2492 Malignant Fibrous Histiocytoma of the Lung Report of Four Cases and Review of the Literature Michele Y. Halyard, M.D. John K. Camoriano, M.D. John A. Culligan, M.D. Louis H. Weiland, M.D. Mark S. Allen, M.D. James R. Pluth, M.D. Peter C. Pairolero, M.D. Mayo Clinic Scottsdale, Scottsdale, Arizona. BACKGROUND. Primary malignant fibrous histiocytoma (MFH) of the lung is a rare clinical entity. Only 23 reports of 49 cases have been reported in the literature. Surgery was the primary mode of therapy, with high rates of local and distant recurrence reported. The role of radiation therapy and chemotherapy has never been clearly defined. METHODS. The records of the Mayo Clinic in Scottsdale and Rochester from 1970 to 1990 were reviewed for cases of primary pulmonary MFH. A review of the literature was also undertaken. RESULTS. Four cases from the Mayo records and 49 cases from a review of the literature were identified. Eight patients were alive at 5 years from diagnosis; all had been treated with surgery as the primary modality. No definite relationship between histologic subtype of MFH and survival could be identified and no definite role of radiation therapy or chemotherapy could be defined. CONCLUSIONS. MFH of the lung should be treated by surgical resection if technically feasible. The role of adjuvant therapy remains undefined. Cancer 1996; 78:2492-7. 0 1996 American Cancer Society. KEYWORDS soft tissue neoplasms, histiocytoma, fibrous, surgery, thoracic neoplasms. Address for reprints: Michele Y. Halyard, M.D., Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259. Received July 8, 1996; accepted August 5, 1996. 8 1996 American Cancer Society Case 1 A 51-year-old female presented with a several-month history of pleuritic chest pain, shortness of breath, and cough. Earlier chest roentgenograms revealed progressive enlargement of a left lower lobe mass from 3 to 5 cm over a 2-month period. At the time of presentation, the chest roentgenogram and a computed tomography (CT) scan of the chest and abdomen showed a 10 cm X 8 cm mass extending from 2 cm below the carina to the diaphragm, causing inferior displacement of the diaphragm (Fig. 1). A large pleural effusion was also present, the cytology of which was negative for malignant cells. The lesion contained a small amount of calcium. Physical exam and a CT scan extending from the chest to the upper abdomen failed to reveal any evidence of a primary site originating elsewhere. A left lower lobectomy removed a well circumscribed, encapsulated tumor that measured 12 cm in greatest dimension. The tumor was firm, partially myxoid, and contained areas of hemorrhage and necrosis. Calcification was noted in the periphery of the tumor. The overlying pleura was intact with the exception of a small area of diaphragmatic invasion. This area was resected with the lower lobe. Microscopically, the tumor was comprised of a spindle cell proliferation without appreciable differentiating qualities (Fig. 2). Mitotic figures were present, and focally there was a typical storiform pattern. MFH of Lung: Cases and Literature Review/Halyard et al. 2493 FIGURE 1. Chest roentgenogram and computed tomography of a left lower lobe malignant fibrous histiocytoma. B y iinrnunoperoxidase stains, the tumor was positive tor vimeritin. but negative for keratin, S-100 protein, and tle.sinin. The features by routine microscopy and special 5tains were typical of malignant fibrous histiocytoma ( M F I I ) . ‘I’he hilar lymph nodes and margins of resectioi I were negative. ‘l’hr patient received 5040-centigray (cGy) postoprmtive rndiarion to the middle and lower left thoracic cavity. She developed radiation pneumonitis, which was successfully treated with a short course of prednisone. The patient was without evidence of recurrence in the chest, nor had another primary site become manifest, 60 months