- Email: [email protected]
Pleomorphic rhabdomyosarcoma in an adult forearm: A case report
Pleomorphic Rhabdomyosarcoma in an Adult Forearm: A Case Report Timothy R. Jones, MD, Marilyn S. Norton, MD, Peter A.S. Johnstone, MD, Edward Kane, MD, San Diego, CA, Alexander Y. Shin, MD, Rochester, MN Pleomorphic rhabdomyosarcoma (RMS) is a rare malignancy, and treatment protocols for this tumor are not established. Although Intergroup Rhabdomyosarcoma Study data have led to improvement in overall and disease-free survival for children with juvenile RMS, the applicability of those findings to adult pleomorphic RMS is uncertain. This report presents the case of a 29-year-old man with pleomorphic RMS of the forearm (a location not previously reported in current literature); reviews the immunohistochemical, ultrastructural, and histologic diagnostic criteria; and discusses treatment. (J Hand Surg 2002;27A:154-159. Copyright © 2002 by the American Society for Surgery of the Hand.) Key words: Pleomorphic rhabdomyosarcoma, adult, upper extremity, treatment.
Since the inception of the first Intergroup Rhabdomyosarcoma Study (IRS) nearly 3 decades ago, important advances in the understanding and treatment of this aggressive mesenchymal neoplasm have been made on the pediatric front.1–3 Although pleomorphic rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma of childhood,4 – 6 it is an unusual and infrequent finding in adults.7–9 Over the past 5 From the Division of Hand and Microvascular Surgery, Department of Orthopaedic Surgery; the Division of Hematology/Oncology, Department of Medicine; the Department of Radiation Oncology; and the Department of Surgical Pathology; Naval Medical Center San Diego, San Diego, CA. The Chief, Bureau of Medicine and Surgery, Navy Department, Washington, DC, Clinical Investigation Program, sponsored this report #84-16-1968-961 as required by HSETCINST 6000.41A. Received for publication July 7, 2000; accepted in revised form September 13, 2001. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. The views expressed in this article are those of the authors and do not reflect the official position of the Department of the Navy, Department of Defense, or the United States Government. Reprint requests: Peter A.S. Johnstone, MD, Clinical Investigation Department, Naval Medical Center San Diego, San Diego, CA 92134-1005. Copyright © 2002 by the American Society for Surgery of the Hand 0363-5023/02/27A01-0002$35.00/0 doi:10.1053/jhsu.2002.29481
154 The Journal of Hand Surgery
decades considerable discussion has ensued concerning the very existence of adult RMS. From the initial treatise by Stout10 in 1946 through the late 1960s, pleomorphic RMS had the distinction of being regarded as one of the most common soft tissue sarcomas of adulthood.9 In the 1970s and 1980s, however, many cases of pleomorphic RMS were reclassified as malignant fibrous histiocytoma, pleomorphic liposarcoma, or leiomyosarcoma, and the diagnosis of pleomorphic RMS became exceedingly rare.7,9,11,12 Not until a study by Gaffney et al8 in 1993 was concrete evidence of rhabdomyoblastic differentiation established, confirming definitively the existence of pleomorphic RMS in adults.8,9 Although there is currently no doubt that pleomorphic RMS exists in adults, there is less certainty regarding its treatment. No dedicated studies of therapeutic modalities have been performed, and the findings of IRS I through III have uncertain applicability to the adult with pleomorphic RMS. This particular tumor was excluded from IRS evaluation because its existence in the pediatric population was in dispute.13
Case Report A 29-year-old man presented to his overseas military medical clinic complaining of a nontender lump
The Journal of Hand Surgery / Vol. 27A No. 1 January 2002 155
Figure 1. Light micrograph showing interconnected fascicles of atypical, spindled, plump polygonal and giant cells (larger arrows) with high-grade atypical nuclear features (smaller arrows). A moderately diffuse lymphocytic infiltrate is noted.
