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Genetic cutaneous disorders with gynecologic tumors
Genetic cutaneous disorders with gynecologic tumors RALPH
H.
WILLIAM Loma
Linda
WALKER, B.
REED,
and Irvine,
M.D. M.D.
California
The
paper will present a brief reference to reports in the literature and a discussion hereditary autosomal dominant cutaneous lesions that have asociated pathology of the reproductive system. The first is a case presentation of basal cell nevi syndrome and multiple ouarian fibromas, and the second is cutaneous leiomyoma associated with leiomyosarcoma of the uterus and hypernephroma.
of 2
ity. She was admitted to St. Joseph Hospital on October 10, 1971, because of a large pelvic mass palpated over the left ovary. Closer examination revealed 2 very small basal cell carcinomas of the left eyelid and one of the right cheek. One of the jaw cysts had increased in size. Dyskeratosis (pitting) was evident on the palms and on the soles of the feet.” On October 11, 1971, left salpingo-oophorectomy and wedge resection of the right ovary, appendectomy, and curettage were carried out. The uterus was very immature, corresponding in size and color to that of a 6-year-old girl. The left ovary (Fig. 1) contained a large oval tumor measuring 6 by 8 by 11.5 cm. and weighing 3 10 grams. Its surface was generally smooth but showed irregular bosselations varying frotn 2 to 20 mm. The Fallopian tube was normal. A section of the tumor showed multiple oval nodules of firm, light tan tissue varying from 5 mm. to 2 cm. in greatest dimension. Pathologic diagnosis was granulosatheta tumor versus fibroma consisting chiefly of interlacing spindle-shaped cells of a fibroblastic type which were generally well differentiated. Some calcific bodies were interspersed in places. In only one area, cells of a small plump type, supported by edematous stroma with the appearance of granulosa cells, were noted. The right ovary (Fig. 2) was grossly approximately 3 times average size with an opaque, smooth, pink surface. The section demonstrated a small fibromatous nodule with numerous cystic follicles in the underlying parenchyma. The postoperative course was uncomplicated and she was discharged.
THE s K I N may be important in the diagnosis of genetic disorders affecting the uterus and ovaries. Presented are 2 case reports of patients with two such genetic disorders, one known for ovarian tumors to dermatologists and clinical geneticists ; the other, rare and unique. A general discussion of genetic cutaneous lesions with documented ovarian tumors reported is included. Case reports Case No. 1. Nevoid basal cell carcinoma syndrome with bilateral ovarian tumors. This 16year-old girl first came to our attention because of amenorrhea. Physically, she was a fully developed girl who had done some modeling. Two years previously, in 1970, a basal cell carcinoma was removed from the abdomen. The face and neck were free of carcinoma at that time. Her father, a radiologic technician, found multiple dental cysts and a vertebral column abnormalFrom the Department of Obstetrics and Gynecology, Loma Linda University and the University of Southern California School of Medicine, and the Department of Medicine (Dermatology), University of California, Irvine. Presented at the Thirty-ninth Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Harrison Hot Springs, British Columbia, Canada, October 3-7, 1972. Reprint requests: Ralph H. Walker, M.D., 10711 Riverside Dr., North Hollywood, California 91602.
485
486
Walker
and Reed
Fig. 1. Left ovary: Section shows irregularly interlacing spindle cells. (Hematoxylin magnification x156.)
of ovarian fibroma bundles of uniform and eosin. Original
On November 9, 1971, the patient was rcadmitted to St. Joseph Hospital for plastic surgery of the 2 very small basal cell carcinomas (Fig. 3) and excision of the periodontal cysts (Fig. -1 :. The ja\v cysts had thin fibrous walls lined by a fairly regular stratified squamous epithrlium; there was no evidence of malignancy. Sections of the skin showed solid basal cell carcinoma. Postoperatively, the patient has had several menstrual periods; the first, one month after operation and then none for 2 months. After one course of clomiphene citrate,* 50 mg. daily for 5 days, she has continued to have menses at 4, to 6 week intervals. The patient’s findings atrihuted to the basal cell nevoid syndrome were: basal cell nevi; skeletal : frontal bossing, hypertelorism, vertebral column anomaly, hrachymetacarpia, mandibular cysts, and dyskeratosis of the palms and soles of feet; ovarian: granulosa-theta cell tumor and fibroma.’ Visibly,
the
‘Clomid, Wm. Inc.. Cincinnati,
patient S. Merrrll Ohio.
did Co..
not
appear
to
Div.
Richardson-Merrcll.
have
Fig. 2. Right ovary: The specimen consisted of a wedge of ovarian tissue measuring 1 by 1.2 by 4.5 cm. The capsule was thick, and thr parenchyma contained numerous cortical cyst\ measurins from 2 to 7 mm., filled with clear fluid. Microscopic examination revealed the cysts to be of follicular origin. lined by Franulosa ~11s. Thr intrrveninr: stroma contained immature ova and small fibroma. (Hematoxylin and eosin. Original mapnificalion X39.)
