Cryosurgery of Skin Cancer—In Proper Perspective SETRAG A. ZAC ARI AN, M.D., F.A.C.P.
A b r ie f review o f cryosurgical instrum entation and m ethodology in cryogenic surgery f o r skin cancers is re viewed. The main object o f this review is not only to discuss the indications f o r cryosurgery o f m alignant tum ors o f the sk in , but to em phasize the author s experience as to the contraindications. There is no single universal therapeutic regim en that is effective and practical f o r all m alignant tum ors o f the skin. Cryosurgery is but an added and a highly effective m ethod fo r the destruction o f skin cancer.
In well over a decade, dermatological cryosurgery, in particular for malignant tumors of the skin, has become well e stab lish ed ^ 3>^5>6>7>8. The dermatologist, pre-eminently trained in the recognition and treatment of skin cancers, has now added another modality to his armamentorium for the management of some cutaneous neoplasms. Liquid nitrogen, properly delivered and controlled, is the only refrigerant effective for the destruction of carcinomas of the skin. Adequate freezing is a function of time9, and the consequences produced by the sudden alteration of temperatures within cells, tissues and blood vessels are well known10. The rapid heat exchange between the heat sink (refrigerant source) and the underlying malignant tissue within the skin is both destructive and irreversible. Even the small percentage of cancer cells which withstand temperatures of —196°C, are eventually destroyed by anoxemia produced by vascular thrombosis and occlusion of microvessels during the freezing11. Dr. Zacarian is the Director of Dermatology Service, Medical Center of Western Mass., Springfield, Mass.; Assistant Clinical Professor of Dermatology, Boston University School of Medicine, Boston, Mass.; Lecturer in Dermatology, Tufts University School of Medicine, Boston, Mass. For reprints, address author, 130 Maple Street, Springfield, Mass. 01103.
After a decade of practice of cryosurgery, an objective appraisal of our instrumentation, methodology, indications and limitations of this new technique are in order. Hindsight is inevitably a better teacher than foresight, and it is upon this theme that I wish to write and share with you my personal experiences. INSTRUMENTATION In the management of malignant tumors of the skin, I have long abandoned the cotton-tip applicator saturated with liquid nitrogen as an effective heat sink. There still are those who feel they can eradicate skin cancers with cotton swabs, foam rubber applicators or metal discs dipped in liquid nitrogen. Except for the most superficial cancers, cryonecrosis is nil at three to five millimeters of tumor depth with these applicators. I know this because I have monitored temperatures at various depths, have examined specimens histologically following such freezings and have found death of tissue inadequate. For the destruction of skin cancers, one needs a continuous action of liquid nitrogen upon the cancer site. A temperature of -100°C upon the tumor surface and at least —25°C five millimeters below the skin surface are required.
J o f Derm Surg 1:3, October 1975
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C R Y O S U R G E R Y OF SKIN C A N C E R
Such degrees of refrigeration can not be achieved with cotton swabs, freon or nitrous oxide. At present we have a number of cryosurgical instruments available. The CE-8®, developed by Dr. Douglas Torre was the first unit available. Then came the Kryospray®, a handheld instrument, and the C-21®, designed by this author, which is also a hand-held device that has safety valves. Currently two other cryosurgical units have been developed and marketed, namely the Tromovitch and most recently the Foster Froster12. All of the above deliver a free flow of liquid nitrogen and have interchangeable adapters of flat discs with various diameters. I have purposely not mentioned other cryosurgical instruments which deliver freon or nitrous oxide because my discourse is confined to cryosurgery of malignant tumors of the skin for which they are inadequate. The liquid nitrogen delivery units are all effective for the eradication of skin cancers and the selection of one or the other is a matter of personal choice and type of practice. Each of the units have some drawbacks and they can be improved upon. With further experience, and by the ingenuity of both cryosurgeons and engineers, improvements certainly will be forthcoming. We have come a long way during the past ten years. The cotton-tip applicator which reigned for fifty years is no match to the versatility of our present cryosurgical instruments. M ETH O D O LO G Y
In preparing to freeze a skin cancer local anesthesia may be used if desirable. This is a matter of choice, but absolutely necessary if a micro-thermocouple needle to monitor depth of freezing is to be implanted. With a skin pencil marker a safe margin is outlined at least 4 to 5mm outside the visible tumor. Then the flow of liquid nitrogen is directed intermittently to the center of the malignant growth. My own technique is to freeze for three to four seconds and stop for one to two seconds and freeze again. If freezing is uninterrupted, a rapid extension of the ice front is developed peripherally at the expense of the ice front in depth below the tumor. Also, continuous freezing will produce droplets of liquid nitrogen that roll down other parts of the skin of the patient and are discomforting. After adequate freezing has been achieved both in extent and in depth one should allow the tumor site to return to its normal color and then freeze again. This is referred to as the double-freeze-thaw technique and will assure a higher cure rate. The second freeze-thaw cycle will be achieved in less time than the first because the micro-vessels are still under partial vasoconstriction from the first freezing and will afford less resistance to the extension of the ice front on the second time around. There appears to be some confusion among operators
34
J o f Derm Surg 1:3, October 1975
Figure I: A patien t with a b a sa l-cell carcinom a ju st fro zen with liquid nitrogen. N ote that the freezin g has exten ded beyo n d the safe margin o f visible tum or (m arked with a skin p en cil). The m icrotherm ocouple needle is p a ssed through the 5mm tract o f the tem plate to accu rately m onitor the extent o f the cryolesion b elow the surface o f the skin.
