Identification of involved tissue during surgical treatment of doxorubicin-induced extravasation necrosis

The extravascular escape of intravenously administered doxorubicin (Adriamycin) leads to a painful, slowly enlarging subcutaneous lesion which, if not diagnosed, will progress to a chronic severe cellulitis with inflammatory reaction, ulceration of the skin, and possible further involve­ment. Past attempts at immediate treatment have failed because of, or have been complicated by, incomplete removal of the doxorubicin with continuing tissue necrosis. Three patients who un­derwent antineoplastic therapy with doxorubicin suffered extravasation leading to deep tissue necrosis requiring skin grafts. In all cases identification of doxorubicin-containing tissue was accomplished by injection of fluorescein. The residual necrotic tissue that did not fluoresce was removed. A protocol is presented to detect doxorubicin extravasation and distinguish the viable from the nonviable components. (J HAND SURG 8:43-5, 1983.)

Fredric J. Cohen, M.D., Joseph Manganaro, M .D., and Richard Craig BelOlO, M.S., Brooklyn, N . Y.

Doxorubicin (Adriamycin, Adria Lab­oratories, Columbus, Ohio) is an antineoplastic drug used in the treatment of a number of disseminated neo­plasms including acute leukemia, Wilm's tumor, neu­roblastoma , soft tissue and bone sarcomas, breast and ovarian cancer, transitional cell bladder carcinoma, thyroid cancer, and malignant lymphomas. Known complications of doxorubicin include hematologic (myelosuppression) and cardiac toxicity, alopecia , nausea, vomiting, mucositis , and skin and soft tissue necrosis secondary to extravasation .!

Extravasation of doxorubicin into the skin or sub­cutaneous tissue can lead to a painful , slowly enlarging subcutaneous lesion which, if not diagnosed and treated promptly, will develop over I week to several months into a chronic, severe , frequently painful ulceration of the skin and subcutaneous tissue , with possible in­volvement of tendon and bone. The exten of the injury is often not apparent by inspection prior to surgical

Presented to the American Association of Hand Surgery, Oct. 18, 1981.

From the Division of Plastic Surgery and Department of Surgery. Victory Memorial Hospital, and Department of Surgery , Brook­dale Medical Center, Brooklyn, N.Y., and St. George's University School of Medicine, Grenada, West Indies .

Received for publication Jan. 12 , 1982 .

Reprint requests: Dr. Frederic J . Cohen . Plastic and Reconstructive Surgery . The Narrows Medical Building , 9920 Fourth Ave. , Suite 205 , Brooklyn, NY 11209.

exploration . I - 3 Immediate local treatment with drugs such as hydrocortisone, lidocaine, phentolamine, or sodium bicarbonate have not been consistently effec­tive in inactivating the extravasated doxorubicin or pre­venting the subsequent development of tissue necrosis and ulceration . 2. ~ . 3 Extravasted doxorubicin has been shown to remain in the affected area for up to 5 months following extravasation . G This chemical necrosis asso­ciated with the administration of doxorubicin is a sig­nificant problem with a reported incidence of 0.5% to 2%. la, 2 . 4 . 7

This report describes a method of identifying tissue containing extravasated doxorubicin during surgical re­pair of skin and subcutaneous areas in which significant amounts of doxorubicin have been extravasated.

Material and methods

Doxorubicin can be identified easily since it is a fluorescent compound . By the use of operating loupes and the application of ultraviolet (UY) light in the darkness, nonviable doxorubicin-infiltrated tissue fluo­resces reddish orange. This differentiates doxorubicin­infiltrated tissue from viable tissue not infiltrated with doxorubicin. UY lamps also produce reflected purple light that must be distinguished from true fluorescence, which causes the tissue to seem to " glow." Clinically , the combination of the purple UY light and reddish­orange doxorubicin fluorescence may impart a violet color to the affected tissue , but it is the fluorescence of

0363·5023 /83/010043+03$00.3010 © 1983 American Society for Surgery of the Hand THE JOURNAL OF HAND SURGERY 43

44 Cohen et al. The Journal of

HAND SURGERY

Fig. 1. Preoperative photograph of painful, enlarging subcutaneous lesion approximately 3 months after extravasation of doxorubicin.

