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Diagnosis and treatment of premalignant lesions of the vulva: A review
Diagnosis and treatment of premalignant
lesions
of the vulva: A review PAUL
B.
UNDERWOOD,
LAWRENCE Charleston,
L. South
HESTER,
JK.,
M.D.
JR.,
M.D.
Carolina
Obstetricians and gynecologists must be aware of any disease process with an increased malignancy potential. The premalignant lesions of the vulva were classified as granulomatous lesions, white lesions, preinvasive lesions, and nevi. Emphasis was placed upon the premalignant potential of the granulomatous lesions with a more conservative approach to the white lesions. Attention should be focused on the entire vulva with the premalignant lesions. Prophylaxis was emphasized with the perineal nevi. The vulva “skinectomy” procedure was endorsed for specific conditions because of the excellent cosmetic results, improved sexual harmon): and hopeful comparative results.
Granulomatous
INVASIVE CARCIALTHOUGH N o M A of the vulva represents less than 5 per cent of gynecologic malignancies and usually occurs in geriatric patients, certain premalignant conditions markedly increase this incidence and frequently are found even in the young woman. Increasing numbers of women are seeking early medical attention for vulva1 irritations and lesions. Obstetricians and gynecologists, therefore, should be aware of any disease process with an increased malignant potential since prevention and/or early diagnosis of any malignancy is the present-day answer to survival. We classified premalignant lesions of the vkllva as shown in Table I. Although other pathologic entities could have been included, their association with vulva1 malignancies is not believed significant enough to be classified as premalignant.
From the Department Gynecology, Medical South Carolina.
lesions
The profound chronic infectious state of granuloma inguinale and long-standing condylomata acuminata with resultant tissue reaction and scarring must be recognized as a carcinogen. Emphasis should be placed on chronicity since in our experience granuloma inguinale and condylomata acuminata if they are treated early rarely resrllt in malignancy. Granuloma inguinale, sometimes referred to as granuloma venerum, has had its etiology attributed to protozoa, viruses, and bacteria, although most agree that a bipolar gramnegative bacterium referred to as Donr)zanin granzdomatis is the causative agent. IL has been classified as a venereal disease; however, it rarely develops in the sexual partner. If it is transmitted by sexual contact, it demonstrates a very low contagious index. This infectious process appears to begin as multiple papules which break down to form many small ulcers with red granular bases and slightly elevated, rolled, purple borders, which rapidly enlarge, coalesce, and spread by auto inoculations to form an enormous esthiomene (Fig. 1). At first they are only slightly tender;
of Obstetrics and University of
Presented by invitation at the Thirtythird Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Atlanta, Georgia, February 7-10, 1971, 849
850
Underwood
and
Table I. Classification
Hester
of premalignant
vulva
lesions Premalignant Granulomatous
Granuloma Condyloma White
lesions
of the vulva
lesion
inguinale accuminatum
lesion
Kraurosis Lichen sclerosus et atrophicus Leukoplakia Atrophic Hypertrophic Preinvasive
lesion
Bowen’s disease Intraepithelial carcinoma Paget’s disease Nevus with junctional
component
but with secondary infection pain may be a chief complaint. In our experience,4 multiple biopsies from the center of the ulcer have been far superior to smears in establishing the diagnoses. With a silver stain (Fig. 2), black “closed safety pin”-appearing organisms in large monocular cells with foamy cytoplasm referred to as Donovan bodies are diagnostic. When present, the epithelium has a pseudoepitheliomatous hyperplastic appearance with marked elongation of the rete pegs which can be confused with carcinoma. Our treatment of choice is four weeks of tetracycline plus meticulous personal hygiene, although oxytetracycline, chloramphenicol, or streptomycin have been used satisfactorily. Healing is slow and may require several weeks for complete epithelialization. A few cases have been seen which healed spontaneously. Marked scarring labial hypertrophy, vaginal stenosis, and brawny edema are frequent permanent complications, and occasionally operation to alleviate these deformities has been required. One cannot state how often these grotesque vulva1 lesions become malignant; however, we have seen several with intraepithelial and/ or invasive squamous cell carcinoma. Therefore, close observation of known healed granuloma inguinale with biopsy of any suspicious areas is mandatory for early diag-
Fig. 1. Granuloma
inguinale
in
the
esthioment:
stage.
nosis. Also, one cannot clinically recognize cancer in active disease (Fig. 3)) again emphasizing the importance of multiple biopsies. Condylomata acuminata, commonly referred to as venereal warts, are of viral origin. Although they may occur as a solitary lesion, usually these papillomas are multiple and if not treated may coalesce into one giant lesion (Fig. 4). Condylomata acuminata occur almost exclusively in genital areas although we have seen one patient with them on the chin and ear (Fig. 5). The incidence of malignant degeneration is unknown ; however, at the Medical University of South Carolina, three of sixty diagnosed vulva1 malignancies arose in condylomata acuminata which compares with the 5 per cent found by others. Is7 Condylomata with malignant changes may grossly appear identical to benign lesions; therefore, all long-standing condylomata, all lesions with ulcerations, and all lesions not responding readily to therapy should have multiple biopsies to rule out invasive carcinoma. The treatment of condylomata acuminata depends on their size, number, and location. The first step is to improve personal hygiene
Voltlme Number
110 G
Diagnosis
Fig. 2. Silver mononuclear
Fig. 3. Active squamous
cell
stain cells).
granuloma carcinoma.
showing
inguinale
Donovan
with
and
bodies
treatment
(“closed
of
premalignant
safety
pin”-appearing
lesions
of
organisms
the
vulva
851
in 1arg.c
invasive
and treat specifically the etiology of the leukorrhca. A 20 per cent solution of podophyllin and benzoin is our preferred treatment of small isolated lesions. Such therapy is usually unsuccessful on lesions over 2 cm. in diameter. Podophyllin is contraindicated in pregnancy due to tissue absorption with smooth
Fig. 1. Giant tains
sevrral
condylomata acuminate which areas of invasive cnrrinllma.