regarding freezing and thawing cycles. Freeze-time is controlled and is directly related to how long one chooses to freeze a given neoplasm. Size, depth, location and clinical judgment are decisive. One has no control of the thaw period which will vary from one and a half times to twice the duration of the freezing period. Cryobiologists have demonstrated that rapid freezing is quickly lethal to cells and even more quickly lethal in the thawing period when recrystalization of ice particles take place. Timing freezetime or monitoring temperatures in depth is mandatory, but timing thaw period is not really necessary because it is entirely out of one’s control. One should bear in mind that freezing a tumor on the forehead, temple or scalp will produce a transient headache in the patient that may last from several minutes to as long as an hour. I have no explanation for this phenomenon and many inquiries by neurologists have produced no satisfactory answer. For cancers situated near the eye, I use a Styrofoam shield to avoid undue spray of liquid nitrogen onto the lids and eyeball. If the tumor involves the lid, after anesthetizing the eye with Pontocaine®, I insert a plastic JaegherBelke lid retractor (Storz Instruments, St. Louis, Mo.) and freeze the cancer without any fear of injuring the eye. Metal shields or instruments should not be used because they may conduct the cold to the eyeball and injure the cornea.
ZACARIAN
Figure II: An u lcera ted an d erosive b a sa l-cell carcinom a behind the right ear with extension to the underlying cartilage.
Figure III: The sam e neoplasm su bjected to cryosurgery a t the end o f fo u r minutes o f freezin g .
Freezing of neoplasms on the forehead, temples and paranasal areas will produce considerable edema of the eyelids, unilaterally or bilaterally. This edema may last several days and although 1 warn patients and give them an instruction sheet, I make a point to have them return the first or second day following cryosurgery for further reassurance. Patients are instructed to wash the area that had been frozen and to gently pat to dry. Daily change of gauze dressings are ordered and once a scab is formed, it is preferable that the treated area no longer be covered. It is not unusual to see mild conjunctivitis of the eye following the use of an eyelid retractor. This may last for several days, and a simple eye-wash used daily will be helpful. Infection is rare. Within four weeks following cryosurgery the average skin cancer on the face is clinically eradicated. The wound site is re-epithelized and may show hypopigmentation. In time, repigmentation will take place in more than half of these cases. Cancers of the skin situated on the neck, chest, back and extremities, depending upon their size, may take two to three times as long to heal. Occasionally one will see pseudo-epitheliomatous hyperplasia at the tumor site four to six weeks following cryosurgery. Within weeks this benign epithelial reaction spontaneously disappears.
is by Ebbehoj13 who in 1951 measured by means of biopsies the depth of basal-cell carcinomas and epidermoid carcinomas prior to radiotherapy. In 208 skin cancers, he observed that 50 per cent of cancers did not extend 2mm from the cutaneous surface and 82.5 per cent of the neoplasms did not extend 5mm. Some 11.5 per cent of the cancers exceeded 5mm, and the majority of this group of skin tumors were epidermoid carcinomas. In a smaller series of 67 basal-cell carcinomas, Newell14, in 1968, noted that 96 per cent of the tumors did not extend beyond 3mm from the integumentary surface. In a series of 123 patients with basal-cell epitheliomas, I found that 96 per cent of the tumors did not invade beyond 3mm of the surface. Only 3.2 per cent of the tumors extended between 4-5mm, and 0.8 per cent beyond 5mm. There is further need for this type of study. An improved classification of morphological types of skin cancers with respect to size, depth and location would be extremely valuable to the cancer therapist. Such data will enable the therapist to select the best and most effective mode of treatment. I imagine that chemosurgeons who deal with microscopic control of depth and extension of skin cancers could well provide us with this needed information.
S K IN C A N C E R D EPTH
There is a paucity of information in the medical literature regarding the average depth or extension of skin cancers below the surface of the skin. The largest series I have noted
M O N I T O R I N G T H E C R Y O L E S IO N
No one should purchase a cryosurgical instrument without thermocouples and a cryometer. Science is measurement and until one has developed sufficient experience in cryosurgery, I would urge that temperatures be monitored
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C R Y O S U R G E R Y OF SKIN C AN CER
Figure IV: The freezin g has been carried to the an terior a spect o f the right ear. through the cartilage into norm al uninvolved integument o f the opposin g side.
Figure V: Two months follow in g cryosu rgery the clinically era dicated tum or site reveals residu al granulation tissue a n d p se u d o -e p i theliom atous hyperplasia. This patien t has now been f o llo w e d f o r three years: there has been no recurrence.
and a sense of time-temperature relationships of size and location of the tumor be developed15. One of the major criticisms leveled against cryosurgery of skin cancers is that we lack microscopic measurement of its effective extent. I am not fully persuaded by this criticism. We lack the same controls in radiotherapy of skin cancers, yet that modality has been long proved effective. And with respect to curettage, I wonder how often the dermatologist is certain, when he curets a malignant growth, that he has removed every cancer cell. There is no doubt in my mind that the oncologic therapist, well-experienced and versed in freezing skin cancers, finds this modality as effective and precise as any other mode of treatment except chemosurgery. The clinical experiences of cryosurgeons in ten years of follow-up attest to its efficacy. In some places refrigeration need not be monitored. The scalp, forehead, temples and bridge of the nose are such sites. The freezing of the tumor is simply continued until the periosteum is reached. Frozen to that depth, the overlying skin becomes immobile. Rarely do skin cancers extend to periosteum. The places where I monitor temperature are the cheek, the naso-labial fold, the part of the face anterior to the ears, and the cutaneous portion of the lips, chin and neck. All nodular, sclerosing and morphea-type tumors deserve monitoring. I generally use a 5mm depth template for measurement, but if the cancer is nodular and raised considerably above the skin surface, I employ a 6 to 8mm depth acrylic jig or
template. These small templates can be obtained from Frigitronics, Inc., of Shelton, Conn. In use, a template does not impede freezing to desired depth. Once one has acquired sufficient clinical experience in cryosurgery of malignant tumors, one can rely upon that experience to decide how long to freeze according to size, morphology, and location of the cancer. The average skin cancer under one centimeter in diameter can be destroyed by one to one and a half minutes of freezing; larger neoplasms may take up to two minutes, and nodular or ulcerated tumors may require three to four minutes. There is no substitute for practical experience gained from monitoring of cryo-effect in depth of many skin cancers by microthermocouple needles and use of templates. I freeze skin cancers overlying the cartilagenous portions of the nose (the alae nasi) and ears through to the opposing cutaneous surface with no fear of chondritis or perforation. For cancers of the eyelid, I freeze from one to several minutes, even if through the tarsal plate. I have encountered no complications in treating 82 skin cancers involving the eyelids, including 20 tumors situated at the medial canthus. Nor have I encountered obstruction of the lacrimal duct or subsequent persistent tearing.
