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Cryosurgery of the uterus: Description of technique and potential application
Current Investigation
Cryosurgery of the uterus: Description of technique and potential application WILLIAM G. CAHAN, M.D. New York, New York
T H ! s preliminary report describes the results achieved in 3 patients following the intrauterine application of cryosurgical instruments and techniques. The underlying reason for this investigation is that we believe that cryosurgical methods could provide a simple, reliable, and economical means of producing destruction of the endometrium and, consequently, organ failure.
this problem which, at the same time, would leave the nearby congelated tissue thermally undisturbed. A detailed description of the probe will be forthcoming in a future communication. Technique
The uterus in most nongravid animals is so thin-walled that it was inadequate fOT experimentation along the lines described below. Therefore, elementary steps in technique were carried out on the human uterus removed at operation or autopsy. In these specimens, thermocouple needles (Fig. 1) * were inserted intramurally, staggering their tips at varying intervals from just below the endometrium to the serosa. This permitted observations of temperature changes at different depths and at different time intervals. Freezing then took place at a tip temperature varying from -70° C. to -140° C. and for 2 to 10 minutes in different specimens. Among several observations made, there was
The instrument
The intrauterine probe (Fig. 1) consists of two tubes, telescoped one within the other, through which liquid nitrogen is circulated. The probe is insulated, except for its 9 em. tip which acts as a freezing source and is patterned after a No. 5 Hegar dilator. Originally, as deep freezing occurred, the probe adhered rigidly to the tissue immediately surrounding it and could not be withdrawn for several minutes. Consequently a rewarming device was added to overcome From the Department of Surgery, Memorial Hospital for Cancer and Allied Diseases. Aided by grants from the Doctors' Special Fund, the Leonard Milton Foundation, and the Albert Schweitzer Fund.
*For this purpose, we designed a multiple six-point thermocouple thermometer made by Douglas Aircraft Cor• poration of Santa Monica, California, using No. 18 gauge needles that can be inserted into tissues as carriers for thermocouples. The temperatw-e readings so obtained are a!Dwst instantaneously recorded on six separate dials and are accurate within 1°.
410
Volume 88 Numbe .. 3
Cryosurgery of uterus
411
Three individuals were selected who were scheduled to have a hysterectomy.* Case 1. The patient, aged 39, had multiple
Fig. 1. Uterus with thermocouple needles, thermocouple thermometer, and probe about to be introduced.
one worth emphasizing: when the tip temperature of -140° C. is maintained for 5 minutes, the serosal surface in an average adult uterus still registered its original temperature even though the frozen area was found upon sectioning to have extended to within Y2 em. of the serosal surface. It was noted that the temperature 1 mm. within the congelated area was in the range of 0° C. to -5° C., yet only 1 mm. away, in the unfrozen tissue, the original temperature was maintained. After repeated trials, it ·became evident that the human uterus seemed naturally suited for cryosurgical procedures on its endometrium. Its thick and normally vascular myometrium, particularly in the supracervical portions, affords an effective insulation against the excessive advance of freezing, thereby providing a margin of safety against inadvertent inclusion and subsequent damage to neighboring stmctures.