nevoid basal cell carcinoma since nearly all patients reported by other authors’:’ have had many hasal cell carcinomas of the face and neck, including carcinomas of the neck appearing as skin tags, by the age of 18 years. Our patient had multiple periodontal cysts and a congenital abnormality of the \-ertebral column, findings frequcntly qecn in the nevoid basal cell carcinoma syndrome. The primary complaint initially was gynecologic amenorrhea and tumor of the ovary. These ovarian tumors have never been known to metastasize, although fibrosarcoma of the ja\j from these cysts”. “1, 2: and medulloblastomas have been reported. The family history unfortunately has been difficult to obtain. Her 2 siblings, although not examined by us. were rt’ported as normal (ages 13 and 9). Her maternal grandmotherl, 6 had multiple skin lesions and a pelvic tumor \vas excised. Two maternal uncle5
Vlrlllrllr Number
116 4
Genetic
Fig. 3. Basal cell: Section of skin reveals a classical basal cell carcinoma composed of columns and sheets of neoplastic basal cells extending from the epidermis into the underlying dermis. (Hematoxylin and eosin. Original magnification x156.)
have multiple skin lesions but have refused to give further information. Case No. 2. Multiple familial cutaneous leiomyomas with leiomyosarcoma of the uterus and hypernephroma of the left ovary. This ZO-yearold woman had normal menstrual periods until one year previously when periods became irregular. She entered St. Joseph Hospital because of severe lower abdominal pain on December 14, 1071. She had missed a menstrual period. She stated that she had never had sexual coitus and gynecologic examination confirmed this. Intravenous pyelogram revealed a pelvic mass and an abnormal calcific lesion in the left flank, displacing the kidney. On December 16, 1971, excision of a tumor of the uterus was carried out. A lobulated, 370 gram mass was shelled away from the myometrium. Pathologically, the tumor was basically a spindle cell neoplasm occurring in strands of cells which tended to interweave with one another (Figs. 5 and 6). The cells showed considerable variation in size. In some areas the nuclei were thin and elongated; in others, they were quite plump and showed ir-
cutaneous
disorders
and
gynecologic
tumors
487
Fig. 4. Periodontal cyst: The specimen consisted of portions of an excised cystic structure which, on reconstruction, measured 1.5 cm. in greatest dimension. Microscopic examination revealed portions of a cyst wall lined by regular stratified squamous epithelium. The cyst was filled with keratin debris and in the surrounding fibrous stroma there was a mild chronic inflammatory reaction. (Hematoxylin and eosin. Original magnification. x39.)
regularity in staining and chromatin content. The diagnosis was leiomyosarcoma, confirmed by outside pathologists also. The patient has multiple, small, slightly red tumors on the arms, chest, neck, and legs (Fig. 7) which had been diagnosed as neurofibromatosis although she had no cafC au lait spots. The lung and skeletal surveys were negative for metastasis. Her 25-year-old brother has several large areas of cutaneous leiomyomas. Both the patient and her older brother developed these lesions at puberty. There are 2 normal female siblings (ages 16 and 7) ; one is without any skin lesions and the other is prepubertal. An intravenous pyelogram of the older brother was normal, and there were no testicular masses. On January 24, 1972, a left nephrectomy was performed. The identifiable kidney measured 4 by 4.5 by 10 cm. and the contiguous mass measured
488
Walker
and
June 1.5. 19i:i Am. J. Obstrt. Gynecol.
Reed
Fig. 5. Uterus: Photomicrograph of a uterine leiomyosarcoma composed of irregularly interlacing bundles of spindle cells showing moderate pleomorphism. (Hematoxylin and eosin. Original magnification x156.1
Fig. 6. Uterus: High-power photomicrograph of the uterine leiomyosarcoma, showing the nuclear pleomorphism and mitotic activity. (Hematoxylin and eosin. Original magnification x390.)
6 by 7 by 12 cm.; total weight was 295 grams (Fig. 8). The tumor surface was irregularly lobular and cystic with both cysts and lobules varying from 0.15 to 5 cm. in greatest dimension. On section, the tumor was seen to originate from and to be contiguous with the renal cortex.
topsy was described by Binkley and Johnson,3 in 195 1, although there were previous case reports. 15. 23 This patient had all the stigmas of the nevoid basal cell carcinoma syndrome : basal cell carcinomas, periodontal cysts with development of a fibrosarcoma of the ja,, and congenital abnormalities of the spine and ribs. She had an ovarian fibroma removed at age 18. One other case was reported in 1960.’ The significance of these ovarian tumors was not suspected until a study done at the National Institutes of Health found that 4 of 6 patients had ovarian fibromas, none associated with menstrual abnormalities.? Our patient (Case No. 1) had bilateral ovarian fibromas. Following Ivedge resection, she is now menstruating. which suggests the Stein-Leventhal syndrome. Ectopic calcification was found in most of these tumors, indicating their benign hamartomatous nature. Congenital kidney abnor-
The tumor was variegated in that it was in part solid and in part cystic. Pathologic diagnosis was hypernephroma because the solid portion showed the characteristic configuration and cytology of a hypemephroma with small nests of cuboidal cells with abundant foamy cytoplasm and centrally placed nuclei, which varied moderately in size, shape, and configuration (Fig. 9). The patient was readmitted to the hospital 6 weeks later for hysterectomy because of the diagnosis of leiomyosarcoma. The uterus was removed, and invasion of this tumor into the uterus was shown.
