Primary Scalp Angiosarcoma With Metastasis to the Liver in an Orthotopic Liver Transplant Patient
Angiosarcoma is a rare malignant neoplasm of vascular endothelial cells. A majority are primarily in the skin. Angiosarcoma of the head and neck is the most common form, but only constitutes 0.1% of all head and neck malignancies. We present an extraordinary case of a 71 year-old male six months status post orthotopic liver transplant secondary to end stage liver disease from cryptogenic cirrhosis, who presented to the liver clinic with a rapidly growing scalp tumor and hypodense lesions within the liver. Further work-up and biopsies confirmed the first documented case of primary scalp angiosarcoma with metastasis to the liver in an orthotopic liver transplant patient.
A 71-year-old man with an orthotopic liver transplant 6 months earlier, secondary to end-stage liver disease from cryptogenic cirrhosis, presented to the liver clinic with abdominal distension and worsening ascites. The patient was otherwise asymptomatic and denied having fever, chills, abdominal pain, nausea, vomiting, and diarrhea. For immunosuppression, he had been receiving tacrolimus 2 mg twice daily, with tacrolimus levels between 5 and 8. An ultrasound, followed by a computed tomography scan and magnetic resonance imaging of the abdomen, showed numerous small cystic lesions with peripheral enhancement throughout the liver. These findings led the team to be concerned about liver abscesses (Figure 1). The patient was admitted to the hospital for a further work-up.
Piperacillin and tazobactam IV were given as antibiotic therapy, and the patient underwent computed tomography-guided paracentesis, aspiration of cystic fluid, and a core needle liver biopsy. The dermatology department was consulted to evaluate a rapidly enlarging and bleeding scalp lesion, present for 5 weeks. A physical examination revealed a bleeding, firm, indurated nodule on the right temporal scalp, with peripheral purpura and ecchymosis extending down the forehead to the right temple (Figure 2). A satellite skin-colored nodule also was noted posterior to the primary lesion. Biopsy of the primary nodule showed dense, diffuse hemorrhagic proliferation of enlarged pleomorphic, mitotic epithelioid, and spindled CD31+ cells, consistent with the diagnosis of epithelioid angiosarcoma (Figure 3). The liver biopsies later showed a high-grade angiosarcoma. Positron emission tomography scanning revealed a hypermetabolic focus in the right frontal scalp, and multiple low-density lesions throughout the liver, but no other areas of abnormal fluorodeoxyglucose uptake, thus confirming the diagnosis of primary scalp epithelioid angiosarcoma, which had metastasized to the liver (Figure 4). The patient was discharged from the hospital, to be followed by the oncology department, which initiated outpatient chemotherapy.
Two weeks later, the patient presented to the oncology clinic with pain, headaches, and clinical worsening of his scalp angiosarcoma. Magnetic resonance imaging of the brain and orbits showed an extensive right scalp mass, with periosteal involvement, but without evidence of cortical, intracranial, or orbital involvement (Figure 5). Chemotherapy was begun with paclitaxel 80 mg/m2 weekly. After 3 weeks of chemotherapy, the patient’s scalp lesions improved, but an abdominal computed tomography scan showed progression of his hepatic metastatic disease. The patient died shortly thereafter, secondary to complications from his metastatic disease.
Angiosarcoma (AS) is a rare malignant neoplasm of the vascular endothelial cells. The majority of cases, primarily occupy the skin. There are 3 principle presentations: AS of the head and neck (most often the scalp of elderly males), postmastectomy AS (Stewart-Treves syndrome), and postirradiation AS.1 Angiosarcoma of the head and neck is the most common form, but it only constitutes 0.1% of all head and neck malignancies.2,3 Angiosarcoma of the head and neck manifests as an ill-defined red plaque that may be mistaken for ecchymosis or vascular rosacea. The “head tilt” sign may help confirm the diagnosis clinically, and help demarcate the extent of tumor.4 Diagnosis is confirmed with a biopsy that demonstrates sheets of widely infiltrating anaplastic endothelial cells. Some cases are diagnostically challenging, with only subtle cytologic atypia. In these cases, assessment of c-Myc by immunohistochemistry or fluorescence in situ hybridization may be helpful.5 Cutaneous AS is an aggressive neoplasm with a strong propensity to metastasize, most commonly to the liver, breast, lungs, skin, spleen, and bone.6,7 The overall 5-year survival rate is less than 30%.
Cutaneous AS is treated with wide local excision with at least 2 cm of unaffected tissue surrounding the tumor; however, recurrence is high with surgery alone.4 According to McKenna and associates,8 surgery followed by chemotherapy or radiotherapy portend the best outcomes. Promising treatment protocols involve wide-field electron beam radiotherapy using 3- to 5-cm margins.