Fig. 2. Following the protocol all doxorubicin tissue has been removed and the area is ready for skin graftin9 and/or plastic flap reconstruction which ever afford the best means for success.

"glow" and not the color which is the important indi­cator useful in detecting doxorubicin in tissue.

Fluorescein (fluorescein sodium injection, U.S.P. [Fluorescite]) is red in aqueous solution. Under UV light, with a UV wavelength of 3600 A, it fluoresces green . K After fluorescein is injected intravenously at a dose of 10 mg/kg, one is able to identify nonnecrotic tissue since fluorescein will only enter viable perfused cells and only these will glow green under UV obser­vation in the darkness.

Case study

Case No. 1. A 64-year-old woman was undergoing com­bination chemotherapy with doxorubicin, 5-fluorouracil, and cyclophosphamide for widely disseminated ovarian carci­noma diagnosed in August, 1979 . In November, 1979, while undergoing intravenous chemotherapy, doxorubicin was ex­travasated into the subcutaneous tissues on the dorsum of her left hand. A painful, progressive ulceration and cellulitis de­veloped for which surgical consultation was not obtained until 20 days after extravasation. On the thirty-fourth day, when the patient's general condition had been stabilized all tissue

Vol. 8, No. I January 1983

that fluoresced from contained doxorubicin was removed from the involved area. Fluorescein was then injected intra­venously at a dose of 10 mg/kg and 15 minutes later all the viable tissue fluoresced with a greenish hue. Residual necrotic tissue that did not fluoresce was then removed. The tissues removed included skin and subcutaneous fat and portions of extensor tendons and blood vessels. The defect was recon­structed with local flaps and split-thickness skin grafts. Dis­tant pedicle flaps could not be used due to the patien's condi­tion. The wounds began to heal slowly. The patient died of her cancer-related problems during the first postoperative month.

Case No.2. A 60-year-old woman underwent doxorubicin chemotherapy for metastatic breast cancer. Within 2 months a deep necrosis of the right antecubital fossa developed. Con­trolled debridement in the operating room with an UV light in the darkness allowed most of the tisseu containing extrava­sated doxorubicin to be removed. The procedure had to be curtailed due to the patient's condition and the previously obtained split-thickness skin graft was applied with pressure dressing. Five days later all the skin graft was completely dissolved and the extravasation site still fluoresced in the darkness.

Case No.3. A 69-year-old woman with disseminated lym­phoma who had undergone chemotherapy with doxorubicin suffered an extravasation causing ulceration of the left forearm. Two months after the extravasation debridement and split-thickness skin grafts were performed with subsequent complete loss of the grafted tissue. One month later debride­ment controlled with UV light monitoring by the described protocol allowed the removal of doxorubicin extravasated tis­sue and preservation of all the viable tissue. The defect was closed with an abdominal-pedicle flap, which was divided 2 weeks later with good results.

Discussion

It is postulated that doxorubicin extravasation begins as a subdermal chemical reaction that inactivates oxi­dative systems in response to reducing properties of the doxorubicin. The reaction progresses through the usual first, second, third, and fourth degree stages that have been described for burns (fourth degree implies tendon and ligamentous injury). The characteristics of this le­sion include (1) ulceration, (2) pain both during infu-

Doxorubicin-induced extravasation necrosis 45

sion and afterwards, (3) dull yellow color at center, red inflammation at the periphery, and (4) absence of sign of granulation tissue or healing.

We recommend that the following precautions be made by physicians who administer doxorubicin to their patients: (1) If extravasation occurs, a hand sur­geon should be notified immediately. (2) If pain per­sists or ulceration begins, local debridement should be done as soon as possible and followed, if necessary, with a skin graft and/f1ap. (3) During surgical debride­ment, doxorubicin-containing tissue should be iden­tified by fluorescence under UV light and surgically excised. (4) Following removal of all indentifiable doxorubicin-containing tissue, fluorescein should be administered intravenously and 15 minutes later the removal of all nonviable tissue that does not fluoresce green should be performed.

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