Comment The
basal
first
cell
with syndrome
patient
nevi
the diagnosis studied with
of au-
Volume Number
116 4
Genetic
Fig. 7. Skin: The
specimen consisted of an oval segment of skin measuring 3 by 5 mm. Microscopic examination revealed an intact and unremarkable epidermis. In the underlying dermis, there was a well-demarcated but unencapsulated tumor, consisting of irregularly interlacing bundles of smooth muscle cells. These showed regular elongated nuclei with no evidence of malignancy. Special stains confirmed the fact that the tumor cells were of smooth muscle origin. (Hematoxylin and eosin. Original magnification x156.)
malities have been found,9, 12. l*l ‘+ ‘6 i.e., fusion of the kidney in a patient reported by Taylor and associateP in 1968. Gorlin and SedanoIl who have done so much to delineate this as a genetic disorder, autosomal dominant in inheritance, have noted in a recent extensive review (1971) that 17 papers have reported this disorder with ovarian fibromas, none of which has been malignant. Interestingly, leiomyomas of the uterus (esophagus and mesentery) have been reported with the syndrome reported in Case No. 2. Kahn and Gordon’P case study reported 50 leiomyomas of the mesentery. Several male patients studied had manifested hypogonadism with cryptorchism, a missing testicle, female pubic hair distribu-
cutaneous
disorders
Fig. 8. Kidney:
tumors
Low-power photomicrograph the junction between
kidney,
showing
renal
parenchyma
(Hematoxylin x39.)
and gynecologic
and
and eosin.
renal Original
489
of normal
adenocarcinoma. magnification
tion, and _gynecomastia or scanty facial hair or both. There have been previous reports of cutaneous and uterine leiomyomas”, lo, I’. I93 *“, ~9 27 with 3 family studies that have shown a genetic disposition.“), w “? Only one of these uterine leiomyomas has been reported”” as malignant. Our patient demonstrated 3 types of tumors: multiple cutaneous leiomyomas, leiomyosarcoma of the uterus, and hypernephroma of the kidney. Her brother had normal kidney studies, but the other younger female siblings must be studied carefully in the future. The father had no stigmas of leiomyomas of the skin. The mother had neither skin stigmas nor uterine leiomyomas. In a large study by Fisher and Helwig” of 38 patients, no skin tumors associated with the uterus were described. An autosomal dominance of the cutaneous leiomyoma was
490
Walker
and
Reed
Fig. 9. Kidney: High-power photomicrograph showing well-differentiated tubular adenocarcinoma of the kidney. (Hematoxylin and eosin. Original magnification X390.)
noted. Whether this is one or 2 genetic disorders will be known only with further family reports. However, Rudner and col1eagueP reported identical twins with both uterine and cutaneous leiomyomas. One had a partial hysterectomy at age 29 and total hysterectomy 10 years later at age 40. Twinning is considered a good indication of genetic predisposition. Rudner and colleagues also reported that a young patient presented
at the Eleventh International Congress of Dermatology in Stockholm, in 1957. had a leiomyosarcoma of the uterus 4 years preceding the development of skin lesions. From the literature, the onset of uterine leiomyomas is in young women in contrast to their usual development in women over 35. There may be 2 disorders present here : cutaneous leiomyomas and cutaneous leiomyomas with uterine and possibly other organ involvement, both autosomal dominant genetic entities. Other authors have described leiomyomas of the skin and uterus in individual cases, none with other tumors. Thus, our young patient is unique in that she has both a leiomyosarcoma and a hypernephroma, and she had hundreds of miliary cutaneous lesions. Rapidly increasing interest and the mass of information introduced by geneticists, cancer research, and other fields of investigation are directing attention to hereditary pathwavs associated with tumor formation. A frequent observation is that if ;I rnammalian has one anomaly other abnormalities may be present and an increased incidence of nroplasia may be expected. Cutaneous lesion syndromes are better known in dcrmatology but, being uncommon, their importance to other specialties as not been well recognized. It may be expected that more reports of uterine and ovarian invol\,cmrnt with cutaneous lesions will be published. Our appreciation is expressed to Ii. E. Horowitz, M.D., Chief Pathologist at the St. Joseph Hospital, to whom we are indebted for the slides and descriptions of the tumor pathology.
REFERENCES
1. Basex, A., Dupre, M., and Parant, A., et al.: Arch. Dermatol. 67: 72, 1960. 2. Berlin, N. I., Van Scott, E. J., Clendenning, W. E., et al.: Ann. Int. Med. 64: 403, 1966. 3. Binkley, G. W., and Johnson, H. H., Jr.: Arch. Dermatol. 63: 73, 1951. 4. Block, J. B., and Clendenning, W. E.: N. Engl. J. Med. 268: 1157, 1963. 5. Blum, P., and Jean, L.: Bull. Sot. Fr. Dermatol. Syphiligr. 61: 349, 1954. 6. Clendenning, W. E., Block, J. B., and Radde,
7.
8. 9. IO. 11.
I. C.: Arch. Dermatol. 90: 38, 1964. Clendenning, W. E., Herdt, J. R., J. B.: AM. J. OBSTET. GYNECOL. 1963. Fisher, W. L., and Helwig, E. Dermatol. 88: 510, 1963. Formas, I.: Z. Haut. Geschlechtskr. 1967. Gerardi, A.: Cronache I. D. I. 6: Gorlin, R. J., and Sedano, H. 0.: tiple Nevoid Basal Cell Carcinoma
and Block, 87: 1008, B.: 42:
Arch. 131,
45 1, 1960. The MulSyndrome
Volume Number
12. 13. 14. 15. 16. 17.