on the volar aspect of the right forearm. The patient was advised that the mass was most likely a lipoma and that he should wait until his return to the United States to have it electively removed in a hospital setting. At initial follow-up in the United States 6 months later, the patient stated that the mass had markedly increased in size. The patient had excisional biopsy, which measured 3.1 ⫻ 2.1 ⫻ 1.9 cm and was isolated to the muscle belly of the brachioradialis without fascial penetration. Light microscopy showed a tumor composed of interconnected fascicles of atypical, spindled, plump polygonal and giant cells with high-grade atypical nuclear features. The cytoplasm was strongly eosinophilic and slightly foamy; cross-striations were not appreciated. Eightyfive percent of the surgical margins were involved. Minor foci of tumor necrosis and a moderately diffuse lymphocytic infiltrate were seen (Fig. 1). Immunohistochemical analysis showed strongly positive desmin staining, focally positive actin staining, negative S-100 staining, and scattered dot-like staining of Coll IV. Smooth muscle antigen staining was negative except for background staining, and cytokeratin stains were not performed. The combined histologic and immunohistochemical findings were interpreted by an expert pathology consultant as pleomorphic RMS. Smooth muscle antigen staining was
believed to be insufficient for a leiomyosarcoma; the staining profile excluded liposarcoma. The patient was immediately referred to our institution for definitive care. The patient denied any constitutional symptoms, paresthesias, muscle weakness, or bone pain. Physical examination revealed no palpable head, neck, supraclavicular, axillary, or epitrochlear lymph nodes. His medical and surgical histories were unremarkable. A bone scan and computed tomography of the chest and abdomen showed no evidence of metastatic disease. A magnetic resonance image of the forearm suggested no indication of tumor extension into surrounding structures (Fig. 2). Complete blood count and chemistry panels were all within normal limits. The tumor site was re-excised with confirmation of clear margins (Fig. 3), and the patient was discussed at a multidisciplinary tumor board meeting. Because the current surgical therapy of sarcomas at our institution does not include lymph node dissection, nodal exploration was not performed. The radiation oncologists considered the condition an adult soft tissue sarcoma and were in favor of postoperative radiotherapy to a local forearm field. The medical oncologists considered the condition best treated with a pediatric chemotherapy regimen, although consultation with subject matter experts throughout the coun-
156 Jones et al / Pleomorphic Rhabdomyosarcoma
try yielded no formal chemotherapeutic treatment consensus. Because of the uncertain approach and negligible data for these lesions, the tumor board recommended the patient be fully briefed on the unclear optimal therapy of his disease as well as the risks and benefits of both adjuvant modalities. After
Figure 3. Intraoperative image showing the right forearm with a tumor isolated in the brachioradialis muscle beneath an 8.0 ⫻ 3.0-cm ellipse of skin.
Figure 2. An axial (A) and sagittal (B) magnetic resonance image of the tumor showing the mass to be isolated within the brachioradialis muscle without fascial penetration.
full discussion and with informed consent, the patient opted for both. The patient was begun on a treatment regimen of concomitant radiation therapy and chemotherapy with vincristine and actinomycin. The IRS data recommend patients receive a full year of vincristine alternating with Adriamycin (Erbamont Inc, Columbus, OH). The patient’s primary medical oncologist advised him that 1 year of such a regimen was probably too long and would pose an undue risk of vincristine toxicity. The patient proceeded with adjuvant radiation therapy to the affected region. A total dose of 66 Gy was delivered to the right proximal forearm using opposed anteroposterior fields after immobilization. The patient also received chemotherapy for a total of 6 months (2 cycles of weekly vincristine for 6 weeks and 2 cycles of Adriamycin). At that point the patient opted to discontinue chemotherapy. Two weeks after his last dose of vincristine he developed a self-limited episode of neurotoxicity
The Journal of Hand Surgery / Vol. 27A No. 1 January 2002 157
that resolved over several months with physical therapy. Postoperative follow-up at 24 months disclosed no evidence of recurrent disease and no residual side effects from therapy.
