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The patient-at-risk for development of vulvar cancer
GYNECOLOGIC
ONCOLOGY
9, 199-208 (1980)
The Patient-at-Risk
for Development
of Vulvar Cancer
HOWARD ZACUR, M.D., RENE GENADRY, M.D., AND J. DONALD WOODRUFF, M.D. Department
of Gynecology
and Obstetrics, Baltimore, Maryland
The Johns 21205
Hopkins
Hospital,
Received April 16, 1979 Although the epithelial changes preceding the development of vulvar cancer were seemingly well defined in the early 20th century, recent changes in terminology have altered the interpretation of premalignant alterations as indefinite. The opportunity to follow the events leading to the development of invasive cancer suggest that chronic pruritis-associated atypical keratotic alterations may be the most significant premalignant features.
In the early 20th century, the precursors of vulvar carcinoma were defined by Taussig [l], Berkley and Bonney [2], and others. Leukoplakia, leukoplakic vulvitis, and similar dermatitides were commonly found in association with the malignancy. During the last two decades, studies have suggested that these relationships may not be valid [3,4]. Conversely, the association between chronic pruritis and neoplasia has been suggested in the histories of the classic patient with vulvar cancer. In 1966, Jeffcoate [5] introduced the term “dystrophy” into the nomenclature to describe abnormal epithelial proliferations. Since that time, there have been various interpretations of the malignant potential for the individual case of “vulvar dystrophy” [5,6]. Lichen sclerosus, as one of the dystrophies, has been studied by investigators in the United States and most have come to the conclusion that this common vulvar abnormality is rarely, if ever, a precursor of vulvar cancer [7,8]. Conversely, in other countries a more definite relationship has been proposed. Whether this relationship represents “incrimination by association” or a truly premalignant alteration has not been established clearly. The vague and nebulous relationship between lichen sclerotic dystrophy and cancer has been echoed by some investigators in studies of the hyperplastic dystrophies, namely that “rarely do any of the dystrophies eventuate in the development of neoplasia.” In evaluating this statement, one must appreciate the difference between the long-standing, unattended epithelial abnormality and those that are carefully observed, repeatedly biopsied, and treated to eliminate the common symptom of pruritis. Furthermore, the physician must be aware of the differences in the age of the patient and the malignant potential of the specific condition. Carcinoma in situ arising in the young patient seems to rarely eventuate in invasive cancer. Conversely, similar lesions in the postmenopausal patient 199 0090-8258/80/020199- lO$O1.00/O Copyright @ 1980 by Academic Press. Inc. All rights of reproduction in any Form reserved.
200
ZACUR,
GENADRY,
AND
WOODRUFF
appear to be associated with a much higher risk for the development of mahgnancy. Finally, the histopathologic differences between the classic epithelial neoplasm of the cervix and vulva must be recognized. It is imperative that the physician resist the temptation to transfer knowledge of precursory malignant changes from one to another area even when they are geographically adjacent. The opportunity to follow the sequence of events in a patient with chronic pruritis eventuating in atypical hyperplastic dystrophy and cancer demonstrated the significance of the unique histology of the hyperplastic lesion, the importance of the age of the patient, and the potential relationship between the chronic irritation of pruritis and irreversible epithelial alterations. CASE
REPORT
H.C. was a 70-year-old white female, who complained of vulvar pruritis since the age of 35 years. On initial visit, the skin of the vulva was excoriated, however there was a solitary firm nodule felt to represent a keratosis. The patient was treated with topical testosterone, but, in 3 months there was little, if any, relief. Consequently, the warty hyperkeratotic lesion was excised and alcohol injection performed. The histopathology of the keratotic lesion demonstrated elongated distorted rete pegs and, most significantly, intraepithelial pearl formation in the rete tips of the epithelium (Figs. 1 and 2). Importantly, there was no evidence of superficial epithelial alteration except the marked keratinization. Mitoses were not demonstrated. The patient was followed at 6-month intervals without recurrence of the pruritis or gross abnormality for 3 years; however she then reappeared with a striking hyperkeratotic lesion involving the entire prepuce (Fig. 3). The latter was excise in toto and biopsies were taken at various sites. There was more striking epithelial atypism, again demonstrated most classically by intraepithelial “pearl formation” at the tips of the rete pegs (Figs. 4 and 5). A diagnosis of marked atypical hyperplastic dystrophy was made. The operative site healed and the patient experienced symptomatic relief. Approximately 9 months after the last procedure, a “reddish area with white epithelial islands” was noted on the right lower vulva. Biopsy of this area revealed minimal hyperkeratosis without atypical epithelial maturation. The patient continued to complain of discomfort and excision was proposed. On admission 2 months later, the patient had developed a localized indurated lesion measuring approximately 1 x 1.5 cm. in diameter (Fig. 6). Excision revealed invasive cancer (Fig. 7) characterized histologically by nests of mature keratinizing cells “dropping off’ the normal surface epithelium. The adjacent epithelium demonstrated no individual cell atypism or “in situ neoplasia.” The biopsy taken 6 months prior to the last operation showed alterations simulating those in the area adjacent to the invasive cancer. DISCUSSION
This case demonstrates three important features of the patient-at-risk for the development of vulvar cancer. (1) The patient had had pruritis of 35 years duration. The excoriations, allowing access of numerous infectious agents and promoting constant reparative processes, have been a well-known feature in the past history of the patient with vulvar cancer.