18.
116 4
Genetic
Revisited. Birth Defects, Original Article Series, 1971, vol. 7, pp. 140-148. Gorlin, R. J., Vickers, R. A., Kelln, E., and Williamson, J. J.: Cancer 18: 89, 1965. Howell, J. B., and Cam, M. R.: Arch. Dermatol. 79: 67, 1959. Howell, J. B., and Mehregan, A, H.: Arch. Dermatol. 102: 586, 1970. Jarisch: Arch. Dermatol. Syph. (Berlin) 28: 163, 1894. Kahn, L. B., and Gordon, W.: S. Afr. Med. J. 41: 832, 1967. Le Coulant, P., Reviere, J., Texier, L., and Cheroux, M.: Bull. Sot. Fr. Dermatol. Syphiligr. p. 197, 1957. Mason, J. K., Helwig, E. G., and Graham, J, H.: Arch. Pathol. 79: 401, 1965.
Discussion
cutaneous
19. 20. 21. 22. 23. 24. 25. 26.
27.
disorders
and
gynecologic
tumors
491
Mezzadra, G.: Minerva Dermatol. 40: 388, 1965. Piredda, A.: Arch. Ital. Dermatol. Venereal. Sessuol. 24: 1, 1957. Reed, J. C.: Arch. Dermatol. 97: 304. 1968. Rudner, E. J., Schwartz, 0. D., and Grekin, J. N.: Arch. Dermatol. 90: 81, 1964. Straith, F. E.: Am. J. Orthod. 25: 673, 1939. Summerly, R., and Hale, A. J.: Trans. St. John’s Hosp. Dermatol. Sot. 41: 77, 196.5. Swanson, A. E., and Jacks, (2. D.: J, Can. Dent. Assoc. 27: 723. 1961. Taylor, W. B., Anderson, D. E., Howell, J. B., and Thurston, C. S.: Arch. Dermatol. 98: 612, 1968. Vogilino, A.: Cronache I. D. I. 2: 138, 1963.
North Hollywood, California. Dr. Walker, in presenting these two very interesting cases, seems to have opened Pandora’s box. In so doing he has turned our attention to the importance of the science of genetics and how knowledge of genetics can be most helpful to us as obstetricians and gyne-
ma1 I sex chromosomes, manifesting cutaneous lesions and associated pelvic disease. Such are the 2 cases reported by the essayist. In the literature, one can find at least 15 rare genetic syndromes with anomalies of the female reproductive system in 46,Xx female subjects. The hasal cell nevus syndrome falls into this category.
cologists, particularly when it comes to counseling our patients. Basically, human variation of normal differences as well as overt pathology can be considered in terms of several etiologic categories. Thus, there may be: ( 1) changes in the normal chromosomal number or structure or both, (2) single gene mutations, (3) cumulative effects of
Scully’ has called our attention to the occurrence of a distinctive ovarian tumor in association with the Peutz-Jrghers syndrome. In his article, which appeared in Cancer, May, 1970, he describes specilic findings in ovarian tumors in patients with the Peutz-Jeghers syndrome, which he describes as “sex cord tumor with annular tubules.”
genes at several c.1) environmental
Examples of changes in the normal chromosomal number or structure are encountered particularly in abnormalities of the X and Y chro-
This syndrome is a familial disorder characterized by an association of gastrointestinal polyps with melanin pigment spots on the skin, lips, and oral mucosa. Ovarian tumors are present in about 5 per
mosomes. These are well known. For instance, a decrease in the X chromosome results in ovarian agenesis (Turner’s syndrome) in the female subject, and an increase in the X chromosome results in Klinefelter’s syndrome in the male snhject. The various types of male pseudohermaphroditism associated with 46,XY individuals are well known. Other abnormalities resulting from an increase in the number of chromosomes, the SOcalled poly-S female and the XYY male, have heen reported. Today, however, our attention is centered upon individuals with normally structured chromosomal components including nor-
cent of the women reported to have this syndrome. The characteristic microscopic findings, as reported by Scully, consist of rounded epithelial cell nests containing eosinophilic hyaline bodies. The nuclei of these cells are irregular in shape, and there is abundant cytoplasm rich in lipid vacuoles. Tumors are multicentric in origin. These tumors tend to undergo extensive hyalinization. Malignancy among these cases has not been reported, although there does seem to be an increased incidence of endometrial hyperplasia associated with this (urnor. In the second case presented, the patient originally was thought to have neurofibromatosis
DR.
CLYDE
VON
loci
DER
AHE,
(polygenic factors.
inheritance),
and
492
Walker
and
June 15, 1973 Am. J. Obstet. Gynecol.
Reed
although cafe au lait spots were not seen. Cases of ovarian cysts, fibromas, isosexual precocity, and clitoral hypertrophy in association with neurofibromatosis have been reported. These are autosomal dominant. In conclusion, Dr. Walker’s 2 cases are unique in that they are illustrative of dramatologic syndromes and associated pelvic pathology rarely seen by the gynecologist.
Their importance is not to be underestimated because they demonstrate the ever-increasing influence of the science of genetics on our profession, and for this we should be most grateful. REFERENCES
1. Simpson, J. L., and Christakos, A. C.: Clin. Obstet. Gynecol. 15: 107, 1972. 2. Scully, R. E.: Cancer 25: 1107, 1970.
H.