Discussion The typical presentation of patients with pleomorphic RMS is one of a rapidly enlarging extremity mass of several months’ duration.8,9 The age range at presentation is between 44 and 58 years,9 and there is a strong prevalence in men. The most frequent site of presentation is the deep musculature of the thigh8,9; this contrasts with pediatric RMS, which may occur nearly anywhere in the body.5 Gross pathology often shows prominent necrosis with focal hemorrhage,8,9 and microscopy reveals a growth pattern that is usually inconsistent and disordered, exhibiting a prominent spindle and eosinophilic, pleomorphic-cell population—the putative rhabdomyoblast—within a dense lymphohistiocytic infiltrate.8,9 Light microscopy findings are nondiagnostic in the absence of cytoplasmic cross-striations, which, unfortunately, are rarely identifiable. Therefore, immunohistochemical and/or ultrastructural evaluation of sarcomeric differentiation are mandatory in making this diagnosis.8,9 Immunohistochemically, pleomorphic RMS is characterized by positive staining for myoglobin, desmin, HHF-35, sarcomeric actin, fast myoglobin, and MyoD1. S-100 protein staining is invariably negative,7–9 and ␣-SMA normally is limited to myofibroblasts and smooth muscle but is occasionally positive in pleomorphic RMS.9 Electron microscopy is often required to make the diagnosis because of the absence of immunohistochemical reactivity secondary to focality of staining or an occasional absence of specific sarcomeric antigen expression.9 Erlandson14 proposed that the minimal ultrastructural diagnostic criteria of pleomorphic RMS should be the presence of myosin-ribosome complexes: a linear arrangement of ribosomes attached to short parallel bundles of myosin filaments. The prognosis for adults with RMS pales when compared with that of children despite the use of new multimodal therapies.15 In a multivariate analysis study of 290 adult and pediatric patients from 1970 to 1991 diagnosed with RMS, age at diagnosis along with local tumor invasiveness, distant metastases, regional lymph node involvement, and histopathologic subtype were determined to be independent predictors of outcome.15 Identification of prognostic
factors is essential because it is through these findings that one may devise and revise appropriate treatment strategies. Although no discrete studies evaluating prognostic factors and therapeutic modalities in adults with RMS are reported in the literature, a wealth of information has been derived from the series of ongoing IRS1–3 in children. Begun in 1972, the stated goal of the studies was to improve the treatment outcome of children with RMS. Intergroup Rhabdomyosarcoma Study staging is based on the degree of tumor remaining after initial surgery and the histologic subtype, categorized as favorable or unfavorable.1–3,5 Each subsequent IRS trial contributed to a significant improvement in overall survival (OS) rate for children with RMS.1–3 Devising a comprehensive treatment plan for the patient in this case study was difficult because of the absence of literature concerning specific therapeutic modalities for adult patients with pleomorphic RMS. As with all tumors, 3 primary modalities must be considered: surgery, chemotherapy, and radiation therapy, either alone or combined. When therapeutic ambiguity exists, this institution’s tumor board recommends that patients be fully briefed on the paucity of available data and be presented the medical and radiation oncologists’ perspectives, along with the alternatives and the risks and benefits of each potential course of treatment. Ultimately, therapeutic decisions are made by the patients based on input from oncologists with surgical, medical, and radiation expertise. Wide en bloc excision with negative microscopic margins is the foundation of treatment for soft tissue extremity sarcomas and the single greatest contributor to outcome and OS.1–19 The postoperative extent of disease remaining in situ is such a profound prognostic indicator of outcome that RMS tumor staging systems, including those of the IRSs, are founded on surgicopathologic stratification.1–3 Historically, amputation was the treatment of choice for extremity sarcomas.20 A number of investigators have shown convincingly, however, that amputation with respect to OS has no inherent advantage and that wide excision plus adjuvant radiation is as effective as amputation or amputation plus chemotherapy.21–24 The implementation of this less draconian combination therapy benefits the patient through preservation of a functional extremity while not compromising survival. The issue of adjuvant radiation and chemotherapy for the patient in this report is less clearly defined. Were his histology consistent with juvenile RMS,
158 Jones et al / Pleomorphic Rhabdomyosarcoma