36
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I N D I C A T I O N S F O R C R Y O S U R G E R Y F O R S K IN CANCERS
In tny own practice of dermatology, I have found well over 95 per cent of skin cancers to be amenable to
Z A C A R IA N
TABLE / C R IT I C A L A R E A S O F S K IN C A N C E R S AM EN A BLE TO C R YO SU RG ER Y Nose: Ears: Eyelids:
25% of all skin cancers 8% of all skin cancers 5% of all skin cancers 38% of all skin cancers are in critical locations of the face.
Eyelid Cancers subjected to cryosurgery
75 BCC 5 Epidermoid 2 Baso-Squamous Carcinomas
endure extensive surgery, are suited for cryosurgery. If not a cure, one can at least afford palliative management of their skin cancers. In cases of numerous malignant neoplasms, cryosurgery is both effective and time saving. My experience in freezing Hutchinson’s melanotic freckle is limited to four cases. To date they have responded very well. I believe cryosurgery can be effective for this neoplasm if freezing is delivered both widely and in-depth, bearing in mind that the tumor very often extends to the hair follicles. The rare sequel of neuritis at a site of freezing will disappear in time. L IM IT A T IO N S OF C R Y O S U R G E R Y OF SK IN C A N C E R S
82 Total 14 (17%) upper eyelid 68 (83%) lower eyelid 20 of the tumors or % were situated in the medial canthus. To date—7 recurrences (8.3%) 3 of the 7 were recurrent to start with 2 of the 7 were palliative procedures
cryosurgery. Primary skin cancers in particular are effectively managed with freezing. Recurrent malignant tumors following irradiation very often can be treated with cryosurgery with no concern about wound healing. Large multicentric carcinomas of the skin, even those exceeding 10 centimeters, can be effectively frozen. In very large tumors I freeze one third or one half initially and after complete wound healing, freeze the rest of the tumor in one or two sittings. In my own series of skin cancers, I have found 38 per cent to be on critical areas of the face (see Table I). Cancers situated on the nose for the most part are well handled by freezing. Cancers on eyelids are also well managed by cryosurgery, although in my own series the recurrence rate is higher than for other sites. Cancers on the ears, where we find epidermoid carcinomas occasionally, are quite amenable to cryosurgery. I often freeze through the cartilage to the opposite side and have had no instances of subsequent chondronecrosis or perforation. Cryosurgery is the treatment of choice in patients who develop keloids following surgery or electrodesiccation. I know of no reported cases of keloid formation following cryosurgery. Infrequently a hypertrophic scar will develop following cryosurgery on such sites as the bulb of the nose, upper lip, chest and back. Simple nightly application of Cordran tape for six to eight weeks will very often correct this type of scar. Intralesional injection of triamcinolone is also corrective. Patients on anticoagulant medications can undergo cryosurgery with no fear of undue bleeding. Patients with large cutaneous neoplasms who are debilitated and can not
In my hands I have found cryosurgery for skin cancers in some locations is not always effective (see Table II). I have abandoned freezing of cancers on the scalp. The recurrence rate of 9.5 per cent is unacceptable to me. Cancers on the alae nasi and naso-labial folds are a therapeutic challenge to both surgeons and radiotherapists. Dermatologists using conventional curettage and electroT A B L E 1/ R A T E S O F H IG H E S T R E C U R R E N C E O F SK IN C A N C E R S F O L L O W IN G C R Y O S U R G E R Y BY A N A T O M IC S IT E Scalp: Eyelids: Alae Nasi: Back & Chest (Large Multicentric BCC)
9.5% 8.3% 6.5% 5.8%
desiccation experience a higher incidence of recurrence at these sites. Cryosurgery is no exception. In well over 400 skin cancers of the nose that I have subjected to freezing, approximately 30 per cent were on the alae nasi. The recurrence rate was 6.5 per cent, third highest in the critical areas (see Table II). Undoubtedly, nests of tumor cells extend deep and peripherally much beyond the usual for skin cancers at other sites. I think that small cancers, 5mm or less, in this area may be handled with cryosurgery but for larger ones chemosurgery is a first choice, and if that is not available, plastic surgery with reconstruction is second. Of all skin cancers, about five per cent involve the eyelids, most often (83 per cent) the lower lids. In my own series of 82 cancers on lids, my recurrence rate is 8.3 per cent. The details and reasons are recorded in Table I. The recurrence rate appears high but it is comparable to those of both radiotherapy and conventional surgery16517. 1 nevertheless believe that cryosurgery of tumors on eyelids is a good method which results in far better wounds, no obstruction to the lacrimal duct nor destruction to the tarsal plate 18>19. Cryosurgery is simple to do and saves the patient hospitalization for reconstruction of the lid. If the cancer extends
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C R Y O S U R G E R Y OF SKIN C A N C E R
TABLE I II
TABLE I V
T E N -Y E A R S T U D Y O F 1445 P A T IE N T S W IT H 2331 M A L I G N A N T T U M O R S O F T H E S K IN C R Y O S U R G IC A L L Y T R E A T E D
F O L L O W -U P O F S K IN C A N C E R S S U B JEC T ED TO CR YO SU RG ERY Cure Rate
Basal Cell Carcinomas Epidermoid Carcinomas Baso-Squamous Cell Carcinomas Bowen's Disease (Carcinoma in situ) Kaposi's Hemorrhagic Sarcoma
21 06 125 69 28 ____ 3 Total
30% of all skin cancers 60% of all skin cancers 10% of all skin cancers
2331 under 1 cm. 1 to 2 cm. over 2 cm.
