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Primary malignant melanoma arising in an ovarian dermoid cyst
Primary malignant melanoma arising in an ovarian dermoid cyst ROBERT Coz~ina,
H.
GREGG,
M.D.
California
melanoma of the ovary is exceedingly rare. Indeed, if the criteria for primacy of Marcial-Rojas and de Arellano’ are used, there have been only six previous cases recorded in the literature.‘-3 Based on the criteria of Martial-Rojas and de Arellano, the present case probably represents the seventh primary malignant melanoma occurring in a dermoid cyst to be reported in the medical literature. PRIMARY
MALIGNANT
Case history A 56-year-old, white woman had increasing lower abdominal distention of 6 months’ duration. Significant physical examination findings included no skin lesions; a smooth, nontender, lower abdominal mass; external genitalia, vaginal walls, and cervix free of lesions; bimanual and rectovaginal examination revealed a large semifirm mass arising out of the pelvis without evidence of rectal shelf. Pelvic ultrasound revealed a cystic lower abdominal mass with solid internal components consistent with teratoma. Barium enema and intravenous pyelogram were negative. Operation included total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and appendectomy. At operation, there was an intact 18 to 20 cm left ovarian cyst without adhesions or papillations. There was a small amount of free serous peritoneal fluid which was submitted for cytologic examination. The right ovary, which measured approximately 8 cm, was deep in the cul-de-sac and slightly fixed to the posterior aspect of the broad ligament and lateral pelvic wall. The cyst was intact and without papillations. There were no demonstrable implants throughout the peri-
Presented
Pa+ Kauai, Reprint
at the Forty-eighth Annual Meeting of the Coast Obstetrical and Gynecological Society, Hawaii, September 27-October 3, 1981. requests: Robert
College Street, Covina, 0002-9378/82/090025+04$00.40/0~
H. Gregg,
M.D.,
210
West
California 91723. 1982 The C.V.Mosby
Co.
toneal cavity including omentum, intestines, gutters, liver, and diaphragms. The para-aortic and pelvic lymph nodes were not palpably enlarged. The pathology report was of an intact cystic left ovary measuring 18.0 by 15.0 by 10.0 cm with a smooth intact external surface. The cut section was cystic, containing brownish, watery fluid, a 3.0 cm ball of soft, grumose, yellow material, and hair. Multiple, brown, soft, fleshy nodules occupied the majority of the surface and ranged from 0.5 to 3.0 cm in diameter but often formed large, confluent masses. The cystic right ovary measured 8.0 by 6.0 by 6.0 cm and had a smooth, intact capsule. Cut section revealed a 5 cm smooth-walled cyst with soft, amorphous, brownish black material. Frozen section of the left ovary revealed a malignant cystic tumor not further classified. Frozen section of the right ovary revealed cyst without gross evidence of malignancy. Microscopic examination revealed a cystic malignant tumor of the left ovary composed of polypoid nodular masses of pleomorphic malignant cells with numerous mitoses, prominent nucleoli, and grey-pink cytoplasm containing brown pigment. Brown pigment granules were also present within stromal histiocytes (Fig. 1). There was extensive tumor necrosis within the nodules. Some tumor extension was seen into the thin wall of the ovary; however, extension through the wall was not noted. One small area of possible blood vessel invasion was present. The right ovary showed a cyst with clear fluid and was lined by a single layer of benign columnar epithehum. It also contained a Brenner tumor. Multiple additional sections of this tumor revealed areas of benign glandular and cartilaginous tissue. Approximately 4 months after operation, the patient was admitted to the hospital in severe congestive heart failure with myocardial insufficiency. Lung scan and ultrasound showed a high probability of pulmonary emboli. Abdominal scan including liver and spleen showed slight enlargement of these organs with multiple defects compatible with metastatic melanoma. On November 15, 1979, the patient died at home. Autopsy was not permitted by the family.
25
26
Gregg
Fig. 1. Photomicrograph of melanoma characterized by large polygonal cells with irregular hyperchromatic nuclei, many of which contain prominent nucleoli. Some of the cells contain granular melanin pigment. (Original magnification X 112.)
