervix cancer are those exposed to HPV during the dynamic periods of metaplasia, early adolescence and lirst pregnancy. The demographic characteristics of patients with microinvasive and invasive cervix cancer support the concept of cervical infection with HPV during periods of rapid metaplasia. The mean age of patients with microinvasive cervix cancer is 47 years old with a range of 22-74 years; a bimodal distribution occurs with peaks at 35-39 years and 60-64 years [ 111.Early age of first intercourse, early age of first pregnancy, multiple sexual partners or partners with multiple partners are important risk factors for cervical cancer. Cigarette smoking is an independent risk factor for cervix cancer. In countries where Pap smear screening is widely available, lack of Pap smear testing remains an important factor for the development of cervix cancer. Although many patients may have seen a physician in the Inr J G.vnecol Obsrrt 36

years preceding the onset of their disease, they were not offered or advised to have a Pap smear. It is the responsibility of all primary care physicians to encourage and facilitate compliance with cancer screening guidelines. Definition

The current definition of microinvasive or Stage Ia cervix cancer is: invasion less than or equal to 5 mm from the base of the epithelium and no more than 7 mm of lateral extension (Table 1). The subgroup Stage Ial is called early stromal invasion (ESI). This group has virtually no risk of lymph node metastasis or distant recurrence. The subgroup Stage la2 is called microinvasive carcinoma (MICA) and includes all of the Stage Ia patients at risk for metastasis. Controversy has surrounded the definition of microinvasive cervix cancer for the last three decades. The International Federation of Gynecology and Obstetrics (FIGO) has

Table 1. FIG0 revised 1985. Stage I

criteria

for Stage I carcinoma

The carcinoma (extension

is strictly to the

confined corpus

of the cervix,

to the cervix should be

disregarded). Stage la

Preclinical carcinoma of the cervix, that is, those diagnosed only by microscopy.

Stage la1

Minimal microscopically vasion.

Stage la2

Lesions detected microscopically that can be measured. The upper limit of the measure-

evident

stromal

in-

ment should not show a depth of invasion of more than 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates. A second dimension, the horizontal spread, must not exceed 7 mm. Larger lesions should be staged as lb. Stage Ib

Lesions of greater dimensions than Stage Ia whether seen clinically or not. Preformed space involvement should not alter the staging but should be specifically recorded so as to determine whether it should affect treatment decisions in the future.

Table 2. Society of Gynecologic microinvasive cervix cancer, 1973.

Oncologists

criteria

for

I. Cases of intraepithelial carcinoma with questionable invasion should be regarded as intraepithelial carcinoma. 2. A microinvasive lesion should be defined as one in which neoplastic epithelium invades the stroma in one or more places to a depth of 3 mm or less below the basement membrane of the epithelium. and in which lymphatic or vascular involvement is not demonstrated.

changed the definition of Stage I cervix cancer at least four times, reflecting a growing appreciation of important prognostic factors. As pathologic and clinical evaluations of these patients have improved, depth of invasion, lateral extent of invasive tumor and possibly lymphvascular space involvement have emerged as the critical prognostic factors. These factors are incorporated in the current FIG0 staging criteria (Table 1) adopted in 1985. In 1973, the Society of Gynecologic Oncologists (SGO) adopted the following principles regarding microinvasive cervix cancer: cases of intraepithelial carcinoma with questionable invasion should be regarded as intraepithelial (not invasive). Microinvasion is invasive carcinoma with neoplastic epithelium invading the stroma in one or more places to a depth of 3 mm or less below the basement membrane without lymphatic or capillary space involvement (Table 2). These SGO criteria parallel the treatment guidelines described later in this monograph. Diagnosis

Microinvasive cancer is a microscopic disease involving the cervical epithelium and the first few millimeters of cervical stroma. The most common signs and symptoms are vaginal bleeding, contact bleeding and vaginal discharge, but less than 50% of patients have any complaints. The diagnosis of microinvasive cervix cancer is a diagnosis of exclusion; invasive cervix

cancer must always be ruled out. Most patients present with an abnormal Pap smear and are referred for colposcopy. In the majority of instances the colposcopic evaluation will be satisfactory and precede a biopsy proven diagnosis of preinvasive disease. When either colposcopy or directed biopsy suggests microinvasion, a cone biopsy with margins free of invasive cancer is required before a definitive diagnosis of microinvasion can be made. The most common colposcopic signs associated with microinvasion are mosaism, coarse punctation, and in about one third of patients, abnormal vessels. A common pitfall is to rely only on colposcopically directed biopsies. Although the directed biopsies may indeed suggest microinvasion, a cone biopsy must be performed to rule out areas of invasion deeper than 5 mm from the surface and less than 7 mm lateral extent of invasive disease. Prognostic factors