after diagnosis. Case 2 A 77-year-old man presented with an asymptomatic pulmonary nodule in the middle lobe of the right lung not seen on roentgenogram 4 years prior. CT scan of the chest revealed a 1.3-cm indeterminate uncalcified nodule and calcified left hilar lymph nodes. The nodule was observed but enlarged to 2.2 cm 4 months later. Physical exam was unremarkable for evidence of another primary site. A right middle lobectomy was performed, and the lesion was found to be a poorly differentiated, pleomorphic type, MFH. Paratracheal, periesophageal, and subcarinal lymph nodes were negative. The patient received no adjuvant therapy and was without evidence of local or distant recurrence 36 months after diagnosis. Case 3 A 38-year-old male presented with a history of an asymptomatic left lower lobe nodule on chest roentgenogram previously removed elsewhere by wedge resection and termed “benign histiocytic tumor.” Upon pathologic review, the lesion was found to be a poorly differentiated MFH of the storiform type. There was no evidence of another primary site at that time. Two years later he developed cough, pain in the left posterior rib cage, weight loss, fatigue, headache, and an elevated sedimentation rate. Chest roentgenogram and CT scan revealed a 9-cm mass in the left lung base, extending to the diaphragm, without intraabdominal involvement. A 2-cm axillary mass, not present at the 2494 CANCER December 15,1996 / Volume 78 I Number 12 left upper lobe. N o other primary sites of disease were identified. Resection of the brain metastasis and the lung lesion were performed. The lung lesion invaded the chest wall and measured 7.5 cm X 6 cm X 4 cm. Pathology revealed both lesions to be poorly differentiated, storiform type MFH. Two of five intrapulmonary lymph nodes contained metastatic disease. Three weeks later, aspiration of a fluid collection in the right parietal area revealed hemorrhagic, poorly differentiated sarcoma. The patient died within several days of transtentorial herniation. DISCUSSION FIGURE 2. Typical malignant fibrous histiocytoma featuring spindle cells in a storiform pattern (magnification X250). initial time of diagnosis, was excised which was consistent with metastatic disease. A completion left lower lobectomy was performed with subtotal resection of the mass, which measured 11 cm X 9 cm X 8 cm. The tumor invaded the visceral pleura and diaphragm. One month later, the patient developed multiple chest wall nodules and another axillary recurrence and received 1200-cGy external beam radiation to the left axilla. Despite systemic chemotherapy, his disease progressed in the chest, abdomen, and axilla. Repeat CT scan revealed extension of the mass into the abdomen. The patient died 30 months after initial diagnosis. Case 4 A 57-year-old female presented with ataxia, headache, and left homonymous hemianopsia. CT scan of the head showed a large cystic mass in the right frontoparietal region, displacing the ventricular system to the left. There was enhancement of the wall of the cyst, with a mural nodule on the medial surface. Chest roentgenogram revealed a 7-cm cavitating mass in the Soft tissue sarcomas are neoplasms that arise largely in mesodermal structures. MFH is the most common soft tissue sarcoma in adults, usually arising in the extremities or trunk. Metastasis to the lung is not an infrequent occurrence. Primary MFH arising of the lung is a rare clinical entity. There must be no evidence of another primary site as determined by careful physical exam and radiologic evaluation before an MFH can be considered as a lung primary rather than as a metastatic lesion. In the current series, three of the patients showed no evidence of another primary lesion at the time of initial presentation. One patient presented with a solitary nodule in the lung and a metastatic lesion in the brain. As