beyond lid margins and into the sulcus, cryosurgery is contraindicated, and should only be used for palliation if no other methods are feasible. Multicentric basal-cell carcinomas, particularly the larger ones, must be carefully followed after any technique of treatment. In my recurrences of 50 skin cancers, this particular type had a recurrence rate of 5.8 per cent. Almost always the recurrence appeared at the edges, no matter how far a margin was frozen initially. In such cases, I merely re-freeze the new sites. Large multicentric tumors with scattered nodules are better treated by other means. In my own experience, sclerosing or morphea-like basal-cell carcinomas do not respond very well to cryosurgery. I now prefer not to subject them to freezing, but refer them to a surgeon for wide excision. I have abandoned freezing cancers of the skin on the legs, particularly on shins, where I have often encountered long delay in would healing (months) and infrequently a smouldering infection. This is not the case with skin cancers on the dorsum of the hands and fingers. Cryosurgery is both safe and effective on these sites.
O f the total patients (1441) 5 0 recurrences (3.8%)
96.2%
O f the total combined cancers (2331) 50 recurrences (2.2%)
97.8%
In the 50 recurrences, 16 or 25% were recurrent cancers to start with. Follow -Up:
40% 40%
3-5 years 5-10 years
80% followed
3-10 years
In m y own series o f recurrences: 43.3% skin cancers recurred within 24.3% skin cancers recurred within 19.0% skin cancers recurred within 3.4% skin cancers recurred within
the the the the
first year. second year. third year. fourth year.
90.0% o f skin cancer recurrences were observed within the first four years. SUM M ARY
In a little over ten and one half years I have treated 1455 patients with a combined total of 2331 malignant tumors of the skin. The morphological classification is noted in Table III and recurrences in Table IV. With any new modality for the destruction of skin cancer there are important considerations, such as: 1) Is it effective? 2) Is the cosmetic end result good? 3) Is there any loss of function? 4) What is the cost factor to the patient or third-party payer? and finally 5) How long does it take? In my opinion and that of the many dermatologists using cryosurgery with whom I have been in personal contact, cryosurgery stands high in answer to these questions.
REFERENCES
1. 2. 3. 4.
5.
10 .
38
Gag e, A. A. and Emin gs , F.: Treatment of hu m an tumors by freezing. Cryobiol. 2:24, 1965. Cahan, W .G .: Cryosurger y of malignant and benign tumors. Fed. Proc. 24 (Suppl. 15):S 2 4 1, 1965. Zacarian, S.A . Cryosurgery of skin cancer and cryogenic techniques in Dermatology. Springfield, 111., Chas. C. T hom as, 1969. Miller D. and Mitzner, D.: Cryosurger y for tumors of the head and neck. Trans. Amer. Acad. Opthalm ol. & Otolaryngol. 73:300, 1969. Torre, D.: Cryosurger y in der matology. In: von Leden, H. and Ca han, W . G . , ed s., Cryogenics in Surgery, Flushing, N .Y ., M e d ical Examinati on Publishing C o., 1971, Chap. 6, pp. 500-527. Torre, D.: Dermatologic cryosurgery. Cutis 1:782, June 1973. Gr ah am , G .F .: Cryosurger y of skin tumors, N. C. Med. J. 32:81, No. 3, 1971. Zacarian, S. A. Cryosurger y of tumors of the skin and oral cavity. Springfield, 111., Chas. C. Tho mas, 1973. M ery m an , H.T .: General principle o f freezing injury in cellular materials. Ann. of N.Y . Acad. Sci. 85: 509, 1960. Ma zu r, P.: Causes of injury in frozen thaw ed cells. Fed. Proc. 24 (Suppl. 15): S 175, 1965.
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1 1 . Zacarian, S . A . , Stone, D. and Clater, M.: Effects of cryogenic
12.
13 14. 15. 16. 17.
19.
temper atures on microcirculation in the golden Syrian hamster chee k pouch. Cryobiol. 7:27, No. 1, 1970. L ubritz, R.R . and Foster, J. Ill: A new simplified cryosurgical instrument: the foster froster. J. Derm. Surg. 1:2, 1975. Ebb eh oj , E.: E xperiences in the treatment o f skin cancer with ultra soft roentgen r a y s , '1933-36. Acta Radiolog. 36:1-17, 1951. Newell , G .B .: Depth o f basal cell epit helioma. Personal co m m u nication, May 15, 1968. Smith, J.J. and Fraser, J.: An estima tion of tissue dam ag e and thermal history in the cryolesion. Cryobiol. 11:151, No. 2, 1974. Ra kofsky, S.I.: The ad equacy of surgical excision of basal cell car cinom a. Ann. o f Opthalm ol. 59 6, May 1973. Abr ah am , J .C ., Ja baley, M .E . and Hoopes , J.E .: Basal cell ca rcino m a o f the medial canthal region. Am. J. of Surg. 126:482, 1973. Zacarian, S.A.: Ca nce r o f the eyelids: a cryosurgical approach. Ann. Op th alm ol . 473, 1972. Beard, C.: Obs ervation in the treatm ent of basal cell ca rc in om a of the eyelids. Paper deliver ed Am. Acad, o f Op th alm ol . & O t ol ar yng ol., Dallas, Nov. 1974, in press.