Prognosis ranges from >99’% 5-year disease-free survival for ES1 to 95-98% for MICA [2,3,6]. Depth of invasion is the most important prognostic factor; virtually no risk of recurrence or lymph node metastasis exists for lesions with less than 3 mm depth of invasion and no lymphvascular space invasion [I 31. In contrast, for lesions between 3 and 5 mm invasion, the incidence of lymph node metastasis is 13% (4 of 30) [8], and the risk of recurrence ranges from less than 1% to about 5% [2,4]. Lateral extent of invasive tumor correlates closely with depth of invasion, tumor volume, and lymphvascular space invasion [5]. When the invasive lesion exceeds 7 mm in lateral extent the likelihood of residual disease after cone biopsy or lymphatic involvement is significant. Roche and Norris demonstrated lymphatic space involvement in 57% of patients with microinvasive cervix cancer; nonetheless all 30 patients had negative lymph node biopsies [lo]. Creasman found lymphatic space in-

8

Schink and Lurain

volvement in 8 of 74 patients (11%) with less than 3 mm invasion and in 7 of 21 patients (33%) with 3 to 5 mm invasion; none of these patients had lymph node metastases [2]. These data suggest that lymphatic space involvement is not significant; however, the sample size of both studies is quite small. If, on the other hand, one examines reports of patients with recurrent disease after treatment for microinvasive cervical cancer, the data suggests that lymphatic space involvement is an important prognostic factor. Van Nagell et al. [ 131found a significant (P < 0.04) increase in the recurrence risk: 12O/ofor all Stage Ia patients with lymphvascular space invasion. Contradictory data such as these suggest that lymphvascular space involvement does not act as an independent risk factor, but increases with other established risk factors. Cone margins involved by tumor are usually a reflection of the depth and lateral extent of tumor. A positive cone margin precludes the diagnosis of microinvasive cervix cancer because the full extent of the tumor cannot be determined. This is a common problem leading to under-treatment of patients. Other pathologic features such as cell type, invasion pattern, and stromal inflammatory response are not related to recurrence rates [ 131. These considerations pertain only to epidermoid (squamous) carcinomas, microinvasive adenocarcinoma of the cervix is not yet well defined. Any invasive adenocarcinoma of the cervix should be treated as a Stage lb cervix cancer regardless of the depth of invasion. Treatment results

In a cooperative study from Germany, Lohe et al. [6] reported results of treatment in 419 patients with early stromal invasion and microinvasive carcinoma of the cervix. Early stromal invasion (ESI) included only isolated, variably shaped projections with early signs of infiltration of the cervical stroma. Microinvasive carcinoma (MICA) included all other cases of microinvasive cancer with true confluent carcinomatous masses with a maximum Inr J Gynecol Obstet 36

width of 10 mm and depth of 5 mm. Of the 285 patients with ESI, 23% were treated by conization and 66O/oby simple hysterectomy. There were only 4 recurrences (1.4%) and no deaths due to cancer in the 285 patients with ESI. In an additional 895 patients with ES1 culled from the literature, 13 (1.5%) had tumor recurrence and 4 (0.4%) died of disease. Of the 134 patients with MICA, 49% had some type of radical hysterectomy with or without subsequent radiotherapy, 3 (2.2%) developed recurrent disease and died. No lymph node metastases were found in the 63 patients undergoing lymphadenectomy. Similarly, out of 435 patients with MICA identified on literature review, 24 (5.5%) developed tumor recurrence and 14 (3%) eventually died of disease. They also determined another 1159 cases of early cervical carcinoma reported in the literature which could not be separated into ES1 or MICA. Only 16 patients (1.4%) had tumor recurrence and 5 patients (0.4O/o)could be determined to have died of their disease. Wilkinson and Komorowski [ 141 similarly separated their cases of microinvasive carcinoma of the cervix into borderline cases with 1 mm or less infiltration below the basement membrane, comparable to Lohe’s ES1 category, and all other cases with microinvasion to a depth of 5 mm. Of the 29 patients with borderline microinvasive cancer, none developed recurrent cancer. Of the remaining 35 patients with microinvasion to a depth of 5 mm, there were 2 deaths from cervical carcinoma, a mortality rate of 5.6%. In both of these patients, the upper margins of the cone specimen were not free of disease, and persistent, deeper tumor in the cervix was later identified. Holzer [3] from Austria reported on the treatment and follow-up of 324 patients with microinvasive carcinoma of the cervix (230 with ES1 and 94 with MICA). Treatment included some type of radical hysterectomy in 108 patients, simple hysterectomy in 151 patients, conization alone in 61 patients, and irradiation in 4 patients. There were no