RISK OF VULVAR
CANCER
FIG. 1. Atypical hyperplastic dystrophy; hyperkeratosis with acanthosis and “pearl formation” rete pegs.
in
202
ZACUR,
GENADRY,
AND WOODRUFF
FIG. 2. High power of Fig. 1 showing “pearl formation” cell atypia other than the keratinization.
in rete peg; note the absence of individual
RISK
OF
VULVAR
CANCER
203
204
ZACLJR, GENADRY,
AND WOODRUFF
FIG. 4. Histology of “atypical hyperplastic dystrophy”;
gross seen in Fig. 3.
RISK OF VULVAR
205
CANCER
FIG. 5. High power of Fig. 4 showing atypical keratinization tion; note keratin infiltration with giant cell formation at arrow.
wth “intraepithelial
pearl” forma-
206
ZACUR,
GENADRY,
AND
WOODRUFF
Invasive cancer on left lower vulva; healed incision above clitoris can be seen (surgery 18 FIG. 6. months prior to present).
FIG. 7. Histopathdogy of squamous carcinoma from lesion noted in Fig. 6. Appreciate the absence of striking ” atypia” Biopsy 8 months prior to excision of cancer revealed only the changes seen in the “nonmalignant” epithelium.
in adjacent
epithelium.
f2 4
208
ZACUR,
GENADRY,
AND WOODRUFF
(2) Patients over the age of 60 years with carcinoma in situ are at higher risk for the development of invasive disease particularly if: (3) The precursory lesion is characterized by atypical maturation, “pearl formation” in the rete tips. The invasive cancer in this case did not develop at the site of the previous major histologic alterations but at a totally separate focus suggesting the diffuse nature of the proliferative process as well as its malignant potential. Whether vulvectomy would have prevented the development to the invasive disease is difficult to establish. Nevertheless, one of the two in situ neoplasms progressing to cancer in a series of 102 cases demonstrated a similar histopathologic picture, was treated by vulvectomy, and still succumbed to recurrent malignancy at the incisional site. Thus, it is important to recognize the significance of the persistent, irritating symptom, specifically pruritis; the nature of the atypical hyperplastic dystrophy characterized by “abnormal maturation in the rete tips; and the patient-at-risk.” REFERENCES 1. Taussig, R. J. Disease of the vulva, Appleton, New York (1923). 2. Berkley, C., and Bonney, V. Leukoplakia vulvae and its relationship to Kraurosis vulvae and carcinoma vulvae, Brit. Med. J. 2, 1739 (1909). 3. Langley, H., Hertig, A. T., and Smith, G. S. Relation of leukoplakia vulvitis to squamous carcinoma of the vulva, Amer. .I. Obsfet. Gynecol. 62, 167 (1951). 4. McAdams, A. J., and Kistner, R. W. The reiationship of chronic vulvar leukoplakia and carcinoma in siru to carcinoma of the vulva, Cancer 11, 740 (1958). 5. Jeffcoate, T. N. A. Chronic vulvar dystrophies, Amer. 1. Obstet. Gynecol. 95, 61 (1966). 6. Kaufman, R. H., Gardner, H. L., Brown, D. J., er al. Vulvar dystrophies: An evaluation, Amer. J. Obstet. Gynecol. 120, 363 (1974). 7. Woodruff, J. D., and Baens, J. S. Interpretation of atrophic and hypertrophic alterations in the vulvar epithelium, Amer. J. Obstet. Gynecol. 86, 713 (1963). 8. Hart, W. R., Norris, H. J., and Hellwig, E. B. Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma, Obstet. Gynecol. 45, 369 (1975).
