Journal of Surgical Oncology 49:259-265 (1992)

Metachronous Second Primary Malignant Fibrous Histiocytoma in Two Skeletal Muscles S. D A V I D NATHANSON, MD, RICHARD J . ZARBO, MD, DMD, AND TERRY SARANTOU, MD From the Departments of Surgery (S.D.N., T.S.) and Pathology (R.I.Z.), Henry Ford Hospital, Detroit, Michigan

The first recorded case of a metachronous second primary malignant fibrous histiocytoma (MFH) of soft tissue is presented. The patient, who has been followed every two months since the treatment of his buttock sarcoma by neoadjuvant therapy, is free of disease 24 months later. The clinical presentations, different histologies, and DNA contents of these two MFHs are consistent with metachronous primary sarcomas. The literature on second primary neoplasms is discussed. 0 1992 WiIey-Liss, ~ n c . ~~

KEYWORDS:buttock sarcoma, soft tissue sarcoma, neoadjuvant therapy

INTRODUCTION

spread, and may even spread to adjacent muscle groups Second primary malignancies in the same patient may [lo], so that a diagnosis of either a second primary or a occur synchronously or metachronously [ 11. Common metastasis should clearly exclude such a possibility. Modern understanding of the mechanisms of carcinoexamples of this phenomenon are cancers of the colon genesis suggests that anatomic systems are exposed to and rectum [2], breast [3], genitourinary tract [4], and carcinogens, such as likely happens in the colon and skin IS]. Patients with certain types of malignant tumors rectum through the stool [ 121. Multiple primary tumors are also at higher risk for developing second tumors of of the urothelium include transitional cancers of the peldifferent histologic type [6]. These are sometimes heredvis, the kidney, the ureter, the bladder, and the urethra itary [ 7 ] although some second primary cancers may be [4]. These are areas that are bathed with urine for many induced by chemotherapy and radiation therapy [8,9]. years and the carcinogens in the urine are likely to induce Although malignant fibrous histiocytoma (MFH) is the [ 131. The etiology of soft tissue sarcomas is these cancers most common soft tissue sarcoma, the appearance of not clearly understood [lo], however, the improved uneither a synchronous or metachronous second primary [ 7 ] and abnormalities derstanding of genetic mechanisms soft tissue sarcoma of MFH histology in the same patient [ 141, and the specuin chromosomes found in sarcomas is previously unreported. Because of this rarity the obser[ 151 lated viral etiology of canine and feline sarcomas vation of a second sarcoma in the skeletal muscle in an make it likely that genetic mechanisms are at least paranatomically distinct region excites some interest. Such tially causative for sarcomas in man. It is thus not surprisan event prompts the question of the likelihood of metastasis of a sarcoma of muscle to another muscle. Me- ing that we encountered a patient with a second primary tastases from soft tissue sarcomas are almost exclusively sarcoma in the skeletal muscle. This paper documents the found in the lungs in the early stages of disease [ 101. diagnosis and management of both of these tumors, and Skeletal metastases are almost always confined to bone, discusses the rationale for the identification of these as and this is usually a late manifestation of the disease. individual primary sarcomas rather than metastasis to Other sites of metastases of soft tissue sarcomas in preter- skeletal muscle. minal patients include the brain, liver, and occasionally, lymph nodes [lo]. Metastasis to skeletal muscle has not been described in MFH [lo]. The only human sarcoma that has previously been noted to metastasize to skeletal Accepted for publication December 18, 1991. muscle is osteogenic sarcoma [ 111. Primary sarcomas of Address reprint requests to S . David Nathanson, MD, E&R 4044, skeletal muscle may invade along tissue planes by direct Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202. 0 1992 Wiley-Liss, Inc.

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Fig. 1. Magnetic resonance image showing a 9 cm tumor in the left gluteus maximus muscle. A: Horizontal cut of a TI weighted image, showing bright signal changes in the relatively homogeneous tumor. B: Sagittal view of a TI weighted image.

CASE REPORT A sixty-nine-year-old black male had a history of a MFH, storifom-pleomorphic type, grade 111, of the right

biceps humerus muscle treated in 1982. This lesion was 6 X 5.5 cm. The biceps muscle was resected from origin to insertion and the patient received 6,000 rads of radiation

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Fig. 2. A: The histomorphology of the malignant fibrous histiocytoma of the arm demonstrates pleomorphic tumor giant cells interspersed in a dominant malignant spindle cell stroma forming storiform patterns. B: In contrast, the malignant fibrous histiocytoma of the buttock contained innumerable sheets of pleomorphic tumor giant cells, with only focal spindle cells forming storiform patterns.

to the arm postoperatively. He was followed carefully and the most recent Computed Tomography (CT) failed to reveal metastases to the lungs. The patient also had no clinical, biochemical, or radiologic evidence of metastasis to the liver or to the skeleton. Eight years later in 1990, the patient presented with a growing mass in the left buttock. This was painless and was found to be 9 X 8.5 cm on magnetic resonance imaging (MRI) (Fig. l), and situated in the gluteus maximus muscle. No bony abnormality was seen. An incision biopsy of the buttock sarcoma was undertaken. It showed a grade I11 storiform-pleomorphic type MFH. The local lesion was treated with intraarterial Adriamycin 30 mg/ day delivered into the common iliac artery on the left by continuous infusion over 72 hours, followed by 2,600 rads of radiation delivered through a linear accelerator in 200 rad fractions per day for 13 days. The patient’s nadir white cell count was 3,500/cu.ml 14 days after initiation of the chemotherapy. He tolerated this neoadjuvant therapy well. Two and a half weeks after completion of radiation, resection of the gluteus maximus and the tumor was undertaken and the patient had an uneventful postoperative recovery. This patient has been followed every two months since the treatment of his buttock sarcoma. He is free of disease 24 months later.

