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Acral Myxoinflammatory Fibroblastic Sarcoma in a Renal Transplant Patient: A Case Report
Acral Myxoinflammatory Fibroblastic Sarcoma in a Renal Transplant Patient: A Case Report R. Flooks, A. Vanacker, J. Van Dorpe, B. Smet, I. Vandewiele, G. De Schoenmakere, and B. Maes ABSTRACT Herein, we have reported a case of a 62-year-old patient who presented at 10 months after renal transplantation with a nodular mass on the dorsum of his foot. Local excision was performed and an acral myxoinflammatory fibroblastic sarcoma was diagnosed. This is a rare, low-grade sarcoma with a high rate of local recurrence, sometimes leading to amputation. Metastasis to the lungs and liver has been reported, but is rare. Since our patient received triple immunosuppressive therapy, our major concern was a much more aggressive behavior. However, more than 2 years after excision of the tumor, the patient is still free of disease. INCE PATIENT SURVIVAL after renal transplantation has improved considerably over the past 30 years, long-term complications, such as malignancies, are becoming a limiting factor for graft and patient survivals. Compared with the general population, renal transplant recipients have a 3- to 5-fold overall higher risk of malignancy, with skin cancers and lymphoma particularly prevalent. Moreover, the biological behavior of these tumors seems to be much more aggressive and the prognosis poorer than in nonimmunosuppressed patients.1 The development of sarcomas during long-term immunosuppressive therapy has been unequivocally documented for human herpesvirus 8-associated Kaposi’s sarcomas and, to a much lesser extent, for Epstein-Barrvirus (EBV)-associated leiomyosarcoma, but the occurrence of other types of sarcomas seems to be rare. Herein, we have reported a case of acral myxoinflammatory fibroblastic sarcoma (MIFS), a rare, low-grade sarcoma, in a patient who underwent renal transplantation 10 months prior.
S
CASE REPORT A 62-year-old renal transplant patient presented to the outpatient clinic with a node on the dorsum of his left foot. He was diagnosed in March 2003 with focal segmental glomerulosclerosis of unknown origin: negative immunohistochemistry and Congo red staining. He experienced a progressive decline in renal function, for which he was started on chronic intermittent hemodialysis on December 1, 2004. He received a deceased donor kidney on February 16, 2006. The HLA match was moderate (1-1-1 mismatch), and the donor’s serologies for autoimmune diseases and infections (cytomegalovirus [CMV], EBV, hepatitis C virus [HCV], hepatitis B virus [HBV], syphilis, and human immunodeficiency virus [HIV]) were negative. Induction immunosuppressive therapy consisted of corticosteroids
(CS; methylprednisolone, Medrol, David Bull Laboratories Pty Ltd, Mulgrave, Australia), cyclosporine (CsA; Sandimmun Neoral, Novartis, Basel, Switzerland), and mycophenolate mofetil (MMF; Cellcept, Roche, Basel, Switzerland). The postoperative period was complicated by a colon perforation, for which he underwent a partial resection of the descending colon with a temporary colostomy. He experienced no subsequent complications under maintenance therapy with low-dose CS (methylprednisolone 2 mg/d), CsA (trough level, 100 –120 g/L), and MMF (2 g/d). Renal function remained stable with a serum creatinine between 1.3 and 1.5 mg/dL, corresponding to a creatinine clearance of 45 to 50 mL/min and no proteinuria. Concomitant medications consisted of atorvastatin (20 mg), metoprolol (200 mg), omeprazole (20 mg), alfacalcidol (0.25 g), and bumetanide (2.5 mg daily). He presented on December 7, 2006, at 10 months after renal transplantation, with a 1.5 ⫻ 1.5 cm mass on the bridge of his left foot. He described the mass as being slow growing, and present for several years. Because of progressive discomfort, he insisted on removal of the nodule, which was performed on December 14. The excisional biopsy measured 1.5 ⫻ 1.5 ⫻ 0.6 cm showing a subcutaneous, vaguely multinodular, poorly circumscribed lesion with 1.2 cm diameter. The lesion was quite cellular, demonstrating a conspicuous inflammatory infiltrate. Small and larger foci of hypocellular myxoid tissue were intermixed with cellular areas, which consisted of plump spindle or more epithelioid, atypical cells. The atypical cells often showed a large vesicular nucleus with a promFrom the Departments of Nephrology, Universitas Hospital Bloemfontein, South Africa (R.F.), and Departments of Nephrology (A.V., I.V., G.D., B.M.), Pathology (J.V.D.), and Surgery (B.S.), Heilig Hartziekenhuis Roeselare-Menen, Roeselare, Belgium. Address reprint requests to Bart Maes, MD, PhD, Heilig Hartziekenhuis Roeselare-Menen, Wilgenstraat 2, Roeselare 8800, Belgium. E-mail: [email protected]