myomas of the uterus, enlarging it to the size of a 4 months' pregnancy. On March 7, 1963, after dilatation and curettage, the cryosurgical probe was inserted and could be advanced only 6 em. because of endometrial distortion. The freezing source, therefore, was also in contact with the endocervix and the external os. With the probe in midline position, freezing was instituted at -137° C. and carried out for 2 minutes at this temperature. With rewarming, the probe was extracted in 1 minute, 10 seconds. A panhysterectomy was done and, at that time, there was no evidence of peritoneal irritation. The specimen was removed 1Y2 hours following completion of cryosurgery. The patient had an uneventful recovery. The gross and microscopic pathological findings showed no evidence of any changes attributable to cryosurgery. Case 2. The patient, aged 44, also had multiple myomas and cryosurgery was carried out as described above. However, in this instance, she was allowed to wait 3 days before the panhysterectomy was performed. During this interval she had evidence of mild peritoneal irritation and, at operation, there was some edema of the broad ligament and a moderate degree of subserosa! congestion over the fundus. The panhysterectomy was performed without technical difficulties and she had an uneventful recovery. The uterus (Fig. 2) was distorted by multiple leiomyomas ranging up to 3 em. in diameter. Serial sagittal sections showed the lower % of the endometrial cavity and the endocervical canal to be lined by a bluish zone extending into the underlying tissues. The width of this zone varied in different portions of the uterus, ranging from 0.2 em. to 1.1 em. The fact that the mucous membrane of both cornua was intact is interpreted as reflecting their inaccessibility both to curettage and freezing because of the intracavitary intrusion of fibroids. There was slight edema of the innermost myometrium, and the serosal reaction seen at operation was not grossly evident. On microscopic examination of representative
*From the Gynecologic Service, Memorial Hospital for Cancer and Allied Diseases, and with the help of Drs. Virginia K. Pierce and Alfred Brockunier.
412
Ft• b 1 IJ. J I
Cahan
Fig. 2. Uterus, Case 2. Note clark zone linin g endome trium, endoce rYix .
sections (by Dr. Robert V. P. Hutter) the bluish zone was found to correspond to a diffuse necrosis. The necrosis was sharply demarcated fr om subjacent tissue in which there was evidence of pericapillary hemorrhage, moderate edema, few leukocytes, destruction of the smooth muscle cells, and early intracapillary thrombus formation. No basal layer endometrial glands were visible (except those found in the intact cornua). As deeper myometrial layers were examined, they appeared normal without any edema or inflammatory reaction. The serosa showed no evidence of inflammation. The endocervix showed a more superficial necrosis than the endometrium and only a rare, n~lative ly deeply placed glandular structure could be observed. The necrosis extended to and about the external os for several millimeters where there was an abrupt transition from absent to intact squamous epithelium. The subepithelial layers in these areas had an appearance which was very similar to that of the uterine cavity.
.·\111.
.J . O h~ l.
\
1. 1~~~~ 1
,\ ( rY!I\'(' .
Case 3. The patien t, aged 73 , had a ,·,·rvical smra r in February. 1963 , that showrd malignam cells suggestive of an in situ carcinoma. Schiller's test and biopsies of various poniom of th" cervix W< ~ rr negative, but the biopsy of the <'ndocervix sho\ved a carcinoma which was questionably in situ or invasiVf'. Two additional l"ervica l smears wr r<> positive and another t' ndocrrvical biopsy showed epidermoid carcinoma. In July, 1963, after a dilatation and endometrial biopsy, the cryoprobe was introduced to permit contact beginning at an area just above the internal os, extending through the end ocervical canal and the external os. Freezing was ca rried out at - 120° C. for I ;12 minutes. Thawing was complete in 5 minutes and the same area was refrozen at the same temperature for 1 minute. Recovery was uneventful and for 3 to { weeks there was a 4· mm. necrosis about the external os. This finally disappeared and 4 subsequent smears showed atypical squamous cells but no evidence of cancer. Because an ovarian mass was thought to be enlarging, a laparotomy and panhysterectomy was performed 8 weeks later. The ovarian tumor was a serous cystadenoma. The uterus showed ( Fig. 3 ) linear hyaliniza· tion of the lining of the endocervix 4 mm. in depth, beginning abruptly just superior to the internal os and extending inferiorly for 3 mm . about the external os. The endometrium just superior to the scar was a trophic. The portion of the cervix beyond the area frozen showed inflammation and epithelial atypia. There was no evidence of any residual cancer. Comment
These 3 experiences reaffirmed previously reported observations on the effects of rapid deep freezing and slow thawing on tissues in general. 1 • 5 In these reports it was found that when tissue temperatures were rapidly dropped below ·-60° C. and thawing permitted to progress slowly, the frozen area eventually becomes necrotic in a unique way. The appearance of necrosis, which almost uniformly involves all tissues, is delayed for severaf hours after freezing has been completed and, when it finally becomes apparent, the necrotic tissue is sharply demarcated from the adjacent, still-viable tissue. In subsequent days the area of necrosis
Volume 88 Number 3
Cryosurgery of uterus
I
I
I
I
I
I
2
3
4
CM
6
7
Fig. 3. Uterus, Case 3. Note endocervical canal hyalinized and its abrupt ending (arrow) just above internal os.