MATERIALS AND METHODS Both tumors were sampled for pathologic examination at approximately one block per square centimeter and hematoxylin and eosin stained slides were prepared for light microscopy. One representative formalin-fixed, paraffin embedded block from each tumor was selected

for preparation of 8 pm sections. These slides were deparaffinized in xylene, hydrated, and stained with the Feulgen method after 5 N hydrochloric acid hydrolysis of the slides at 25°C for 50 minutes. Static DNA image analysis was performed with a computerized digital imaging system consisting of an Olympus BH-2 photomicroscope with images photographed by an MTI video camera (Dage-MTI, Michigan City, IN) and processed by a Hewlett Packard Vecta ES PC compatible microcomputer (Hewlett Packard, Sunnyvale, CA) using a PC-vision imaging board (Imaging Technology, Woburn, MA) and ImageMeasure software (Microscience, Inc., Federal Way, WA). Data were analyzed with CSS (Statsoft, Inc., Tulsa, OK), a menu-driven statistics and graphics package based on MS/DOS. DNA histograms of Feulgen stained nuclei vs. cell number were generated separately from stained nuclei of neoplastic spindled cells and multinucleate tumor giant cells in each tumor. These cytophotometric measurements were obtained using 560 nm monochromatic light at X400 magnification. The DNA content of the morphologically distinct cell populations was expressed in arbitrary optical density units summating all nuclear gray levels computed against the background intensity corrected for the video camera black level. Each histogram is composed of measurements from 50 control cell nuclei (lymphocytes and endothelial cells) within each tumor and 75-150 tumor cell nuclei.

RESULTS The histomorphologic appearances of both the arm and buttock sarcomas were similar, showing the malignant spindled cell stroma arranged in short fascicles and stori-

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Second Primary Sarcoma in Skeletal Muscle

form cartwheels with variable numbers of interspersed enlarged, pleomorphic mononuclear and multinucleate giant cells characteristic of the storiform-pleomorphic type MFH (Fig. 2A,B). The buttock tumor had solid sheets composed of innumerable pleomorphic multinucleate tumor giant cells whereas these cells were fewer and interspersed among the mononuclear spindled cells in the arm tumor. Both of these grade 111 MFH exhibited patchy tumor necrosis and numerous abnormal mitotic figures. Static image analysis of the spindle cell and pleomorphic giant cell populations in the arm and buttock sarcomas disclosed similar diploid-range DNA content in the mononuclear spindled cells (DNA indices 1.14 and 1 .18, respectively) and different hypertetraploid aneuploid DNA indices of 2.4 and 4.02, respectively, in the pleomorphic giant cell populations (Fig. 3A,B). The percent of cells with DNA content exceeding 5C (the 5C exceeding rate) was 50 times greater in the buttock MFH that morphologically exhibited the sheets of pleomorphic giant cells.

DISCUSSION The case that we have presented represents a second primary MFH in skeletal muscle of the buttock in a patient who had a previous MFH resected from the skeletal muscle of the arm. The clinical presentations, different histologies, and DNA contents of these two MFH are consistent with metachronous primary sarcomas. An extensive search of the literature has failed to reveal another example of multicentric MFH. Multiple primary tumors are well known and may be benign or malignant. Examples of benign multiple primary tumors are lipomas [ 161, nasal papillomas [ 171, vaginal neoplasms [ 181, and giant cell tumor of bone [ 191. Multiple primary malignant tumors may occur in the same organ and be of the same histology, such as epithelial cancers of the colon and rectum [2], lung [20], skin [5], breast [3], stomach [21], kidney [22], ureters [23], bladder [4], head and neck epithelial cancers [24], and melanoma [25]. Examples of

Fig. 3. A: Arm sarcoma DNA histogram shows the relative DNA content of the control diploid cell (open bars), mononuclear spindled cells (grey bars), and pleomorphic tumor giant cells (black bars). The spindled cells have a GI mean DNA value within 2 SD of control cell value (near-diploid DNA content) while the giant cells have a mean DNA value 2.4 times that of the control cells with few of these tumor cells exhibiting a relative DNA content greater than Sn. B: DNA histogram from the buttock sarcoma also shows the relative DNA content of the control diploid cell (open bars), mononuclear spindled cells (grey bars), and pleomorphic tumor giant cells (black bars). Again, the spindled cells have a GI mean DNA value within 2 SD of control cell value (near-diploid DNA content). In contrast, the giant cells show a mean DNA value that is 4 times that of the control cells with all of these tumor cells demonstrating a relative DNA content greater than Sn. The spindled cells have G1 mean DNA values within 2 SD of control cell values (near-diploid DNA content).

