¹Department of Surgery, BUMC; ²Baylor-Charles A. Sammons Cancer Center, BUMC; ³Department of Colon & Rectal Surgery, BUMC; ⁴Red River Valley Pathology Lab, Paris, Texas; ⁵Department of Radiation Oncology, BUMC; ⁶Department of Medical Oncology, BUMC

Skin cancer is the most frequently seen malignancy in the USA. Although most physicians have experience dealing with skin cancer in the general population, transplant patients are particularly susceptible to complications of these neoplasms, and their treatment warrants special consideration. Because of immune suppression, seemingly innocuous lesions can become large, locally aggressive, and at times life threatening. Patient and physician education is needed to address the specific issues of skin cancer prevention and treatment in general, with emphasis on the immune-compromised patient.

One of every 3 newly diagnosed cancers is found on the skin. Because of a rapidly increasing incidence, skin cancer will affect almost one half of the US population by age 65 (1, 2). Skin type and ultraviolet radiation exposure are primary risk factors in the development of these tumors (Table 1). The most common forms of skin cancer are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). There were an estimated 900,000 new cases of these cancers in the USA in 1997 (3). A number of ablative procedures, including electrodesiccation/curettage and cryoablation, are efficacious in treating BCC and SCC (4), but these may not be adequate in organ transplant recipients and should be discouraged. The following patients should be counseled and treated aggressively in the pretransplant and posttransplant intervals: those with skin types I–III, those with a previous history of skin cancers, and those with solar-damaged skin or preexisting actinic keratoses. Avoiding sun exposure, wearing sun-protective clothing and hats, and using sunscreen are several simple measures that are beneficial for preventing skin cancer in organ transplant patients. These patients should have complete skin examinations at least once a year or, for those with continuing or developing skin problems, more often. Patient instruction relating to skin cancer prophylaxis and self-examination must be part of the transplant candidates’ education.

STUDY POPULATION

The cardiothoracic transplant program at Baylor University Medical Center began in 1986. Through December 1996, 177 patients have received heart transplants. Cancer has developed in 42 patients (24%). Skin cancer (18/42 or 43%) and posttransplant lymphoproliferative disorders (11/42 or 26%) are the most common. We have had experience with 7 heart transplant patients with cancers of the head and neck region (Table 2). Two of these patients had aggressive SCC of the skin. Two seemingly innocuous skin cancers became life threatening. We shall review the clinical courses of these patients and previous publications on this subject.

Several articles have addressed the topic of head and neck sequelae of cardiac transplantation, including oral candidiasis, upper respiratory infections, oral cavity ulceration (5), cyclosporine-induced gingival hyperplasia (5, 6), and mucosal squamous carcinoma of the upper aerodigestive tract (7). Proper treatment of advanced skin cancer in transplant (8) and nontransplant (3, 9) patients is very important.

CASE RECORDS

Patient 1, a fair-skinned, blue-eyed male, had a 2-cm squamous carcinoma (T1 N0 M0) (Table 3) removed from his right cheek in June 1989. Three months later, a 3-cm recurrence (rT2 N0 M0) was resected. Multiple margins were removed until clear tissue was achieved. After 3 more months, he presented with a 4-cm X 5-cm X 2-cm plaque of carcinoma (rT4 N0 M0) invading the substance of the right cheek. He had midface facial nerve paralysis of 2-weeks’ duration. He had had a heart transplant in April 1988 for idiopathic dilated cardiomyopathy that was refractory to medical management.

The tumor was resected by removing the mass of the right cheek and the total parotid, and a modified right radical neck dissection sparing the spinal accessory nerve was done. A positive facial nerve margin necessitated a mastoidectomy to achieve a negative margin. Permanent margins were negative; however, there was extensive perineural involvement of the facial and small nerves, even the nerves to the erector pili muscles in the subcutis (Figure 1). All nodes were negative. Because of the wide areas of invasion, we felt the patient had microscopic residual disease (R1) (Table 4). For this, he received postoperative irradiation therapy to 5000 cGy to the involved areas.