in the other three patients, there was no evidence of another primary site. A review of the English literature revealed only 49 reported cases of primary MFH originating in the lung, excluding those arising from pulmonary arteries and pleura (Table 1). Several additional cases have been reported in the European and Asian literature as we]].15.24-213 The origin of these tumors is not certain, although a histiocytic origin with fibroblastic differentiation is postulated. The histiocytic features of primary malignant fibrous histiocytomas of the lung have been reported to be similar to their counterparts arising elsewhere. The median age of these patients, including those in the current series, was 55 years, with a range of 10-80 years. Pediatric cases have been d e s ~ r i b e d . ’ ~ ~ ~ ~ Female predominance has been suggested, but a review of the literature revealed 30 male and 23 female patients. The majority of the patients presented, as did one of the current study patients, with chest pain and dyspnea. Cough, weight loss, hemoptysis, and fatigue were also commonly observed. Hypertrophic pulmonary osteoarthropathy, pulmonary thromboembolism, hypoglycemia, and neutrophilia are less common presenting problems.8,”~’9 As observed in the current series, patients may be asymptomatic at presentation. Radiographically, primary MFH of the lung tends to be large, solitary, noncavitating, and peripheral, MFH of Lung: Cases and Literature Review/Halyard et al. 2495 TABLE 1 Malignant Fibrous Histiocytoma of the Lung: Literature Review Series Age Sex Bedrossian et al.' 51 M Kern et al.' Chowden er al:' Sajjad et al.' Paulsen et al.' \fills et al," Sritiinpai er a].' hfisra et a]." Larsen et 31.'' Lee et al.'" Lessel and Ilrhstosser" Silverman and Coalson" Tanino et al.'" McDonnell et al." Ilsitt et al.'..' luettner et d'" Ismailer et a1.lYousem anti Hoccholzer'" Case\. and Peddle'9 Palmer et iil.'" White et al." Reifsnyder et al." hfarrhan et a]." Present series 53 52 65 53 60 41 45 75 62 54 69 62 67 35 56 75 73 71 58 68 12 54 33 59 73 64 42 57 80 74 18 46 52 52 74 69 40 hl F F F F M M M M M h4 F M F M M F F M M F F M M F M F F M M M F F F F F F 71 hl 19 63 36 32 21 46 62 55 58 10 5s 77 38 57 M M hZ M M M F M M F F M M M Site LLL RML RLL RLL RML LLL RLL RLL RLL RUL LLL LUI. RUL LLL LUL RLL LUL LUL LLL RUL RLL LLL RUL RLL RUL RLL LUL RUL LLL RUL LUL LUL RLL RUL RLL LUL RUL RUL LLL RML LUL LLL RLL LLL RUL LLL RLL RUL RLL LLL LLL RML LLL LUL Sue (cm) Histology Surgery Radiationlchemotherapy 5-FU (mos) 2 Storiform Lobectomy Biopsy Lobectomy No DOD 14 No Chemotherapy Chemotherapy No No No Radiation DUD 12 DOD 4 DOD 5 DOD 36 ALVD 18 DOD 18 DOD 10 NED 10 NED 12 DOD 7 NED 8 KED 120 NED 60 DOD 12 AWD 3 DOD 5 DOD 3 NED 10 DOD 12 DOD 12 AND 12 NED 108 NED 84 NED 65 NED 36 NED 16 NED 122 DNED 1 DEED 1 DOD 2 1)OD DOD 8 DOD 9 DOD 72 DOD 24 DOD 36 DOD 24 DOD 8 DOD 14 DOD 14 DOD 12 DOD 3 NED 96 KED 8 DOD 14 DOD 4 Unk Unk NED GO NED 36 DOD 30 DOD 1 4 8 5 11.5 4 10 9 16 2.5 6 7 8 5 4 25 8 5 6.5 5 5.5 20 9 1.7 3.8 5.9 8.5 5 3 4 3 Unk 10 6 Unk 4 14 8 4 Unk Unk 7 3 11 3 10 Unk Unk 5.5 5 12 2.2 I1 7.5 Stori-Pleo Pleomorphic Storiform Storiform Pleomorphic Storiform Storiform Storiform Stori-Plea Stori-Plea Stori-Plea Stori-Pleo Stori-Pleo Stori-Pleo Myxoid Storiform Stori-Pleo Storiform Storiform Stori-Pleo Storiform Stori-Pleo Stori-Pleo Stori-Pleo Stori-Plea Stori-Pleo Stori-Pleo Stori-Pleo Stori-Plea Stori-Pleo Stori-Pleo Stori-Pleo Stori-Pleo Stori-Plea Stori-Pleo Stori-Pleo Inflammatory Stori-Pleo Myxoid InflammatoqI Stori-Pleo Stori-Pleo Stori-Pleo Unk Storiform Storiform Unk Unk Storifom Pleomorphic Storiform Storiform NO Pneumonectomy Lobectomy Lobectomy Lohectomy Biopsy Wedge Lobectomy Biopsy Pneumonectomy Lohectoniy Lobectomy Biopsy Biopsy Autopsy Lohectomy Lobectomy Lohectomy Biopsy Lobectomy Lohectomy Lohectomy Lohectomy Pneumonectomy