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multicentric primary tumors of different histology and occurring in different viscera are found in multiple endocrine neoplasia syndromes [26], the association between retinoblastoma and osteosarcoma [27], familial cancers of the breast and ovary [28], and Li-Fraumeni syndrome [7]. Second primary neoplasms do occur in patients with MFH in about 10% of the cases but these are all of another histology [lo]. This incidence may not be statistically meaningful in view of the older age of recurrence of these patients and their susceptibility to the other common cancers [ 101. The overall incidence of metastasis in MFH is about 42% [ 101. Most of these metastases occur within 2 years of diagnosis, although up to 1/3 of patients may develop metastases at a later stage [lo]. The only sarcoma that has an incidence of multiple primaries is the schwannoma, particularly that found in congenital neurofibromatosis [29]. This tumor in man may sometimes originate in skeletal muscle [lo]. Patients who survive for a long time after the treatment of a potentially lethal malignant tumor may be at higher risk of developing second primary cancers [30]. The current understanding of carcinogenesis of malignant tumors [31] predicts the susceptibility of whole organs to the carcinogenic agent. It is not surprising that many tumors are multicentric. A common surgical principle is removal of the whole organ at the time of surgical resection for tumor indicating the respect for the concept of multicentricity and also for local recurrence [32]. Indeed, it is quite surprising that there are no previous references to multiple primary MFHs since it is likely that these lesions have a common etiology [ 101. It is unlikely that the MFH of the gluteus maximus muscle in our patient is a metastasis from the original MFH in the biceps humerus muscle on the right. MFH usually metastasizes to the lungs, liver, bone, mesentery, bowel, adrenal glands, mediastinum, spleen, pancreas, kidney, skin, brain, and lymph nodes [lo]. In those patients where metastasis from primary epithelial malignancies to muscle has been documented there are usually widespread metastases and the patient often dies soon after the diagnosis has been made [33]. In some of these cases involvement of skeletal muscle, although initially thought to be by blood borne hematogenous metastasis, appeared on further analysis to be more likely a direct invasion from the site of the primary [34]. A feature apparently common to tumors that metastasize to skeletal muscle is the presentation with severe pain [35], which was absent in our patient. Although skeletal muscle comprises 215 to 3/7 of the weight of the adult human, and has a blood flow that may increase up to 800 fold after exercise [36], it is distinctly unusual for malignant tumors to metastasize to skeletal muscle. Skeletal muscle extract inhibits the growth of tumors in vitro [37]. Tumors that are known to metastasize rarely to skeletal muscle are cancers of the colon

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[33,34,38,39], kidney [40-42], prostate [43], stomach [44], lung [35], lymphoma [45], lip [46], breast [47], and pancreas [48]. In animals, adenocarcinoma of the lung in cats [49], thyroid tumors in rats [50], and malignant schwannoma of rats [511 have been shown to metastasize spontaneously to skeletal muscle. A progressively higher incidence of DNA aneuploidy in sarcomas has been shown to correlate with increasing tumor grade [52]. The literature on DNA ploidy analysis of high grade (111 and IV) MFH by flow cytometry has shown 83% (30/36) to have aneuploid DNA content [52541. This compares with a rate of 14% aneuploidy in benign soft tissue tumors, 25% aneuploidy in grade I sarcomas, and 42% aneuploidy in grade I1 sarcomas of all types [52]. These rates of aneuploidy in sarcomas are derived from flow cytometry studies. These analyses are dependent on cell suspensions of dissociated sarcomas and therefore cannot discriminate between the DNA content of the two morphologically distinct tumor cell populations of MFH. By using static image analysis of tissue sections, we have been able to discern the DNA content of the two cell populations in each of these MFHs in this patient. This more refined measurement of ploidy in these cases suggests similarity between the near-diploid DNA content profile of the mononuclear spindled cells but different hypertetraploid DNA contents of the mutlinucleate pleomorphic tumor giant cells in these two MFHs. Although corroborative, this is not absolute evidence to distinguish between a skeletal muscle metastasis vs. a metachronous second primary tumor. However, it is unlikely that a delay of 8 years would occur before metastasis, and we would expect some manifestation of metastases elsewhere in the 24 months following the management of the second primary malignancy. In summary we present the first recorded case of a metachronous second primary MFH of soft tissue.

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EDITORIAL COMMENTS Although one may not be able to completely rule out the possibility that the second tumor was a metastasis, the evidence, both clinical and pathologic, which the authors thoughtfully present, constitutes a cogent argument in favor of this being a second primary. It is important to bear in mind the possibility of second primary tumors of the same or other histologic type in the follow-up patients with a history of malignancy. Second primary tumors should be treated aggressively and generally carry a better prognosis than metastases, even when the latter are solitary. Furthermore, these cases present increased opportunities for the researchers to identify the underlying causative mechanism(s) for these multiple primary tumors. Constantine P. Karakousis, MD, Phi) Roswell Park Cancer Institute Buffalo. New York 14263