In September 1994, patient 1 developed drainage from the right external ear canal. A biopsy confirmed recurrent SCC with extensive perineural involvement (rT4 N0 M0). Metastatic evaluation was negative. Resection included a subtotal removal of the pinna, a lateral temporal bone resection, and removal of the ascending mandibular ramus and pterygoid plates and muscles. A pectoralis myocutaneous flap was used to close the defect. Final margins were positive in the pterygoid space, and the lingual nerve was positive at the foramen ovale. Microscopic cancer was found in the temporal bone and periosteum of the mandible. We again felt that he had R1 disease. Repeat irradiation therapy was recommended, with the realization that there was an increased risk of complications due to the previous irradiation therapy treatment. The patient was treated to 5000 cGy using 3D conformal planning to minimize complications. Treatment was completed in January 1995.

Following patient 1’s heart transplant, he was started on triple-drug immune suppression. Initially he took cyclosporine, 2 mg/kg/day; azathioprine, 150 mg/day; and prednisone, 10 mg/day. After cancer developed, doses were decreased: cyclosporine, 2 mg/kg/day; azathioprine, 100 mg/day; and prednisone, 7.5 mg/day. He recently was taken off prednisone. He has had no rejection episodes, and, as of December 1998, he has had no evidence of recurrence. The patient was started on cis-retinoic acid, 2 mg/kg/day, in February 1997, and no new skin cancers have developed since therapy began.

Our second patient presented with a similar problem; however, his course has been quite different.

Patient 2 grew up in West Virginia. He worked in hay fields without a shirt or hat and sunburned annually because he had fair skin. He received a heart transplant for idiopathic dilated cardiomyopathy on August 3, 1991. Posttransplant medication included triple-drug immune suppression (cyclosporine, 5 mg/kg/day; azathioprine, 125 mg/day; and prednisone, 5 mg/day). He experienced one episode of acute rejection in the posttransplant period. Four years later, in October 1995, he developed a 2-cm lesion (T1) of the scalp on the vertex, just anterior to the posterior hairline of his male-pattern baldness. He had a moderately to poorly differentiated SCC that was curetted and cauterized. The area never healed. In January 1996, a biopsy of this area showed SCC. He saw a Mohs micrographic surgeon who resected a 2-cm mass to clear margins, with a resultant defect of 10 cm (rT4 N0 M0). There was perineural involvement in the left frontoparietal area. Closure was effected with local rotation flaps. He received 5000 cGy of local scalp irradiation therapy. He finished irradiation therapy in March 1996. Coincident with cessation of this therapy, a 1-cm nodule appeared in the left frontal area. A biopsy confirmed recurrent SCC. The Mohs surgeon resected this area, and the patient received total scalp irradiation therapy to 5000 cGy.

Three months later, in August 1996, the patient had a 3-cm postauricular mass that was attached to the mastoid process and a 3-cm mass in the left posterior triangle. Fine-needle aspiration cytology was compatible with SCC. There was no evidence of cancer in the scalp. Computed tomography (CT) scans showed the palpable masses and no other lesions or distant metastasis. We staged him rT0 N1 M0 (see Table 3).

On August 21, 1996, we did a left extended radical neck dissection with excision of the skin overlying the postauricular mass; a subtotal temporal bone resection; and resection of the digastric muscle, occipital artery, and parotid. A free rectus muscle flap and split thickness skin graft were used for the closure. The pathology report described a moderately to poorly differentiated SCC within 2 subcutaneous masses (6.5 cm and 3.5 cm) and extensive blood and lymphatic vessel involvement (Figure 2). There was cancer in the soft tissue around the occipital artery and infiltrating the wall of the internal jugular vein (Figure 3). In several sections, the margins were close but not involved with cancer. He was classified R1, at high risk for local, regional, and distant spread.