ONCOLOGY
9, 199-208 (1980)
The Patient-at-Risk
for Development
of Vulvar Cancer
HOWARD ZACUR, M.D., RENE GENADRY, M.D., AND J. DONALD WOODRUFF, M.D. Department
of Gynecology
and Obstetrics, Baltimore, Maryland
The Johns 21205
Hopkins
Hospital,
Received April 16, 1979 Although the epithelial changes preceding the development of vulvar cancer were seemingly well defined in the early 20th century, recent changes in terminology have altered the interpretation of premalignant alterations as indefinite. The opportunity to follow the events leading to the development of invasive cancer suggest that chronic pruritis-associated atypical keratotic alterations may be the most significant premalignant features.
In the early 20th century, the precursors of vulvar carcinoma were defined by Taussig [l], Berkley and Bonney [2], and others. Leukoplakia, leukoplakic vulvitis, and similar dermatitides were commonly found in association with the malignancy. During the last two decades, studies have suggested that these relationships may not be valid [3,4]. Conversely, the association between chronic pruritis and neoplasia has been suggested in the histories of the classic patient with vulvar cancer. In 1966, Jeffcoate [5] introduced the term “dystrophy” into the nomenclature to describe abnormal epithelial proliferations. Since that time, there have been various interpretations of the malignant potential for the individual case of “vulvar dystrophy” [5,6]. Lichen sclerosus, as one of the dystrophies, has been studied by investigators in the United States and most have come to the conclusion that this common vulvar abnormality is rarely, if ever, a precursor of vulvar cancer [7,8]. Conversely, in other countries a more definite relationship has been proposed. Whether this relationship represents “incrimination by association” or a truly premalignant alteration has not been established clearly. The vague and nebulous relationship between lichen sclerotic dystrophy and cancer has been echoed by some investigators in studies of the hyperplastic dystrophies, namely that “rarely do any of the dystrophies eventuate in the development of neoplasia.” In evaluating this statement, one must appreciate the difference between the long-standing, unattended epithelial abnormality and those that are carefully observed, repeatedly biopsied, and treated to eliminate the common symptom of pruritis. Furthermore, the physician must be aware of the differences in the age of the patient and the malignant potential of the specific condition. Carcinoma in situ arising in the young patient seems to rarely eventuate in invasive cancer. Conversely, similar lesions in the postmenopausal patient 199 0090-8258/80/020199- lO$O1.00/O Copyright @ 1980 by Academic Press. Inc. All rights of reproduction in any Form reserved.
200
ZACUR,
GENADRY,
AND
WOODRUFF
appear to be associated with a much higher risk for the development of mahgnancy. Finally, the histopathologic differences between the classic epithelial neoplasm of the cervix and vulva must be recognized. It is imperative that the physician resist the temptation to transfer knowledge of precursory malignant changes from one to another area even when they are geographically adjacent. The opportunity to follow the sequence of events in a patient with chronic pruritis eventuating in atypical hyperplastic dystrophy and cancer demonstrated the significance of the unique histology of the hyperplastic lesion, the importance of the age of the patient, and the potential relationship between the chronic irritation of pruritis and irreversible epithelial alterations. CASE
REPORT
H.C. was a 70-year-old white female, who complained of vulvar pruritis since the age of 35 years. On initial visit, the skin of the vulva was excoriated, however there was a solitary firm nodule felt to represent a keratosis. The patient was treated with topical testosterone, but, in 3 months there was little, if any, relief. Consequently, the warty hyperkeratotic lesion was excised and alcohol injection performed. The histopathology of the keratotic lesion demonstrated elongated distorted rete pegs and, most significantly, intraepithelial pearl formation in the rete tips of the epithelium (Figs. 1 and 2). Importantly, there was no evidence of superficial epithelial alteration except the marked keratinization. Mitoses were not demonstrated. The patient was followed at 6-month intervals without recurrence of the pruritis or gross abnormality for 3 years; however she then reappeared with a striking hyperkeratotic lesion involving the entire prepuce (Fig. 3). The latter was excise in toto and biopsies were taken at various sites. There was more striking epithelial atypism, again demonstrated most classically by intraepithelial “pearl formation” at the tips of the rete pegs (Figs. 4 and 5). A diagnosis of marked atypical hyperplastic dystrophy was made. The operative site healed and the patient experienced symptomatic relief. Approximately 9 months after the last procedure, a “reddish area with white epithelial islands” was noted on the right lower vulva. Biopsy of this area revealed minimal hyperkeratosis without atypical epithelial maturation. The patient continued to complain of discomfort and excision was proposed. On admission 2 months later, the patient had developed a localized indurated lesion measuring approximately 1 x 1.5 cm. in diameter (Fig. 6). Excision revealed invasive cancer (Fig. 7) characterized histologically by nests of mature keratinizing cells “dropping off’ the normal surface epithelium. The adjacent epithelium demonstrated no individual cell atypism or “in situ neoplasia.” The biopsy taken 6 months prior to the last operation showed alterations simulating those in the area adjacent to the invasive cancer. DISCUSSION
This case demonstrates three important features of the patient-at-risk for the development of vulvar cancer. (1) The patient had had pruritis of 35 years duration. The excoriations, allowing access of numerous infectious agents and promoting constant reparative processes, have been a well-known feature in the past history of the patient with vulvar cancer.