Lohect omy Lohectomy Pneumonectomy Lobectomy Biopsy Lohectomy Lobectomy Biopsy Lobectomy Lohectomy Biopsy Lohectomy Biopsy Lobectomy Biopsy Excisional biopsy Pneumonectomy Lobectomy Lohectomy Lobectomy Biopsy Lohectomy Lobectomy Lohectomp Lobectomy Excisional biopsy Lohectomy NO No Chemotherapy Radiation Radiation No No Chemotherapy No NO No No No No No No NO No Radiation No No No KO No postop Radiation Chemotherapy Radiationichemotherapy NO Radiation Radiation Radiation Radiationichemotherapy No No Radiationichemotherapy No No No NO No No Radiation No No NO 1.Y: lymph nodes; 5-FU: 5-fluorouracil; Ivl: male; F: female; LLL: left lower lobe; R M L right middle lobe; R1.L right lower lobe; RUL: right tipper lobe; LUL left upper lobe: Unk unknown: Stori-Pleo: storiformuleomoruhic; Keg: neeatire; Pos: oositive; DOD: dead of disease; A W D alive with disease; N E D no evidence of disease; DNED: dead, no evidence of disease. 2496 CANCER December 15,1996 / Volume 78 / Number 12 with a slight preponderance to occur in the middle and lower lobes. Pleural plaques have also been described in association with the dominant massz2Unlike the first case in the current study, calcification of the lesions has not been described in the adult literature, but has been described in a pediatric case by lsmalier et aI.l7 These tumors appear on CT to be of soft tissue density, sometimes with areas of low attenuation centrally. Approximately 20% of patients have an associated pleural effusion.'2 The microscopic features of MFH of the lung are those of a malignant spindle cell neoplasm. Specific microscopic characteristics are generally lacking, and MFH can have histologic similarity to other soft tissue neoplasms. Likewise, satisfactory specific immunohistochemical stains for MFH do not exist. However, other soft tissue sarcomas, with microscopic similarity to MFH on routine stains, can be excluded with immunohistochemical stains that do have specificity. Thus, immunohistochemical stains for desmin, actin, and stains for neurogenic tumors are generally used in the laboratory examination of these tumors. As described by Weiss and Enzinger, storiform, pleomorphic, myxoid, inflammatory, giant cell, and angiomatoid variants may occur." The majority of the primary lung tumors are of the storiform variety. Forty patients underwent gross total resection either by excisional biopsy, wedge resection, lobectomy, or pneumonectomy. Of the 23 patients undergoing definitive resection who ultimately died of disease, the median survival was 12 months with a range of 1 to 72 months. Seventeen resected patients were reported to be alive without evidence of disease with a median survival of 60 months (range, 8-122 months). Two patients were alive with disease at 12 and 18 months, respectively, whereas 2 patients died without evidence of disease recurrence within 1 month of resection. Of those 11 patients who underwent biopsy only and died of disease, the median survival was 9 months (range, 2-36 months). Some reports suggest that long term survivors are rare. The current literature review revealed 8 patients alive without evidence of disease more than 5 years after diagnosis, including the authors' 1 long term survivor, who was alive 60 months after diagnosis. A gross total resection of the primary tumor was performed in all eight patients. Eight patients were alive with a short reported follow-up of 8 to 36 months. Of the patients who died of their disease, the survival ranged from 1 to 72 months, with a median survival of 10 months. No definite relationship between survival and histology could be identified because of the predominance of the storiform subtype. The authors' 2 survivors, as well as those reported in the literature, all had negative lymph nodes with the exception of 1 patient alive at 36 months despite mediastinal adenopathy.","','"'"" Systemic