The postoperative course was uncomplicated. Triple-drug immune suppression continued, although the dose of cyclosporine was decreased from 5 mg/kg/day to 2 mg/kg/day. He continued azathioprine, 125 mg/day, and prednisone, 5 mg/day. Postoperatively, the patient received 6000 cGy to the area of the left ear, upper neck, and periauricular area. Both sides of the lower neck and right periauricular area received 4600 cGy with 6-mV x-rays with a 1000-cGy boost to the region of the previous left posterior triangle mass. Treatment was completed October 1996.

Four months later, patient 2 felt dizzy and congested. A history and physical examination failed to explain the symptoms. A CT scan was interpreted as showing osteomyelitis of the remaining portion of the left temporal bone. A CT-guided, fine-needle aspiration biopsy obtained acute inflammatory cells and no evidence of neoplasm. The patient received intravenous antibiotics and hyperbaric oxygen treatments without improvement. Two weeks later (February 25), a repeat CT scan showed progression of the bone lesion. Another CT-guided, fine-needle aspiration biopsy obtained cells compatible with recurrent SCC (rT0 N0 M1). In March 1997, the azathioprine was discontinued, and patient 2 continued taking cyclosporine, 125 mg, twice a day, and prednisone, 5 mg/day. Patient 2 was unable to tolerate concomitant chemotherapy/irradiation therapy; therefore, he was switched to cisplatin and paclitaxel. In November 1997, a CT scan showed progression of the bone defect, and the chemotherapy was changed to methotrexate and 5-fluorouracil every 2 weeks. As of December 1998, the patient was alive with stable disease. He had a single cancer with multiple nodal and bone metastases. His cancer began 49 months after heart transplantation.

We have presented 2 cases of skin cancer with entirely different courses. Both cancers were incompletely excised and became life threatening, requiring major ablation and reconstruction. The first patient had a locally aggressive cancer with local recurrence. He also has had multiple primary skin cancers that have been controlled with excision with histologic margin control. He has had no regional or distant metastasis. The second patient had only one cancer; however, it recurred locally, regionally, and distantly. Neither patient experienced rejection during the treatment period or showed evidence of acute or chronic rejection on cardiac biopsy. Heart function is stable in both. Cutaneous malignancies that generally are treated successfully with routine methods can prove to be quite virulent in the immune-compromised patient.

INCIDENCE

Transplant recipients develop cancer at an earlier age (mean, 45 years) compared with the general population (mean, 65.5 years) (10). Overall, posttransplant malignancies have been diagnosed in 4% to 18% (mean, 6%) of renal recipients and 3% to 9% (mean, 6%) of cardiac patients (11). The most common cancers are skin cancer (37%), lymphomas (primarily non-Hodgkin’s type) (17%), and lung cancer (6%) (11). The average age of cardiac recipients is 56 compared with 40 years for renal recipients. Time to first tumor after transplant averages 3.73 and 8.75 years, respectively (12). Heart patients (and other extrarenal organ recipients) are subjected to intense immunosuppression that lasts a lifetime (12, 13). This may be the reason for the shortened delay in cancer development (12). Immune suppression may be decreased over time, depending on the philosophy and experience of the transplant team. Renal recipients who develop cancer can have their suppression decreased or stopped; if rejection occurs, the patients can resume dialysis. This option is not available to nonrenal organ recipients.

The incidence of cancer increases with time posttransplantation. After heart transplant, the incidence of cancer is 3% at 1 year and 26% at 5 years (14). Squamous cell carcinoma of the skin is more common and more aggressive in transplant patients than in the general population (15, 16). In a carefully studied cohort of nontransplant patients with nonmelanoma skin cancer, a high risk of developing more skin malignancies in the follow-up period was found (up to 50% at 5 years in fair-skinned males over 60 years who previously had skin cancer and severe actinic skin damage) (17). The ratio of SCC:BCC is 0.2:1.0 in nontransplant patients. After transplant, the ratio changes. The incidence of SCC increases greatly, but BCC increases only slightly, resulting in a ratio of SCC:BCC of 1.8:1.0 (16). Skin cancer is responsible for 5% of the deaths in the transplant group. Squamous cell carcinoma is responsible for 60% of these deaths, malignant melanoma for 33%, and BCC, 1% (16).