one could make a strong case for strict adherence to IRS III protocol. The patient, however, had a subtype not recognized under IRS protocol. From a broader context the question is, should adult pleomorphic RMS be considered primarily RMS and treated under IRS direction, or should it be ranked under the general classification of adult soft tissue sarcoma and treated as such? The answer is unclear at present. In considering the former, IRS III guidelines would categorize the patient in group I: complete removal of localized disease with negative regional nodes (if sampled).1 Within this group patients are subdivided based on “favorable” or “unfavorable” histology. For purposes of IRS classification we considered this patient’s pleomorphic RMS to fall more appropriately in the favorable category because it was not alveolar. Intergroup Rhabdomyosarcoma Study III showed that patients with favorable histology who received cyclic-sequential vincristine and actinomycin for 12 months had 5-year progression-free survival and survival rates of 83% and 93%, respectively.1 Radiation therapy is conspicuously absent from this regimen; IRS I showed it provided no benefit over chemotherapy alone.2 Radiation therapy, then, would be excluded from the patient’s treatment regimen based on IRS III results. Adult soft tissue sarcoma literature, however, suggests a very different approach. Although the many varieties of these mesenchymal soft tissue tumors arise from disparate cellular origins, they have one thing in common: as a group they tend to behave similarly,19 and as such they can often be treated similarly. For extremity soft tissue tumors the literature is unequivocal: postoperative radiation therapy with or without adjuvant chemotherapy in the treatment of high-grade extremity sarcomas is clearly indicated21–26 and may be justified for low-grade lesions as well.19 Data continue to show that grade is more important on multivariate analysis than size with respect to local recurrence (LR),27 so radiotherapy should also be considered for small high-grade lesions, especially if resected with close margins. Radiation therapy in conjunction with limb-sparing surgery has proven to be a worthy alternative to amputation with respect to OS, and for this reason the rate of amputations in the United States for extremity sarcomas has decreased to less than 10%.26,28 Similarly, recent data from the National Cancer Institute show that external-beam radiation therapy significantly reduces the rate of LR in patients with high- and low-grade extremity tumors.26 Marcus et al19 reviewed the long-term outcome of 87
patients with low-grade soft tissue sarcoma and showed, too, that the absence of adjuvant radiation and positive margins were notable indicators of LR. In a study of Ewing’s sarcoma, alveolar RMS, and non-RMS soft tissue sarcoma of the hands and feet, Johnstone et al22 also showed that excellent local control with preservation of limb function is possible with combined modality therapy. Although minimization of LR is desirable, the impact of LR on OS is obscure. The rate of distant metastases and OS have not been shown to be affected by radiation therapy.19,26 Two retrospective studies show compromised OS in patients experiencing LR29,30 and thus suggest an association of LR with increased tumor dissemination. It is unclear, however, whether this observation is a reflection of the disposition of an inherently more virulent tumor in general.21,31,32 This position is supported by the work of Trovik et al33 who showed that, as a group, patients with LR but without concurrent metastasis have a similar prognosis as those who remain LRfree, suggesting a noncausal relationship between LR and metastasis. The role of adjuvant chemotherapy in the treatment of adult pleomorphic RMS and extremity soft tissue sarcomas is equivocal. As discussed, IRS III data showed a clear survival advantage in pediatric patients treated with vincristine and actinomycin who underwent complete resection of their juvenile RMS with no residual margins and no positive lymph nodes.1 Several small studies during the late 1980s to early 1990s showed a trend toward improved disease-free survival with adjuvant chemotherapy, although none was statistically significant.34 These findings prompted formal review of the data, and in 1997 data from a meta-analysis by Tierney et al35 presented at the Connective Tissue Oncology Society annual meeting did indeed show statistically improved distant-metastasis–free survival, overall disease-free survival, and OS.34 Most recently, a small randomized study reported by the Italian Cooperative Group and presented in abstract form at the 1997 Annual Society of Clinical Oncology showed a survival advantage for soft tissue extremity sarcomas.36 This study used a more current chemotherapeutic regimen of epirubicin and ifosfamide; final results are eagerly awaited. Thus, although controversy remains concerning the use of adjuvant chemotherapy in patients with soft tissue sarcoma, recent data suggest that all patients with extremity sarcoma should receive adjuvant chemotherapy.
