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Gonadoblastoma in a patient with gonadal dysgenesis
Gonadoblastoma
in a patient
with gonadal dysgenesis I.
J.
Canal
THE
Zone,
M.D.,
tumor
is
containing
mesenchymal
germ
cell is to
with
gonadal
negative,
Case
report
cells,
2, 3 The such
in female
rare
a
and and
Leyof
in
association
a
chromatin
with
was soft, flat, and not tender. A firm mass !~a< felt rising out of the pelvis from the suprapuhic arca to a point three finger breadths below the umhiliclls. This did not extend laterally to the pelvic walls, but it came out of the pelvir as :I well-delineated mass. This was not tender and was fixed to abdominal examination. Rectal and pelvic examination revealed that she had normal external genitals. The patient was a virgin and the introitus barely admitted a finger tip. A probe could be passed in the vagina for a distance of 4 cm. Rectal examination revealed a firm, fixed, nontender masq filling the pelvis; rrn the inferior surface on the left there were m111tiple nodular excrescences. The mass was not cystic but felt more rubbery and firnl. The I‘Xtrcmitirs were negative. The skin ~‘as negative and the lymphatic system contained no nc~dulcs. The impression on admission \~as olsarian not-
primitive
purpose
a case
dysgenesis
phenotypical
chromosome
granulosal
sex cord
elements.‘,
paper
F.A.C.S.
Panama
GONADOBLASTOMA
ovarian dig
STRUMPF,
male
this
XY
structure. report
A
l”-L year-old white female complained of mild abdominal pain of approximately 6 days’ duration. In addition to this mild discomfort, the patient had had no menstrual periods. She was referred to Gorgas Hospital and admitted for study. The patient was a student of above averagr intelligence in the seventh grade. Her mother and father were living and well, and there werr no family illncsscs. There was no family history of diabetes, cancer, or allergies. She had had the usual childhood diseases without sequelae. She had had no operations. Review of systems was entirely negative. Notably, she had had no difficulties with bleeding disorders, and she was well adjusted socially in school. A general physical examination on admission to the hospital on May 10, 1964, revealed a young, normal-looking, robust, well-nourished, subteen female. She weighed 110 pounds and was 61 inches tall. She had normal development of the secondary sex characteristics and notably she had beginning breast development. She was in no distress and was very cooperative. Head, eyes, ears, nose, and throat were negative. The chest was clear to auscultation and percussion. She had good lung expansion with no dullness in either base. The heart had a normal sinus rhythm without murmur or thrill. The abdomen From
Gorgas
plasm,
probably
dysgerminoma. The admission urinal+ was essentially negative. Specific gravity \vas 1.014. The white blood count was 3,600 ivith normal differential, and the hemoglobin was 1 I .>I Gm. with a microhematocrit of 38 per CCII(. Serology was nonreactive. :11x x-ray of the c‘hcu(
Laboratory
findings.
was negative. Intravenous pyelogram demonstrated kidneys of normal size and shape; thert, was prompt appearanre of contrast media iu both upper collecting systems on the 5 minutr film. However, hoth upper collecting systems and the proximal two third? of the urctcrs wcr(* slightly dilated and indicative of a mild obstructivr Iuopathy which was felt to be present a~ thP pelvic brim. On the outlines of the bladder \\‘:I’; subadjaccnt c,xtrinsic. pressurt’. ‘l’h~, thaw impreshiotl was Grade I ur~~t~~ropyelocalie(.t~~si~~. scnt.ondary to a large pelvic ~IUYS. Barium cncnI:a revealed a large pelvic mass which displaced the distal sigmoid colon posteriorly, creating pressllre on this structure. Extrinsic prrssllre \\‘;I<
Hospital. 992
Volume
92
Gonadoblastoma
IVumber 7
again seen on the urinary bladder as a result of the intravenous pyelogram. It was felt that the pelvic mass was in the peritoneal cavity and not a retroperitoneal mass. A Papanicolaou smear taken from the vagina was a Class I, and the comment was “high maturation.” Hospital course. On May 13, 1964, the patient was taken to the operating room where an exploratory laparotomy was carried out. Aspiration of the abdominal fluid at the time of abdominal laparotomy contained insufficient sediment for cell block; however, Papanicolaou smear of this material showed no malignant cells free in the fluid. The findings at operation were of a large solid right ovarian tumor which was fixed in the pelvis and, after removal, presented the clinical impression of malignancy. The tumor measured 15 x 10 x 10 cm. and weighed 600 grams. The uterus was a small structure in the midline and the ovary on the left side was a white streak of tissue, rudimentary in nature. A total hysterectomy and bilateral salpingooophorectomy was then carried out. Incidental appendectomy of a retrocecal appendix was carried out. The patient did well postoperatively, although she ran a low-grade fever up to 101” F. from the first to the fourth days. By the end of the fourth hospital day, she was afebrile and, thereafter, had an uneventful convalescence. The pathological diagnosis on frozen section of the tumor of the right ovary was Brenner tumor, but on examination of the paraffin block, this was corrected to dysgerminoma. Tumor was also found in the rudimentary ovary on the left side. No ova were present in any of the sections. Following surgery, May 13, 1964, a clinical diagnosis of cqonadohlastoma in a patient with
Fig.