The primacy of malignant melanoma arising in an ovarian dermoid cyst is quite possible when the totipotent characteristics of teratomas within which melanogenie tissue can exist are considered.3 Martial-Rojas and de Arellano were the first to demonstrate intraepithelial malignant melanoma with junctional activity in a dermoid cyst. They accepted three previously reported cases as primary. Since then, two
May I, 19112 Am. J. Obstet. Gynecol.
additional cases showing intraepithelial junctional activity in a dermoid cyst have been reported.’ The great majority of primary malignant melanomas in the body show cutaneous junctional nevi with melanotic (pagetoid) cells. Even though a history of a preexisting pigmented lesion has been reported in more than 60% of patients, histologic confirmation of residual junctional nevus activity is not commonly seen. Indeed, some investigators’ do not accept the view rhat a majority of melanomas develop from antecedent junctional nevi. It has been demonstrated that primary malignant melanoma may arise de novo wherever epidermal or neural crest ectodermal melanocytes exist. The features of this case which seem to “qualify” it as an instance of primary malignant melanoma arising in an ovarian dermoid cyst are as follows: (1) abundant pigmentiferous epithelial structures occurring unilaterally in a dermoid cyst; (2) symptomatic pelvic and lower abdominal mass; (3) no clinical evidence of extragonadal primary lesion in past or present history; (3) no evidence of metastases at time of operation; (5) no microscopic evidence of mestatases in the omentum and no evidence of malignant cells in peritoneal fluid; (6) squamous epithelium with underlying melanoma but without junctional activity. The discovery of a primary site (junctional activity) was not demonstrated in the sections taken in this case. It is not improbable that the abundant tumor growth and extensive necrosis of the melanotic tissue in this very large dermoid cyst obliterated detection of a primary site. Strict adherence to the criteria of Martial-Rojas and de Arellano for establishing the primacy of ovarian origin requires deleting cases accepted by them. Whethei malignant junctional activity can truly be accepted as the sine qua non diagnostic criterion is open to question in light of the protean natural history of malignant melanomas and the teratomatous nature of the ovar) itself. Other gross and microscopic pathologic characteristics as well as the clinical history must be taken into consideration until further refinements in diagnosis become available.
REFERENCES
1. Marcial-Rojas, R. A., and de Arellano, G. A. R.: Malignant melanoma arising in a dermoid cyst of the ovary, Cancer 9:523, 1956. 2. Morrow, C. P., and Disaia, P. J.: Malignant melanoma of the female genitalia: a clinical analysis, Obstet. Gynecol. Surv. 31:233, 1976.
3. Peterson, F. P.: Malignant degeneration of benign cystic teratomas of the ovary. A collective review of the literature, Obstet. Gynecol. Surv. 12:793, 1957. 4. Woodruff, J. M.: Pathology of malignant melanoma. Part 1, Clin. Bull. 6:15, 1976.
Malignant
Editor.:’ note: This manuscript discussions were presented.