The Journal of Hand Surgery / Vol. 27A No. 1 January 2002 159
References 1. Crist W, Gehan EA, Ragab AH, et al. The third intergroup rhabdomyosarcoma study. J Clin Oncol 1995;13:610 – 630. 2. Maurer HM, Beltangady M, Gehan EA, et al. The intergroup rhabdomyosarcoma study-I: a final report. Cancer 1988;61:209 –220. 3. Maurer HM, Gehan EA, Beltangady M, et al. The intergroup rhabdomyosarcoma study-II. Cancer 1993;71:1904 – 1922. 4. LaQuaglia MP. Extremity rhabdomyosarcoma: biological principles, staging, and treatment. Semin Surg Oncol 1993; 9:510 –519. 5. Pappo AS, Shapiro DN, Crist WM, Maurer HM. Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 1995;13:2123–2139. 6. Pappo AS, Shapiro DN, Crist WM. Rhabdomyosarcoma: biology and treatment. Pediatr Oncol 1997;44:953–972. 7. De Jong ASH, Van Kessel-Van Vark M, Albus-Lutter CE. Pleomorphic rhabdomyosarcoma in adults: immunohistochemistry as a tool for its diagnosis. Hum Pathol 1987;18: 298 –303. 8. Gaffney EF, Dervan PA, Fletcher CDM. Pleomorphic rhabdomyosarcoma in adulthood. Analysis of 11 cases with definition of diagnostic criteria. Am J Surg Pathol 1993;17:601– 609. 9. Hollowood K, Fletcher CDM. Rhabdomyosarcoma in adults. Semin Diagn Pathol 1994;11:47–57. 10. Stout AP. Rhabdomyosarcoma of the skeletal muscles. Ann Surg 1946;123:447– 472. 11. Miettinen M. Rhabdomyosarcoma in patients older than 40 years of age. Cancer 1988;62:2060 –2065. 12. Molenaar WM, Oosterhuis AM, Ramaekers FCS. The rarity of rhabdomyosarcomas in the adult. A morphologic and immunohistochemical study. Pathol Res Pract 1985;80: 400 – 404. 13. Kodet R, Newton WA Jr, Hamoudi AB, Asmar L, Jacobs DL, Maurer HM. Childhood rhabdomyosarcoma with anaplastic (pleomorphic) features. A report of the Intergroup Rhabdomyosarcoma Study. Am J Surg Pathol 1993;17: 443– 453. 14. Erlandson RA. The ultrastructural distinction between rhabdomyosarcoma and other undifferentiated “sarcomas.” Ultrastruct Pathol 1987;11:83–101. 15. LaQuaglia MP, Heller G, Ghavimi F, et al. The effect of age at diagnosis on outcome in rhabdomyosarcoma. Cancer 1994;73:109 –117. 16. Brennan MF. The management of soft tissue sarcomas. Br J Surg 1984;71:964 –967. 17. Collin C, Hajdu SI, Godbold J, Friedrich C, Brennan MF. Localized operable soft tissue sarcoma of the upper extremity. Ann Surg 1987;205:331–339. 18. LaQuaglia MP, Ghavimi F, Penenberg D, et al. Factors predictive of mortality in pediatric extremity rhabdomyosarcoma. J Pediatr Surg 1990;25:238 –244. 19. Marcus SG, Merino MJ, Glatstein E, et al. Long-term outcome in 87 patients with low-grade soft-tissue sarcoma. Arch Surg 1993;128:1336 –1343. 20. Stinson SF, DeLaney TF, Greenberg J, et al. Acute and long-term effects on limb function of combined modality