1. Cut
section
of tumor.
and
gonadal
dysgenesis
993
gonadal dysgenesis was made on the basis of the incongruity of the vaginal smear showing “high maturation effect” and the operative finding of nonfunctioning ovarian tissue with a nonhormone-producing dysgerminoma. Examination of a buccal smear at this time was reported chromatin negative. Resurvey of the pathological specimen with this suggested clinical diagnosis was requested. On the pathological basis of dysgerminoma, the Gorgas Hospital Tumor Board recommended supervoltage therapy rather than therapy with the 250 kv. machine available, and they recommended transfer of the patient to Walter Reed Hospital for this therapy. Transfer of patient and original slides was accomplished on May 21, 1964. On review by the Armed Forces Institute of Pathology, diagnosis was made of “ovary, gonadohlastoma, right.” The entire wet tissue was requested. This was sent on June 25, 1964. Upon subsequent review and study of the full specimen by Drs. Taylor and Norris of the Armed Forces Institute of Pathology, the diagnosis was made of “ovary, bilateral, gonadoblastoma.” X-ray therapy was not recommended, and the patient was referred back to Gorgas Hospital for further follow-up. No treatment was given. At the present time, the patient is well, appears well adjusted, and has no complaints. Pathology. Gorgas Hospital’s original diagnosis was amended on August 26, 1964 (S-64-1506). Tissue sections from the right ovary showed some areas which were very cellular and others where the stroma predominated. The predominant cellular picture was that of dysgerminoma. However, in many areas there were smaller cells with denser nuclear and cytoplasmic material. These were seen in clusters or lined up about dysgerminoma cells or amorphous pink deposits. This latter arrangement was very similar to that of Call-Exner bodies. The stroma was rather dense, and calcified areas could he seen. In both the cellular and the stromal areas there were collections of cells with slightly granular eosinophilic cytoplasm and vesicular nuclei with prominent reddish nucleoli. These cells had an “endocrine” appearance and resembled Leydig or hilar cells. Some appeared multinucleated. These groups of cells were often surrounded by an infiltrate of lymphocytes. No ova were found in this ovary. The right tube was unremarkable except for edema and chronic inflammatorv infiltrates in the mesosalpinx.
994
Strumpf
Sections of myometrium showed no remarkable changes. The endometrium sho\vcd fairly dense stroma and tubular glands with no mitoscs. Sections of the cervix showed suhrpitheliat chronic inflammatory infiltrates and squamous metaplasia. Sections of the left ovary showed the same features described in the right ovary exrept that the stroma was more predominant and large1 arcas of calcifying, amorphous, pink material were seen. No ova were found. Sections of the appendix and left fallopian tuhe showed no remarkable abnormalities. The diagnosis was gonadoblastoma of the left and right ovaries. The Armed Forces Institute of Pathology (Accession C 283-64) report was in agreement. Comment Dysgerminomas have been reported as being nonhormone pr0ducing.l Those with endocrine effects have usually been reclassified Fig. 3. A higher power view of thr center Tut ttrc, area pictured in the previous figurr. Note island of dysgerminoma cells in the uppt>r Id‘t with thr “Call-Exner body.” In the lower right hand
Fig. 2. Scattered in the stroma of the right ovar) are nests of dysgerminoma cells. To the left of center, one of the nests shows a round hyalinf mass surrounded by small cells. This structurr resembles the so-called “Call-Exner body.” Below and to the right of center is a mass of cells with abundant, slightly granular cytoplasm. These arc interpreted as representing hilar cells or Leydig
cells. (x10.)