WILLIAM Loma
Linda
WALKER, B.
REED,
and Irvine,
M.D. M.D.
California
The
paper will present a brief reference to reports in the literature and a discussion hereditary autosomal dominant cutaneous lesions that have asociated pathology of the reproductive system. The first is a case presentation of basal cell nevi syndrome and multiple ouarian fibromas, and the second is cutaneous leiomyoma associated with leiomyosarcoma of the uterus and hypernephroma.
of 2
ity. She was admitted to St. Joseph Hospital on October 10, 1971, because of a large pelvic mass palpated over the left ovary. Closer examination revealed 2 very small basal cell carcinomas of the left eyelid and one of the right cheek. One of the jaw cysts had increased in size. Dyskeratosis (pitting) was evident on the palms and on the soles of the feet.” On October 11, 1971, left salpingo-oophorectomy and wedge resection of the right ovary, appendectomy, and curettage were carried out. The uterus was very immature, corresponding in size and color to that of a 6-year-old girl. The left ovary (Fig. 1) contained a large oval tumor measuring 6 by 8 by 11.5 cm. and weighing 3 10 grams. Its surface was generally smooth but showed irregular bosselations varying frotn 2 to 20 mm. The Fallopian tube was normal. A section of the tumor showed multiple oval nodules of firm, light tan tissue varying from 5 mm. to 2 cm. in greatest dimension. Pathologic diagnosis was granulosatheta tumor versus fibroma consisting chiefly of interlacing spindle-shaped cells of a fibroblastic type which were generally well differentiated. Some calcific bodies were interspersed in places. In only one area, cells of a small plump type, supported by edematous stroma with the appearance of granulosa cells, were noted. The right ovary (Fig. 2) was grossly approximately 3 times average size with an opaque, smooth, pink surface. The section demonstrated a small fibromatous nodule with numerous cystic follicles in the underlying parenchyma. The postoperative course was uncomplicated and she was discharged.
THE s K I N may be important in the diagnosis of genetic disorders affecting the uterus and ovaries. Presented are 2 case reports of patients with two such genetic disorders, one known for ovarian tumors to dermatologists and clinical geneticists ; the other, rare and unique. A general discussion of genetic cutaneous lesions with documented ovarian tumors reported is included. Case reports Case No. 1. Nevoid basal cell carcinoma syndrome with bilateral ovarian tumors. This 16year-old girl first came to our attention because of amenorrhea. Physically, she was a fully developed girl who had done some modeling. Two years previously, in 1970, a basal cell carcinoma was removed from the abdomen. The face and neck were free of carcinoma at that time. Her father, a radiologic technician, found multiple dental cysts and a vertebral column abnormalFrom the Department of Obstetrics and Gynecology, Loma Linda University and the University of Southern California School of Medicine, and the Department of Medicine (Dermatology), University of California, Irvine. Presented at the Thirty-ninth Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Harrison Hot Springs, British Columbia, Canada, October 3-7, 1972. Reprint requests: Ralph H. Walker, M.D., 10711 Riverside Dr., North Hollywood, California 91602.
485
486
Walker
and Reed
Fig. 1. Left ovary: Section shows irregularly interlacing spindle cells. (Hematoxylin magnification x156.)
of ovarian fibroma bundles of uniform and eosin. Original
On November 9, 1971, the patient was rcadmitted to St. Joseph Hospital for plastic surgery of the 2 very small basal cell carcinomas (Fig. 3) and excision of the periodontal cysts (Fig. -1 :. The ja\v cysts had thin fibrous walls lined by a fairly regular stratified squamous epithrlium; there was no evidence of malignancy. Sections of the skin showed solid basal cell carcinoma. Postoperatively, the patient has had several menstrual periods; the first, one month after operation and then none for 2 months. After one course of clomiphene citrate,* 50 mg. daily for 5 days, she has continued to have menses at 4, to 6 week intervals. The patient’s findings atrihuted to the basal cell nevoid syndrome were: basal cell nevi; skeletal : frontal bossing, hypertelorism, vertebral column anomaly, hrachymetacarpia, mandibular cysts, and dyskeratosis of the palms and soles of feet; ovarian: granulosa-theta cell tumor and fibroma.’ Visibly,
the
‘Clomid, Wm. Inc.. Cincinnati,
patient S. Merrrll Ohio.
did Co..
not
appear
to
Div.
Richardson-Merrcll.
have
Fig. 2. Right ovary: The specimen consisted of a wedge of ovarian tissue measuring 1 by 1.2 by 4.5 cm. The capsule was thick, and thr parenchyma contained numerous cortical cyst\ measurins from 2 to 7 mm., filled with clear fluid. Microscopic examination revealed the cysts to be of follicular origin. lined by Franulosa ~11s. Thr intrrveninr: stroma contained immature ova and small fibroma. (Hematoxylin and eosin. Original mapnificalion X39.)