RISK OF VULVAR
CANCER
FIG. 1. Atypical hyperplastic dystrophy; hyperkeratosis with acanthosis and “pearl formation” rete pegs.
in
202
ZACUR,
GENADRY,
AND WOODRUFF
FIG. 2. High power of Fig. 1 showing “pearl formation” cell atypia other than the keratinization.
in rete peg; note the absence of individual
RISK
OF
VULVAR
CANCER
203
204
ZACLJR, GENADRY,
AND WOODRUFF
FIG. 4. Histology of “atypical hyperplastic dystrophy”;
gross seen in Fig. 3.
RISK OF VULVAR
205
CANCER
FIG. 5. High power of Fig. 4 showing atypical keratinization tion; note keratin infiltration with giant cell formation at arrow.
wth “intraepithelial
pearl” forma-
206
ZACUR,
GENADRY,
AND
WOODRUFF
Invasive cancer on left lower vulva; healed incision above clitoris can be seen (surgery 18 FIG. 6. months prior to present).
FIG. 7. Histopathdogy of squamous carcinoma from lesion noted in Fig. 6. Appreciate the absence of striking ” atypia” Biopsy 8 months prior to excision of cancer revealed only the changes seen in the “nonmalignant” epithelium.
in adjacent
epithelium.
f2 4
208
ZACUR,
GENADRY,
AND WOODRUFF
(2) Patients over the age of 60 years with carcinoma in situ are at higher risk for the development of invasive disease particularly if: (3) The precursory lesion is characterized by atypical maturation, “pearl formation” in the rete tips. The invasive cancer in this case did not develop at the site of the previous major histologic alterations but at a totally separate focus suggesting the diffuse nature of the proliferative process as well as its malignant potential. Whether vulvectomy would have prevented the development to the invasive disease is difficult to establish. Nevertheless, one of the two in situ neoplasms progressing to cancer in a series of 102 cases demonstrated a similar histopathologic picture, was treated by vulvectomy, and still succumbed to recurrent malignancy at the incisional site. Thus, it is important to recognize the significance of the persistent, irritating symptom, specifically pruritis; the nature of the atypical hyperplastic dystrophy characterized by “abnormal maturation in the rete tips; and the patient-at-risk.” REFERENCES 1. Taussig, R. J. Disease of the vulva, Appleton, New York (1923). 2. Berkley, C., and Bonney, V. Leukoplakia vulvae and its relationship to Kraurosis vulvae and carcinoma vulvae, Brit. Med. J. 2, 1739 (1909). 3. Langley, H., Hertig, A. T., and Smith, G. S. Relation of leukoplakia vulvitis to squamous carcinoma of the vulva, Amer. .I. Obsfet. Gynecol. 62, 167 (1951). 4. McAdams, A. J., and Kistner, R. W. The reiationship of chronic vulvar leukoplakia and carcinoma in siru to carcinoma of the vulva, Cancer 11, 740 (1958). 5. Jeffcoate, T. N. A. Chronic vulvar dystrophies, Amer. 1. Obstet. Gynecol. 95, 61 (1966). 6. Kaufman, R. H., Gardner, H. L., Brown, D. J., er al. Vulvar dystrophies: An evaluation, Amer. J. Obstet. Gynecol. 120, 363 (1974). 7. Woodruff, J. D., and Baens, J. S. Interpretation of atrophic and hypertrophic alterations in the vulvar epithelium, Amer. J. Obstet. Gynecol. 86, 713 (1963). 8. Hart, W. R., Norris, H. J., and Hellwig, E. B. Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma, Obstet. Gynecol. 45, 369 (1975).