on resut,vey.” The finding of “high maturation” in this 12-year-old girl prior to surgery aroused no suspicion because one o\par)might have been present and functioning. Pregnancies have been reported before and after surgery for dysgerminonlas.7 However, following surgery and the findimg of a nonfunctioning left ovary which was iriconlpatible with the vaginal smear finding madr the diagnosis of a pure dysgerminoma insupportable. The absence of mature ovarian stroma in a rudimentary gonad with ts\idence of tumor growth in the other ovar! and negative sex chromatin is suggestive evidence of a tumor in a dysgenetic gonad. Subsequently, on July 9, 1964, a report was received of confirmation of the diagnosis of CI gonadoblastoma and verification of the negative buccal smear and chromosome analysis with modal count of 46 chromosomes with an XY pattern. The association of tumor formation in cases of gonadal dysgenesis has been frequently commented upon in
Volume 92 Number
Gonadoblastoma
7
and
gonadal
dysgenesis
995
the literature.‘+ 8 The malformed gonads of hermaphrodites and pseudohermaphrodites apparently frequently give rise to tumors of this type.“‘ I” Although Fine3 suggests that virilization has characterized all patients with gonadoblastoma and that the virilism was believed to be caused by the secretion of androgen by the tumor, this was not the case in this patient who showed no evidence of virilization and did show high estrogen maturation effect on the vaginal mucosa. The presence of apparently normal tubes and uterus classifies this case as one of ovarian rather than testicular dys
1. A case is presented of gonadal dysgenesis in a phenotypical female with XY chromosome structure with the development of an ovarian tumor containing the basic primitive cell types conforming to the criteria for gonadoblastomas. 2. It is suggested that the granulosa cells within the tumor exerted sufficient hormonal influence to produce a vaginal secretion with high estrogen effect. Had Leydig cell remnants been hormonally dominant, this patient might have exhibited signs of masculinization,‘, I? 3. Removal of the tumor has no effect on the genital anomaly.
Fig. 4. Chromosome somes,
XY
analyses. Forty-six
chromo-
pattern.
We wish to thank the Armed Forces Institute of Pathology, notably Drs. Taylor and Norris for making the pathologic diagnosis, the Pediatric Section at Walter Reed Hospital for corroborating the clinical diagnosis, and also Dr. Michael Gass of Gorgas Hospital for his patience and effort.
REFERENCES
Cancer 6: 455, 1953. 1. ScuIIy, Robert: P. Teter, J,, and Tarlowski, R.: AM. & GYNEC. 79: 321, 1960. 3. Fine, Gerald: Am. J. Clin. Path. 1962. 4. Hain, -4. M.: J. Clin. Endocrinol. 1949. 5. McArthur, J. W.: New England 245: 905, 1951. Surg. 37: 697, 6. Seegar, G. E.: Arch. 7. Etabler and Thompson: J. Obst. & Brit. Emp. 44: 705, 1937.
8. J.
OBST.
38:
615,
9:
1349,
J.
Med.
1938. Gynaec.
9. 10. 11. 12. 13.
Warren, J. C., Erkman, B., Cheatum, S, and Holman, G.: Lancet 1: 141, 1964. Novak, J.: AM. J. OBST. & GYNEC. 45: 1943. Sailer, S.: Am. J. Cancer 38: 473, 1940. Newberger, R. O., and Theiss, E. A.: Am. J. Clin. Path. 38: 52, 1962. Uszims, H.: Cancer 9: 736, 1956. Newbecker. R., and Breen, J.: Am. J. Clin. Path. 38: 60, 1962.