recurrent cancers or deaths in the women treated for ESI. Four patients were found to have residual carcinoma in situ in the vagina within 1 year of treatment and were successfully treated. Ninety (95.7%) of 94 patients treated for MICA remained without evidence of recurrent disease. Four patients were subsequently treated for persistent, new or recurrent disease; only one of these patients died of metastatic cervical cancer. Of interest were the 61 patients with microinvasion (53 ES1 and 8 MICA) treated by conization only. All 60 patients with pathologically determined complete tumor removal were alive and well 3 years or longer. Van Nagell et al. [13] reported on 177 patients with squamous cell carcinoma that invaded the cervical stroma to a depth of 5 mm or less. Treatment was by abdominal or vaginal hysterectomy in 93 patients and radical hysterectomy and pelvic lymphadenectomy in 84 patients. Among 145 patients with lesions that invaded to a depth of 3 mm or less, there were no lymph node metastases identified in the 52 patients undergoing lymphadenectomy, only two intraepithelial recurrences, and no deaths from cancer. Conversely, in the 32 patients with carcinoma invading the stroma to 3.1-5.0 mm, there were three patients (9.4%) with lymph node metastases, three invasive cancer recurrences, and two deaths. Creasman et al. [2] reviewed 114 patients with early carcinoma of the cervix treated at their institution. In 74 patients with less than 3 mm invasion, no recurrence developed irrespective of the type of treatment. Recurrences developed in 1 (5%) of 21 patients with 3.1-5.0 mm invasion and in 2 (10%) of 19 patients with 5.1-7.0 mm invasion. All three patients who recurred had positive conization margins with persistent invasive cancer in the hysterectomy specimen. Only two of 45 patients who had free surgical margins on conization had persistent invasive disease of 0.5 mm and 0.26 mm, respectively. The only patients with positive lymph nodes had greater than 5 mm invasion. Simon et al. [12] studied 125 patients with

squamous cell carcinoma of the cervix invading to a depth of 5 mm or less. Treatment modalities included conization alone (7%) vaginal or abdominal hysterectomy (38%) and radical or moditied radical hysterectomy with pelvic lymphadenectomy (56”X). One of the latter two extended operations was chosen for any lesion with invasion exceeding 3 mm in depth or if confluence or lymphvascular space invasion were observed. There was only one intraepithelial recurrence. One (1.4%) of 69 patients with dissected nodes had a single lymph node metastasis; the depth of invasion was 5 mm and the width of the lesion was 10 mm in this patient. Maiman et al. [8] reported on 117 women with superticially invasive (l-5 mm) squamous cell carcinoma of the cervix. Radical or modified radical hysterectomy with pelvic lymphadenectomy was usually performed for women with more than 1 mm invasion; the other 23%) had vaginal or abdominal hysterectomy. node Lymph metastasis occurred in no patients with 1 mm invasion or less, in 2% of patients (l/41) with invasion between 1 and 3 mm, and in 13% of patients (4/30) with invasion greater than 3 mm. All except one of these patients had more than one quadrant of the cervix involved, indicating a high volume tumor not reflected by measurement of depth of invasion alone. There were no recurrences of invasive cancer in this series. Recently, Kolstad [4] from the Norwegian Radium Hospital reported on the treatment and follow-up of 643 patients with microinvasive squamous cell carcinoma of the cervix (233 stage Ial and 411 stage Ia2). Treatment methods were conization (7.5%) simple hysterectomy (21.5%) modified radical hysterectomy (37.6%) radical hysterectomy and pelvic lymphadenectomy (10.6%), and radiotherapy (22.9%)). There were four recurrences in the cervix after conization (only one invasive) and eleven recurrences in the vagina after hysterectomy. Eight of these recurrences occurred in cases with tumor identified at the margin of the surgical specimen. All 14 local Review Article