seems to retain the shadow of its original architecture, giving the appearance of an ischemic infarct. Slowly, over a period of weeks, it is gradually rejected or reabsorbed. The surrounding viable tissue also reacts in a singular manner. Shortly after the procedure, there are evidences of interstitial edema and hemorrhage, intracapillary thrombus formation, and a few leukocytes. After 4 to 5 weeks, granulation tissue becomes more developed in the viable tissues as the slough it surrounds separates. The resulting raw surface eventually heals with a thin, pliable scar and, if there is adjacent epithelium, these elements subsequently spread and cover the treated surface. This pattern of healing after freezing in animals seemed to be duplicated to some extent in the 3 uterine specimens. For example, the uterus that was removed 1Y:z hours after freezing showed no remarkable gross and microscopic findings. However, the uterus that was allowed to remain 3 days before extirpation showed that in the area
413
frozen necrosis was so complete that no endometrium or endocervical lining remained. The uterus that was allowed to remain 8 weeks showed well-established hyalinization confined to the endocervix, and covered by a thin layer of epithelial cells. It is probable that if the first 2 uteri had been allowed to remain for 8 or more weeks, they might have healed in a similar fashion. In using electrocautery over large areas there is always a threat of hemorrhage from the slough that frequently results. Cryosurgery definitely differs in this respect for although there may be interstitial hemorrhage immediately following congelation, this is very rapidly self-limiting. At a later time, when the slough separates, there is no hemorrhage. This holds true in animals even when such vascular organs as liver, heart muscle, and kidney were subjected to cryosurgery and has even been true when large vessels such as the aorta, carotid, and inferior vena cava were intentionally frozen. On capillaries and vessels of small caliber, freezing in this manner would seem to exert a hemostatic effect. Implications
This preliminary experience, although small, has encouraged us to pursue the study further. Undoubtedly, there is still much to be clarified; instruments and techniques must be refined; intimate cryobiologic changes need better understanding; and more clinical and histological experience is required before the overall value of this modality can be assessed. Nevertheless, one fact stands out : it has now been shown that it is feasible to alter the lining of the uterus in a new and relatively simple fashion. If this can be done consistently and with safety, it may have many and varied gynecologic applications. For instance, it might have value in conception control, abnormal uterine bleeding, and in the treatment of certain uterine cancers. Further speculation as to its possible applications is almost limitless, confined only by the realization that the measure of success
414
Cahan
of any new modality is not whether it can perform a given task as well as presently established methods, but whether it can provide new benefits or simplify or refine old techniques. It is our belief that cryo-
Febn'"'' L 1<164
,\m,
J.
Obst. & Gyn••c
surgery will prove its value in this regard. Grateful acknowledgment is made to Kurt Bender, Joe Thomas, Earl Winter, and Max Shufer, without whose assistance the instrument could not have been completed.
REFERENCES
1. Hass, G. M., and Taylor, C. B.: Arch. Path. 45: 563, 1948. 2. McDonald, James H., Taylor, C. Bruce, and Heckel, Norris J.: J. Urol. 64: 326, 1950. 3. Breedis, Charles: The action of extreme cold on leukemic cells of mice. J. Exper, Med. 76: 221, 1942. 4. Hass, George M., and Taylor, C. Bruce: A. M. A. Arch. Neurol. & Psychiat. 69: 145, 1953.
5. Clasen, Raymond A., Brown, David V. L., Leavitt, Seymour, and Hass, George M.: Surg. Gynec. & Obst. 96: 605, 1953. 6. Economou, Steven G., Taylor, C. Bruce, Beattie, Edward J., Jr., and Davis, Clark B., Jr.: Surgery 47: 21, 1960. 7. Cooper, Irving S.: New England J. Med. 268: 743, 1963.