was revised
after these
Discussion DR. EDWARD C. HILL, San Francisco, California. Seldom does one have the opportunity to hear a report of the seventh reported case of anything in the world’s medical literature, so we are indebted to Dr. Gregg for bringing to our attention not only the fact that the usually benign dermoid cyst is capable of malignant degeneration but also that the malignancy can take the form of a melanoma. He informs us that primary melanoma of the ovary is a medical rarity and that, inasmuch as most ovarian melanomas are metastatic, rigid criteria should be met before such a tumor is labeled as primary. He uses the standards ostensibly outlined by Marcial-Rojas and de Arellano to establish the ovarian primacy of his case and does this quite convincingly, pointing out that the only criterion which is lacking is the pathologic demonstration of junctional activity in the tumor he reports. In reviewing Dr. Gregg’s paper, I can find little to criticize. One might ask for mention of an ophthalmoscopic examination, to search for a possible primary source in the retinal choroid, or esophagogastroscopy and colonoscopy, to look for the small gastrointestinal mucosal primary lesion. An autopsy might have provided additional information. This is not to detract from the worth of Dr. Gregg’s case report. It is highly unlikely, had there been a hidden primary site elsewhere, that the dermoid cyst in his patient would have been the only site of metastasis. The evidence that he presents has convinced me that this tumor did, indeed, arise de nova in a dermoid cyst. The absence ofjunctional activity should not dissuade one from this opinion. In the Marcial-Rojas-de Arellano paper, it is immediately apparent that the authors were reporting for the first time junctional activity in a dermoid cyst and using that as further evidence that the melanoma was primary in the ovary. There was no implication in that article that such a finding was an absolute prerequisite. They did state, however, that preexistent pigmentiferous epithelial strUctures, as those of dermoid cysts, are essential for the developing of authenticated cases of primary ovarian melanoma. In reviewing the literature to learn more about this topic, I was astounded by the knowledge which has been acquired with reference to the pigment cell. There are five volumes in our medical library which deal with recent studies of the melanocyte. Individuals are devoting their life’s work to the study of this one cell. Annual international conferences on the pigment cell are held. It is now categorically stated that the melanocyte is derived from the neural crest and can be recognized ultrastructurally in human epidermis by the eighth week of gestation. In Caucasoids nonmelanized
melanoma
in ovarian
dermoid
cyst
27
melanosomes are seen within the cell at this time, and by the tenth week early stages of melanization can be detected. In the juxtaposition of the melanocyte and the epidermal cell, a melanosome-containing dendritic process of the melanocyte is phagocytosed by the keratinocyte and the melanosomes are then dispersed within the cytoplasm of the keratinocyte. Thus, in mammals, the so-called “epidermal-melanin unit” is functioning to maintain normal hair color and skin color. If the melanocyte develops primarily from neural tissue, then, although it is desirable, there should be little reason to require the demonstration of junctional activity in the epidermis of a dermoid cyst. One can postulate the development of a melanoma of the ovary arising primarily from the melanocyte itself. In support of this, I would like to bring to your attention the only reported case in the literature of a melanotic ovarian neoplasm resembling the “retinal anlage” tumor.’ This is a primary malignant melanotic neoplasm of the ovary which has histopathologic features of a medulloepithelioma of the retina, a tumor which has its origin in the neural groove rather than the neural crest, from which all other human melanocyte systems are derived. Two cases have also been reported in the uterus.’ I enjoyed Dr. Gregg’s paper and commend him for this contribution to our medical knowledge. REFERENCES
1. Hameed, I(., and Burslem, M. R. G.: A melanotic ovarian neoplasm resembling the “retinal anlage” tumor, Cancer 25:564, 1970. 2. Teilum, G.: Special Tumors of the Ovary, Philadelphia, 1971, J. B. Lippincott Co. DR. RALPH BENSON, Portland, Oregon. In Dr. Nishijima’s absence I shall give his comments on certain features of Dr. Gregg’s very provocative paper. With the interest that Dr. Nishijima has had in dermoids (as you recall, the dermoid cyst is the most common ovarian tumor in Japan), he decided to review the experience with dermoid cysts at the Kapiolani Hospital for a 20year period. In an effort to identify a melanoma in this group, a search of the material was carried out but no melanomas were identified. However, the spin-off was interesting, because three malignancies were identified. All patients with a malignancy were multiparous and the cancers were all incidentally discovered. After treatment, all are living and well, more than 5 years following removal of the tumors. The first was an invasive, poorly differentiated epidermoid carcinoma in a woman of 55. The second was a carcinoid; the third was a neuroblastoma but without melanotic inclusions. There was minimal invasion in the squamous cell carcinoma. No extension was noted in the carcinoid or the neuroblastoma because none of these tumors had ac-
28 Gregg
tually penetrated the capsule. The same pathologist was responsible for the discovery of the cancerous facies in each of these cases, although numerous pathologtsts were mvolved in the total 20-year experience. Dockerty at the Mayo Clinic demonstrated that the more slides one examines of dermoids, the more one can open the Pandora’s box of pathologic variations
May 1, 1962 Am. J. Obscet. Gynecol.
and curiosities in the dermoid tumors. Thus, we should require that the pathologist search diligently for one of these unusual tumors. DR. GREGG (Closing). I would also like to thank the Program Committee for asking me to present this paper at our Fiftieth Anniversary.