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.09.023
Transplantation Proceedings, 41, 3437–3439 (2009)
3437
3438 inent macronucleolus, imparting a resemblance to virocytes. Some cells had a Reed-Sternberg-like appearance containing a bilobar or multilobar highly atypical nucleus. Some pseudolipoblasts with multivacuolated cytoplasm were present in the myxoid areas. The inflammatory infiltrate was mainly composed of small mature lymphocytes, which sometimes formed small aggregates, and rarer neutrophils. Several mitotic figures were seen in the cellular areas. There was no necrosis. The lesion extended into the excisional margins (Fig 1). Immunohistochemically, the atypical spindle and more epithelioid cells stained strongly for vimentin and variably for CD68. Immunostains for S100 protein, HMB 45, and CD34 were negative. A reexcision specimen revealed a residual nodule of inflammatory myxohyaline tumor extending into the deep surgical margins. The diagnosis of an acral myxoinflammatory fibroblastic sarcoma was established. Based on the pathological examination and the evolution in nontransplanted patients, the patient was advised to undergo a broader resection of the lesion, involving partial resection of the foot extensors. Because of the invalidating consequences, the patient refused this surgical intervention. Careful follow-up at more than 2 years after the initial resection has revealed no recurrence of the lesion, despite a triple immunosuppressive drug regimen.
DISCUSSION
Acral MIFS is also known as inflammatory myxohyaline tumor of the distal extremities or inflammatory myxoid tumors with bizarre giant cells. It was described for the first time in the late 1990s.2– 4 It is a low-grade sarcoma, with a predilection for the acral areas: hands, wrists, feet, and ankles (in order of decreasing frequency). However, it has also been described in the neck, upper back, and groin.5–7 It
Fig 1. Histological examination of the removed acral myxoinflammatory fibroblastic sarcoma. (A) Medium-power view of a cellular hyaline area. Several small lymphocytic infiltrates are present. A virocyte-like cell with a prominent nucleolus is indicated by a small arrow. (B) Low-power view of a hypocellular myxoid area. (C) High magnification showing several virocyte-like (small arrow) and Reed-Sternberg-like cells with an atypical nucleus containing a prominent nucleolus surrounded by a halo (large arrow). (D) High-power view of bizarre pseudolipoblasts with multivacuolated cytoplasm. Two hyalinized vessels are present on the left.
FLOOKS, VANACKER, VAN DORPE ET AL
is a rare type of tumor most commonly seen in adults, with a peak incidence in the fourth and fifth decades and an equal sex distribution. MIFS is a very slow growing tumor, which usually takes years to develop. It has a high rate of local recurrence (sometimes necessitating amputation) and a low rate of metastasis. After a median follow-up of 5 years, MeisKindblom et al2 reported that local recurrences occurred among 24 of 36 patients (67%), necessitating amputation in 10 patients. Only 1 patient developed a histologically proven lymph node metastasis. Another patient developed lung metastases, although these were not documented histologically.2 A second study by Montgomery et al3 reported local recurrences in 6 of 27 patients (22%; follow-up intervals of 15 months to 10 years). There was no development of metastases or tumor-related deaths.3 Treatment of MIFS usually includes wide local excision. Histological examination usually shows a multinodular tumor, typically located in the dermis or subcutis. It can invade the surrounding tissues. It has myxoid and fibrotic zones with hyalinized areas and a dense inflammatory infiltrate. Leukocytes and plasma cells seem to predominate with variable amounts of myxoid and hyaline tissue. The constituent cells may vary from spindle-shaped to epithelioid. The spindle-shaped cells seem to have some atypia, but rarely are mitotic figures noted. These cells may stain positive for CD68, CD34, and vimentin, but negative for the other epithelial markers. In all cases, various numbers are present of bizarre giant cells with large, lobulated or multiple nuclei, imitating Reed-Sternberg cells.8