Box 247 Balboa Heights, Canal Zone
in a patient
with gonadal dysgenesis I.
J.
Canal
THE
Zone,
M.D.,
tumor
is
containing
mesenchymal
germ
cell is to
with
gonadal
negative,
Case
report
cells,
2, 3 The such
in female
rare
a
and and
Leyof
in
association
a
chromatin
with
was soft, flat, and not tender. A firm mass !~a< felt rising out of the pelvis from the suprapuhic arca to a point three finger breadths below the umhiliclls. This did not extend laterally to the pelvic walls, but it came out of the pelvir as :I well-delineated mass. This was not tender and was fixed to abdominal examination. Rectal and pelvic examination revealed that she had normal external genitals. The patient was a virgin and the introitus barely admitted a finger tip. A probe could be passed in the vagina for a distance of 4 cm. Rectal examination revealed a firm, fixed, nontender masq filling the pelvis; rrn the inferior surface on the left there were m111tiple nodular excrescences. The mass was not cystic but felt more rubbery and firnl. The I‘Xtrcmitirs were negative. The skin ~‘as negative and the lymphatic system contained no nc~dulcs. The impression on admission \~as olsarian not-
primitive
purpose
a case
dysgenesis
phenotypical
chromosome
granulosal
sex cord
elements.‘,
paper
F.A.C.S.
Panama
GONADOBLASTOMA
ovarian dig
STRUMPF,
male
this
XY
structure. report
A
l”-L year-old white female complained of mild abdominal pain of approximately 6 days’ duration. In addition to this mild discomfort, the patient had had no menstrual periods. She was referred to Gorgas Hospital and admitted for study. The patient was a student of above averagr intelligence in the seventh grade. Her mother and father were living and well, and there werr no family illncsscs. There was no family history of diabetes, cancer, or allergies. She had had the usual childhood diseases without sequelae. She had had no operations. Review of systems was entirely negative. Notably, she had had no difficulties with bleeding disorders, and she was well adjusted socially in school. A general physical examination on admission to the hospital on May 10, 1964, revealed a young, normal-looking, robust, well-nourished, subteen female. She weighed 110 pounds and was 61 inches tall. She had normal development of the secondary sex characteristics and notably she had beginning breast development. She was in no distress and was very cooperative. Head, eyes, ears, nose, and throat were negative. The chest was clear to auscultation and percussion. She had good lung expansion with no dullness in either base. The heart had a normal sinus rhythm without murmur or thrill. The abdomen From
Gorgas
plasm,
probably
dysgerminoma. The admission urinal+ was essentially negative. Specific gravity \vas 1.014. The white blood count was 3,600 ivith normal differential, and the hemoglobin was 1 I .>I Gm. with a microhematocrit of 38 per CCII(. Serology was nonreactive. :11x x-ray of the c‘hcu(
Laboratory
findings.
was negative. Intravenous pyelogram demonstrated kidneys of normal size and shape; thert, was prompt appearanre of contrast media iu both upper collecting systems on the 5 minutr film. However, hoth upper collecting systems and the proximal two third? of the urctcrs wcr(* slightly dilated and indicative of a mild obstructivr Iuopathy which was felt to be present a~ thP pelvic brim. On the outlines of the bladder \\‘:I’; subadjaccnt c,xtrinsic. pressurt’. ‘l’h~, thaw impreshiotl was Grade I ur~~t~~ropyelocalie(.t~~si~~. scnt.ondary to a large pelvic ~IUYS. Barium cncnI:a revealed a large pelvic mass which displaced the distal sigmoid colon posteriorly, creating pressllre on this structure. Extrinsic prrssllre \\‘;I<
Hospital. 992
Volume
92
Gonadoblastoma
IVumber 7
again seen on the urinary bladder as a result of the intravenous pyelogram. It was felt that the pelvic mass was in the peritoneal cavity and not a retroperitoneal mass. A Papanicolaou smear taken from the vagina was a Class I, and the comment was “high maturation.” Hospital course. On May 13, 1964, the patient was taken to the operating room where an exploratory laparotomy was carried out. Aspiration of the abdominal fluid at the time of abdominal laparotomy contained insufficient sediment for cell block; however, Papanicolaou smear of this material showed no malignant cells free in the fluid. The findings at operation were of a large solid right ovarian tumor which was fixed in the pelvis and, after removal, presented the clinical impression of malignancy. The tumor measured 15 x 10 x 10 cm. and weighed 600 grams. The uterus was a small structure in the midline and the ovary on the left side was a white streak of tissue, rudimentary in nature. A total hysterectomy and bilateral salpingooophorectomy was then carried out. Incidental appendectomy of a retrocecal appendix was carried out. The patient did well postoperatively, although she ran a low-grade fever up to 101” F. from the first to the fourth days. By the end of the fourth hospital day, she was afebrile and, thereafter, had an uneventful convalescence. The pathological diagnosis on frozen section of the tumor of the right ovary was Brenner tumor, but on examination of the paraffin block, this was corrected to dysgerminoma. Tumor was also found in the rudimentary ovary on the left side. No ova were present in any of the sections. Following surgery, May 13, 1964, a clinical diagnosis of cqonadohlastoma in a patient with
Fig.