Cryosurgery of the uterus: Description of technique and potential application WILLIAM G. CAHAN, M.D. New York, New York
T H ! s preliminary report describes the results achieved in 3 patients following the intrauterine application of cryosurgical instruments and techniques. The underlying reason for this investigation is that we believe that cryosurgical methods could provide a simple, reliable, and economical means of producing destruction of the endometrium and, consequently, organ failure.
this problem which, at the same time, would leave the nearby congelated tissue thermally undisturbed. A detailed description of the probe will be forthcoming in a future communication. Technique
The uterus in most nongravid animals is so thin-walled that it was inadequate fOT experimentation along the lines described below. Therefore, elementary steps in technique were carried out on the human uterus removed at operation or autopsy. In these specimens, thermocouple needles (Fig. 1) * were inserted intramurally, staggering their tips at varying intervals from just below the endometrium to the serosa. This permitted observations of temperature changes at different depths and at different time intervals. Freezing then took place at a tip temperature varying from -70° C. to -140° C. and for 2 to 10 minutes in different specimens. Among several observations made, there was
The instrument
The intrauterine probe (Fig. 1) consists of two tubes, telescoped one within the other, through which liquid nitrogen is circulated. The probe is insulated, except for its 9 em. tip which acts as a freezing source and is patterned after a No. 5 Hegar dilator. Originally, as deep freezing occurred, the probe adhered rigidly to the tissue immediately surrounding it and could not be withdrawn for several minutes. Consequently a rewarming device was added to overcome From the Department of Surgery, Memorial Hospital for Cancer and Allied Diseases. Aided by grants from the Doctors' Special Fund, the Leonard Milton Foundation, and the Albert Schweitzer Fund.
*For this purpose, we designed a multiple six-point thermocouple thermometer made by Douglas Aircraft Cor• poration of Santa Monica, California, using No. 18 gauge needles that can be inserted into tissues as carriers for thermocouples. The temperatw-e readings so obtained are a!Dwst instantaneously recorded on six separate dials and are accurate within 1°.
410
Volume 88 Numbe .. 3
Cryosurgery of uterus
411
Three individuals were selected who were scheduled to have a hysterectomy.* Case 1. The patient, aged 39, had multiple
Fig. 1. Uterus with thermocouple needles, thermocouple thermometer, and probe about to be introduced.
one worth emphasizing: when the tip temperature of -140° C. is maintained for 5 minutes, the serosal surface in an average adult uterus still registered its original temperature even though the frozen area was found upon sectioning to have extended to within Y2 em. of the serosal surface. It was noted that the temperature 1 mm. within the congelated area was in the range of 0° C. to -5° C., yet only 1 mm. away, in the unfrozen tissue, the original temperature was maintained. After repeated trials, it ·became evident that the human uterus seemed naturally suited for cryosurgical procedures on its endometrium. Its thick and normally vascular myometrium, particularly in the supracervical portions, affords an effective insulation against the excessive advance of freezing, thereby providing a margin of safety against inadvertent inclusion and subsequent damage to neighboring stmctures.
myomas of the uterus, enlarging it to the size of a 4 months' pregnancy. On March 7, 1963, after dilatation and curettage, the cryosurgical probe was inserted and could be advanced only 6 em. because of endometrial distortion. The freezing source, therefore, was also in contact with the endocervix and the external os. With the probe in midline position, freezing was instituted at -137° C. and carried out for 2 minutes at this temperature. With rewarming, the probe was extracted in 1 minute, 10 seconds. A panhysterectomy was done and, at that time, there was no evidence of peritoneal irritation. The specimen was removed 1Y2 hours following completion of cryosurgery. The patient had an uneventful recovery. The gross and microscopic pathological findings showed no evidence of any changes attributable to cryosurgery. Case 2. The patient, aged 44, also had multiple myomas and cryosurgery was carried out as described above. However, in this instance, she was allowed to wait 3 days before the panhysterectomy was performed. During this interval she had evidence of mild peritoneal irritation and, at operation, there was some edema of the broad ligament and a moderate degree of subserosa! congestion over the fundus. The panhysterectomy was performed without technical difficulties and she had an uneventful recovery. The uterus (Fig. 2) was distorted by multiple leiomyomas ranging up to 3 em. in diameter. Serial sagittal sections showed the lower % of the endometrial cavity and the endocervical canal to be lined by a bluish zone extending into the underlying tissues. The width of this zone varied in different portions of the uterus, ranging from 0.2 em. to 1.1 em. The fact that the mucous membrane of both cornua was intact is interpreted as reflecting their inaccessibility both to curettage and freezing because of the intracavitary intrusion of fibroids. There was slight edema of the innermost myometrium, and the serosal reaction seen at operation was not grossly evident. On microscopic examination of representative
*From the Gynecologic Service, Memorial Hospital for Cancer and Allied Diseases, and with the help of Drs. Virginia K. Pierce and Alfred Brockunier.