ACRAL MYXOINFLAMMATORY FIBOBLASTIC SARCOMA
Since our patient received triple immunosuppressive therapy (methylprednisolone, CsA, and MMF), we were aware of the increased risk of a more aggressive history of this tumor and worse prognosis. This can be explained not only by the impaired immunosurveillance of neoplastic cells, but also by direct cancer promoting effects of immunosuppressive drugs. Some studies have suggested an increased incidence of posttransplant malignancy after introduction of the calcineurin inhibitor CsA. In contrast, proliferation signal inhibitors (mTOR inhibitors) appear to be associated with a reduced risk of some malignancies. Furthermore, conversion from calcineurin inhibitors to mTOR inhibitors can produce regression of Kaposi’s sarcoma in renal transplant recipients. This strategy is now part of the accepted standard of care for this tumor in this setting.9,10 For this reason, we considered the possibility of conversion from CsA to sirolimus in our patient. However, we decided to continue his immunosuppressive therapy with CsA. Until now, more than 2 years after the first resection of the lesion, the patient is free of disease. We have concluded that patients on chronic immunosuppression show a high risk to develop various (and rare) types of malignancies. Since their local behavior may be much more aggressive and they may have enhanced metastatic potential, even low malignancy cancerous lesions should be observed carefully.
3439
REFERENCES 1. Dantal J, Pohanka E: Malignancies in renal transplantation: an unmet medical need. Nephrol Dial Transplant 22(suppl 1):i4, 2007 2. Meis-Kindblom JM, Kindblom LG: Acral myxoinflammatory fibroblastic sarcoma: a low-grade tumor of the hands and feet. Am J Surg Pathol 22:911, 1998 3. Montgomery EA, Devaney KO, Giordano TJ, et al: Inflammatory myxohyaline tumor with virocyte or Reed-Sternberg-like cells: a distinctive lesion with features simulating inflammatory conditions, Hodgkin’s disease, and various sarcomas. Mod Pathol 11:384, 1998 4. Michal M: Inflammatory myxoid tumor of the soft parts with bizarre giant cells. Pathol Res Pract 194:529, 1998 5. McFarlane R, Meyers AD, Golitz L: Myxoinflammatory fibroblastic sarcoma of the neck. J Cutan Pathol 32:375, 2005 6. Premalata CS, Rao CR, Padma M, et al: Myxoinflammatory fibroblastic sarcoma—report of a rare case at an unusual site with review of the literature. Int J Dermatol 47:68, 2008 7. Bar-Meir E, Fridman E, Zilinsky I, et al: Myxoinflammatory fibroblastic sarcoma in an unreported area (groin). J Cutan Pathol 34:276, 2007 8. Jurcic V, Zidar A, Montiel MD, et al: Myxoinflammatory fibroblastic sarcoma: a tumor not restricted to acral sites. Ann Diagn Pathol 6:272, 2002 9. Campistol JM, Gutierrez-Dalmau A, Torregrose JV: Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation 77:760, 2004 10. Stallone G, Schena A, Infante B, et al: Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 352:1317, 2005
S
CASE REPORT A 62-year-old renal transplant patient presented to the outpatient clinic with a node on the dorsum of his left foot. He was diagnosed in March 2003 with focal segmental glomerulosclerosis of unknown origin: negative immunohistochemistry and Congo red staining. He experienced a progressive decline in renal function, for which he was started on chronic intermittent hemodialysis on December 1, 2004. He received a deceased donor kidney on February 16, 2006. The HLA match was moderate (1-1-1 mismatch), and the donor’s serologies for autoimmune diseases and infections (cytomegalovirus [CMV], EBV, hepatitis C virus [HCV], hepatitis B virus [HBV], syphilis, and human immunodeficiency virus [HIV]) were negative. Induction immunosuppressive therapy consisted of corticosteroids