~‘on-
muscle spasm. We have recently seen txo such cases treated in the early third trimester with premature labor resulting. Surgical escision or electrodesiccation is our procedure
852
Underwood
and
Hester
Fig. 5. Condylomata
Amer.
acuminata
of choice in large lesions. With extensive condylomatous lesions or when other methods fail, autogenous vaccine@ have been used with complete healing. We presently have three patients on vaccines, but it is too early to predict the outcome. Irradiation is condemned. The
white
lesion
Much confusion exists over the terms kraurosis, lichensclerosus et atrophicus, and atrophic and hypertrophic leukoplakia. The more one studies the subject, the more convinced one becomes that Jeffcoate and Woodcock’s5 suggestion of placing all these lesions under a heading of chronic epithelial dystrophies prefixed with atrophic or hypertrophic is preferable. Gross and microscopic views compatible with each of these diagnoses can be found on the same vulva. Either the vulva1 epithelium responds in different ways to stimuli or these lesions are various stages of the same disease process. The atrophic vulvitises are essentially represented by white, thin, tight, vulva1 skin with a loss of the labia minora, phimosis of the clitoris, and introital contraction. Microscopically, one sees hyperkeratosis, a thin epithelial layer devoid of rete pegs, and hyalinization of the superficial dermis, with an inflammatory reaction in the mid-dermis. Although these changes are generally seen in the postmenopausal woman, they can occur in children (Fig. 6) ; however, the prognosis
of chin,
ear, and vulva
July lj, 1971 J. Obntet. Gyncc.
of same patient.
differs since generally these changes totally disappear with puberty, suggesting that hormones are involved in this disease process. The hypertrophic lesions appear as thickened, piled-up, whitish plaques surrounded by reddened edematous dry skin in which one frequently sees cracks and fissures. As the disease progresses, vulva1 landmarks are lost and stenosis of the introitus results. Histologically, hyperkeratosis, increased number and depth of penetration of the rete pegs, varying degrees of epithelial atypicalities, especially in rete pegs, and hyalinization with inflammatory infiltrate in the underlying dermis are seen. Since the etiologic factors for each are unknown, it appears of far greater importance to know the malignant potential of these lesions than a specific diagnosis. Although over 50 per cent of vulva1 carcinomas are associated with leukoplakia, only 5 per cent of the leukoplakias actually develops a malignancy. The majority of these neoplasms are associated with hypertrophic leukoplakia although atrophic and hypertrophic vulvitis may be seen side by side, thereby making it difficult to state the origin of the malignant neoplasm. Our management of the white vulva1 lesion is random biopsy for the degree of cellular atypicalities followed by close observation and symptomatic relief. Follow-up examination should be every four to six months with biopsy of all suspicious areas. Symptomatic relief has been reported with multiple prep-
Diagnosis
and
treatment
Fig.
of
premalignant
7. Bowen’s
disease
lesions
of the
vulva
853
of vulva.
plakia. Although we agree that reculrrnt leukoplakia may develop in this patient, this operation was performed over one year ago and she continues to remain symptom-free without clinical evidence of recurrcn( e, Preinvasive
Fig. 6. Twelve-year-old
girl with atrophic
valvitis.
arations; however, a multiple preparation of hydrocortisone acetate, vitamin A, estrone, and pyrilamine maleate” has been the most successful for us. The malignant potential of the white lesion has been overemphasized, and leukoplakia frequently recurs; therefore, vulvectomy should be undertaken only when colIsrrvative measures fail or cellular atypic&ties are severe. Rutledge and Sinclair!’ reported a “skinectomy” procedure in which thr~ vulva1 skin QX.S removed and replaced wilh a split-thickness skin graft. We have performed one SIKH oprration for leuko-
lesions
Rowen’s disease was first described in 19 12, but it was not until the 1920’s that tllis entity was reported on the vulva. Charac tvristically. it appears (Fi,q. 7) as a rpd. “.l~t-, oozing, slightly elevated lesion. i,t!sions arc frequently multifocal and latrr coalesc~t IO involve the entire vulva. Intraepithelial (‘a~‘cinema more often appears as a white Ie&tl, although it may be identical to Ho\xc~~‘s Microscol~ically, Bo~ven’s clisl~a~c~ disease. shows changes typical of any intrael)ithr4ial malignancy but it individualized b>. the atypicalities with l.tr:rck marked cellular hyperchromatic nuclei md frcxluently 111ultiriuclc3tecl cf4ls rc~forrcd to ;I< ISo\\ f*l10icl cells. Since both are the same diseasc and se,,arable only by histologic cellular atypicaIitic*s, their treatment should be identical. As with
854
Underwood
and
Hester
Fig. 8. Vulva one month post cedure. Note the near normal vulva and prominence of clitoris.