nevoid basal cell carcinoma since nearly all patients reported by other authors’:’ have had many hasal cell carcinomas of the face and neck, including carcinomas of the neck appearing as skin tags, by the age of 18 years. Our patient had multiple periodontal cysts and a congenital abnormality of the \-ertebral column, findings frequcntly qecn in the nevoid basal cell carcinoma syndrome. The primary complaint initially was gynecologic amenorrhea and tumor of the ovary. These ovarian tumors have never been known to metastasize, although fibrosarcoma of the ja\j from these cysts”. “1, 2: and medulloblastomas have been reported. The family history unfortunately has been difficult to obtain. Her 2 siblings, although not examined by us. were rt’ported as normal (ages 13 and 9). Her maternal grandmotherl, 6 had multiple skin lesions and a pelvic tumor \vas excised. Two maternal uncle5
Vlrlllrllr Number
116 4
Genetic
Fig. 3. Basal cell: Section of skin reveals a classical basal cell carcinoma composed of columns and sheets of neoplastic basal cells extending from the epidermis into the underlying dermis. (Hematoxylin and eosin. Original magnification x156.)
have multiple skin lesions but have refused to give further information. Case No. 2. Multiple familial cutaneous leiomyomas with leiomyosarcoma of the uterus and hypernephroma of the left ovary. This ZO-yearold woman had normal menstrual periods until one year previously when periods became irregular. She entered St. Joseph Hospital because of severe lower abdominal pain on December 14, 1071. She had missed a menstrual period. She stated that she had never had sexual coitus and gynecologic examination confirmed this. Intravenous pyelogram revealed a pelvic mass and an abnormal calcific lesion in the left flank, displacing the kidney. On December 16, 1971, excision of a tumor of the uterus was carried out. A lobulated, 370 gram mass was shelled away from the myometrium. Pathologically, the tumor was basically a spindle cell neoplasm occurring in strands of cells which tended to interweave with one another (Figs. 5 and 6). The cells showed considerable variation in size. In some areas the nuclei were thin and elongated; in others, they were quite plump and showed ir-
cutaneous
disorders
and
gynecologic
tumors
487
Fig. 4. Periodontal cyst: The specimen consisted of portions of an excised cystic structure which, on reconstruction, measured 1.5 cm. in greatest dimension. Microscopic examination revealed portions of a cyst wall lined by regular stratified squamous epithelium. The cyst was filled with keratin debris and in the surrounding fibrous stroma there was a mild chronic inflammatory reaction. (Hematoxylin and eosin. Original magnification. x39.)
regularity in staining and chromatin content. The diagnosis was leiomyosarcoma, confirmed by outside pathologists also. The patient has multiple, small, slightly red tumors on the arms, chest, neck, and legs (Fig. 7) which had been diagnosed as neurofibromatosis although she had no cafC au lait spots. The lung and skeletal surveys were negative for metastasis. Her 25-year-old brother has several large areas of cutaneous leiomyomas. Both the patient and her older brother developed these lesions at puberty. There are 2 normal female siblings (ages 16 and 7) ; one is without any skin lesions and the other is prepubertal. An intravenous pyelogram of the older brother was normal, and there were no testicular masses. On January 24, 1972, a left nephrectomy was performed. The identifiable kidney measured 4 by 4.5 by 10 cm. and the contiguous mass measured
488
Walker
and
June 1.5. 19i:i Am. J. Obstrt. Gynecol.
Reed
Fig. 5. Uterus: Photomicrograph of a uterine leiomyosarcoma composed of irregularly interlacing bundles of spindle cells showing moderate pleomorphism. (Hematoxylin and eosin. Original magnification x156.1
Fig. 6. Uterus: High-power photomicrograph of the uterine leiomyosarcoma, showing the nuclear pleomorphism and mitotic activity. (Hematoxylin and eosin. Original magnification x390.)
6 by 7 by 12 cm.; total weight was 295 grams (Fig. 8). The tumor surface was irregularly lobular and cystic with both cysts and lobules varying from 0.15 to 5 cm. in greatest dimension. On section, the tumor was seen to originate from and to be contiguous with the renal cortex.
topsy was described by Binkley and Johnson,3 in 195 1, although there were previous case reports. 15. 23 This patient had all the stigmas of the nevoid basal cell carcinoma syndrome : basal cell carcinomas, periodontal cysts with development of a fibrosarcoma of the ja,, and congenital abnormalities of the spine and ribs. She had an ovarian fibroma removed at age 18. One other case was reported in 1960.’ The significance of these ovarian tumors was not suspected until a study done at the National Institutes of Health found that 4 of 6 patients had ovarian fibromas, none associated with menstrual abnormalities.? Our patient (Case No. 1) had bilateral ovarian fibromas. Following Ivedge resection, she is now menstruating. which suggests the Stein-Leventhal syndrome. Ectopic calcification was found in most of these tumors, indicating their benign hamartomatous nature. Congenital kidney abnor-
The tumor was variegated in that it was in part solid and in part cystic. Pathologic diagnosis was hypernephroma because the solid portion showed the characteristic configuration and cytology of a hypemephroma with small nests of cuboidal cells with abundant foamy cytoplasm and centrally placed nuclei, which varied moderately in size, shape, and configuration (Fig. 9). The patient was readmitted to the hospital 6 weeks later for hysterectomy because of the diagnosis of leiomyosarcoma. The uterus was removed, and invasion of this tumor into the uterus was shown.