metastases are not infrequently reported. As in the current series, the brain is a common site of metastasis.2.4.8 17.20 According to White et al. this may be due to a high incidence of vascular invasion by these tumors observed in at least 50% of patients." Radiation therapy has not commonly been used in the treatment regimen. One of the current study patients experienced long term control with adjuvant radiation. The 10-year survivor reported by Lee et al. received 5400-cGy preoperative radiation therapy.'" However, the role of radiation has not been defined. Systemic chemotherapy has been used largely for metastatic disease. Of the eight patients treated with chemotherapy as definitive or adjuvant treatment, no patients were long term survivors. Drugs used for treatment included doxorubicin, dacarbazine, cyclophosphamide, vincristine, and cisplatin. No series reported the response to chemotherapy in which measurable disease was present. The natural history of soft tissue sarcomas of the extremities, including the MFH variety, is better known due to greater numbers of reported cases. These tumors are surrounded by a pseudocapsule that allows infiltration of surrounding tissues into adjacent tissue. Marginal en bloc excision of these tumors can result in a local recurrence rate of 70-9070, whereas even wide local excision results in a local recurrence rate of approximately 50-70%.2RAlthough amputation and radical local excision result in a low local recurrence rate of 5%," limb salvage with more conservative surgery and radiation has increased in prevalence. The less radical surgery is commonly preceded or is followed by radiation therapy to enhance local contr01.2Y."OInvolvement of lymph nodes occurs in approximately 5% of patients.'" Metastasis to the lung is not an infrequent occurrence, occurring in 30-50% of high grade lesions.3zThe majority of patients who develop metastatic disease do so within the first 5 years of diagnosis, as is the case with primary MFH of the lung. Five-year survival is highly dependent on the tumor grade. Results varied from 95% for Grade 1, 86% for Grade 2, and 50% for Grade 3 tumors in a series by Jensen et al.33The value of systemic chemotherapy in these tumors is not yet definitely known, its role being limited to those patients with a poor prognosis including large tumor size, high grade, or metastatic disease. SUMMARY In summary, MFH of the lung is a rare clinical entity with variable outcome. Long term survivors have been reported, yet many patients have died of their disease. MFH of Lung: Cases and Literature Review/Halyard et al. Aggressive surgery remains the mainstay of treatment. The role of adjuvant remains undefined. REFERENCES 1. 2. 3. 4. .). 6. 7. 8. 9. in. 1 I. 12. 13. 14. 15. Bedrossian CWM, Verani R, Unger KM, Salman J. Pulmonary malignant fibrous histiocpoma: light and electron microscopic studies of one case. Chest 1979;75:186-9. Kern WH, Hughes RK, Meyer BW, Harley DP. Malignant fihroiis histiocytoma of the lung. Cancer 1979;44:1793-801. Chowdeiy LN, Swerdlow MA, Jao W, Kathpalia S, Desser RK. Postirradiation of malignant fibrous histiocytoma of the lung. Ikmonstration of alpha-1-antitrypsin-like material in neoplastic cells. A m I Clin Pathol 1980;742320-6. Sajjad SM. Begin LK, Dail DH, Lukeman JM. Fibrous histiocytoma of lung: a clinicopathologic study of two cases. Histo/I“ l h O / O a 1981:51325-34. F’aulson SMK, Egeblad K, Christensen J. Malignant fibrous histiocytoma of the lung. Virchows Arch A Pathol Anat HistofI[Itltol 1981;395:167-76. Mills SA, Breyer FR, Johnston FR, Hudspeth AS, Marshall 1313, Choplin KH, et al. Malignant fibrous histiocytoma of the mediastinum and lung: a report of three cases. I Thorac Cilrrlioimsc% Slug 1982;84:367-72. Sriumpai S, Dharamadhach A, Suchatlampong V. Malignant fibrous histiocytoma (MFH) of the lung: a case report. J Med Assoc Thai 1982;65:667-73. Misra DP, Sunderrajan EV, Rossenholtz MJ, Hurst DJ. Malignant librous histiocytoma in the lung masquerading as recurrent pulmonary thromboembolism. Cancer 1983;5153841. I.arsen K, Vejlsted H, Hariri J. Primary malignant fibrous histiocytoma of the lung: a case report. Scand J Thorac Ccdiuvrtsc Surg 1984;18:89-91. Lee ]I’,Shelbume JI>, Linder J. Primary malignant fibrous histio’cytoma of the lung: a clinicopathologic and ultrastructural study of five cases. Cancer 1984;53:1124-30. 