According to a study in 2005, which examined 8 patients with AS, 5 were treated with paclitaxel and experienced major response to treatment. Three had a partial response, and 2 had complete remission. Seven of the 8 patients were given continuous therapy for 6 days. The authors found paclitaxel to have unique activity in angiosarcoma of the scalp and face, owing to its angiogenic potential.7,9 Ono and associates reported partial remission in 2 patients with inoperable cutaneous AS of the scalp treated with sorafenib 400 mg twice daily. Sorafenib, an oral multiple-kinase inhibitor of KIT, FLT-3, VEGFR-1,2,3, and PDGFR-β, leads to a dose-dependent reduction in tumor growth.10
More recently, immunotherapy with recombinant interleukin-2 has emerged as an effective strategy in preventing distant metastases. Recombinant interleukin-2 activates lymphokine-activated killer cells and natural killer cells, which subsequently bind to vascular endothelial cells causing their lysis. Ohguri and associates11 reported 20 patients with scalp AS treated with radiotherapy plus recombinant interleukin-2. Their results demonstrated a median survival time for overall, local recurrence-free, and distant metastasis-free survival of 36.2, 11.1, and 17.8 months, respectively bevacizumab, a recombinant humanized antibody against vascular endothelial growth factor, also has emerged as a promising agent for treating AS because vascular endothelial growth factor is overexpressed in over 80% of AS.9 Koontz and associates12 reported that 1 of 2 patients with nasal AS achieved complete remission when treated with bevacizumab and radiotherapy.
Our patient was not a surgical candidate because of his metastatic disease. He was started on chemotherapy with paclitaxel 80 mg/m2. After 3 treatments, repeat imaging showed progression of his hepatic disease.
Our case is rare, in that the patient presented with metastatic angiosarcoma of the head and neck in the setting of postliver transplant immunosuppression. Six months earlier, during the perioperative period, the patient was given immunosuppression consisting of steroids, mycophenolate mofetil, and tacrolimus. The prednisone was tapered off completely over the first 10 weeks, and mycophenolate mofetil was withdrawn completely after 3 months (per institutional protocol) leaving the patient on tacrolimus monotherapy. Tacrolimus target levels were 6 to 12 for the first month, 6 to 10 for the next 2 months, and then tapered to levels of 5 to 8 at 6 months. When he first presented, he was receiving tacrolimus 2 mg twice daily as monotherapy with tacrolimus levels between 5 and 8.
The increased incidence of certain cancers in solid-organ transplant patients is well documented, especially for malignancies caused by viruses. Further, a malignancy in the posttransplant patient usually has a worse prognosis, is more resistant to treatment, and advances more rapidly.13,14 In a retrospective study of over 1800 liver transplant recipients, 70 of them (3.83%) developed posttransplant malignant neoplasms, including 29 visceral solid tumors, 17 skin cancers, 17 hematologic disorders, and 7 sarcomas including Kaposi sarcoma. The mean time to diagnosis of the malignancy was 30.7 months after the transplant.15 Two of 70 patients (3%) had a pretransplant diagnosis of cryptogenic cirrhosis similar to our patient.
Of the sarcomas, only Kaposi sarcoma has been shown to have an increased incidence in transplant patients and represents approximately 4% of all de novo posttransplant malignancies. The risk of Kaposi sarcoma is 500 times greater for the transplanted patient than it is for the general population.16,17 A recent study by Bhatia and associates18 that examined the incidence of non-Kaposi sarcoma in immuno-compromised patients, found that angiosarcoma likely occurred disproportionately, comprising 18% of all non-Kaposi sarcoma in organ transplant patients as compared to 3.8% in the general population. Overall, the authors identified 18 cases of posttransplant angiosarcoma, with all cases occurring exclusively in renal transplant patients. Interestingly, 11 of 18 cases of angiosarcoma after a renal transplant occurred at an arteriovenous fistula.18 No cases of angiosarcoma occurred after a liver transplant.
Managing malignancy in posttransplant patients is difficult and requires a balance between reducing net immunosuppression while avoiding organ rejection. There are no current guidelines for treating angiosarcoma in an immunosuppressed patient, as there are relatively few cases. However, when managing a de novo posttransplant malignancy in general, most authors advocate reducing or eliminating calcineurin inhibitors and/or starting an mTOR inhibitor.19 In the case of Kaposi sarcoma, reducing or eliminating calcineurin inhibitors and adding sirolimus is an effective treatment strategy in renal transplant patients.20 For our patient, the plan was to reduce his dosage of tacrolimus and add sirolimus. However, the patient died of metastatic disease, while on tacrolimus at a goal FK level of 3 before sirolimus was initiated.
In summary, we report the first case of postliver transplant metastatic angiosarcoma. This case highlights the extraordinarily aggressive behavior that can be seen in head and neck AS, especially in the setting of posttransplant immunosuppression. Early diagnosis, followed by treatment with surgery, chemotherapy or radiotherapy, and mTOR inhibitors (instead of calcineurin inhibitors), would likely yield the best outcome in a transplant patient with AS.
Volume : 12
From the 1Kansas Medical Center, Department of Medicine, Division
of Dermatology, Kansas City, Kansas; the 2University of
Missouri-Kansas City School of Medicine, Kansas City, Missouri; the 3University
of Kansas Medical Center, Department of Medicine, Division of Hepatology; and
the 4University of Kansas Medical Center, Department of Pathology and Laboratory
Medicine, Kansas City, Kansas
Figure 1. Computed Tomography Scan With Contrast
Figure 2. Red, Violaceous Tumor on the Right Parietal Scalp
Figure 3. Punch Biopsy-Right Parietal Scalp
Figure 4. Positron Emission Tomography Scan
Figure 5. Magnetic Resonance Imaging
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