(CS; methylprednisolone, Medrol, David Bull Laboratories Pty Ltd, Mulgrave, Australia), cyclosporine (CsA; Sandimmun Neoral, Novartis, Basel, Switzerland), and mycophenolate mofetil (MMF; Cellcept, Roche, Basel, Switzerland). The postoperative period was complicated by a colon perforation, for which he underwent a partial resection of the descending colon with a temporary colostomy. He experienced no subsequent complications under maintenance therapy with low-dose CS (methylprednisolone 2 mg/d), CsA (trough level, 100 –120 g/L), and MMF (2 g/d). Renal function remained stable with a serum creatinine between 1.3 and 1.5 mg/dL, corresponding to a creatinine clearance of 45 to 50 mL/min and no proteinuria. Concomitant medications consisted of atorvastatin (20 mg), metoprolol (200 mg), omeprazole (20 mg), alfacalcidol (0.25 g), and bumetanide (2.5 mg daily). He presented on December 7, 2006, at 10 months after renal transplantation, with a 1.5 ⫻ 1.5 cm mass on the bridge of his left foot. He described the mass as being slow growing, and present for several years. Because of progressive discomfort, he insisted on removal of the nodule, which was performed on December 14. The excisional biopsy measured 1.5 ⫻ 1.5 ⫻ 0.6 cm showing a subcutaneous, vaguely multinodular, poorly circumscribed lesion with 1.2 cm diameter. The lesion was quite cellular, demonstrating a conspicuous inflammatory infiltrate. Small and larger foci of hypocellular myxoid tissue were intermixed with cellular areas, which consisted of plump spindle or more epithelioid, atypical cells. The atypical cells often showed a large vesicular nucleus with a promFrom the Departments of Nephrology, Universitas Hospital Bloemfontein, South Africa (R.F.), and Departments of Nephrology (A.V., I.V., G.D., B.M.), Pathology (J.V.D.), and Surgery (B.S.), Heilig Hartziekenhuis Roeselare-Menen, Roeselare, Belgium. Address reprint requests to Bart Maes, MD, PhD, Heilig Hartziekenhuis Roeselare-Menen, Wilgenstraat 2, Roeselare 8800, Belgium. E-mail: [email protected]
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.09.023
Transplantation Proceedings, 41, 3437–3439 (2009)
3437
3438 inent macronucleolus, imparting a resemblance to virocytes. Some cells had a Reed-Sternberg-like appearance containing a bilobar or multilobar highly atypical nucleus. Some pseudolipoblasts with multivacuolated cytoplasm were present in the myxoid areas. The inflammatory infiltrate was mainly composed of small mature lymphocytes, which sometimes formed small aggregates, and rarer neutrophils. Several mitotic figures were seen in the cellular areas. There was no necrosis. The lesion extended into the excisional margins (Fig 1). Immunohistochemically, the atypical spindle and more epithelioid cells stained strongly for vimentin and variably for CD68. Immunostains for S100 protein, HMB 45, and CD34 were negative. A reexcision specimen revealed a residual nodule of inflammatory myxohyaline tumor extending into the deep surgical margins. The diagnosis of an acral myxoinflammatory fibroblastic sarcoma was established. Based on the pathological examination and the evolution in nontransplanted patients, the patient was advised to undergo a broader resection of the lesion, involving partial resection of the foot extensors. Because of the invalidating consequences, the patient refused this surgical intervention. Careful follow-up at more than 2 years after the initial resection has revealed no recurrence of the lesion, despite a triple immunosuppressive drug regimen.
DISCUSSION
Acral MIFS is also known as inflammatory myxohyaline tumor of the distal extremities or inflammatory myxoid tumors with bizarre giant cells. It was described for the first time in the late 1990s.2– 4 It is a low-grade sarcoma, with a predilection for the acral areas: hands, wrists, feet, and ankles (in order of decreasing frequency). However, it has also been described in the neck, upper back, and groin.5–7 It
Fig 1. Histological examination of the removed acral myxoinflammatory fibroblastic sarcoma. (A) Medium-power view of a cellular hyaline area. Several small lymphocytic infiltrates are present. A virocyte-like cell with a prominent nucleolus is indicated by a small arrow. (B) Low-power view of a hypocellular myxoid area. (C) High magnification showing several virocyte-like (small arrow) and Reed-Sternberg-like cells with an atypical nucleus containing a prominent nucleolus surrounded by a halo (large arrow). (D) High-power view of bizarre pseudolipoblasts with multivacuolated cytoplasm. Two hyalinized vessels are present on the left.