“skinectomy” appearance
proof the
all lower genital tract malignancies, carcinogenic stimuli are in contact with the entire vulva, thereby most often resulting in multifocal origin of these lesions. For this reason, treatment should be directed to the entire vulva, although some reports of local excision have proved successful. In the past, simple vulvectomy has been the treatment of choice; however, marked cosmetic changes, vaginal stenosis, loss of the clitoris, dyspareunia, and sexual disharmony have been major problems. We have performed three of Rutledge and Sinclair’9 ‘3kinectomy” procedures on young women with this disease within the past year with gratifying results (Fig. 8). Only time will tell if this
approach is effective for intraepithelial malignancies; however, since they are limited to the epithelium and do not extend into hair shafts or sebaceous glands, one would predict a successful prognosis. Topical use of 2 and 5 per cent 5-fluorouracil has gained popularity in treatment of some premalignant and malignant skin lesions.ll Although very little experience has been gained with its use on the genital tract, it may show promise in the future. We are presently evaluating this therapy but have no results to report. Less than 100 cases of Paget’s disease arising on the vulva have been reported in the literature.6 The histogenesis of this neoplasm appears to be an intraepithelial spread of an adenocarcinoma which most likely arises in apocrine glands. Grossly, the lesion appears identical to intraepithelial carcinoma and Bowen’s disease. Histologically, large cells with clear cytoplasm are seen deep within the epidermis, appearing in greater numbers near the center of the lesion and especially in the rete pegs. They frequently form glands as well as follow hair shafts. With diligent histologic examination, minute adenocarcinomas of the apocrine glands can frequently be found. Only occasionally are these of significant size to be clinically important to warrant treatment as invasive disease. Woodruff and PauersteinlZ studied the metabolic status of Paget’s cells in the epithelium of the vulva and found them to be of a very low activity approaching that of atrophic vulvitis. Differentiating this disease from amelanotic melanomas and squamous cell carcinomas can present a problem. If present, glandular formation within the epithelium is diagnostic of Paget’s disease. Although squamous cell carcinomas do not extend down hair shafts, melanomas may do so on occasion. Histochemical studies may be necessary for differentiation since Paget’s disease is mucicarmine and periodic ac&Schiff positivr, whereas melanomas and squamous cell carcinoma are negative for both stains.6 The treatment consists of a wide simple vulvectomy. Adequate margins cannot be
Diagnosis
and
overemphasized since the disease frequently ext,ends farther than it appears grossly; therefore, local recurrence is very common. If invasive adenocarcinoma is present, the treatment should include bilateral groin dissections. The “skinectomy” procedure would be contraindicated since this neoplasm extends into skin appendages, News Although nevi occur on all skin surfaces of the body, a distinct malignant potential exists in the perineal nevus. This is verified b,. the fact that the perineum represents 1 per cent of the body surface area, yet 5 per cent of all melanomas occur in this region. Irritation and trauma would appear to play a major role in such conversion; however, junctional nevi which have the highest malignant potential appear to be more common on the vulva and thereby may contribute to this increased frequency. Most genital melanomas should be preventable since characteristically these nevi are present from childhood and malignant changes usually occur after age 503, lo and rarely under age 30. Wide cold-knife surgical excision of all hairless nevi of the perineal area at the time of delivery or with gynecologic examinations is worthwhile preventive medicine. There is usually little or no concern for disability, functional impairment, or cosmetic results. Histologic examination is mandatory; therefore, cauterization is to be condemned.
treatment
of
premalignant
lesions
of
the
vulva
855
granulomatous diseases and leukoplakia. toward neoplastic changes of the vulva. Granuloma inguinale has been seen almost exclusively in the young Negro, while condylomata acuminata are associated with poor personal hygiene and sexual promiscuity, with both more frequent in the lower socioeconomic groups. Therefore, granulomatous disease reflects its influence toward the etiology of vulva1 cancer in the young indigent patient. Leukoplakia, on the other hand, develops primarily in postmenopausal Caucasian women, especially in the middle and upper socioeconomic brackets. When one is faced with the difficult problem of where to biopsy a diffuse vulva1 lesion, staining with 1 per cent toluidine blue which, after drying, is rinsed with 1 per cent acetic acid may be helpful. Areas remaining blue are interpreted as positive and should be biopsied. Toluidine blue is a nuclear stain; therefore, any process, cancerous or inflammatory, in which nucleated cells are OJI the surface will give positive results. In our experience, vulva1 smears have been inatlcquate in evaluating lesions. Much controversy exists about several of the lesions discussed. All may contribute toward the development of an invasive carcinoma of the vulva. With this in mincl, regardless of one’s individual beliefs of the specific disease process, obstetricians and gynecologists should practice good prevrntive medicine by frequent and close observation of all patients with these diseases.
Comment Race and socioeconomic status the frequency of the carcinogenic
influence effect of
REFERENCES
1. 2. 3. 4. 5. 6.
Birch, H.: Southern Med. J. 59: 1487, 1965. Bowen, J. T.: J. Cutan. Dis. Incl. Syph. 30: “41, 1912. Gupton, T. D., and D’Urso, J.: Surg. Obstet. Gynec. 119: 1074, 1964. Hester, L. L., Jr.: AMER. J. OBSTET. GYNEC. 62: 312, 1951. Jeffcoate, T. N. A., and Woodcock, A. S.: Brit. Med. T. 2: 127. 1961. Koss, L. d., Ladinsky, S., and Brockunier, *4., Jr.: Obstet. Gynec. 31: 513, 1968.
7.
Mickal, A., Andonie, J. A., and Dougherty, C. M.: Obstet. Gynec. 28: 670, 1966. 8. Powell, L. C., Jr., Pollard, M., and Jinkins, J. I,., Sr.: Southern Med. J. 63: 202, 1970. 9. Rutledge. F., and Sinclair. M.: AMER. 1. OBSTE;. GYN’EC. 102: 806, 1968. 10. Symmonds, R. E., Pratt, J. H., and Dcxkcrty, M. B.: Obstet. Gynec. 15: 543, 1960. 11. Williams. A. C.. and Klein. E.: Cancer 25: 450, 19io. ’ 12. Woodruff, J. D., and Pauerstein, C. J.: Obstet. Gynec. 28: 663, 1966.
856
Underwood
and
Hester
Discussion H. RIDLEY, Atlanta, Georgia. The term “premalignant” is more of a clinical warning than an actual pathologic diagnosis. When the clinician, the gynecologist in this case, tells a patient that she has a premalignant lesion, or at least proceeds to treat her for such, he has based his decision on past observation and actual clinical experience. He is correct in this assumption because many of these lesions have an apparently positive procession toward actual malignancy. However, what causes some lesions to become malignant and others to remain benign within the same geographic skin area continues to be one of the greatest enigmas of medicine today. Multicentric cancer lesions are not uncommon in the genital tract, and their possible existence must be thought of in our careful search and observation. Whether there is a reversibility of a premalignant lesion is up to serious question, Some investigators have indicated by long-term follow-up that the incidence of malignancy is much lower than would be expected in the so-called premalignant lesion. The vulva is a skin area richly endowed with all skin elements and, in addition, is a target for venereal disease, trauma, constant bacterial soilage, and hormone effect. What true carcinogenic factors affect this area are unknown, but there may be one or several factors. Nevertheless, it is universally agreed that the warning term of “premalignant” can be well used with lesions of the vulva more appropriately than any other area in the body. Numerous observers have generally agreed that about 50 per cent of invasive carcinomas of the vulva had their origin in premalignant lesions. However, only 5 per cent of the latter seem to go eventually into invasive carcinoma. A review of the past eleven years, 1959 to 1970 inclusively, at the Grady Memorial Hospital of Atlanta shows that 43 cases of carcinomas of the vulva were diagnosed and treated. There have been 1,836 cases of female genital cancer, excluding the breast, recorded in this same eleven-year period. The incidence of vulvar cancer is 2.3 per cent. It has also been shown that 18 (42 per cent) had what was thought to be a precursor, one or more of the peculiar controversial conditions of the vulva. I do not know how many cases of “leukoplakia” have been seen in the outpatient clinics because these diagnoses are not coded until the patient is admitted to the hospital. As Dr. Underwood has shown by categorization, there are really four large groups of soDR.