Comment The
basal
first
cell
with syndrome
patient
nevi
the diagnosis studied with
of au-
Volume Number
116 4
Genetic
Fig. 7. Skin: The
specimen consisted of an oval segment of skin measuring 3 by 5 mm. Microscopic examination revealed an intact and unremarkable epidermis. In the underlying dermis, there was a well-demarcated but unencapsulated tumor, consisting of irregularly interlacing bundles of smooth muscle cells. These showed regular elongated nuclei with no evidence of malignancy. Special stains confirmed the fact that the tumor cells were of smooth muscle origin. (Hematoxylin and eosin. Original magnification x156.)
malities have been found,9, 12. l*l ‘+ ‘6 i.e., fusion of the kidney in a patient reported by Taylor and associateP in 1968. Gorlin and SedanoIl who have done so much to delineate this as a genetic disorder, autosomal dominant in inheritance, have noted in a recent extensive review (1971) that 17 papers have reported this disorder with ovarian fibromas, none of which has been malignant. Interestingly, leiomyomas of the uterus (esophagus and mesentery) have been reported with the syndrome reported in Case No. 2. Kahn and Gordon’P case study reported 50 leiomyomas of the mesentery. Several male patients studied had manifested hypogonadism with cryptorchism, a missing testicle, female pubic hair distribu-
cutaneous
disorders
Fig. 8. Kidney:
tumors
Low-power photomicrograph the junction between
kidney,
showing
renal
parenchyma
(Hematoxylin x39.)
and gynecologic
and
and eosin.
renal Original
489
of normal
adenocarcinoma. magnification
tion, and _gynecomastia or scanty facial hair or both. There have been previous reports of cutaneous and uterine leiomyomas”, lo, I’. I93 *“, ~9 27 with 3 family studies that have shown a genetic disposition.“), w “? Only one of these uterine leiomyomas has been reported”” as malignant. Our patient demonstrated 3 types of tumors: multiple cutaneous leiomyomas, leiomyosarcoma of the uterus, and hypernephroma of the kidney. Her brother had normal kidney studies, but the other younger female siblings must be studied carefully in the future. The father had no stigmas of leiomyomas of the skin. The mother had neither skin stigmas nor uterine leiomyomas. In a large study by Fisher and Helwig” of 38 patients, no skin tumors associated with the uterus were described. An autosomal dominance of the cutaneous leiomyoma was
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and
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Fig. 9. Kidney: High-power photomicrograph showing well-differentiated tubular adenocarcinoma of the kidney. (Hematoxylin and eosin. Original magnification X390.)
noted. Whether this is one or 2 genetic disorders will be known only with further family reports. However, Rudner and col1eagueP reported identical twins with both uterine and cutaneous leiomyomas. One had a partial hysterectomy at age 29 and total hysterectomy 10 years later at age 40. Twinning is considered a good indication of genetic predisposition. Rudner and colleagues also reported that a young patient presented
at the Eleventh International Congress of Dermatology in Stockholm, in 1957. had a leiomyosarcoma of the uterus 4 years preceding the development of skin lesions. From the literature, the onset of uterine leiomyomas is in young women in contrast to their usual development in women over 35. There may be 2 disorders present here : cutaneous leiomyomas and cutaneous leiomyomas with uterine and possibly other organ involvement, both autosomal dominant genetic entities. Other authors have described leiomyomas of the skin and uterus in individual cases, none with other tumors. Thus, our young patient is unique in that she has both a leiomyosarcoma and a hypernephroma, and she had hundreds of miliary cutaneous lesions. Rapidly increasing interest and the mass of information introduced by geneticists, cancer research, and other fields of investigation are directing attention to hereditary pathwavs associated with tumor formation. A frequent observation is that if ;I rnammalian has one anomaly other abnormalities may be present and an increased incidence of nroplasia may be expected. Cutaneous lesion syndromes are better known in dcrmatology but, being uncommon, their importance to other specialties as not been well recognized. It may be expected that more reports of uterine and ovarian invol\,cmrnt with cutaneous lesions will be published. Our appreciation is expressed to Ii. E. Horowitz, M.D., Chief Pathologist at the St. Joseph Hospital, to whom we are indebted for the slides and descriptions of the tumor pathology.
REFERENCES
1. Basex, A., Dupre, M., and Parant, A., et al.: Arch. Dermatol. 67: 72, 1960. 2. Berlin, N. I., Van Scott, E. J., Clendenning, W. E., et al.: Ann. Int. Med. 64: 403, 1966. 3. Binkley, G. W., and Johnson, H. H., Jr.: Arch. Dermatol. 63: 73, 1951. 4. Block, J. B., and Clendenning, W. E.: N. Engl. J. Med. 268: 1157, 1963. 5. Blum, P., and Jean, L.: Bull. Sot. Fr. Dermatol. Syphiligr. 61: 349, 1954. 6. Clendenning, W. E., Block, J. B., and Radde,
7.
8. 9. IO. 11.
I. C.: Arch. Dermatol. 90: 38, 1964. Clendenning, W. E., Herdt, J. R., J. B.: AM. J. OBSTET. GYNECOL. 1963. Fisher, W. L., and Helwig, E. Dermatol. 88: 510, 1963. Formas, I.: Z. Haut. Geschlechtskr. 1967. Gerardi, A.: Cronache I. D. I. 6: Gorlin, R. J., and Sedano, H. 0.: tiple Nevoid Basal Cell Carcinoma
and Block, 87: 1008, B.: 42:
Arch. 131,
45 1, 1960. The MulSyndrome
Volume Number
12. 13. 14. 15. 16. 17.