412
Ft• b 1 IJ. J I
Cahan
Fig. 2. Uterus, Case 2. Note clark zone linin g endome trium, endoce rYix .
sections (by Dr. Robert V. P. Hutter) the bluish zone was found to correspond to a diffuse necrosis. The necrosis was sharply demarcated fr om subjacent tissue in which there was evidence of pericapillary hemorrhage, moderate edema, few leukocytes, destruction of the smooth muscle cells, and early intracapillary thrombus formation. No basal layer endometrial glands were visible (except those found in the intact cornua). As deeper myometrial layers were examined, they appeared normal without any edema or inflammatory reaction. The serosa showed no evidence of inflammation. The endocervix showed a more superficial necrosis than the endometrium and only a rare, n~lative ly deeply placed glandular structure could be observed. The necrosis extended to and about the external os for several millimeters where there was an abrupt transition from absent to intact squamous epithelium. The subepithelial layers in these areas had an appearance which was very similar to that of the uterine cavity.
.·\111.
.J . O h~ l.
\
1. 1~~~~ 1
,\ ( rY!I\'(' .
Case 3. The patien t, aged 73 , had a ,·,·rvical smra r in February. 1963 , that showrd malignam cells suggestive of an in situ carcinoma. Schiller's test and biopsies of various poniom of th" cervix W< ~ rr negative, but the biopsy of the <'ndocervix sho\ved a carcinoma which was questionably in situ or invasiVf'. Two additional l"ervica l smears wr r<> positive and another t' ndocrrvical biopsy showed epidermoid carcinoma. In July, 1963, after a dilatation and endometrial biopsy, the cryoprobe was introduced to permit contact beginning at an area just above the internal os, extending through the end ocervical canal and the external os. Freezing was ca rried out at - 120° C. for I ;12 minutes. Thawing was complete in 5 minutes and the same area was refrozen at the same temperature for 1 minute. Recovery was uneventful and for 3 to { weeks there was a 4· mm. necrosis about the external os. This finally disappeared and 4 subsequent smears showed atypical squamous cells but no evidence of cancer. Because an ovarian mass was thought to be enlarging, a laparotomy and panhysterectomy was performed 8 weeks later. The ovarian tumor was a serous cystadenoma. The uterus showed ( Fig. 3 ) linear hyaliniza· tion of the lining of the endocervix 4 mm. in depth, beginning abruptly just superior to the internal os and extending inferiorly for 3 mm . about the external os. The endometrium just superior to the scar was a trophic. The portion of the cervix beyond the area frozen showed inflammation and epithelial atypia. There was no evidence of any residual cancer. Comment
These 3 experiences reaffirmed previously reported observations on the effects of rapid deep freezing and slow thawing on tissues in general. 1 • 5 In these reports it was found that when tissue temperatures were rapidly dropped below ·-60° C. and thawing permitted to progress slowly, the frozen area eventually becomes necrotic in a unique way. The appearance of necrosis, which almost uniformly involves all tissues, is delayed for severaf hours after freezing has been completed and, when it finally becomes apparent, the necrotic tissue is sharply demarcated from the adjacent, still-viable tissue. In subsequent days the area of necrosis
Volume 88 Number 3
Cryosurgery of uterus
I
I
I
I
I
I
2
3
4
CM
6
7
Fig. 3. Uterus, Case 3. Note endocervical canal hyalinized and its abrupt ending (arrow) just above internal os.