JOHN
called premalignant lesions. The granulomatous lesion which, whether it be of a true venereal origin or the condyloma accuminata, definitely is known to have a certain incidence of malignancy, whether this be localized or multicentric. But there yet remains the most controversial group known collectively as “white lesions,” as Dr. Underwood has enumerated. In reviewing most of the current articles on this catch-all diagnosis, it seems that there can be a coexistence of kraurosis, lichen sclerosis et atrophicus, and atrophic and hypertrophic leukoplakia. Dr. Paul Hodgkinsonl published a paper on the leukoplakic vulva, September, 1963, and at that time endorsed for the clinician the common designation by Jef&oate and Woodcock’ of “chronic epithelial dystrophy.” He pointed out that in one patient 12 map biopsies were taken, even on “normal skin,” and the pathologist was satisfied that there were 5 distinct conditions diagnosed microscopically in this one patient. These ranged from normal skin through the premalignant changes and into the diagnosis of carcinoma in situ. The clinician is interested in knowing if the lesion is carcinoma in situ, invasive carcinoma, or a benign condition. Even though there are interesting and subtle differences microscopically that justify the pathologist in so labeling these various premalignant lesions, the treatment must be the same, that is, removing a dangerous or potentially dangerous area form the vulva and controlling the distressing symptoms of pruritis and burning that can occur with these lesions. Generally speaking, these premalignant lesions of the vulva can be treated specifically according to their obvious diagnosis whether it be of granulomatous origin or of the typical so-called “white lesion.” As the areas improve under specific treatment, whether it be by antibiotics, hormones, steroids, or other topical applications, we are obligated to search for and to perform full skin-thickness biopsies of any suspicious regions, or those which seem to be undergoing a change in character. Even the simple vulvectomy is a mutilating procedure and should be reserved for those cases where conservative treatment has failed to give relief and where there has been a demonstrable microscopic change toward carcinoma in situ. Although we resort to wide excisional biopsies and simple vulvectomies in refractive and suspicious cases, we have had no experience as yet with the “skinectomy” of Rutledge. It seems to be a logical conservative approach to a lesion which
Voiume Number
110 G
Diagnosis
and
remains within the superficial layers of the skin. We endorse the use of frequent or incidental biopsy of vulvar lesions, such as the pigmented nevus and stubborn skin cyst, because of the rr:tl possibility that we may find a melanoma or metastatic adenocarcinoma that can be confused with hidradenoma or other rare mal@ancy.
REFERENCES
1. Hodgkinson, C. P., Patton, R. B. P., and Avers. Henrv’ Ford Hosnital Med. B;ll. ‘11:M. A.: 1963. 1 279, 2. Jeffcoate, T. N. A., and Woodcock, A. S.: Brit. Med. J. 3: 127, 1961. DR. JOSEPH W. SCOTT, Miami, Florida. This topic is always timely, but particularly so now, because premalignant lesions of the vulva are being encountered in younger women. Whether this is due to increasing atmospheric radiation, oml contraceptive agents, changing sexual habits of society in the younger generation, or to the use of those widely advertised antiseptic soaps and feminine deodorants and sprays I cannot tell you. ‘I am pleased to see condyloma accuminata included as premalignant, because this has not been commonly recognized. I stopped treating these lesions with podophyllum in 1965 when Kaminetzky, Swerdlow, and McGrew showed that this agent could produce dysplasia in cervical epithelium. I consider the vulva1 skin and cervical epithelium to possess similar characteristics, and until such time as podophyllum can be shown to be noncarcinogenic when applied to the vulva1 skin I hesitate to use it again. When condyloma accuminata are present, I examine the vulva with a colposcope. Arr:as with maximum colposcopic change are exe-ised for biopsy. If histologically benign, the remaining lesions can be safely treated by cryo-
treatment
of premalignant
lesions
of
the
vulva
857
surgical cauterization, or electrosurgical desiccation. However, it is important to remembrr that cryosurgically these lesions require a douhlefreeze injury if treatment is to be successltd. I do not believe that any vulva1 lesion should bt: cauterized, coagulated, or frozen unless it is known with certainty that it is a benign condition. Because of the ever-decreasing age at Mrhich we find these premalignancies, a plea is made> for more conservative management than has usually been advocated. Carcinoma in situ and leukoplakia of the vulva are no longer mysterious invisible foci of disease in the vas: expanse of skin of the vulva. Even tiny areas can be found with the colposcope and removed with ease. The authors recommended random biopsy of white lesions. I plead for sampling spot biopsy of areas of maximum colposcopic change under colposcopic guidance. In this way maximum pathologic change in any vulva is easily cletcrmined prior to definitive treatment. The extent of all those lesions is easily determinable culposcopically. I agree that older women with these lesions require radical treatment. However, in contrast to the authors, who recommend “skinectomy,” and Collins who recommends vulvectom y, I prefer wide local excision in young patients, with adequate frequent follow-up. More estensive treatment is reserved for older women. fol lesions with multiple foci, for multiple rf’currences, and for women who have insu&:ient medical intelligence to submit to adequate control and follow-up. The “skinectomy” operation is worth! of trial. A Z Plasty in the suture line on both sides of the introital suture line should bc performed to minimize stenosis, as I describc,d in 1963. I ask the authors if there is some special reason for omitting erythroplasia of Queyr~$1 ?
lesions
of the vulva: A review PAUL
B.