A b r ie f review o f cryosurgical instrum entation and m ethodology in cryogenic surgery f o r skin cancers is re viewed. The main object o f this review is not only to discuss the indications f o r cryosurgery o f m alignant tum ors o f the sk in , but to em phasize the author s experience as to the contraindications. There is no single universal therapeutic regim en that is effective and practical f o r all m alignant tum ors o f the skin. Cryosurgery is but an added and a highly effective m ethod fo r the destruction o f skin cancer.
In well over a decade, dermatological cryosurgery, in particular for malignant tumors of the skin, has become well e stab lish ed ^ 3>^5>6>7>8. The dermatologist, pre-eminently trained in the recognition and treatment of skin cancers, has now added another modality to his armamentorium for the management of some cutaneous neoplasms. Liquid nitrogen, properly delivered and controlled, is the only refrigerant effective for the destruction of carcinomas of the skin. Adequate freezing is a function of time9, and the consequences produced by the sudden alteration of temperatures within cells, tissues and blood vessels are well known10. The rapid heat exchange between the heat sink (refrigerant source) and the underlying malignant tissue within the skin is both destructive and irreversible. Even the small percentage of cancer cells which withstand temperatures of —196°C, are eventually destroyed by anoxemia produced by vascular thrombosis and occlusion of microvessels during the freezing11. Dr. Zacarian is the Director of Dermatology Service, Medical Center of Western Mass., Springfield, Mass.; Assistant Clinical Professor of Dermatology, Boston University School of Medicine, Boston, Mass.; Lecturer in Dermatology, Tufts University School of Medicine, Boston, Mass. For reprints, address author, 130 Maple Street, Springfield, Mass. 01103.
After a decade of practice of cryosurgery, an objective appraisal of our instrumentation, methodology, indications and limitations of this new technique are in order. Hindsight is inevitably a better teacher than foresight, and it is upon this theme that I wish to write and share with you my personal experiences. INSTRUMENTATION In the management of malignant tumors of the skin, I have long abandoned the cotton-tip applicator saturated with liquid nitrogen as an effective heat sink. There still are those who feel they can eradicate skin cancers with cotton swabs, foam rubber applicators or metal discs dipped in liquid nitrogen. Except for the most superficial cancers, cryonecrosis is nil at three to five millimeters of tumor depth with these applicators. I know this because I have monitored temperatures at various depths, have examined specimens histologically following such freezings and have found death of tissue inadequate. For the destruction of skin cancers, one needs a continuous action of liquid nitrogen upon the cancer site. A temperature of -100°C upon the tumor surface and at least —25°C five millimeters below the skin surface are required.
J o f Derm Surg 1:3, October 1975
33
C R Y O S U R G E R Y OF SKIN C A N C E R
Such degrees of refrigeration can not be achieved with cotton swabs, freon or nitrous oxide. At present we have a number of cryosurgical instruments available. The CE-8®, developed by Dr. Douglas Torre was the first unit available. Then came the Kryospray®, a handheld instrument, and the C-21®, designed by this author, which is also a hand-held device that has safety valves. Currently two other cryosurgical units have been developed and marketed, namely the Tromovitch and most recently the Foster Froster12. All of the above deliver a free flow of liquid nitrogen and have interchangeable adapters of flat discs with various diameters. I have purposely not mentioned other cryosurgical instruments which deliver freon or nitrous oxide because my discourse is confined to cryosurgery of malignant tumors of the skin for which they are inadequate. The liquid nitrogen delivery units are all effective for the eradication of skin cancers and the selection of one or the other is a matter of personal choice and type of practice. Each of the units have some drawbacks and they can be improved upon. With further experience, and by the ingenuity of both cryosurgeons and engineers, improvements certainly will be forthcoming. We have come a long way during the past ten years. The cotton-tip applicator which reigned for fifty years is no match to the versatility of our present cryosurgical instruments. M ETH O D O LO G Y
In preparing to freeze a skin cancer local anesthesia may be used if desirable. This is a matter of choice, but absolutely necessary if a micro-thermocouple needle to monitor depth of freezing is to be implanted. With a skin pencil marker a safe margin is outlined at least 4 to 5mm outside the visible tumor. Then the flow of liquid nitrogen is directed intermittently to the center of the malignant growth. My own technique is to freeze for three to four seconds and stop for one to two seconds and freeze again. If freezing is uninterrupted, a rapid extension of the ice front is developed peripherally at the expense of the ice front in depth below the tumor. Also, continuous freezing will produce droplets of liquid nitrogen that roll down other parts of the skin of the patient and are discomforting. After adequate freezing has been achieved both in extent and in depth one should allow the tumor site to return to its normal color and then freeze again. This is referred to as the double-freeze-thaw technique and will assure a higher cure rate. The second freeze-thaw cycle will be achieved in less time than the first because the micro-vessels are still under partial vasoconstriction from the first freezing and will afford less resistance to the extension of the ice front on the second time around. There appears to be some confusion among operators
34
J o f Derm Surg 1:3, October 1975
Figure I: A patien t with a b a sa l-cell carcinom a ju st fro zen with liquid nitrogen. N ote that the freezin g has exten ded beyo n d the safe margin o f visible tum or (m arked with a skin p en cil). The m icrotherm ocouple needle is p a ssed through the 5mm tract o f the tem plate to accu rately m onitor the extent o f the cryolesion b elow the surface o f the skin.
regarding freezing and thawing cycles. Freeze-time is controlled and is directly related to how long one chooses to freeze a given neoplasm. Size, depth, location and clinical judgment are decisive. One has no control of the thaw period which will vary from one and a half times to twice the duration of the freezing period. Cryobiologists have demonstrated that rapid freezing is quickly lethal to cells and even more quickly lethal in the thawing period when recrystalization of ice particles take place. Timing freezetime or monitoring temperatures in depth is mandatory, but timing thaw period is not really necessary because it is entirely out of one’s control. One should bear in mind that freezing a tumor on the forehead, temple or scalp will produce a transient headache in the patient that may last from several minutes to as long as an hour. I have no explanation for this phenomenon and many inquiries by neurologists have produced no satisfactory answer. For cancers situated near the eye, I use a Styrofoam shield to avoid undue spray of liquid nitrogen onto the lids and eyeball. If the tumor involves the lid, after anesthetizing the eye with Pontocaine®, I insert a plastic JaegherBelke lid retractor (Storz Instruments, St. Louis, Mo.) and freeze the cancer without any fear of injuring the eye. Metal shields or instruments should not be used because they may conduct the cold to the eyeball and injure the cornea.
