An Important Variant of Malignant Fibrous Histiocytoma Highly

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Fibrous Histiocytoma Highly Responsive to Chemotherapy ... Four consecutive patients were treated with inflammatory fibrous ..... nucleus, prominent nucleoli, and eosinophilic granular cytoplasm, admixed with benign foam cells, neufrophils,.

(10%) (3). The volume and composition of fluid are determined by hydrostatic and oncotic forces, membrane permeability, and lymphatic drainage. Thus the accumulation of pleural fluid can result from any process that alters pleural hemodynamics, plasma or pleural space oncotic pressures, capillary permeability, pleural capillary surface area, or lymphatic drainage. Pregnancy is characterized by increased blood volume (4) and decreased colloid osmotic pressure (5); these factors may contribute to the development of postpartum effusion. In addition, the Valsalva maneuvers typical of the second stage of labor could impair lymphatic drainage of the pleural space by elevating systemic venous pressure (1). The protein content of edema fluid in normal pregnancy is less than 0.4 g/dL (6) and most evidence shows that capillary permeability is not altered during pregnancy. Small pleural effusions occur frequently after delivery, and moderate effusions may be found occasionally. Although the mechanism is not known, the presence of pleural effusions in a large proportion of asymptomatic postpartum women would seem an exception to the general rule that pleural effusion should initiate a search for

its cause. In the absence of symptoms or signs of illness, no intervention is necessary. However, any evidence of cardiopulmonary compromise, particularly when a large effusion is seen, should arouse suspicion and lead to appropriate investigation. ACKNOWLEDGMENTS: The authors thank Preston Nelson and the residents of the Department of Reproductive Medicine for their help in this study. • Requests for reprints should be addressed to William G. Hughson, M.D.; Pulmonary Division-H772, University Hospital. 225 Dickinson Street; San Diego. CA 92103.

References L RlGLKR LG. Roentgen diagnosis of small pieural effusions: a new roentgenographic position. JAMA. 1931;96;104-8, 2. COl.LtNS JD. BURWKt t. D, FURMANSKl S, LORBER P. STECKEL RJ. Minimal detectabk pleural effusions: a roentgen pathology model. Radiology. 1972;105:51-3. 3. BLACK LF. The pleural space and pleural fluid. Mayo Clinic Proc. 1972:47:493-506. 4. PRITCHARD J A . Changes in the blood volume during pregnancy and delivery. Anesthesiology. 1965;26:393-9, 5. CHESLt-w LC. Weight changes and water balance in normal and toxic pregnancy. Am J Obsrei GynecoL 1944:48:565-93. 6. CHtSl.E^' LC. Hypertensive Disorders in Pregnancy. New York: Appleton-Century-Crofts: 1978:216-7,

Inflammatory Fibrous Histiocytoma: An Important Variant of Malignant Fibrous Histiocytoma Highly Responsive to Chemotherapy MAN-CHIU POON, M.D.; JOHN R. DURANT. M.D.; MICHAEL J. NORGARD, M.D.; and VIVIEN Y-H. CHANG-POON, M.D.; Birmingham and Montgomery. Alabama Inflammatory fibrous histiocytoma is a recently recognized variant of malignant fibrous histiocytoma. Patients managed with surgical excision or radiation therapy usually have had multiple recurrences, often with metastases. The disease is insidious but ultimately fatal. Four consecutive patients were treated with inflammatory fibrous histiocytoma with alkylating agents with or without anthracyclines and produced prolonged and sustained remissions. Inflammatory fibrous histiocytoma may be another highly chemotherapeutically responsive tumor that deserves active case identification for aggressive curative therapy. INFLAMMATORY FIBROUS histiocytoma is a distinct variant of malignant fibrous histiocytoma. Pathologically. both tumors are composed of differing proportions of cells similar to histiocytes and fibroblasts, arranged in a storiform pattern with pleomorphic giant cells and inflammatory cells (1, 2). Inflammatory fibrous histiocytoma is distinguished by the presence of a diffuse, at time.s intense, neutrophilic infiltration unassociated with tissue necrosis (1), Since inflammatory fibrous histiocytoma was originally • From Ihe Comprehensive Cancer Center and ihc Division of Hemiitology/Oncology. Department of Medicine, University of Alabama in Birniiiigharii: The Veterans Administration Medical Center; the Cunningham Palhcilngy Associates: Birmingham, Alabama: and the Baplist Medical Cemer; Momgomery. Alnhama.