H.
GREGG,
M.D.
California
melanoma of the ovary is exceedingly rare. Indeed, if the criteria for primacy of Marcial-Rojas and de Arellano’ are used, there have been only six previous cases recorded in the literature.‘-3 Based on the criteria of Martial-Rojas and de Arellano, the present case probably represents the seventh primary malignant melanoma occurring in a dermoid cyst to be reported in the medical literature. PRIMARY
MALIGNANT
Case history A 56-year-old, white woman had increasing lower abdominal distention of 6 months’ duration. Significant physical examination findings included no skin lesions; a smooth, nontender, lower abdominal mass; external genitalia, vaginal walls, and cervix free of lesions; bimanual and rectovaginal examination revealed a large semifirm mass arising out of the pelvis without evidence of rectal shelf. Pelvic ultrasound revealed a cystic lower abdominal mass with solid internal components consistent with teratoma. Barium enema and intravenous pyelogram were negative. Operation included total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and appendectomy. At operation, there was an intact 18 to 20 cm left ovarian cyst without adhesions or papillations. There was a small amount of free serous peritoneal fluid which was submitted for cytologic examination. The right ovary, which measured approximately 8 cm, was deep in the cul-de-sac and slightly fixed to the posterior aspect of the broad ligament and lateral pelvic wall. The cyst was intact and without papillations. There were no demonstrable implants throughout the peri-
Presented
Pa+ Kauai, Reprint
at the Forty-eighth Annual Meeting of the Coast Obstetrical and Gynecological Society, Hawaii, September 27-October 3, 1981. requests: Robert
College Street, Covina, 0002-9378/82/090025+04$00.40/0~
H. Gregg,
M.D.,
210
West
California 91723. 1982 The C.V.Mosby
Co.
toneal cavity including omentum, intestines, gutters, liver, and diaphragms. The para-aortic and pelvic lymph nodes were not palpably enlarged. The pathology report was of an intact cystic left ovary measuring 18.0 by 15.0 by 10.0 cm with a smooth intact external surface. The cut section was cystic, containing brownish, watery fluid, a 3.0 cm ball of soft, grumose, yellow material, and hair. Multiple, brown, soft, fleshy nodules occupied the majority of the surface and ranged from 0.5 to 3.0 cm in diameter but often formed large, confluent masses. The cystic right ovary measured 8.0 by 6.0 by 6.0 cm and had a smooth, intact capsule. Cut section revealed a 5 cm smooth-walled cyst with soft, amorphous, brownish black material. Frozen section of the left ovary revealed a malignant cystic tumor not further classified. Frozen section of the right ovary revealed cyst without gross evidence of malignancy. Microscopic examination revealed a cystic malignant tumor of the left ovary composed of polypoid nodular masses of pleomorphic malignant cells with numerous mitoses, prominent nucleoli, and grey-pink cytoplasm containing brown pigment. Brown pigment granules were also present within stromal histiocytes (Fig. 1). There was extensive tumor necrosis within the nodules. Some tumor extension was seen into the thin wall of the ovary; however, extension through the wall was not noted. One small area of possible blood vessel invasion was present. The right ovary showed a cyst with clear fluid and was lined by a single layer of benign columnar epithehum. It also contained a Brenner tumor. Multiple additional sections of this tumor revealed areas of benign glandular and cartilaginous tissue. Approximately 4 months after operation, the patient was admitted to the hospital in severe congestive heart failure with myocardial insufficiency. Lung scan and ultrasound showed a high probability of pulmonary emboli. Abdominal scan including liver and spleen showed slight enlargement of these organs with multiple defects compatible with metastatic melanoma. On November 15, 1979, the patient died at home. Autopsy was not permitted by the family.
25
26
Gregg
Fig. 1. Photomicrograph of melanoma characterized by large polygonal cells with irregular hyperchromatic nuclei, many of which contain prominent nucleoli. Some of the cells contain granular melanin pigment. (Original magnification X 112.)