21. 22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
limb sparing therapy for extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys 1991;21:1493–1499. Brennan MF, Hilaris B, Shiu MH, et al. Local recurrence in adult soft tissue sarcoma. Arch Surg 1987;122:1289 –1293. Johnstone PA, Wexler LH, Venzon DJ, et al. Sarcomas of the hand and foot: analysis of local control and functional result with combined modality therapy in extremity preservation. Int J Radiat Oncol Biol Phys 1994;29:735–745. Lindberg RD, Martin RG, Romsdahl MM, Barkley HT Jr. Conservative surgery and postoperative radiotherapy in 300 adults with soft-tissue sarcomas. Cancer 1981;47:2391–2397. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities. Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305–315. Suit HD, Russell WO, Martin RG. Sarcoma of soft tissue: clinical and histopathologic parameters and response to treatment. Cancer 1975;35:1478 –1483. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197–203. Coindre JM, Terrier P, Bui NB, et al. Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 1996;14:869 – 877. Lawrence W Jr, Donegan WL, Natarajan N, Mettlin C, Beart R, Winchester D. Adult soft tissue sarcomas: a pattern of care survey of the American College of Surgeons. Ann Surg 1987;205:349 –359. Collin CF, Friedrich C, Godbold J, Hajdu S, Brennan MF. Prognostic factors for local recurrence and survival in patients with localized extremity soft-tissue sarcoma. Semin Surg Oncol 1988;4:30 –37. Stotter AT, A’Hern RP, Fisher C, Mott AF, Fallowfield ME, Westbury G. The influence of local recurrence of extremity soft tissue sarcoma on metastasis and survival. Cancer 1990;65:1119 –1129. Gustafson P, Ro¨o¨ser B, Rydholm A. Is local recurrence of minor importance for metastases in soft tissue sarcoma? Cancer 1991;67:2083–2086. Ro¨o¨ser B, Gustafson P, Rydholm A. Is there no influence of local control on the rate of metastases in high-grade soft tissue sarcoma? Cancer 1990;65:1727–1729. Trovik C, Gustafson P, Bauer H, et al. Consequences of local recurrence of soft tissue sarcoma: 205 patients from the Scandinavian Sarcoma Group Register. Acta Orthop Scand 2000;71:488 – 495. Benjamin RS. Evidence for using adjuvant chemotherapy as standard treatment of soft tissue sarcoma. Semin Radiat Oncol 1999;4:349 –351. Tierney J, Stewart L, Parmar M, et al. Adjuvant chemotherapy for localized respectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 1997;350: 1647–1654. Frustaci S, Gherlinzoni F, DePaoli A, et al. Preliminary results of an adjuvant randomized trial on high risk extremity soft tissue sarcomas (STS): the interim analysis. Proc Am Soc Clin Oncol 1997;16:496a (abstr).