Other cancers occur at relatively predictable intervals in the posttransplant period: Kaposi’s sarcoma at a mean of 21 months; lymphoma (primarily non-Hodgkin’s type) at an average of 32 months; epithelial carcinomas (excluding vulvar and perineal) on an average of 67 months; and carcinoma of the vulva, perineum, and carcinoma in situ of the cervix with an average of 112 months (11). Interestingly, the incidence of lung, prostate, rectal, breast, and invasive carcinoma of the uterine cervix is not increased in this cohort, although it is prevalent in the general population (18). This may be due to a longer latent period for these cancers in the nontransplant group.

ETIOLOGY

Skin cancers are prevalent in locales with high sun exposure rates. Citizens in urban areas who have indoor occupations and outdoor recreational pursuits and those in rural areas comprising farming and ranching communities (particularly persons with fair complexions) have many skin lesions, both benign and malignant. Ultraviolet A and B radiations cause sunburn and skin damage in fair-skinned persons and can damage the local immune function in patients of all skin types. Ultraviolet radiation can produce p53 tumor-suppressor gene mutations that can promote skin cancer. There is also a well-characterized deficit in immune function with advancing age (19). These older patients tend to accumulate genetic damage over time that can result in cancer. Age-related impairment of the deoxyribonucleic acid repair mechanism may account for the earlier development of cancer in older organ recipients than in the general population (19).

Cyclosporine inhibits the production of interleukin-1 and interleukin-2 by macrophages and lymphocytes. This inhibition interferes with antigen presentation (by Langerhans cells in the skin [20]) and blunts the immune response at its inception (20–22). Azathioprine-treated patients may have an increased incidence of skin cancers, because azathioprine’s breakdown products, imidazoles, sensitize the skin to sunlight. An active metabolite of azathioprine, 6-thioguanine, is claimed to be carcinogenic to the skin (23).

Neoplasms in patients who have primary and acquired immune deficiency and in patients who have autoimmune and inflammatory diseases treated with immunosuppressive drugs show a striking similarity to the tumors that affect transplant patients (24). Activation of oncogenic viruses, blunting of the immune surveillance and response, and stimulation of oncogenesis are involved (11).

The immune-suppressed state may allow activation of oncogenic viruses, resulting in cancer. Some well-known examples are Epstein-Barr virus associated with non-Hodgkin’s lymphoma; human papillomavirus and herpesvirus associated with cancers of the skin, vulva, cervix, and anus; hepatitis viruses B and C associated with hepatocellular carcinoma; and human herpesvirus 8 associated with Kaposi’s sarcoma (18, 25). Posttransplant patients are often given antiviral prophylaxis. Our patients take acyclovir daily.

CANCER AND TRANSPLANTATION

While previous skin cancer does not preclude organ transplantation, a history of internal malignancy has been a contraindication to transplantation in the past (26). However, recent studies of carefully selected patients with antecedent cancers who had received transplants report good results (18, 26, 27). These studies include patients who had childhood cancer (usually due to anthracycline-induced cardiomyopathy) (28) or adult cancers (18, 29, 30). Penn (31) estimated the potential for recurrence of cancer as low (0%–10%) for incidentally found renal tumors, lymphomas, and testicular, uterine, cervical, and thyroid cancers; intermediate (11%–25%) for carcinomas of the uterine body, colon, prostate, breast, and Wilms’ tumor; and high (>26%) for cancer of the bladder, sarcoma, malignant melanoma, symptomatic renal carcinoma, nonmelanoma skin cancer, and myeloma. The recommendation of a 2-year waiting period for transplant following cancer treatment seems prudent for most renal transplant patients; waiting more than 2 years for transplant is necessary for most melanoma, breast, and colorectal cancer patients. Cancers that arose and were treated after transplantation recurred in 23% of the cases, with a short follow-up period (52 months) (31).