UNDERWOOD,
LAWRENCE Charleston,
L. South
HESTER,
JK.,
M.D.
JR.,
M.D.
Carolina
Obstetricians and gynecologists must be aware of any disease process with an increased malignancy potential. The premalignant lesions of the vulva were classified as granulomatous lesions, white lesions, preinvasive lesions, and nevi. Emphasis was placed upon the premalignant potential of the granulomatous lesions with a more conservative approach to the white lesions. Attention should be focused on the entire vulva with the premalignant lesions. Prophylaxis was emphasized with the perineal nevi. The vulva “skinectomy” procedure was endorsed for specific conditions because of the excellent cosmetic results, improved sexual harmon): and hopeful comparative results.
Granulomatous
INVASIVE CARCIALTHOUGH N o M A of the vulva represents less than 5 per cent of gynecologic malignancies and usually occurs in geriatric patients, certain premalignant conditions markedly increase this incidence and frequently are found even in the young woman. Increasing numbers of women are seeking early medical attention for vulva1 irritations and lesions. Obstetricians and gynecologists, therefore, should be aware of any disease process with an increased malignant potential since prevention and/or early diagnosis of any malignancy is the present-day answer to survival. We classified premalignant lesions of the vkllva as shown in Table I. Although other pathologic entities could have been included, their association with vulva1 malignancies is not believed significant enough to be classified as premalignant.
From the Department Gynecology, Medical South Carolina.
lesions
The profound chronic infectious state of granuloma inguinale and long-standing condylomata acuminata with resultant tissue reaction and scarring must be recognized as a carcinogen. Emphasis should be placed on chronicity since in our experience granuloma inguinale and condylomata acuminata if they are treated early rarely resrllt in malignancy. Granuloma inguinale, sometimes referred to as granuloma venerum, has had its etiology attributed to protozoa, viruses, and bacteria, although most agree that a bipolar gramnegative bacterium referred to as Donr)zanin granzdomatis is the causative agent. IL has been classified as a venereal disease; however, it rarely develops in the sexual partner. If it is transmitted by sexual contact, it demonstrates a very low contagious index. This infectious process appears to begin as multiple papules which break down to form many small ulcers with red granular bases and slightly elevated, rolled, purple borders, which rapidly enlarge, coalesce, and spread by auto inoculations to form an enormous esthiomene (Fig. 1). At first they are only slightly tender;
of Obstetrics and University of
Presented by invitation at the Thirtythird Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Atlanta, Georgia, February 7-10, 1971, 849
850
Underwood
and
Table I. Classification
Hester
of premalignant
vulva
lesions Premalignant Granulomatous
Granuloma Condyloma White
lesions
of the vulva
lesion
inguinale accuminatum
lesion
Kraurosis Lichen sclerosus et atrophicus Leukoplakia Atrophic Hypertrophic Preinvasive
lesion
Bowen’s disease Intraepithelial carcinoma Paget’s disease Nevus with junctional
component
but with secondary infection pain may be a chief complaint. In our experience,4 multiple biopsies from the center of the ulcer have been far superior to smears in establishing the diagnoses. With a silver stain (Fig. 2), black “closed safety pin”-appearing organisms in large monocular cells with foamy cytoplasm referred to as Donovan bodies are diagnostic. When present, the epithelium has a pseudoepitheliomatous hyperplastic appearance with marked elongation of the rete pegs which can be confused with carcinoma. Our treatment of choice is four weeks of tetracycline plus meticulous personal hygiene, although oxytetracycline, chloramphenicol, or streptomycin have been used satisfactorily. Healing is slow and may require several weeks for complete epithelialization. A few cases have been seen which healed spontaneously. Marked scarring labial hypertrophy, vaginal stenosis, and brawny edema are frequent permanent complications, and occasionally operation to alleviate these deformities has been required. One cannot state how often these grotesque vulva1 lesions become malignant; however, we have seen several with intraepithelial and/ or invasive squamous cell carcinoma. Therefore, close observation of known healed granuloma inguinale with biopsy of any suspicious areas is mandatory for early diag-
Fig. 1. Granuloma
inguinale
in
the
esthioment:
stage.
nosis. Also, one cannot clinically recognize cancer in active disease (Fig. 3)) again emphasizing the importance of multiple biopsies. Condylomata acuminata, commonly referred to as venereal warts, are of viral origin. Although they may occur as a solitary lesion, usually these papillomas are multiple and if not treated may coalesce into one giant lesion (Fig. 4). Condylomata acuminata occur almost exclusively in genital areas although we have seen one patient with them on the chin and ear (Fig. 5). The incidence of malignant degeneration is unknown ; however, at the Medical University of South Carolina, three of sixty diagnosed vulva1 malignancies arose in condylomata acuminata which compares with the 5 per cent found by others. Is7 Condylomata with malignant changes may grossly appear identical to benign lesions; therefore, all long-standing condylomata, all lesions with ulcerations, and all lesions not responding readily to therapy should have multiple biopsies to rule out invasive carcinoma. The treatment of condylomata acuminata depends on their size, number, and location. The first step is to improve personal hygiene
Voltlme Number
110 G
Diagnosis
Fig. 2. Silver mononuclear
Fig. 3. Active squamous
cell
stain cells).
granuloma carcinoma.
showing
inguinale
Donovan
with
and
bodies
treatment
(“closed
of
premalignant
safety
pin”-appearing
lesions
of
organisms
the
vulva
851
in 1arg.c
invasive
and treat specifically the etiology of the leukorrhca. A 20 per cent solution of podophyllin and benzoin is our preferred treatment of small isolated lesions. Such therapy is usually unsuccessful on lesions over 2 cm. in diameter. Podophyllin is contraindicated in pregnancy due to tissue absorption with smooth
Fig. 1. Giant tains
sevrral
condylomata acuminate which areas of invasive cnrrinllma.