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Annals of Internal Medicine. 1982;97:858-863.

reported, at least 18 patients with documented cases (Table 1) have been described (1, 3-12). Previous reports have described the pathologic features and natural history. The literature suggests that the tumor runs an insidious but aggressive and ultimately fatal course. Conventional surgical and radiation treatments provide only transient responses, with local recurrences and distant metastases being the rule. Chemotherapy has been given either in palients with end-stage disease, or as singleagent treatment, and has not been effective. We recently reported successful combination chemotherapy in one patient with inoperable inflammatory fibrous histiocytoma (6). Since then we have seen three other patients with either inoperable or recurrent inflammatory fibrous histiocytoma. We describe the response to chemotherapy of these four patients. Case Reports PATIl£NT 1

The salient features of ihis case have been previously reported (6) and are briefly summarized in Table 1. A 22-year-old white woman presented in July 1977 with a tumor mass overlying the sacrum and tumor involvement ofthe iliac marrow. She received radiation therapy to the tumor mass (stopped after 1925 rad because of leukopenia and diarrhea) and six 4-week courses of chemotherapy consisting of intravenous doxorubicin. © 1982 American College ot Physicians

50 mg/m^ body surface area: and cyclophosphamidc, 500 mg/ m-. Intravenous methotrexate, 200 mg/m- every 6 hours for four doses, with folinic acid rescue was given with the first course, but could not be given again except with the fourth course because of inadequate renal function. She became asymptomatic after four courses of chemotherapy and was disease-free after the sixth course. The patient was last seen in April 1982, 58 months after the initiation of chemotherapy, and has remained well and disease-free, PATIENT 2

The preliminary results of chemotherapy in this palient were cited in the addendum ofthe previous report (6) and are briefly summarized in Table I. A 31-year-old woman presented in July 1979 with a right upper anterior mediastinal mass. She received five 4-week courses of chemotherapy consisting of intravenous cyclophosphamide, 600 nig/m-^ body surface area on days 1 and 8; vincristine, 2 mg on days 1 and 8; oral procarbazine, 100 mg/ m' body surface area • d for 10 days; and prednisone. 100 mg/d for 10 days. Her mediastinal mass completely disappeared 4 weeks after the initiation of chemotherapy. The patient was last seen in June 1982, 34 months after the initiation of chemotherapy; at that time she continued to be well and disease-free. PATIFNT 3

A 61-year-old white man first noted a small asymptomatic nodule over the dorsum of his right foot in February 1978. This nodule increased progressively in size, to 5-by-5-by-l,6-cm by August 1979, and was widely excised with no definitive pathologic diagnosis. A similar lesion recurred just proximal lo the previous excision site within 6 weeks. In April 1980, another 2by-2-cm lesion developed on the medial aspect of the right calf and was excised. The pathologic findings were similar lo those ofthe previous biopsy, but one consultant raised the possibility of lymphoma. Results of staging studies including chest roentgenogram: abdominal and pelvic ultrasound scans, and gallium scans of bone, liver, and spleen were normal. The bone marrow did not contain tumor, but showed prominence of eosinophilic precursors. The serum chemistry profile and hematologic variables were normal. When the foot lesion continued to grow and another new l-by-2-cm lesion developed in the right pretibial region, the patient was referred to University of Alabama in Birmingham Medical Center in August 1980. At this time, both biopsies were interpreted as inflammatory fibrous histiocytoma (Figure 1). Chemotherapy was started on 22 August 1980 and consisted of cyclophosphamide, 600 mg/m- body surface area intravenously; doxorubicin, 60 mg/m- intravenously; vincristine, I mg/m* intravenously; and prednisone, 100 mg/d orally for 10 days. A total of nine courses of therapy given at 3-week intervals were given without undue side effects. The lesions began to respond after the first course and completely disappeared after the eighth course of chemotherapy. One month after the completion of chemotherapy, the patient developed pulmonary edema that responded to diuretics and digitalis. A first-pass and gated radionuclide scan showed decreased ejection fraction (less than 20% the normal value). He subsequently developed intractable heart failure and died on 27 May 1981. Clinically the patient had remained disease-free at the time of his death, but an autopsy was denied. PATIENT 4

