Tumori, 92: 549-551, 2006 SKELETAL MUSCLE METASTASES FROM RENAL CELL CARCINOMA: A CASE REPORT Antonio Manzelli, Piero Rossi, Adriano De Majo, Giorgio Coscarella, lwona Gacek, and Achille Lucio Gaspari General Surgery Division, Department of Surgery, University of Rome Tor Vergqta, Rome, Italy In this paper, we describe a case of a 73-year old female with late skeletal muscle metastases from a clear-type renal cell carcinoma 8 years after total nephrectomy. The metastases were located in the right femoral quadriceps, in the sartorius muscle and adductor magnus muscle. A full clinical work-up was performed with blood examinations, radiological and pathological assessment. A complete surgical resection with a wide margin was performed for all lesions, and the final pathological report deposed for metastatic renal carcinoma clear-type cells. In this case report, we discuss the crucial rule of accurate radiological and pathological assessment and aggressive surgical management. Key words: neoplasm metastasis, renal cell carcinoma, skeletal muscle. Introduction Although skeletal muscle constitutes about 43% of the total body weight, it is a rare site for metastatic disease1. Based on two autopsy studies of cancer patients, the incidence of muscle metastasis is less than 1% in patients who die from cancer2 3 . The incidence of clinically evident metastases to muscle is extremely rare. Nevertheless, renal cell carcinoma (RCC) can give metastasis to skeletal muscles, with about 20 cases reported to date4 . In this paper, we describe a case of a 73year-old female with late skeletal muscle metastases from a clear-type RCC 8 years after total nephrectomy. Case report A 73-year-old Caucasian female with history of previously resected primary renal carcinoma was referred to the Department of Surgery at the Tor Vergata University Hospital in Rome because of nodules in her right leg. In her history, a total right nephrectomy was performed 8 years before for renal carcinoma clear-type cells as a Grawitz tumor. No local-regional nodes were found positive, no distant metastases were diagnosed, with a pathological staging of pT2NOMO and Furhman grade II. No adjuvant chemotherapy was given. Six years after surgery, she noticed the presence of a painless mass on the III medium anterior portion of her right leg. Clinical and radiological assessment was performed. A total body computer topography (TBCT) scan and regional magnetic resonance imaging (MRn were performed to define clinical staging and limits of the nodules and exclude a deep involvement of vascular and muscular structures. A surgical biopsy was performed one month later. Blood tests revealed an elevated level of carcinoembryonic antigen. MRI revised with algorithm MIP demonstrated a large mass in the right leg (Figure 1) of the III medium anterior portion in a subfascial position, in the ventral portion of the femoral quadriceps muscle measuring 5 x 4 x 9 cm. A greater vascularization, coming from the femoral artery was noted in the upper side of the mass (Figure 2). Additional nodules with similar radiological features were found in the sartorius muscle and adductor magnus muscle, with maximum diameters of 3.5 cm and 3 cm, respectively. The TBCT scan did not show the presence of any other distant metastases. The pathology report for the surgical biopsy demonstrated metastatic carcinoma clear-type cells from the kidney primary tumor. In the first phase following diagnosis, a therapy based on IL-2, IFN-a and MAP was performed 8 times without clinical improvement. This phase was also followed by therapy with isolated leg perfusion with no real benefit. Figure 1 - MRI slmws a large mass in the right leg. Correspondence to: Antonio Manzelli, MD, Department of Surgery, General Surgery Division, Tor Vergata University Hospital, University of Rome Tor Vergata, V.le Oxford 81, 00133 Roma, Italy. Tel +39-06-20902928; fax +39-06-76967548; e-mail manzelli@med.uniroma2.it Received March 2, 2006; accepted May 4, 2006. 550 A MANZELLI, P ROSSI, A DE MAJO ET AL Figure 3 - Macroscopic examination. Figure 2 - Vascular supply coming from the femoral artery. This protocol was followed according to the Department of Oncology at the Regina Elena Hospital Cancer Institute in Rome. A new regional MRI and total body CT scan for local and general new staging were performed before the surgery. Clinical condition was not modified, and no distant metastases were found. Total body bone scintigraphy showed no local or general uptake. Exactly 8 years after nephrectomy, the patient underwent surgery of the compartmental resection of metastatic lesions of the right leg. During intervention, with the patient in a supine position, an elliptical incision was made including the previous biopsy site, and a compartmental exeresis on wide and safe margins of the mass was performed. A second incision was made posteriorly with the patient in a prone position for resection of the nodules located in the sartorius muscle and adductor magnus muscle. Macroscopic examination showed nodular lesions with a fibrotic capsula in the ventral portion of femoral quadriceps as well as in the sartoius muscle and adductor magnus muscle (Figure 3). The final pathological report confirmed for metastatic renal carcinoma cleartype cells in all lesions. ·Six months later, the patient presented no systemic or local recurrence and is now in clinical follow-up with outpatient examinations scheduled each year. Discussion Late metastases are not a rare event and are considered when several years have passed from resection of a primary tumor far from the classical