seems to retain the shadow of its original architecture, giving the appearance of an ischemic infarct. Slowly, over a period of weeks, it is gradually rejected or reabsorbed. The surrounding viable tissue also reacts in a singular manner. Shortly after the procedure, there are evidences of interstitial edema and hemorrhage, intracapillary thrombus formation, and a few leukocytes. After 4 to 5 weeks, granulation tissue becomes more developed in the viable tissues as the slough it surrounds separates. The resulting raw surface eventually heals with a thin, pliable scar and, if there is adjacent epithelium, these elements subsequently spread and cover the treated surface. This pattern of healing after freezing in animals seemed to be duplicated to some extent in the 3 uterine specimens. For example, the uterus that was removed 1Y:z hours after freezing showed no remarkable gross and microscopic findings. However, the uterus that was allowed to remain 3 days before extirpation showed that in the area
413
frozen necrosis was so complete that no endometrium or endocervical lining remained. The uterus that was allowed to remain 8 weeks showed well-established hyalinization confined to the endocervix, and covered by a thin layer of epithelial cells. It is probable that if the first 2 uteri had been allowed to remain for 8 or more weeks, they might have healed in a similar fashion. In using electrocautery over large areas there is always a threat of hemorrhage from the slough that frequently results. Cryosurgery definitely differs in this respect for although there may be interstitial hemorrhage immediately following congelation, this is very rapidly self-limiting. At a later time, when the slough separates, there is no hemorrhage. This holds true in animals even when such vascular organs as liver, heart muscle, and kidney were subjected to cryosurgery and has even been true when large vessels such as the aorta, carotid, and inferior vena cava were intentionally frozen. On capillaries and vessels of small caliber, freezing in this manner would seem to exert a hemostatic effect. Implications
This preliminary experience, although small, has encouraged us to pursue the study further. Undoubtedly, there is still much to be clarified; instruments and techniques must be refined; intimate cryobiologic changes need better understanding; and more clinical and histological experience is required before the overall value of this modality can be assessed. Nevertheless, one fact stands out : it has now been shown that it is feasible to alter the lining of the uterus in a new and relatively simple fashion. If this can be done consistently and with safety, it may have many and varied gynecologic applications. For instance, it might have value in conception control, abnormal uterine bleeding, and in the treatment of certain uterine cancers. Further speculation as to its possible applications is almost limitless, confined only by the realization that the measure of success
414
Cahan
of any new modality is not whether it can perform a given task as well as presently established methods, but whether it can provide new benefits or simplify or refine old techniques. It is our belief that cryo-
Febn'"'' L 1<164
,\m,
J.
Obst. & Gyn••c
surgery will prove its value in this regard. Grateful acknowledgment is made to Kurt Bender, Joe Thomas, Earl Winter, and Max Shufer, without whose assistance the instrument could not have been completed.
REFERENCES
1. Hass, G. M., and Taylor, C. B.: Arch. Path. 45: 563, 1948. 2. McDonald, James H., Taylor, C. Bruce, and Heckel, Norris J.: J. Urol. 64: 326, 1950. 3. Breedis, Charles: The action of extreme cold on leukemic cells of mice. J. Exper, Med. 76: 221, 1942. 4. Hass, George M., and Taylor, C. Bruce: A. M. A. Arch. Neurol. & Psychiat. 69: 145, 1953.
5. Clasen, Raymond A., Brown, David V. L., Leavitt, Seymour, and Hass, George M.: Surg. Gynec. & Obst. 96: 605, 1953. 6. Economou, Steven G., Taylor, C. Bruce, Beattie, Edward J., Jr., and Davis, Clark B., Jr.: Surgery 47: 21, 1960. 7. Cooper, Irving S.: New England J. Med. 268: 743, 1963.