1. Cut
section
of tumor.
and
gonadal
dysgenesis
993
gonadal dysgenesis was made on the basis of the incongruity of the vaginal smear showing “high maturation effect” and the operative finding of nonfunctioning ovarian tissue with a nonhormone-producing dysgerminoma. Examination of a buccal smear at this time was reported chromatin negative. Resurvey of the pathological specimen with this suggested clinical diagnosis was requested. On the pathological basis of dysgerminoma, the Gorgas Hospital Tumor Board recommended supervoltage therapy rather than therapy with the 250 kv. machine available, and they recommended transfer of the patient to Walter Reed Hospital for this therapy. Transfer of patient and original slides was accomplished on May 21, 1964. On review by the Armed Forces Institute of Pathology, diagnosis was made of “ovary, gonadohlastoma, right.” The entire wet tissue was requested. This was sent on June 25, 1964. Upon subsequent review and study of the full specimen by Drs. Taylor and Norris of the Armed Forces Institute of Pathology, the diagnosis was made of “ovary, bilateral, gonadoblastoma.” X-ray therapy was not recommended, and the patient was referred back to Gorgas Hospital for further follow-up. No treatment was given. At the present time, the patient is well, appears well adjusted, and has no complaints. Pathology. Gorgas Hospital’s original diagnosis was amended on August 26, 1964 (S-64-1506). Tissue sections from the right ovary showed some areas which were very cellular and others where the stroma predominated. The predominant cellular picture was that of dysgerminoma. However, in many areas there were smaller cells with denser nuclear and cytoplasmic material. These were seen in clusters or lined up about dysgerminoma cells or amorphous pink deposits. This latter arrangement was very similar to that of Call-Exner bodies. The stroma was rather dense, and calcified areas could he seen. In both the cellular and the stromal areas there were collections of cells with slightly granular eosinophilic cytoplasm and vesicular nuclei with prominent reddish nucleoli. These cells had an “endocrine” appearance and resembled Leydig or hilar cells. Some appeared multinucleated. These groups of cells were often surrounded by an infiltrate of lymphocytes. No ova were found in this ovary. The right tube was unremarkable except for edema and chronic inflammatorv infiltrates in the mesosalpinx.
994
Strumpf
Sections of myometrium showed no remarkable changes. The endometrium sho\vcd fairly dense stroma and tubular glands with no mitoscs. Sections of the cervix showed suhrpitheliat chronic inflammatory infiltrates and squamous metaplasia. Sections of the left ovary showed the same features described in the right ovary exrept that the stroma was more predominant and large1 arcas of calcifying, amorphous, pink material were seen. No ova were found. Sections of the appendix and left fallopian tuhe showed no remarkable abnormalities. The diagnosis was gonadoblastoma of the left and right ovaries. The Armed Forces Institute of Pathology (Accession C 283-64) report was in agreement. Comment Dysgerminomas have been reported as being nonhormone pr0ducing.l Those with endocrine effects have usually been reclassified Fig. 3. A higher power view of thr center Tut ttrc, area pictured in the previous figurr. Note island of dysgerminoma cells in the uppt>r Id‘t with thr “Call-Exner body.” In the lower right hand
Fig. 2. Scattered in the stroma of the right ovar) are nests of dysgerminoma cells. To the left of center, one of the nests shows a round hyalinf mass surrounded by small cells. This structurr resembles the so-called “Call-Exner body.” Below and to the right of center is a mass of cells with abundant, slightly granular cytoplasm. These arc interpreted as representing hilar cells or Leydig
cells. (x10.)