~‘on-
muscle spasm. We have recently seen txo such cases treated in the early third trimester with premature labor resulting. Surgical escision or electrodesiccation is our procedure
852
Underwood
and
Hester
Fig. 5. Condylomata
Amer.
acuminata
of choice in large lesions. With extensive condylomatous lesions or when other methods fail, autogenous vaccine@ have been used with complete healing. We presently have three patients on vaccines, but it is too early to predict the outcome. Irradiation is condemned. The
white
lesion
Much confusion exists over the terms kraurosis, lichensclerosus et atrophicus, and atrophic and hypertrophic leukoplakia. The more one studies the subject, the more convinced one becomes that Jeffcoate and Woodcock’s5 suggestion of placing all these lesions under a heading of chronic epithelial dystrophies prefixed with atrophic or hypertrophic is preferable. Gross and microscopic views compatible with each of these diagnoses can be found on the same vulva. Either the vulva1 epithelium responds in different ways to stimuli or these lesions are various stages of the same disease process. The atrophic vulvitises are essentially represented by white, thin, tight, vulva1 skin with a loss of the labia minora, phimosis of the clitoris, and introital contraction. Microscopically, one sees hyperkeratosis, a thin epithelial layer devoid of rete pegs, and hyalinization of the superficial dermis, with an inflammatory reaction in the mid-dermis. Although these changes are generally seen in the postmenopausal woman, they can occur in children (Fig. 6) ; however, the prognosis
of chin,
ear, and vulva
July lj, 1971 J. Obntet. Gyncc.
of same patient.
differs since generally these changes totally disappear with puberty, suggesting that hormones are involved in this disease process. The hypertrophic lesions appear as thickened, piled-up, whitish plaques surrounded by reddened edematous dry skin in which one frequently sees cracks and fissures. As the disease progresses, vulva1 landmarks are lost and stenosis of the introitus results. Histologically, hyperkeratosis, increased number and depth of penetration of the rete pegs, varying degrees of epithelial atypicalities, especially in rete pegs, and hyalinization with inflammatory infiltrate in the underlying dermis are seen. Since the etiologic factors for each are unknown, it appears of far greater importance to know the malignant potential of these lesions than a specific diagnosis. Although over 50 per cent of vulva1 carcinomas are associated with leukoplakia, only 5 per cent of the leukoplakias actually develops a malignancy. The majority of these neoplasms are associated with hypertrophic leukoplakia although atrophic and hypertrophic vulvitis may be seen side by side, thereby making it difficult to state the origin of the malignant neoplasm. Our management of the white vulva1 lesion is random biopsy for the degree of cellular atypicalities followed by close observation and symptomatic relief. Follow-up examination should be every four to six months with biopsy of all suspicious areas. Symptomatic relief has been reported with multiple prep-
Diagnosis
and
treatment
Fig.
of
premalignant
7. Bowen’s
disease
lesions
of the
vulva
853
of vulva.
plakia. Although we agree that reculrrnt leukoplakia may develop in this patient, this operation was performed over one year ago and she continues to remain symptom-free without clinical evidence of recurrcn( e, Preinvasive
Fig. 6. Twelve-year-old
girl with atrophic
valvitis.
arations; however, a multiple preparation of hydrocortisone acetate, vitamin A, estrone, and pyrilamine maleate” has been the most successful for us. The malignant potential of the white lesion has been overemphasized, and leukoplakia frequently recurs; therefore, vulvectomy should be undertaken only when colIsrrvative measures fail or cellular atypic&ties are severe. Rutledge and Sinclair!’ reported a “skinectomy” procedure in which thr~ vulva1 skin QX.S removed and replaced wilh a split-thickness skin graft. We have performed one SIKH oprration for leuko-
lesions
Rowen’s disease was first described in 19 12, but it was not until the 1920’s that tllis entity was reported on the vulva. Charac tvristically. it appears (Fi,q. 7) as a rpd. “.l~t-, oozing, slightly elevated lesion. i,t!sions arc frequently multifocal and latrr coalesc~t IO involve the entire vulva. Intraepithelial (‘a~‘cinema more often appears as a white Ie&tl, although it may be identical to Ho\xc~~‘s Microscol~ically, Bo~ven’s clisl~a~c~ disease. shows changes typical of any intrael)ithr4ial malignancy but it individualized b>. the atypicalities with l.tr:rck marked cellular hyperchromatic nuclei md frcxluently 111ultiriuclc3tecl cf4ls rc~forrcd to ;I< ISo\\ f*l10icl cells. Since both are the same diseasc and se,,arable only by histologic cellular atypicaIitic*s, their treatment should be identical. As with
854
Underwood
and
Hester
Fig. 8. Vulva one month post cedure. Note the near normal vulva and prominence of clitoris.