A 29-year-old white woman was found to have an asymptomatic sternal mass on 15 August 1981, 2 days after delivery ofa full-term healthy infant and was transferred to the University of Alabama in Birmingham Medical Center. She had an 8-by-8by-2-cm soft, nontender mass overlying the manubrium. She was mildly anemic (hemoglobin, 11.4 g/dL), with ieukocytosis (leukocytes 20 times tOVL with 69% neutrophils, 7% band forms, 1% metamyelocytes, and 1% myelocytes). She had a slightly increased alkaline phosphatase and globulin levels (156 IU/dL and 3.7 g/dL, respectively). Chest roentgenogram and tomogram showed an osteolytic manubrial lesion 6 cm in diameter extending posteriorly into the anterior mediastinum and anteriorly into the soft tissue ofthe chest wall. A thoracic computed tomographic (CT) scan showed the lesion extending

around both the aorta and the pulmonary artery. Abdominal ultrasound and abdominal CT scan did not show intra-abdominal disease. Bone marrow obtained from both iliac crests was normal. Biopsy of the sternal lesion showed inflammatory fibrous histiocytoma (Figure 1). Chemotherapy consisting of intravenous doxorubicin, 50 mg/m- body surface area; cyclophosphamide. 600 mg/m^: and vincristine, I mg/m-, was started on 2 September 1981. The patient completed a total of six 3-week courses without undue side effects. Follow-up chest roentgenogram 3 weeks after the initiation of chemotherapy showed only minimal residual disease, and that after three courses of chemotherapy was normal. At the conclusion of chemotherapy, the tomogram continued to show lytic and blastic lesions in the manubrium lesion. A repeat biopsy of that area in February 1982 however showed only fibrous tissue without evidence of tumor. The patient was last seen in August 1982, 11 months after the initiation of chemotherapy, and continued to be well and disease-free. Discussion All four consecutive patients responded to combinafion chemotherapy with sustained complete remission. These patients received different dosage regimens as well as different chemotherapeutic agents. Cyclophosphamide was the only common drug involved in the various combinations, with doxorubicin being used in three of the patients. Radiation therapy was given to Patiertt 1 only. The absorbed dose, 1925 rad, was far short of the originally planned dosage of 5000 rad; it is impossible to assess the contribution of radiation therapy to her remission. Combination chemotherapy for malignant fibrous histiocytoma has been reported by Leite and associates (13). Using combinations of cyclophosphamide, vincristine, doxorubicin, and dacarbazine (DTIC). or cyclophosphamide, vincristine, doxorubicin, and dactinomycin, they achieved seven partial responses in 18 evaluable patients lasting for 2 to 14 months (median, 2 months). There were no complete responses. Bassett and Weiss (14) reported a single patient treated with doxorubicin alone who had a complete remission for greater than 40 months. Chemotherapy for inflammatory fibrous histiocytoma had been used in seven ofthe 17 patients reported by others (1, 3, 11) without response; two of these patients had received cyclophosphamide either as single agent or in combination with vincristine and one patient had received doxorubicin, vincristine, cyclophosphamide, and dactinomycin during end-stage disease (1). Both malignant and inflammatory fibrous histiocytoma are known to have a protracted clinical course with a significant number of patients developing recurrences or metastases after 2 years, which emphasizes the need for long follow-up ofthe patients. Previously, this tumor has been considered aggressive and lethal. The observation of sustained response to chemotherapy may change the outlook of patients with this tumor. Inflammatory fibrous histiocytoma is a rarely recognized tumor. Except for Patient 4, each of the other three patients had been given other diagnoses by a number of consultants who reviewed the histopathologic slides. Undifferentiated carcinoma had been the diagnosis of Patient 1; malignant fibrous histiocytoma and rather ambiguous fibrous histiocytoma with inflammation for Patient Poonetal. • Inflammatory Fibrous Histiocytoma