ZACARIAN
Figure II: An u lcera ted an d erosive b a sa l-cell carcinom a behind the right ear with extension to the underlying cartilage.
Figure III: The sam e neoplasm su bjected to cryosurgery a t the end o f fo u r minutes o f freezin g .
Freezing of neoplasms on the forehead, temples and paranasal areas will produce considerable edema of the eyelids, unilaterally or bilaterally. This edema may last several days and although 1 warn patients and give them an instruction sheet, I make a point to have them return the first or second day following cryosurgery for further reassurance. Patients are instructed to wash the area that had been frozen and to gently pat to dry. Daily change of gauze dressings are ordered and once a scab is formed, it is preferable that the treated area no longer be covered. It is not unusual to see mild conjunctivitis of the eye following the use of an eyelid retractor. This may last for several days, and a simple eye-wash used daily will be helpful. Infection is rare. Within four weeks following cryosurgery the average skin cancer on the face is clinically eradicated. The wound site is re-epithelized and may show hypopigmentation. In time, repigmentation will take place in more than half of these cases. Cancers of the skin situated on the neck, chest, back and extremities, depending upon their size, may take two to three times as long to heal. Occasionally one will see pseudo-epitheliomatous hyperplasia at the tumor site four to six weeks following cryosurgery. Within weeks this benign epithelial reaction spontaneously disappears.
is by Ebbehoj13 who in 1951 measured by means of biopsies the depth of basal-cell carcinomas and epidermoid carcinomas prior to radiotherapy. In 208 skin cancers, he observed that 50 per cent of cancers did not extend 2mm from the cutaneous surface and 82.5 per cent of the neoplasms did not extend 5mm. Some 11.5 per cent of the cancers exceeded 5mm, and the majority of this group of skin tumors were epidermoid carcinomas. In a smaller series of 67 basal-cell carcinomas, Newell14, in 1968, noted that 96 per cent of the tumors did not extend beyond 3mm from the integumentary surface. In a series of 123 patients with basal-cell epitheliomas, I found that 96 per cent of the tumors did not invade beyond 3mm of the surface. Only 3.2 per cent of the tumors extended between 4-5mm, and 0.8 per cent beyond 5mm. There is further need for this type of study. An improved classification of morphological types of skin cancers with respect to size, depth and location would be extremely valuable to the cancer therapist. Such data will enable the therapist to select the best and most effective mode of treatment. I imagine that chemosurgeons who deal with microscopic control of depth and extension of skin cancers could well provide us with this needed information.
S K IN C A N C E R D EPTH
There is a paucity of information in the medical literature regarding the average depth or extension of skin cancers below the surface of the skin. The largest series I have noted
M O N I T O R I N G T H E C R Y O L E S IO N
No one should purchase a cryosurgical instrument without thermocouples and a cryometer. Science is measurement and until one has developed sufficient experience in cryosurgery, I would urge that temperatures be monitored
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C R Y O S U R G E R Y OF SKIN C AN CER
Figure IV: The freezin g has been carried to the an terior a spect o f the right ear. through the cartilage into norm al uninvolved integument o f the opposin g side.
Figure V: Two months follow in g cryosu rgery the clinically era dicated tum or site reveals residu al granulation tissue a n d p se u d o -e p i theliom atous hyperplasia. This patien t has now been f o llo w e d f o r three years: there has been no recurrence.
and a sense of time-temperature relationships of size and location of the tumor be developed15. One of the major criticisms leveled against cryosurgery of skin cancers is that we lack microscopic measurement of its effective extent. I am not fully persuaded by this criticism. We lack the same controls in radiotherapy of skin cancers, yet that modality has been long proved effective. And with respect to curettage, I wonder how often the dermatologist is certain, when he curets a malignant growth, that he has removed every cancer cell. There is no doubt in my mind that the oncologic therapist, well-experienced and versed in freezing skin cancers, finds this modality as effective and precise as any other mode of treatment except chemosurgery. The clinical experiences of cryosurgeons in ten years of follow-up attest to its efficacy. In some places refrigeration need not be monitored. The scalp, forehead, temples and bridge of the nose are such sites. The freezing of the tumor is simply continued until the periosteum is reached. Frozen to that depth, the overlying skin becomes immobile. Rarely do skin cancers extend to periosteum. The places where I monitor temperature are the cheek, the naso-labial fold, the part of the face anterior to the ears, and the cutaneous portion of the lips, chin and neck. All nodular, sclerosing and morphea-type tumors deserve monitoring. I generally use a 5mm depth template for measurement, but if the cancer is nodular and raised considerably above the skin surface, I employ a 6 to 8mm depth acrylic jig or
template. These small templates can be obtained from Frigitronics, Inc., of Shelton, Conn. In use, a template does not impede freezing to desired depth. Once one has acquired sufficient clinical experience in cryosurgery of malignant tumors, one can rely upon that experience to decide how long to freeze according to size, morphology, and location of the cancer. The average skin cancer under one centimeter in diameter can be destroyed by one to one and a half minutes of freezing; larger neoplasms may take up to two minutes, and nodular or ulcerated tumors may require three to four minutes. There is no substitute for practical experience gained from monitoring of cryo-effect in depth of many skin cancers by microthermocouple needles and use of templates. I freeze skin cancers overlying the cartilagenous portions of the nose (the alae nasi) and ears through to the opposing cutaneous surface with no fear of chondritis or perforation. For cancers of the eyelid, I freeze from one to several minutes, even if through the tarsal plate. I have encountered no complications in treating 82 skin cancers involving the eyelids, including 20 tumors situated at the medial canthus. Nor have I encountered obstruction of the lacrimal duct or subsequent persistent tearing.