The primacy of malignant melanoma arising in an ovarian dermoid cyst is quite possible when the totipotent characteristics of teratomas within which melanogenie tissue can exist are considered.3 Martial-Rojas and de Arellano were the first to demonstrate intraepithelial malignant melanoma with junctional activity in a dermoid cyst. They accepted three previously reported cases as primary. Since then, two
May I, 19112 Am. J. Obstet. Gynecol.
additional cases showing intraepithelial junctional activity in a dermoid cyst have been reported.’ The great majority of primary malignant melanomas in the body show cutaneous junctional nevi with melanotic (pagetoid) cells. Even though a history of a preexisting pigmented lesion has been reported in more than 60% of patients, histologic confirmation of residual junctional nevus activity is not commonly seen. Indeed, some investigators’ do not accept the view rhat a majority of melanomas develop from antecedent junctional nevi. It has been demonstrated that primary malignant melanoma may arise de novo wherever epidermal or neural crest ectodermal melanocytes exist. The features of this case which seem to “qualify” it as an instance of primary malignant melanoma arising in an ovarian dermoid cyst are as follows: (1) abundant pigmentiferous epithelial structures occurring unilaterally in a dermoid cyst; (2) symptomatic pelvic and lower abdominal mass; (3) no clinical evidence of extragonadal primary lesion in past or present history; (3) no evidence of metastases at time of operation; (5) no microscopic evidence of mestatases in the omentum and no evidence of malignant cells in peritoneal fluid; (6) squamous epithelium with underlying melanoma but without junctional activity. The discovery of a primary site (junctional activity) was not demonstrated in the sections taken in this case. It is not improbable that the abundant tumor growth and extensive necrosis of the melanotic tissue in this very large dermoid cyst obliterated detection of a primary site. Strict adherence to the criteria of Martial-Rojas and de Arellano for establishing the primacy of ovarian origin requires deleting cases accepted by them. Whethei malignant junctional activity can truly be accepted as the sine qua non diagnostic criterion is open to question in light of the protean natural history of malignant melanomas and the teratomatous nature of the ovar) itself. Other gross and microscopic pathologic characteristics as well as the clinical history must be taken into consideration until further refinements in diagnosis become available.
REFERENCES
1. Marcial-Rojas, R. A., and de Arellano, G. A. R.: Malignant melanoma arising in a dermoid cyst of the ovary, Cancer 9:523, 1956. 2. Morrow, C. P., and Disaia, P. J.: Malignant melanoma of the female genitalia: a clinical analysis, Obstet. Gynecol. Surv. 31:233, 1976.
3. Peterson, F. P.: Malignant degeneration of benign cystic teratomas of the ovary. A collective review of the literature, Obstet. Gynecol. Surv. 12:793, 1957. 4. Woodruff, J. M.: Pathology of malignant melanoma. Part 1, Clin. Bull. 6:15, 1976.
Malignant
Editor.:’ note: This manuscript discussions were presented.
was revised
after these
Discussion DR. EDWARD C. HILL, San Francisco, California. Seldom does one have the opportunity to hear a report of the seventh reported case of anything in the world’s medical literature, so we are indebted to Dr. Gregg for bringing to our attention not only the fact that the usually benign dermoid cyst is capable of malignant degeneration but also that the malignancy can take the form of a melanoma. He informs us that primary melanoma of the ovary is a medical rarity and that, inasmuch as most ovarian melanomas are metastatic, rigid criteria should be met before such a tumor is labeled as primary. He uses the standards ostensibly outlined by Marcial-Rojas and de Arellano to establish the ovarian primacy of his case and does this quite convincingly, pointing out that the only criterion which is lacking is the pathologic demonstration of junctional activity in the tumor he reports. In reviewing Dr. Gregg’s paper, I can find little to criticize. One might ask for mention of an ophthalmoscopic examination, to search for a possible primary source in the retinal choroid, or esophagogastroscopy and colonoscopy, to look for the small gastrointestinal mucosal primary lesion. An autopsy might have provided additional information. This is not to detract from the worth of Dr. Gregg’s case report. It is highly unlikely, had there been a hidden primary site elsewhere, that the dermoid cyst in his patient would have been the only site of metastasis. The evidence that he presents