Since the inception of the first Intergroup Rhabdomyosarcoma Study (IRS) nearly 3 decades ago, important advances in the understanding and treatment of this aggressive mesenchymal neoplasm have been made on the pediatric front.1–3 Although pleomorphic rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma of childhood,4 – 6 it is an unusual and infrequent finding in adults.7–9 Over the past 5 From the Division of Hand and Microvascular Surgery, Department of Orthopaedic Surgery; the Division of Hematology/Oncology, Department of Medicine; the Department of Radiation Oncology; and the Department of Surgical Pathology; Naval Medical Center San Diego, San Diego, CA. The Chief, Bureau of Medicine and Surgery, Navy Department, Washington, DC, Clinical Investigation Program, sponsored this report #84-16-1968-961 as required by HSETCINST 6000.41A. Received for publication July 7, 2000; accepted in revised form September 13, 2001. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. The views expressed in this article are those of the authors and do not reflect the official position of the Department of the Navy, Department of Defense, or the United States Government. Reprint requests: Peter A.S. Johnstone, MD, Clinical Investigation Department, Naval Medical Center San Diego, San Diego, CA 92134-1005. Copyright © 2002 by the American Society for Surgery of the Hand 0363-5023/02/27A01-0002$35.00/0 doi:10.1053/jhsu.2002.29481
154 The Journal of Hand Surgery
decades considerable discussion has ensued concerning the very existence of adult RMS. From the initial treatise by Stout10 in 1946 through the late 1960s, pleomorphic RMS had the distinction of being regarded as one of the most common soft tissue sarcomas of adulthood.9 In the 1970s and 1980s, however, many cases of pleomorphic RMS were reclassified as malignant fibrous histiocytoma, pleomorphic liposarcoma, or leiomyosarcoma, and the diagnosis of pleomorphic RMS became exceedingly rare.7,9,11,12 Not until a study by Gaffney et al8 in 1993 was concrete evidence of rhabdomyoblastic differentiation established, confirming definitively the existence of pleomorphic RMS in adults.8,9 Although there is currently no doubt that pleomorphic RMS exists in adults, there is less certainty regarding its treatment. No dedicated studies of therapeutic modalities have been performed, and the findings of IRS I through III have uncertain applicability to the adult with pleomorphic RMS. This particular tumor was excluded from IRS evaluation because its existence in the pediatric population was in dispute.13
Case Report A 29-year-old man presented to his overseas military medical clinic complaining of a nontender lump
The Journal of Hand Surgery / Vol. 27A No. 1 January 2002 155
Figure 1. Light micrograph showing interconnected fascicles of atypical, spindled, plump polygonal and giant cells (larger arrows) with high-grade atypical nuclear features (smaller arrows). A moderately diffuse lymphocytic infiltrate is noted.
on the volar aspect of the right forearm. The patient was advised that the mass was most likely a lipoma and that he should wait until his return to the United States to have it electively removed in a hospital setting. At initial follow-up in the United States 6 months later, the patient stated that the mass had markedly increased in size. The patient had excisional biopsy, which measured 3.1 ⫻ 2.1 ⫻ 1.9 cm and was isolated to the muscle belly of the brachioradialis without fascial penetration. Light microscopy showed a tumor composed of interconnected fascicles of atypical, spindled, plump polygonal and giant cells with high-grade atypical nuclear features. The cytoplasm was strongly eosinophilic and slightly foamy; cross-striations were not appreciated. Eightyfive percent of the surgical margins were involved. Minor foci of tumor necrosis and a moderately diffuse lymphocytic infiltrate were seen (Fig. 1). Immunohistochemical analysis showed strongly positive desmin staining, focally positive actin staining, negative S-100 staining, and scattered dot-like staining of Coll IV. Smooth muscle antigen staining was negative except for background staining, and cytokeratin stains were not performed. The combined histologic and immunohistochemical findings were interpreted by an expert pathology consultant as pleomorphic RMS. Smooth muscle antigen staining was
believed to be insufficient for a leiomyosarcoma; the staining profile excluded liposarcoma. The patient was immediately referred to our institution for definitive care. The patient denied any constitutional symptoms, paresthesias, muscle weakness, or bone pain. Physical examination revealed no palpable head, neck, supraclavicular, axillary, or epitrochlear lymph nodes. His medical and surgical histories were unremarkable. A bone scan and computed tomography of the chest and abdomen showed no evidence of metastatic disease. A magnetic resonance image of the forearm suggested no indication of tumor extension into surrounding structures (Fig. 2). Complete blood count and chemistry panels were all within normal limits. The tumor site was re-excised with confirmation of clear margins (Fig. 3), and the patient was discussed at a multidisciplinary tumor board meeting. Because the current surgical therapy of sarcomas at our institution does not include lymph node dissection, nodal exploration was not performed. The radiation oncologists considered the condition an adult soft tissue sarcoma and were in favor of postoperative radiotherapy to a local forearm field. The medical oncologists considered the condition best treated with a pediatric chemotherapy regimen, although consultation with subject matter experts throughout the coun-
156 Jones et al / Pleomorphic Rhabdomyosarcoma
try yielded no formal chemotherapeutic treatment consensus. Because of the uncertain approach and negligible data for these lesions, the tumor board recommended the patient be fully briefed on the unclear optimal therapy of his disease as well as the risks and benefits of both adjuvant modalities. After
Figure 3. Intraoperative image showing the right forearm with a tumor isolated in the brachioradialis muscle beneath an 8.0 ⫻ 3.0-cm ellipse of skin.