36
J o f Derm Surg 1:3, October 1975
I N D I C A T I O N S F O R C R Y O S U R G E R Y F O R S K IN CANCERS
In tny own practice of dermatology, I have found well over 95 per cent of skin cancers to be amenable to
Z A C A R IA N
TABLE / C R IT I C A L A R E A S O F S K IN C A N C E R S AM EN A BLE TO C R YO SU RG ER Y Nose: Ears: Eyelids:
25% of all skin cancers 8% of all skin cancers 5% of all skin cancers 38% of all skin cancers are in critical locations of the face.
Eyelid Cancers subjected to cryosurgery
75 BCC 5 Epidermoid 2 Baso-Squamous Carcinomas
endure extensive surgery, are suited for cryosurgery. If not a cure, one can at least afford palliative management of their skin cancers. In cases of numerous malignant neoplasms, cryosurgery is both effective and time saving. My experience in freezing Hutchinson’s melanotic freckle is limited to four cases. To date they have responded very well. I believe cryosurgery can be effective for this neoplasm if freezing is delivered both widely and in-depth, bearing in mind that the tumor very often extends to the hair follicles. The rare sequel of neuritis at a site of freezing will disappear in time. L IM IT A T IO N S OF C R Y O S U R G E R Y OF SK IN C A N C E R S
82 Total 14 (17%) upper eyelid 68 (83%) lower eyelid 20 of the tumors or % were situated in the medial canthus. To date—7 recurrences (8.3%) 3 of the 7 were recurrent to start with 2 of the 7 were palliative procedures
cryosurgery. Primary skin cancers in particular are effectively managed with freezing. Recurrent malignant tumors following irradiation very often can be treated with cryosurgery with no concern about wound healing. Large multicentric carcinomas of the skin, even those exceeding 10 centimeters, can be effectively frozen. In very large tumors I freeze one third or one half initially and after complete wound healing, freeze the rest of the tumor in one or two sittings. In my own series of skin cancers, I have found 38 per cent to be on critical areas of the face (see Table I). Cancers situated on the nose for the most part are well handled by freezing. Cancers on eyelids are also well managed by cryosurgery, although in my own series the recurrence rate is higher than for other sites. Cancers on the ears, where we find epidermoid carcinomas occasionally, are quite amenable to cryosurgery. I often freeze through the cartilage to the opposite side and have had no instances of subsequent chondronecrosis or perforation. Cryosurgery is the treatment of choice in patients who develop keloids following surgery or electrodesiccation. I know of no reported cases of keloid formation following cryosurgery. Infrequently a hypertrophic scar will develop following cryosurgery on such sites as the bulb of the nose, upper lip, chest and back. Simple nightly application of Cordran tape for six to eight weeks will very often correct this type of scar. Intralesional injection of triamcinolone is also corrective. Patients on anticoagulant medications can undergo cryosurgery with no fear of undue bleeding. Patients with large cutaneous neoplasms who are debilitated and can not
In my hands I have found cryosurgery for skin cancers in some locations is not always effective (see Table II). I have abandoned freezing of cancers on the scalp. The recurrence rate of 9.5 per cent is unacceptable to me. Cancers on the alae nasi and naso-labial folds are a therapeutic challenge to both surgeons and radiotherapists. Dermatologists using conventional curettage and electroT A B L E 1/ R A T E S O F H IG H E S T R E C U R R E N C E O F SK IN C A N C E R S F O L L O W IN G C R Y O S U R G E R Y BY A N A T O M IC S IT E Scalp: Eyelids: Alae Nasi: Back & Chest (Large Multicentric BCC)
9.5% 8.3% 6.5% 5.8%
desiccation experience a higher incidence of recurrence at these sites. Cryosurgery is no exception. In well over 400 skin cancers of the nose that I have subjected to freezing, approximately 30 per cent were on the alae nasi. The recurrence rate was 6.5 per cent, third highest in the critical areas (see Table II). Undoubtedly, nests of tumor cells extend deep and peripherally much beyond the usual for skin cancers at other sites. I think that small cancers, 5mm or less, in this area may be handled with cryosurgery but for larger ones chemosurgery is a first choice, and if that is not available, plastic surgery with reconstruction is second. Of all skin cancers, about five per cent involve the eyelids, most often (83 per cent) the lower lids. In my own series of 82 cancers on lids, my recurrence rate is 8.3 per cent. The details and reasons are recorded in Table I. The recurrence rate appears high but it is comparable to those of both radiotherapy and conventional surgery16517. 1 nevertheless believe that cryosurgery of tumors on eyelids is a good method which results in far better wounds, no obstruction to the lacrimal duct nor destruction to the tarsal plate 18>19. Cryosurgery is simple to do and saves the patient hospitalization for reconstruction of the lid. If the cancer extends
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C R Y O S U R G E R Y OF SKIN C A N C E R
TABLE I II
TABLE I V
T E N -Y E A R S T U D Y O F 1445 P A T IE N T S W IT H 2331 M A L I G N A N T T U M O R S O F T H E S K IN C R Y O S U R G IC A L L Y T R E A T E D
F O L L O W -U P O F S K IN C A N C E R S S U B JEC T ED TO CR YO SU RG ERY Cure Rate
Basal Cell Carcinomas Epidermoid Carcinomas Baso-Squamous Cell Carcinomas Bowen's Disease (Carcinoma in situ) Kaposi's Hemorrhagic Sarcoma
21 06 125 69 28 ____ 3 Total
30% of all skin cancers 60% of all skin cancers 10% of all skin cancers
2331 under 1 cm. 1 to 2 cm. over 2 cm.