18.
116 4
Genetic
Revisited. Birth Defects, Original Article Series, 1971, vol. 7, pp. 140-148. Gorlin, R. J., Vickers, R. A., Kelln, E., and Williamson, J. J.: Cancer 18: 89, 1965. Howell, J. B., and Cam, M. R.: Arch. Dermatol. 79: 67, 1959. Howell, J. B., and Mehregan, A, H.: Arch. Dermatol. 102: 586, 1970. Jarisch: Arch. Dermatol. Syph. (Berlin) 28: 163, 1894. Kahn, L. B., and Gordon, W.: S. Afr. Med. J. 41: 832, 1967. Le Coulant, P., Reviere, J., Texier, L., and Cheroux, M.: Bull. Sot. Fr. Dermatol. Syphiligr. p. 197, 1957. Mason, J. K., Helwig, E. G., and Graham, J, H.: Arch. Pathol. 79: 401, 1965.
Discussion
cutaneous
19. 20. 21. 22. 23. 24. 25. 26.
27.
disorders
and
gynecologic
tumors
491
Mezzadra, G.: Minerva Dermatol. 40: 388, 1965. Piredda, A.: Arch. Ital. Dermatol. Venereal. Sessuol. 24: 1, 1957. Reed, J. C.: Arch. Dermatol. 97: 304. 1968. Rudner, E. J., Schwartz, 0. D., and Grekin, J. N.: Arch. Dermatol. 90: 81, 1964. Straith, F. E.: Am. J. Orthod. 25: 673, 1939. Summerly, R., and Hale, A. J.: Trans. St. John’s Hosp. Dermatol. Sot. 41: 77, 196.5. Swanson, A. E., and Jacks, (2. D.: J, Can. Dent. Assoc. 27: 723. 1961. Taylor, W. B., Anderson, D. E., Howell, J. B., and Thurston, C. S.: Arch. Dermatol. 98: 612, 1968. Vogilino, A.: Cronache I. D. I. 2: 138, 1963.
North Hollywood, California. Dr. Walker, in presenting these two very interesting cases, seems to have opened Pandora’s box. In so doing he has turned our attention to the importance of the science of genetics and how knowledge of genetics can be most helpful to us as obstetricians and gyne-
ma1 I sex chromosomes, manifesting cutaneous lesions and associated pelvic disease. Such are the 2 cases reported by the essayist. In the literature, one can find at least 15 rare genetic syndromes with anomalies of the female reproductive system in 46,Xx female subjects. The hasal cell nevus syndrome falls into this category.
cologists, particularly when it comes to counseling our patients. Basically, human variation of normal differences as well as overt pathology can be considered in terms of several etiologic categories. Thus, there may be: ( 1) changes in the normal chromosomal number or structure or both, (2) single gene mutations, (3) cumulative effects of
Scully’ has called our attention to the occurrence of a distinctive ovarian tumor in association with the Peutz-Jrghers syndrome. In his article, which appeared in Cancer, May, 1970, he describes specilic findings in ovarian tumors in patients with the Peutz-Jeghers syndrome, which he describes as “sex cord tumor with annular tubules.”
genes at several c.1) environmental
Examples of changes in the normal chromosomal number or structure are encountered particularly in abnormalities of the X and Y chro-
This syndrome is a familial disorder characterized by an association of gastrointestinal polyps with melanin pigment spots on the skin, lips, and oral mucosa. Ovarian tumors are present in about 5 per
mosomes. These are well known. For instance, a decrease in the X chromosome results in ovarian agenesis (Turner’s syndrome) in the female subject, and an increase in the X chromosome results in Klinefelter’s syndrome in the male snhject. The various types of male pseudohermaphroditism associated with 46,XY individuals are well known. Other abnormalities resulting from an increase in the number of chromosomes, the SOcalled poly-S female and the XYY male, have heen reported. Today, however, our attention is centered upon individuals with normally structured chromosomal components including nor-
cent of the women reported to have this syndrome. The characteristic microscopic findings, as reported by Scully, consist of rounded epithelial cell nests containing eosinophilic hyaline bodies. The nuclei of these cells are irregular in shape, and there is abundant cytoplasm rich in lipid vacuoles. Tumors are multicentric in origin. These tumors tend to undergo extensive hyalinization. Malignancy among these cases has not been reported, although there does seem to be an increased incidence of endometrial hyperplasia associated with this (urnor. In the second case presented, the patient originally was thought to have neurofibromatosis
DR.
CLYDE
VON
loci
DER
AHE,
(polygenic factors.
inheritance),
and
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and
June 15, 1973 Am. J. Obstet. Gynecol.
Reed
although cafe au lait spots were not seen. Cases of ovarian cysts, fibromas, isosexual precocity, and clitoral hypertrophy in association with neurofibromatosis have been reported. These are autosomal dominant. In conclusion, Dr. Walker’s 2 cases are unique in that they are illustrative of dramatologic syndromes and associated pelvic pathology rarely seen by the gynecologist.
Their importance is not to be underestimated because they demonstrate the ever-increasing influence of the science of genetics on our profession, and for this we should be most grateful. REFERENCES
1. Simpson, J. L., and Christakos, A. C.: Clin. Obstet. Gynecol. 15: 107, 1972. 2. Scully, R. E.: Cancer 25: 1107, 1970.