10

Schink and Lurain

recurrences were successfully treated with additional surgery or intracavitary irradiation. During the follow-up period of 3-17 years, there were four deaths from cervical cancer, a mortality rate of 0.6%. Three of these patients had 4 or 5 mm invasion and the other patient had 2 mm invasion with vascular space involvement. The lymph nodes were not sampled or treated in any of the four patients. Based on these series of reports on treatment and follow-up of patients with microinvasive carcinoma of the cervix, several conclusions can be reached. (1) Decisions on treatment of microinvasive carcinoma of the cervix must be based on careful evaluation of cervical conization specimens with free margins of excision. (2) Geographic extension from the cervical tumor to the parametrial tissues does not occur in lesions invading 5 mm or less without attendant lymphvascular space invasion. (Supported by the Judith M. Patience Memorial Fund 3) Lymph node metastases occur in less than 1% of patients with tumor invading 3 mm or less and in 3-9s of patients with tumor invading 3.1 to 5.0 mm. Treatment recommendations As a clearer understanding of the definition of microinvasive cervix carcinoma has emerg-

Table 3. Treatment vical carcinoma.

recommendations

I. Invasion

for microinvasive

5 3 mm, no lymphvascular (a) Conization, if future fertility

(b) Extrafascial

hysterectomy

cer-

space involvement desired or

(vaginal

or abdominal)

2. Invasion ~3 mm, lymphvascular space involvement Extrafascial or modified radical hysterectomy and pelvic lymphadenectomy 3. Invasion 3.1-5.0 mm Modified radical hysterectomy denectomy 4. Conization

margins

involved

(a) Radical hysterectomy or (b) Radiation therapy

In! J Gynecol Obstet 36

and

pelvic

with microinvasive

lympha-

cancer

and pelvic lymphadenectomy

ed based on risks for lymph node metastasis and recurrence, increasing numbers of patients have been offered and have accepted more conservative therapy. Some patients have been treated by conization, thereby preserving fertility, while many others have had extrafascial hysterectomy as treatment, thereby avoiding the complications of more radical surgical procedures or radiation therapy. In order to justify such an approach, the risk of recurrence and/or death from microinvasive cervix carcinoma ideally should be no greater than the mortality from radical hysterectomy and pelvic lymphadenectomy or radiotherapy, which is approximately 1%. Modern management plans for microinvasive cervix cancer strive for minimal, effective, and safe treatment. Table 3 lists the recommended treatment and options. Patients with early stromal invasion of 1 mm or less (Stage Ial) should be treated very conservatively. The incidence of lymph node metastasis in this group of patients is virtually zero, and the risk of recurrence and death is extremely low [3]. Conization is adequate treatment if the woman wishes to preserve fertility. Extrafascial hysterectomy, either vaginal or abdominal, is appropriate therapy if future fertility is not an issue. Treatment for patients with Stage Ia (microcarcinoma 15 mm depth of invasion and 17 mm in diameter) must be selected carefully. Those patients with invasion of 3 mm or less without lymphvascular space involvement can be treated conservatively, similarly to patients with Stage Ial, either by conization if future fertility is desired or by vaginal or abdominal extrafascial hysterectomy. If, on the other hand, lymphvascular space invasion is present in association with microinvasive cancer of 3 mm or less, optimal treatment remains controversial, but extrafascial abdominal hysterectomy or modified radical hysterectomy should be considered in conjunction with pelvic lymphadenectomy. Patients with microinvasive cancer to a depth of 3.1-5.0 mm should be treated by modified radical hysterectomy and pelvic lymphadenectomy.