has convinced me that this tumor did, indeed, arise de nova in a dermoid cyst. The absence ofjunctional activity should not dissuade one from this opinion. In the Marcial-Rojas-de Arellano paper, it is immediately apparent that the authors were reporting for the first time junctional activity in a dermoid cyst and using that as further evidence that the melanoma was primary in the ovary. There was no implication in that article that such a finding was an absolute prerequisite. They did state, however, that preexistent pigmentiferous epithelial strUctures, as those of dermoid cysts, are essential for the developing of authenticated cases of primary ovarian melanoma. In reviewing the literature to learn more about this topic, I was astounded by the knowledge which has been acquired with reference to the pigment cell. There are five volumes in our medical library which deal with recent studies of the melanocyte. Individuals are devoting their life’s work to the study of this one cell. Annual international conferences on the pigment cell are held. It is now categorically stated that the melanocyte is derived from the neural crest and can be recognized ultrastructurally in human epidermis by the eighth week of gestation. In Caucasoids nonmelanized
melanoma
in ovarian
dermoid
cyst
27
melanosomes are seen within the cell at this time, and by the tenth week early stages of melanization can be detected. In the juxtaposition of the melanocyte and the epidermal cell, a melanosome-containing dendritic process of the melanocyte is phagocytosed by the keratinocyte and the melanosomes are then dispersed within the cytoplasm of the keratinocyte. Thus, in mammals, the so-called “epidermal-melanin unit” is functioning to maintain normal hair color and skin color. If the melanocyte develops primarily from neural tissue, then, although it is desirable, there should be little reason to require the demonstration of junctional activity in the epidermis of a dermoid cyst. One can postulate the development of a melanoma of the ovary arising primarily from the melanocyte itself. In support of this, I would like to bring to your attention the only reported case in the literature of a melanotic ovarian neoplasm resembling the “retinal anlage” tumor.’ This is a primary malignant melanotic neoplasm of the ovary which has histopathologic features of a medulloepithelioma of the retina, a tumor which has its origin in the neural groove rather than the neural crest, from which all other human melanocyte systems are derived. Two cases have also been reported in the uterus.’ I enjoyed Dr. Gregg’s paper and commend him for this contribution to our medical knowledge. REFERENCES
1. Hameed, I(., and Burslem, M. R. G.: A melanotic ovarian neoplasm resembling the “retinal anlage” tumor, Cancer 25:564, 1970. 2. Teilum, G.: Special Tumors of the Ovary, Philadelphia, 1971, J. B. Lippincott Co. DR. RALPH BENSON, Portland, Oregon. In Dr. Nishijima’s absence I shall give his comments on certain features of Dr. Gregg’s very provocative paper. With the interest that Dr. Nishijima has had in dermoids (as you recall, the dermoid cyst is the most common ovarian tumor in Japan), he decided to review the experience with dermoid cysts at the Kapiolani Hospital for a 20year period. In an effort to identify a melanoma in this group, a search of the material was carried out but no melanomas were identified. However, the spin-off was interesting, because three malignancies were identified. All patients with a malignancy were multiparous and the cancers were all incidentally discovered. After treatment, all are living and well, more than 5 years following removal of the tumors. The first was an invasive, poorly differentiated epidermoid carcinoma in a woman of 55. The second was a carcinoid; the third was a neuroblastoma but without melanotic inclusions. There was minimal invasion in the squamous cell carcinoma. No extension was noted in the carcinoid or the neuroblastoma because none of these tumors had ac-
28 Gregg
tually penetrated the capsule. The same pathologist was responsible for the discovery of the cancerous facies in each of these cases, although numerous pathologtsts were mvolved in the total 20-year experience. Dockerty at the Mayo Clinic demonstrated that the more slides one examines of dermoids, the more one can open the Pandora’s box of pathologic variations
May 1, 1962 Am. J. Obscet. Gynecol.
and curiosities in the dermoid tumors. Thus, we should require that the pathologist search diligently for one of these unusual tumors. DR. GREGG (Closing). I would also like to thank the Program Committee for asking me to present this paper at our Fiftieth Anniversary.