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Table 1. Clinical Data on 21 Patients with Inflammatory Fibrous HJstiocytoma Patient

Age/Sex

yrs

42/F

Primary Tumor Site

Retropcritaiicum

Hemoglobin

HeituitOLTil

Leukocyte Count (Differential Count)

g/dL 11.8

niL/dL

X lOVL 15.0 ncutrophils)

Abdomen Femoral

66/M 48/F

Pleural space Retroperi toneum

60/M

Ret roperi t one-ti m

34

30,0 8,3

26.0 (63%

9.9

neutrophils)

7

81/M

Oral

8

60/M

Pleural space

9

51/M

Rctropcritonciiiii

10

33/F

11

47/M

33.7

.9.8

13 14

54/M 49/F

15

13/F

16 17 18

71/F 62/M 22/F

19

17.6

Bronchus Thigh

30.0

Ret roperi toneuni

12

28.2 (85% neutrophils)

Retroperitoncum Lower extremity

8.2

33.4

28.4 (88% neutrophils. 9% band forms)

26.1

10.0 (81% neutrophils) 15.0 (77% neutrophils, 7% band forms, 3% eosinophils)

Abdomen

Ret roperi toneuni Ret roperi toneum Sacrum

Mediastinum

8,9

11.B

20.

34.6

17.0 (67% neutrophils, 16% band forms)

6.4 (53%,' neutrophils, 4% band forms)

20

21

61/M

Lower exiremitv

7.9 (65%

14.4

Sternum

33:

neutrophils, 3% eosinophils) 20.0 (69% neutrophils, 7% band forms, 1% melamyelocytes, 1% myeiocytes)

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December 2 982 • Annals ol Internal Medicine • Volume-: 97 • Number 6

Table 1. (Continued) Initial Therapy Therapy

Disease-Free Period mos 7

Clinical Course

Survival

Reference

mos 60

Kyriakoset al.(l)

19 4

Kyriakoset al.(l) Kyriakos et al.(l)

82 124

Kyriakos et al.(l) Kyriakoset al.(l)

Metastasis

77

Kyriakos et al.(l)

Radiation therapy (4000 rad)

Rapidly fatal

1.5

Kyriakoset al.(l)

Surgery

Recurrent, tost to follow-up Lost to fol low-up

4+

Kay(3)

8+

Kay (3)

Surgery

Surgery Surgery Surgery Surgery Cyclophosphamide (five doses) Surgery Radiation therapy (3800 rad)

41 57

Surgery

Recurrent, metastasis Recurrent Recurrent, metastasis Recurrent Recurrent, metastasis

Herczeg et al.(4) Surgery Radiation therapy (6138 rad) Busulfan, surgery

16

Recurrent

240 +

7

Recurrent

11

Recurrent

Surgery Radiation therapy (4500 rad) Surgery Surgery Combination chemotherapy Radiation therapy (1925 rad)

53 +

Sustained complete remission

Combination chemotherapy

33 +

Sustained complete remission

Combination chemotherapy

Roqueset al.(7)

Fakan(8) Miller etal. (9)

Surgery

Surgery

Asirwatham et al.(5)

1.S

9+

Recurrent

Sustained complete remission

12

Merino el al.(lO)