1,essel W, Erbstosser E. Malignant fibrous histiocytoma of the lung. Z Erkrank Atm Org 1984; 163:70-4. Silvernian JF, Coalson JI. Primary malignant myxoid fibrous histiocytoma of the lung: light and ultrastructural examination with review of the literature. Arch Pathol Lab Med 1984: 108:49-54. ‘l’anino M , Odashima S, Sugiura H, Matsue ‘r, Kajikawa M, Maeda S. Malignant fibrous histiocytoma of the lung. Acta I’utho/ jprz 1985:35:945-50. Mc1)trnnell T, Kyriakos M, Roper C, Mazoujian G. Malignant fibrous histiocytorna of the lung. Cancer 1988;61:137-45. I Isiu I(;, Kreuger JK, D’Amato NA, Morris LR. Primary malignant fibrous histiocytoma of the lung: fine needle aspiration cytologic features. Acta Cyrol 1987;31:345-50. 2497 16. Juettner FM, Popper €3, Sommersglltter K, Smolle J, Friehs GB. Malignant fibrous histiocytoma of the lung: prognosis and therapy of a rare disease. Thorac Cardiovasc Surg 1987;35:226-31. 17. Ismailer I, Khan A, Leonidas JC, Wind E, Herman P. Computed tomography of primary malignant fibrohistiocytoma of the lung. Comput Radiol 1987; 11:37-40. 18. Yousem SA, Hochholzer L. Malignant fibrous histiocytoma of the lung. Cancer 1987;60:2532-41. 19. Casey TC, Peddle LM. Primary pulmonary fibrous histiocytoma: report of three cases. Can J Suvg 1988;31:251-3. 20. Palmer AS, Passman JM, Vega JG. Malignant fibrous histiocytoma of the lung. Illinois Med J 1988;174:290-1. 21. White A, Graeme-Cooke F, Fitzgerald GR, Clancy L. Malignant fibrous histiocytoma of the lung. Kespir Med 1989;83:521-3. 22. Reifsnyder AC, Smith HI, Mullhollan TJ, Lee EL. Malignant fibrous histiocytoma of the lung in a patient with a history of asbestos exposure. Am Roentgenol 1990; 1 5 4 5 - 6 . 23. Marchan RF, Perez C. Malignant fibrous histiocytoma of the lung. Bol Asoc Med P R 1990;82362-3. 24. Byun HJ, Kang KH, Kim JS, Yo0 SH. A case of pulmonary malignant fibrous histiocytoma associated with pulmonary artery obstruction. Korean J Intern Med 1990;5:179-82. 25. Toochika H, Kimino K, Tagawa Y, Kawahara K, Ayabe H. Malignant fibrous histiocytoma in the chest cavity, report of four resected cases. J Jpn Assoc Thorac Surg 1990;38:64753. 26. Kodama H, Anzai T, Kato M, Kawabe M, Ohtani Y, Ito H. A case of primary malignant histiocytoma of the right lung. So Gun No Rinsho 1988;34:799-802. 27. Weiss SW, Enzinger FM. Malignant fibrous histiocytoma: an analysis of 200 cases. Cancer 1978;41:2250-66. 28. Nee1 MD, Enneking WF. Surgical management of extremity soft tissue sarcomas. Cancer Causes Cuntrol 1994; 1586-91. 29. Sadoski C,Suit HD, Rosenberg A, Mankin H, Efrid J. Preoperative radiation, surgical margins, and local control of extremity sarcomas of the soft tissues. J Surg Oncol 1993; 52223-30. 30. Stinson SF, Delaney TF, Greenberg J. Acute and long-term effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma. Intl Radiat Oncol B i d Phys 1991;21:1493-9. 31. Weingrad DN, Rosenberg SA. Early lymphatic spread of osteogenic and soft tissue sarcomas. Surgery 1978;84:23 1-40. 32. Suit HD. Patterns of failure after treatment of sarcoma of soft tissue by radical surgery or conservative surgery and radiation. Cancer Treat Symp 1983;2:241-6. 33. Jensen OM, Hgh J, Ostgaard SE. Histopathological grading of soft tissue tumours: prognostic significance in a prospective study of 278 consecutive cases. J Pathol 1991; 163:19-24.