“skinectomy” appearance
proof the
all lower genital tract malignancies, carcinogenic stimuli are in contact with the entire vulva, thereby most often resulting in multifocal origin of these lesions. For this reason, treatment should be directed to the entire vulva, although some reports of local excision have proved successful. In the past, simple vulvectomy has been the treatment of choice; however, marked cosmetic changes, vaginal stenosis, loss of the clitoris, dyspareunia, and sexual disharmony have been major problems. We have performed three of Rutledge and Sinclair’9 ‘3kinectomy” procedures on young women with this disease within the past year with gratifying results (Fig. 8). Only time will tell if this
approach is effective for intraepithelial malignancies; however, since they are limited to the epithelium and do not extend into hair shafts or sebaceous glands, one would predict a successful prognosis. Topical use of 2 and 5 per cent 5-fluorouracil has gained popularity in treatment of some premalignant and malignant skin lesions.ll Although very little experience has been gained with its use on the genital tract, it may show promise in the future. We are presently evaluating this therapy but have no results to report. Less than 100 cases of Paget’s disease arising on the vulva have been reported in the literature.6 The histogenesis of this neoplasm appears to be an intraepithelial spread of an adenocarcinoma which most likely arises in apocrine glands. Grossly, the lesion appears identical to intraepithelial carcinoma and Bowen’s disease. Histologically, large cells with clear cytoplasm are seen deep within the epidermis, appearing in greater numbers near the center of the lesion and especially in the rete pegs. They frequently form glands as well as follow hair shafts. With diligent histologic examination, minute adenocarcinomas of the apocrine glands can frequently be found. Only occasionally are these of significant size to be clinically important to warrant treatment as invasive disease. Woodruff and PauersteinlZ studied the metabolic status of Paget’s cells in the epithelium of the vulva and found them to be of a very low activity approaching that of atrophic vulvitis. Differentiating this disease from amelanotic melanomas and squamous cell carcinomas can present a problem. If present, glandular formation within the epithelium is diagnostic of Paget’s disease. Although squamous cell carcinomas do not extend down hair shafts, melanomas may do so on occasion. Histochemical studies may be necessary for differentiation since Paget’s disease is mucicarmine and periodic ac&Schiff positivr, whereas melanomas and squamous cell carcinoma are negative for both stains.6 The treatment consists of a wide simple vulvectomy. Adequate margins cannot be
Diagnosis
and
overemphasized since the disease frequently ext,ends farther than it appears grossly; therefore, local recurrence is very common. If invasive adenocarcinoma is present, the treatment should include bilateral groin dissections. The “skinectomy” procedure would be contraindicated since this neoplasm extends into skin appendages, News Although nevi occur on all skin surfaces of the body, a distinct malignant potential exists in the perineal nevus. This is verified b,. the fact that the perineum represents 1 per cent of the body surface area, yet 5 per cent of all melanomas occur in this region. Irritation and trauma would appear to play a major role in such conversion; however, junctional nevi which have the highest malignant potential appear to be more common on the vulva and thereby may contribute to this increased frequency. Most genital melanomas should be preventable since characteristically these nevi are present from childhood and malignant changes usually occur after age 503, lo and rarely under age 30. Wide cold-knife surgical excision of all hairless nevi of the perineal area at the time of delivery or with gynecologic examinations is worthwhile preventive medicine. There is usually little or no concern for disability, functional impairment, or cosmetic results. Histologic examination is mandatory; therefore, cauterization is to be condemned.
treatment
of
premalignant
lesions
of
the
vulva
855
granulomatous diseases and leukoplakia. toward neoplastic changes of the vulva. Granuloma inguinale has been seen almost exclusively in the young Negro, while condylomata acuminata are associated with poor personal hygiene and sexual promiscuity, with both more frequent in the lower socioeconomic groups. Therefore, granulomatous disease reflects its influence toward the etiology of vulva1 cancer in the young indigent patient. Leukoplakia, on the other hand, develops primarily in postmenopausal Caucasian women, especially in the middle and upper socioeconomic brackets. When one is faced with the difficult problem of where to biopsy a diffuse vulva1 lesion, staining with 1 per cent toluidine blue which, after drying, is rinsed with 1 per cent acetic acid may be helpful. Areas remaining blue are interpreted as positive and should be biopsied. Toluidine blue is a nuclear stain; therefore, any process, cancerous or inflammatory, in which nucleated cells are OJI the surface will give positive results. In our experience, vulva1 smears have been inatlcquate in evaluating lesions. Much controversy exists about several of the lesions discussed. All may contribute toward the development of an invasive carcinoma of the vulva. With this in mincl, regardless of one’s individual beliefs of the specific disease process, obstetricians and gynecologists should practice good prevrntive medicine by frequent and close observation of all patients with these diseases.
Comment Race and socioeconomic status the frequency of the carcinogenic
influence effect of
REFERENCES
1. 2. 3. 4. 5. 6.
Birch, H.: Southern Med. J. 59: 1487, 1965. Bowen, J. T.: J. Cutan. Dis. Incl. Syph. 30: “41, 1912. Gupton, T. D., and D’Urso, J.: Surg. Obstet. Gynec. 119: 1074, 1964. Hester, L. L., Jr.: AMER. J. OBSTET. GYNEC. 62: 312, 1951. Jeffcoate, T. N. A., and Woodcock, A. S.: Brit. Med. T. 2: 127. 1961. Koss, L. d., Ladinsky, S., and Brockunier, *4., Jr.: Obstet. Gynec. 31: 513, 1968.
7.
Mickal, A., Andonie, J. A., and Dougherty, C. M.: Obstet. Gynec. 28: 670, 1966. 8. Powell, L. C., Jr., Pollard, M., and Jinkins, J. I,., Sr.: Southern Med. J. 63: 202, 1970. 9. Rutledge. F., and Sinclair. M.: AMER. 1. OBSTE;. GYN’EC. 102: 806, 1968. 10. Symmonds, R. E., Pratt, J. H., and Dcxkcrty, M. B.: Obstet. Gynec. 15: 543, 1960. 11. Williams. A. C.. and Klein. E.: Cancer 25: 450, 19io. ’ 12. Woodruff, J. D., and Pauerstein, C. J.: Obstet. Gynec. 28: 663, 1966.
856
Underwood
and
Hester
Discussion H. RIDLEY, Atlanta, Georgia. The term “premalignant” is more of a clinical warning than an actual pathologic diagnosis. When the clinician, the gynecologist in this case, tells a patient that she has a premalignant lesion, or at least proceeds to treat her for such, he has based his decision on past observation and actual clinical experience. He is correct in this assumption because many of these lesions have an apparently positive procession toward actual malignancy. However, what causes some lesions to become malignant and others to remain benign within the same geographic skin area continues to be one of the greatest enigmas of medicine today. Multicentric cancer lesions are not uncommon in the genital tract, and their possible existence must be thought of in our careful search and observation. Whether there is a reversibility of a premalignant lesion is up to serious question, Some investigators have indicated by long-term follow-up that the incidence of malignancy is much lower than would be expected in the so-called premalignant lesion. The vulva is a skin area richly endowed with all skin elements and, in addition, is a target for venereal disease, trauma, constant bacterial soilage, and hormone effect. What true carcinogenic factors affect this area are unknown, but there may be one or several factors. Nevertheless, it is universally agreed that the warning term of “premalignant” can be well used with lesions of the vulva more appropriately than any other area in the body. Numerous observers have generally agreed that about 50 per cent of invasive carcinomas of the vulva had their origin in premalignant lesions. However, only 5 per cent of the latter seem to go eventually into invasive carcinoma. A review of the past eleven years, 1959 to 1970 inclusively, at the Grady Memorial Hospital of Atlanta shows that 43 cases of carcinomas of the vulva were diagnosed and treated. There have been 1,836 cases of female genital cancer, excluding the breast, recorded in this same eleven-year period. The incidence of vulvar cancer is 2.3 per cent. It has also been shown that 18 (42 per cent) had what was thought to be a precursor, one or more of the peculiar controversial conditions of the vulva. I do not know how many cases of “leukoplakia” have been seen in the outpatient clinics because these diagnoses are not coded until the patient is admitted to the hospital. As Dr. Underwood has shown by categorization, there are really four large groups of soDR.