0.25 4 58 +

Vilanova et al.(11) Chudacek(12) Smith et al.(6) and present series: Patient I

34 +

Present series: Patient 2

39

Present series: Patient 3

U+

Present series: Patient 4

Poon et al. • Intlammalory Fibrous Histiocytoma

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Figure 1. HistopathologJc findings of inflammatory fibrous histiocytoma. A. Patient 2, The tumor shows a polymorphous infiltrate of neutrophils, foamy histiocytes. and atypical histiocytes in a loose edematous fibroblastic stroma containing numerous dilated capillaries. Occasional eosinophils. lymphocytes, and plasma cells are present. (Original magnification, • 50.) B. Patient 4. Atypical histiocytic cell (arrow) with eccentric nucleus, prominent nucleoli, and eosinophilic granular cytoplasm, admixed with benign foam cells, neufrophils, eosinophils, and lymphocytes is shown. (Original magnification, • 200.) C. Patient 3. Bizarre tumor giant cell with large irregular nucleus and coarse chromatin pattern present along with smaller histiocytes and acute and chronic inflammatory cells. (Original magnification, X 200.) D. Patient 1. Atypical histiocytic cells containing phagocytosed neutrophils in an edematous fibrous stroma. (Original magnification, X 200.). All these pathologic features are found in the tumors of each of the four patients. Tissue necrosis is conspicuous by its absence in all the tumors. All tissues stained with hematoxylin and eosin.

2; erythetna induratum, nodular vasculitis, lymphoid hyperplasia, lymphoproliferative disorder, and possible lytnphoma for Patient 3. Because we found that this tumor is responsive to combination chemotherapy, it is important to accurately identify it with unified and utiatiibiguous terminology. The term "inflammatory ftbrous histiocytoma" has been widely used (1, 3-8, 11, 12). To denote its malignant nature, others have also called it "malignant inflammatory histiocytoma" (9) or "inflammatory malignant fibrous histiocytoma" (10). The number of patients in this report is small, but complete response to chemotherapy in four consecutive cases should represent more than a chance occurrence. We feel that inflammatory fibrous histiocytoma, although rare, may be another tumor responsive to chemotherapy and should be treated with curative rather than palliative intent. Three of our four patients are young women. Whether young age or female sex, or both, may be important factors for chemotherapeutic responsiveness remains to be 862

clarified, Our observation in these four patients should generate interest in more active case identification for further investigation. ACKNOWLF.15GMENTS: Thu- auLhors thank Richard McElvein, M.D.; Dorui J. Biiischo, M.D.. William W. Helvie, M.D.; Richard A, Harris, M.U.; Ben M. Grimes. M.D,; A.S. Rnsemiire. M D,; Daniel M. Scarbrough, M.D.: and Ran Workman, M.D.. for ihe opporlunity to assist in the management of the reported patienls; and Ms. Valerie Baker for help in preparing the manuscnpi. • Reqiiesis For repnnls shoulii be addressed to Man-Chm Poon. M.D.; Division of Hem:Uulngy/OnL-ology. Dcpartmeni of Medieine, Universiiy of Alabamit in Ilirmiiighan:. L'nivi.Tsity Stalion; Birmingham, AL 35294.

References 1. K^uiAKOs M. Kr.MPSON K I . lnllamniiitory fibrous histiocyioma: an aggressive and lelhal Icsinn. Cj/ifer. l976;37:i5S4-606. 2. Wi.iss SW. F.N7INC1I K FM. Malignant fibrous histiocyioma: an analysis ofSOOeases C^IIILLT l'*7H;4l:22.'iO-()t). 3. K A ^ 5 inHammalory fibrous histiocytoma (? Xanthogranuliima): report nf Iwii L-ases wilh ultraslruL'tural observations in (lne. Am / Surg I'nlliol U)7S:2:_M3-'>, 4. HhRcv.i.c, E. W'i issKi RI D, Ai.M69-70.

December 1982 • Annals ot Internal Medicine • Volume 97 " Number 6

5. AsiRWATHAM JE, PiCKRLN JW. Inflammatory fibrous histiocyioma: case report. Cancer 1978;41il467-7l. 6. SMITH D K , POON M-C, Fr.lNl' A. Inflammatory fibrous hisliocytoma: response lo nonsurgicai Iherapy: a case repnn. Med Pediatr Oncol. 197

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