beyond lid margins and into the sulcus, cryosurgery is contraindicated, and should only be used for palliation if no other methods are feasible. Multicentric basal-cell carcinomas, particularly the larger ones, must be carefully followed after any technique of treatment. In my recurrences of 50 skin cancers, this particular type had a recurrence rate of 5.8 per cent. Almost always the recurrence appeared at the edges, no matter how far a margin was frozen initially. In such cases, I merely re-freeze the new sites. Large multicentric tumors with scattered nodules are better treated by other means. In my own experience, sclerosing or morphea-like basal-cell carcinomas do not respond very well to cryosurgery. I now prefer not to subject them to freezing, but refer them to a surgeon for wide excision. I have abandoned freezing cancers of the skin on the legs, particularly on shins, where I have often encountered long delay in would healing (months) and infrequently a smouldering infection. This is not the case with skin cancers on the dorsum of the hands and fingers. Cryosurgery is both safe and effective on these sites.
O f the total patients (1441) 5 0 recurrences (3.8%)
96.2%
O f the total combined cancers (2331) 50 recurrences (2.2%)
97.8%
In the 50 recurrences, 16 or 25% were recurrent cancers to start with. Follow -Up:
40% 40%
3-5 years 5-10 years
80% followed
3-10 years
In m y own series o f recurrences: 43.3% skin cancers recurred within 24.3% skin cancers recurred within 19.0% skin cancers recurred within 3.4% skin cancers recurred within
the the the the
first year. second year. third year. fourth year.
90.0% o f skin cancer recurrences were observed within the first four years. SUM M ARY
In a little over ten and one half years I have treated 1455 patients with a combined total of 2331 malignant tumors of the skin. The morphological classification is noted in Table III and recurrences in Table IV. With any new modality for the destruction of skin cancer there are important considerations, such as: 1) Is it effective? 2) Is the cosmetic end result good? 3) Is there any loss of function? 4) What is the cost factor to the patient or third-party payer? and finally 5) How long does it take? In my opinion and that of the many dermatologists using cryosurgery with whom I have been in personal contact, cryosurgery stands high in answer to these questions.
REFERENCES
1. 2. 3. 4.
5.
10 .
38
Gag e, A. A. and Emin gs , F.: Treatment of hu m an tumors by freezing. Cryobiol. 2:24, 1965. Cahan, W .G .: Cryosurger y of malignant and benign tumors. Fed. Proc. 24 (Suppl. 15):S 2 4 1, 1965. Zacarian, S.A . Cryosurgery of skin cancer and cryogenic techniques in Dermatology. Springfield, 111., Chas. C. T hom as, 1969. Miller D. and Mitzner, D.: Cryosurger y for tumors of the head and neck. Trans. Amer. Acad. Opthalm ol. & Otolaryngol. 73:300, 1969. Torre, D.: Cryosurger y in der matology. In: von Leden, H. and Ca han, W . G . , ed s., Cryogenics in Surgery, Flushing, N .Y ., M e d ical Examinati on Publishing C o., 1971, Chap. 6, pp. 500-527. Torre, D.: Dermatologic cryosurgery. Cutis 1:782, June 1973. Gr ah am , G .F .: Cryosurger y of skin tumors, N. C. Med. J. 32:81, No. 3, 1971. Zacarian, S. A. Cryosurger y of tumors of the skin and oral cavity. Springfield, 111., Chas. C. Tho mas, 1973. M ery m an , H.T .: General principle o f freezing injury in cellular materials. Ann. of N.Y . Acad. Sci. 85: 509, 1960. Ma zu r, P.: Causes of injury in frozen thaw ed cells. Fed. Proc. 24 (Suppl. 15): S 175, 1965.
J o f Derm Surg 1:3, October 1975
1 1 . Zacarian, S . A . , Stone, D. and Clater, M.: Effects of cryogenic
12.
13 14. 15. 16. 17.
19.
temper atures on microcirculation in the golden Syrian hamster chee k pouch. Cryobiol. 7:27, No. 1, 1970. L ubritz, R.R . and Foster, J. Ill: A new simplified cryosurgical instrument: the foster froster. J. Derm. Surg. 1:2, 1975. Ebb eh oj , E.: E xperiences in the treatment o f skin cancer with ultra soft roentgen r a y s , '1933-36. Acta Radiolog. 36:1-17, 1951. Newell , G .B .: Depth o f basal cell epit helioma. Personal co m m u nication, May 15, 1968. Smith, J.J. and Fraser, J.: An estima tion of tissue dam ag e and thermal history in the cryolesion. Cryobiol. 11:151, No. 2, 1974. Ra kofsky, S.I.: The ad equacy of surgical excision of basal cell car cinom a. Ann. o f Opthalm ol. 59 6, May 1973. Abr ah am , J .C ., Ja baley, M .E . and Hoopes , J.E .: Basal cell ca rcino m a o f the medial canthal region. Am. J. of Surg. 126:482, 1973. Zacarian, S.A.: Ca nce r o f the eyelids: a cryosurgical approach. Ann. Op th alm ol . 473, 1972. Beard, C.: Obs ervation in the treatm ent of basal cell ca rc in om a of the eyelids. Paper deliver ed Am. Acad, o f Op th alm ol . & O t ol ar yng ol., Dallas, Nov. 1974, in press.