JOHN
called premalignant lesions. The granulomatous lesion which, whether it be of a true venereal origin or the condyloma accuminata, definitely is known to have a certain incidence of malignancy, whether this be localized or multicentric. But there yet remains the most controversial group known collectively as “white lesions,” as Dr. Underwood has enumerated. In reviewing most of the current articles on this catch-all diagnosis, it seems that there can be a coexistence of kraurosis, lichen sclerosis et atrophicus, and atrophic and hypertrophic leukoplakia. Dr. Paul Hodgkinsonl published a paper on the leukoplakic vulva, September, 1963, and at that time endorsed for the clinician the common designation by Jef&oate and Woodcock’ of “chronic epithelial dystrophy.” He pointed out that in one patient 12 map biopsies were taken, even on “normal skin,” and the pathologist was satisfied that there were 5 distinct conditions diagnosed microscopically in this one patient. These ranged from normal skin through the premalignant changes and into the diagnosis of carcinoma in situ. The clinician is interested in knowing if the lesion is carcinoma in situ, invasive carcinoma, or a benign condition. Even though there are interesting and subtle differences microscopically that justify the pathologist in so labeling these various premalignant lesions, the treatment must be the same, that is, removing a dangerous or potentially dangerous area form the vulva and controlling the distressing symptoms of pruritis and burning that can occur with these lesions. Generally speaking, these premalignant lesions of the vulva can be treated specifically according to their obvious diagnosis whether it be of granulomatous origin or of the typical so-called “white lesion.” As the areas improve under specific treatment, whether it be by antibiotics, hormones, steroids, or other topical applications, we are obligated to search for and to perform full skin-thickness biopsies of any suspicious regions, or those which seem to be undergoing a change in character. Even the simple vulvectomy is a mutilating procedure and should be reserved for those cases where conservative treatment has failed to give relief and where there has been a demonstrable microscopic change toward carcinoma in situ. Although we resort to wide excisional biopsies and simple vulvectomies in refractive and suspicious cases, we have had no experience as yet with the “skinectomy” of Rutledge. It seems to be a logical conservative approach to a lesion which
Voiume Number
110 G
Diagnosis
and
remains within the superficial layers of the skin. We endorse the use of frequent or incidental biopsy of vulvar lesions, such as the pigmented nevus and stubborn skin cyst, because of the rr:tl possibility that we may find a melanoma or metastatic adenocarcinoma that can be confused with hidradenoma or other rare mal@ancy.
REFERENCES
1. Hodgkinson, C. P., Patton, R. B. P., and Avers. Henrv’ Ford Hosnital Med. B;ll. ‘11:M. A.: 1963. 1 279, 2. Jeffcoate, T. N. A., and Woodcock, A. S.: Brit. Med. J. 3: 127, 1961. DR. JOSEPH W. SCOTT, Miami, Florida. This topic is always timely, but particularly so now, because premalignant lesions of the vulva are being encountered in younger women. Whether this is due to increasing atmospheric radiation, oml contraceptive agents, changing sexual habits of society in the younger generation, or to the use of those widely advertised antiseptic soaps and feminine deodorants and sprays I cannot tell you. ‘I am pleased to see condyloma accuminata included as premalignant, because this has not been commonly recognized. I stopped treating these lesions with podophyllum in 1965 when Kaminetzky, Swerdlow, and McGrew showed that this agent could produce dysplasia in cervical epithelium. I consider the vulva1 skin and cervical epithelium to possess similar characteristics, and until such time as podophyllum can be shown to be noncarcinogenic when applied to the vulva1 skin I hesitate to use it again. When condyloma accuminata are present, I examine the vulva with a colposcope. Arr:as with maximum colposcopic change are exe-ised for biopsy. If histologically benign, the remaining lesions can be safely treated by cryo-
treatment
of premalignant
lesions
of
the
vulva
857
surgical cauterization, or electrosurgical desiccation. However, it is important to remembrr that cryosurgically these lesions require a douhlefreeze injury if treatment is to be successltd. I do not believe that any vulva1 lesion should bt: cauterized, coagulated, or frozen unless it is known with certainty that it is a benign condition. Because of the ever-decreasing age at Mrhich we find these premalignancies, a plea is made> for more conservative management than has usually been advocated. Carcinoma in situ and leukoplakia of the vulva are no longer mysterious invisible foci of disease in the vas: expanse of skin of the vulva. Even tiny areas can be found with the colposcope and removed with ease. The authors recommended random biopsy of white lesions. I plead for sampling spot biopsy of areas of maximum colposcopic change under colposcopic guidance. In this way maximum pathologic change in any vulva is easily cletcrmined prior to definitive treatment. The extent of all those lesions is easily determinable culposcopically. I agree that older women with these lesions require radical treatment. However, in contrast to the authors, who recommend “skinectomy,” and Collins who recommends vulvectom y, I prefer wide local excision in young patients, with adequate frequent follow-up. More estensive treatment is reserved for older women. fol lesions with multiple foci, for multiple rf’currences, and for women who have insu&:ient medical intelligence to submit to adequate control and follow-up. The “skinectomy” operation is worth! of trial. A Z Plasty in the suture line on both sides of the introital suture line should bc performed to minimize stenosis, as I describc,d in 1963. I ask the authors if there is some special reason for omitting erythroplasia of Queyr~$1 ?