DIAGNOSIS AND TREATMENT

Physicians who care for immunocompromised patients need to understand that several recommendations may help control skin cancers. Before transplantation, the routine workup should include taking a history of sun exposure, taking family and personal histories of malignancy, and performing complete cutaneous and head and neck examinations. All suspicious skin lesions should be biopsied and removed. Keratoses can be treated with electrodesiccation/curettage, cryotherapy, and topical 5-fluorouracil. A high index of suspicion and the frequent use of skin biopsies are critical. Immunocompromised patients have an increased incidence of both premalignant and malignant lesions that may be atypical in presentation and appearance (16). We also recommend that these patients avoid sun exposure as much as possible and that they follow the guidelines of the American Academy of Dermatology if they must be in the sun (Table 5). Warts should be removed, because they are often associated with human papillomavirus and can lead to the formation of cutaneous malignancies (21, 24, 31).

After transplantation, routine skin examinations are critical (13, 21, 32, 33), with the frequency guided by the patient’s history and posttransplant course. These patients have a high incidence of multiple lesions, 44% in one series (11). All skin lesions suspicious for malignancy should be biopsied and then removed, with histologic margin control of malignancies. If there is a question about adequacy of resection, more tissue should be removed. This precaution will result in cancer control in most instances. Most recurrent or locally advanced primaries T2, T3, or T4 (see Table 3) (see definition of T4 [deeply invasive, e.g., muscle, bone, nerve]) should be referred to a Mohs micrographic surgeon for resection. This technique yields a lower recurrence rate than does routine resection (34), particularly with poorly differentiated cancers and difficult lesions near or involving the eyes, ears, nose, and lips. These head and neck primary lesions are in functionally and cosmetically critical areas where clear (wide) margins are difficult if not impossible. Irradiation therapy can be used as primary treatment in similar cases, with preservation of anatomic structures and function (35). Postoperative irradiation therapy should be considered in an effort to increase local and regional control. Even using these modalities, control may not be complete, as seen in our patients.

Frequent use of CT scans to search for metastatic disease is recommended, because heart transplant recipients have a significant risk of primary lung cancer (36–39), particularly if there is a history of smoking.

Modified or radical neck dissection should be done for patients with positive nodes or when the neck is entered to remove the primary lesion. Resection of involved tissues must be done aggressively to give the best opportunity for cure. The right jugular vein should be preserved, if oncologically feasible, to facilitate heart biopsies. Although other veins can be used, the approach is more difficult.

Decreasing the level of immune suppression should be considered at the time of recurrence or with the appearance of an advanced primary tumor (8). Euvrard and associates reported on 5 posttransplantation patients (kidney: n = 3; heart: n = 2) with aggressive skin cancer (8). Cyclosporine was discontinued in all patients on triple-drug therapy, and azathioprine was omitted in all but 1 cardiac patient whose dose was lowered to 25 mg/day. Despite this drastic reduction in immune suppression, there were no episodes of rejection in the follow-up period.

Chemoprevention using cis- or trans-retinoic acid (40–42) or topical retinoids is a consideration for preventing skin cancer. Although this intervention can help, high doses must be used, and attendant side effects such as mucosal dryness and hyperlipidemia may occur. The recurrence rate is high after decreasing or discontinuing therapy. The addition of interferon- to cis-retinoic acid has been used with encouraging results (40); however, treatment with a cytokine may stimulate a rejection reaction (8).

Chemotherapy has produced some successful results for advanced (43) and metastatic (44) skin cancer, using a combination of cisplatin and 5-fluorouracil ? bleomycin sulfate. Rowe et al raised the question of triple therapy, with induction chemotherapy, surgery, and radiation for difficult cases (4).

As the drugs and techniques for posttransplant immune suppression improve, these patients will live longer. Perhaps we will see an increase in the more common cancers (45). Conversely, as suppression regimens improve, it may be possible to target only those clones of cells responsible for rejection, making the insult to the immune system more specific and limited, possibly leading to a decrease in the incidence of cancer. At present, it is advantageous to keep maintenance immune suppression at the lowest level compatible with survival and function of the transplanted organ.