FLOOKS, VANACKER, VAN DORPE ET AL
is a rare type of tumor most commonly seen in adults, with a peak incidence in the fourth and fifth decades and an equal sex distribution. MIFS is a very slow growing tumor, which usually takes years to develop. It has a high rate of local recurrence (sometimes necessitating amputation) and a low rate of metastasis. After a median follow-up of 5 years, MeisKindblom et al2 reported that local recurrences occurred among 24 of 36 patients (67%), necessitating amputation in 10 patients. Only 1 patient developed a histologically proven lymph node metastasis. Another patient developed lung metastases, although these were not documented histologically.2 A second study by Montgomery et al3 reported local recurrences in 6 of 27 patients (22%; follow-up intervals of 15 months to 10 years). There was no development of metastases or tumor-related deaths.3 Treatment of MIFS usually includes wide local excision. Histological examination usually shows a multinodular tumor, typically located in the dermis or subcutis. It can invade the surrounding tissues. It has myxoid and fibrotic zones with hyalinized areas and a dense inflammatory infiltrate. Leukocytes and plasma cells seem to predominate with variable amounts of myxoid and hyaline tissue. The constituent cells may vary from spindle-shaped to epithelioid. The spindle-shaped cells seem to have some atypia, but rarely are mitotic figures noted. These cells may stain positive for CD68, CD34, and vimentin, but negative for the other epithelial markers. In all cases, various numbers are present of bizarre giant cells with large, lobulated or multiple nuclei, imitating Reed-Sternberg cells.8
ACRAL MYXOINFLAMMATORY FIBOBLASTIC SARCOMA
Since our patient received triple immunosuppressive therapy (methylprednisolone, CsA, and MMF), we were aware of the increased risk of a more aggressive history of this tumor and worse prognosis. This can be explained not only by the impaired immunosurveillance of neoplastic cells, but also by direct cancer promoting effects of immunosuppressive drugs. Some studies have suggested an increased incidence of posttransplant malignancy after introduction of the calcineurin inhibitor CsA. In contrast, proliferation signal inhibitors (mTOR inhibitors) appear to be associated with a reduced risk of some malignancies. Furthermore, conversion from calcineurin inhibitors to mTOR inhibitors can produce regression of Kaposi’s sarcoma in renal transplant recipients. This strategy is now part of the accepted standard of care for this tumor in this setting.9,10 For this reason, we considered the possibility of conversion from CsA to sirolimus in our patient. However, we decided to continue his immunosuppressive therapy with CsA. Until now, more than 2 years after the first resection of the lesion, the patient is free of disease. We have concluded that patients on chronic immunosuppression show a high risk to develop various (and rare) types of malignancies. Since their local behavior may be much more aggressive and they may have enhanced metastatic potential, even low malignancy cancerous lesions should be observed carefully.
3439
REFERENCES 1. Dantal J, Pohanka E: Malignancies in renal transplantation: an unmet medical need. Nephrol Dial Transplant 22(suppl 1):i4, 2007 2. Meis-Kindblom JM, Kindblom LG: Acral myxoinflammatory fibroblastic sarcoma: a low-grade tumor of the hands and feet. Am J Surg Pathol 22:911, 1998 3. Montgomery EA, Devaney KO, Giordano TJ, et al: Inflammatory myxohyaline tumor with virocyte or Reed-Sternberg-like cells: a distinctive lesion with features simulating inflammatory conditions, Hodgkin’s disease, and various sarcomas. Mod Pathol 11:384, 1998 4. Michal M: Inflammatory myxoid tumor of the soft parts with bizarre giant cells. Pathol Res Pract 194:529, 1998 5. McFarlane R, Meyers AD, Golitz L: Myxoinflammatory fibroblastic sarcoma of the neck. J Cutan Pathol 32:375, 2005 6. Premalata CS, Rao CR, Padma M, et al: Myxoinflammatory fibroblastic sarcoma—report of a rare case at an unusual site with review of the literature. Int J Dermatol 47:68, 2008 7. Bar-Meir E, Fridman E, Zilinsky I, et al: Myxoinflammatory fibroblastic sarcoma in an unreported area (groin). J Cutan Pathol 34:276, 2007 8. Jurcic V, Zidar A, Montiel MD, et al: Myxoinflammatory fibroblastic sarcoma: a tumor not restricted to acral sites. Ann Diagn Pathol 6:272, 2002 9. Campistol JM, Gutierrez-Dalmau A, Torregrose JV: Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation 77:760, 2004 10. Stallone G, Schena A, Infante B, et al: Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 352:1317, 2005