follow-up. The most frequent sites of late metastasis are lung, liver, brain, pancreas, spleen, bone, and bowel. Metastases to the skeletal muscles are very rare and represent less than 1% of all hematogenous metastases from the lung, colon, kidney, or stomach, and less commonly from the breast, bladder, cervix, or thyroid 5 •6 • RCC is notorious for distant and late metastasis with no clinical suggestion of the primary lesion. Metastases of RCC usually occur in lungs (76%), bone (42%) and liver (41 %)7. However, skeletal muscles represent one of the rare sites for RCC late metastases present in the literature. This peculiarity of RCC has lead to the following clinical maxim: never assume that a patient with RCC is disease-free and show the difficulty in predicting RCC evolution. The literature offers isolated cases of RCC with metastases in muscle, and no preferred muscular site is found. The true incidence of muscle skeletal metastases for RCC is difficult to determine since they are rarely present clinically and are not routinely searched for, not even on autopsy. McNichols et al. 8 studied the problem of late recurrence from RCC after total nephrectomy. He examined 158 patients treated surgically for RCC and showed 11 % late recurrence in those who survived more than 10 years. Moreover, 16 of the 18 patients reported by McNichols et al. had differentiated type RCC of grade 1 and 2. Thus it appears that late recurrence may occur in well-differentiated RCC, as in our patient8 • The actual mechanism behind this unusual metastatic site is at present unknown. Several theories have been proposed to explain the causes of late recurrence. The most accredited theories depose for an immunological participation. A decrease in the immunological response of the host would be responsible for an increase in tumor growth 9 •10 • Another theory regards muscle resistance. Muscle, particularly striated muscle, is highly resistant to both primary and metastatic cancer. This resistance is thought to be connected with the lactic acidproducing activities of tumors. Lactic acid is an anoxia signal in the body, to which blood vessels tend to re- SKELETAL MUSCLE METASTASES spond with a sprouting reaction. New vessels seek out the source of anoxia and vascularize it. The reaction of the body to incipient cancer is probably two-fold. Fibroblasts treat cancer cells as foreign bodies and attempt to encapsulate them, whereas blood vessels tend to perpetuate cancer cells by supplying them with nutrients. The fate of the tumor may be decided by the relative speed of the two reactions. Muscles are lactic acid producers themselves, hence their blood vessels must be conditioned to a greater tolerance of it than in other tissues. This may be the crucial factor in preventing incipient tumors from establishing themselves in muscle. However, further complementary studies are needed to explain the late recurrence mechanism 11 • The unpredictable behavior of RCC makes lifelong follow-up of patients necessary. In our opinion, this report of the involvement of multiple nodular lesions in multiple muscle groups, visualized as solid and ring enhancements in MRI, suggests how a patient with a history of a malignancy and subtle symptoms or signs in the muscle or soft tissues needs a definite investiga- 551 tion. Postoperative surveillance following nephrectomy for RCC is being conducted with constantly improving CT /MRI equipment and scanning techniques. Delayed and unusual sites of recurrent disease are now recognized more frequently. Therefore, accurate CT/MR assessment is crucial. MRI is a valuable imaging modality to establish the diagnosis and to plan treatment strategy. MRI with intravenous gadolinium enhancement was particularly helpful when planning the biopsy or surgery of these lesions as it is useful to evaluate the vascularity of the tumor. Treatment of these patients may depend on the clinical setting and the condition of the patient. Treatment options may include radiotherapy, chemotherapy and surgical excision. In general, wide excision, chemotherapy, radiotherapy and a combination of the three usually provide satisfactory results. In our experience, treatment with IL-2, alpha-interferon and isolated perfusion of the leg treatment failed to arrest the disease, and aggressive surgical management was warranted. References 1. Basmajian JV, Slonecker CE: A clinical problem-solving approach. In: Grant's Method of Anatomy, Boileau Grant JC, Basmajian JV, Slonecker CE (Eds), 11th ed, pp 18-24, Williams and Wilkins, Baltimore, 1989. 2. Bennington JL, Kradjian RM: Site of metastases at autopsy in 523 cases of renal cell carcinoma. In: Renal Carcinoma, Bennington JL, Kradjian RM (Eds), pp 156-169, WB Saunders, Philadelphia, 1967. 3. Willis RA: Carcinoma. In: Pathology of tumors, Willis RA (Ed), pp 163-190, 4th ed, Appleton-Century-Crofts, New York, 1967. 4. Karakousis CP, Rao U, Jennings E: Renal cell carcinoma metastatic to skeletal muscle mass: a case report. J Surg Oncol, 17: 287-293, 1981. 5. Menard 0, Parache RM: Muscle metastasis of cancers. Ann Med Inteme (Paris), 142: 423-428, 1991. 6. Araki K, Kobayashi M, Ogata T, Takuma K: Colorectal carcinoma metastasis to skeletal muscle. Hepatogastroenterology, 41: 405-408, 1994. 7. Munk PL, Gock S, Gee R, Connell DG, Quenville NF: Case report 708: Metastasis of renal cell carcinoma to skeletal muscle (right trapezius). Skeletal Radiol, 21: 56-59, 1992. 8. McNichols DW, Segura JW, DeWeerd JH: Renal cell carcinoma: long-term survival and late recurrence. J Urol, 126: 1723, 1981. 9. 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