The definitions for microinvasive carcinoma (Stage Ia) are not met if the conization margins are involved with microinvasive carcinoma, if the depth of invasion exceeds 5 mm, or if the lateral extension of the microinvasion is more than 7 mm. In any of these circumstances, the patient should be treated for frankly invasive (Stage lb) cervix cancer with either radical hysterectomy and radiation pelvic lymphadenectomy or therapy.

papillomavirus

2

3

DNA of cervical car-

mann L, Parker RT: Management of stage IA carcinoma of the cervix. Am J Obstet Gynecol 153: 164. 1985. Holzer E: Microinvasive carcinoma of the cervix-clinical aspects. treatment and follow-up. Clin Oncol 1: 315. 1982.

4

Kolstad P: Follow-up study of 232 patients with stage lal and 41 I patients with stage la2 squamous cell carcinoma of the cervix (microinvasive carcinoma). Gynecol Oncol 33: 265, 1989.

5

Leman MH Jr. Benson WL, Kurman RJ, Park RC: Microinvasive carcinoma of the cervix. Obstet Gynecol 4X: 571, 1976. Lohe KJ. Burghardt E, Hillemanns HG. Kaufmann C. Ober KG. Zander J: Early squamous cell carcinoma of the uterine cervix. 11. Clinical results of a cooperative study in the management of 419 patients with early stromal invasion and microinvasion. Gynecol Oncol 6: 31. 1978.

Summary 6

Microinvasive cervix cancer is the earliest stage of squamous carcinoma of the cervix. Human papillomavirus (HPV) infection is associated with 80-90% of cases [7]. Risk factors for microinvasive and invasive cervix cancer include multiple sexual partners, early age of first intercourse, cigarette smoking and absence of Pap smear screening. The pretreatment diagnosis of microinvasive cervix cancer can only be made on a cone biopsy specimen with negative surgical margins. Depth of invasion is the most important prognostic factor, but lateral extent of invasive tumor and lymphvascular space involvement must also be considered for appropriate management of these patients. Ignoring extensive lateral spread of tumor or positive cone margins are the most common causes of undertreatment in these patients. Future fertility can be preserved if the tumor is small (57 mm lateral extent) and has 13 mm of invasion without lymphvascular space involvement. Hysterectomy is required for tumors with >3 mm invasion. Strict adherence to treatment guidelines should result in a recurrence rate of only l-2’%.

type I6 into cellular

cinoma: preferential deletion of the E2 gene and invariable retention of the long control region and the E6/E7 open reading frames. Virology 16/: 259, 1987. Creasman WT. Fetter BF, Clarke-Pearson DL. Kauf-

I

Lorincz AT. Temple GF, Kurman RJ. Jensen AB. Lancaster WD: Oncogenic association of specific human papillomavirus types with cervical neoplasia. J Natl Cancer Inst 79: 671, 1987.

8

Maiman MA, Fruchter RG, DiMaio TM, Boyce JG: Superficially invasive squamous cell carcinoma of the cervix. Obstet Gynecol 72: 399, 1988. Rigoni-Stern D: Fatti statistici relativi alle malattse

9 IO II

12

13

I4

cancerose. Giov Servive Roche WD. Norris HJ: cervix. Cancer 36: 180. Rome RM. Chanen W.

Prog Pathol Terap 2: 507. 1842. Microinvasive carcinoma of the 1975. Ostor AG: Preclinical cancer of

the cervix: diagnostic pitfalls. Gynecol Oncol 22: 302, 1985. Simon NL, Gore H. Shingleton HM. Soong SJ. Orr JWJr. Hatch KD: Study of superficially invasive carcinoma of the cervix. Obstet Gynecol 68: 19. 1986. Van Nagell JRJr. Greenwell N. Powell DF. Donaldson ES. Hanson MB. Gay EC: Microinvasive carcinoma of the cervix. Am J Obstet Gynecol 145: 981. 1983. Wilkinson

EJ.

vasive carcinoma

Komorowski

RA:

15

Woodworth

CD. Doniger J. DiPaolo JA. Immortalization foreskin

human

papillomavirus

with cervical

keratinocytes

Section of Gynecologic Oncology

References

Northwestern

J.C. Schink Department

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333 East Superior Street, Suite 420

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This study was supported by the Judith M. Patience Memorial Fund.

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Acknowledgment

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Chicago, IL 6061 I, USA