on resut,vey.” The finding of “high maturation” in this 12-year-old girl prior to surgery aroused no suspicion because one o\par)might have been present and functioning. Pregnancies have been reported before and after surgery for dysgerminonlas.7 However, following surgery and the findimg of a nonfunctioning left ovary which was iriconlpatible with the vaginal smear finding madr the diagnosis of a pure dysgerminoma insupportable. The absence of mature ovarian stroma in a rudimentary gonad with ts\idence of tumor growth in the other ovar! and negative sex chromatin is suggestive evidence of a tumor in a dysgenetic gonad. Subsequently, on July 9, 1964, a report was received of confirmation of the diagnosis of CI gonadoblastoma and verification of the negative buccal smear and chromosome analysis with modal count of 46 chromosomes with an XY pattern. The association of tumor formation in cases of gonadal dysgenesis has been frequently commented upon in
Volume 92 Number
Gonadoblastoma
7
and
gonadal
dysgenesis
995
the literature.‘+ 8 The malformed gonads of hermaphrodites and pseudohermaphrodites apparently frequently give rise to tumors of this type.“‘ I” Although Fine3 suggests that virilization has characterized all patients with gonadoblastoma and that the virilism was believed to be caused by the secretion of androgen by the tumor, this was not the case in this patient who showed no evidence of virilization and did show high estrogen maturation effect on the vaginal mucosa. The presence of apparently normal tubes and uterus classifies this case as one of ovarian rather than testicular dys
1. A case is presented of gonadal dysgenesis in a phenotypical female with XY chromosome structure with the development of an ovarian tumor containing the basic primitive cell types conforming to the criteria for gonadoblastomas. 2. It is suggested that the granulosa cells within the tumor exerted sufficient hormonal influence to produce a vaginal secretion with high estrogen effect. Had Leydig cell remnants been hormonally dominant, this patient might have exhibited signs of masculinization,‘, I? 3. Removal of the tumor has no effect on the genital anomaly.
Fig. 4. Chromosome somes,
XY
analyses. Forty-six
chromo-
pattern.
We wish to thank the Armed Forces Institute of Pathology, notably Drs. Taylor and Norris for making the pathologic diagnosis, the Pediatric Section at Walter Reed Hospital for corroborating the clinical diagnosis, and also Dr. Michael Gass of Gorgas Hospital for his patience and effort.
REFERENCES
Cancer 6: 455, 1953. 1. ScuIIy, Robert: P. Teter, J,, and Tarlowski, R.: AM. & GYNEC. 79: 321, 1960. 3. Fine, Gerald: Am. J. Clin. Path. 1962. 4. Hain, -4. M.: J. Clin. Endocrinol. 1949. 5. McArthur, J. W.: New England 245: 905, 1951. Surg. 37: 697, 6. Seegar, G. E.: Arch. 7. Etabler and Thompson: J. Obst. & Brit. Emp. 44: 705, 1937.
8. J.
OBST.
38:
615,
9:
1349,
J.
Med.
1938. Gynaec.
9. 10. 11. 12. 13.
Warren, J. C., Erkman, B., Cheatum, S, and Holman, G.: Lancet 1: 141, 1964. Novak, J.: AM. J. OBST. & GYNEC. 45: 1943. Sailer, S.: Am. J. Cancer 38: 473, 1940. Newberger, R. O., and Theiss, E. A.: Am. J. Clin. Path. 38: 52, 1962. Uszims, H.: Cancer 9: 736, 1956. Newbecker. R., and Breen, J.: Am. J. Clin. Path. 38: 60, 1962.
Box 247 Balboa Heights, Canal Zone