Figure 2. An axial (A) and sagittal (B) magnetic resonance image of the tumor showing the mass to be isolated within the brachioradialis muscle without fascial penetration.
full discussion and with informed consent, the patient opted for both. The patient was begun on a treatment regimen of concomitant radiation therapy and chemotherapy with vincristine and actinomycin. The IRS data recommend patients receive a full year of vincristine alternating with Adriamycin (Erbamont Inc, Columbus, OH). The patient’s primary medical oncologist advised him that 1 year of such a regimen was probably too long and would pose an undue risk of vincristine toxicity. The patient proceeded with adjuvant radiation therapy to the affected region. A total dose of 66 Gy was delivered to the right proximal forearm using opposed anteroposterior fields after immobilization. The patient also received chemotherapy for a total of 6 months (2 cycles of weekly vincristine for 6 weeks and 2 cycles of Adriamycin). At that point the patient opted to discontinue chemotherapy. Two weeks after his last dose of vincristine he developed a self-limited episode of neurotoxicity
The Journal of Hand Surgery / Vol. 27A No. 1 January 2002 157
that resolved over several months with physical therapy. Postoperative follow-up at 24 months disclosed no evidence of recurrent disease and no residual side effects from therapy.
Discussion The typical presentation of patients with pleomorphic RMS is one of a rapidly enlarging extremity mass of several months’ duration.8,9 The age range at presentation is between 44 and 58 years,9 and there is a strong prevalence in men. The most frequent site of presentation is the deep musculature of the thigh8,9; this contrasts with pediatric RMS, which may occur nearly anywhere in the body.5 Gross pathology often shows prominent necrosis with focal hemorrhage,8,9 and microscopy reveals a growth pattern that is usually inconsistent and disordered, exhibiting a prominent spindle and eosinophilic, pleomorphic-cell population—the putative rhabdomyoblast—within a dense lymphohistiocytic infiltrate.8,9 Light microscopy findings are nondiagnostic in the absence of cytoplasmic cross-striations, which, unfortunately, are rarely identifiable. Therefore, immunohistochemical and/or ultrastructural evaluation of sarcomeric differentiation are mandatory in making this diagnosis.8,9 Immunohistochemically, pleomorphic RMS is characterized by positive staining for myoglobin, desmin, HHF-35, sarcomeric actin, fast myoglobin, and MyoD1. S-100 protein staining is invariably negative,7–9 and ␣-SMA normally is limited to myofibroblasts and smooth muscle but is occasionally positive in pleomorphic RMS.9 Electron microscopy is often required to make the diagnosis because of the absence of immunohistochemical reactivity secondary to focality of staining or an occasional absence of specific sarcomeric antigen expression.9 Erlandson14 proposed that the minimal ultrastructural diagnostic criteria of pleomorphic RMS should be the presence of myosin-ribosome complexes: a linear arrangement of ribosomes attached to short parallel bundles of myosin filaments. The prognosis for adults with RMS pales when compared with that of children despite the use of new multimodal therapies.15 In a multivariate analysis study of 290 adult and pediatric patients from 1970 to 1991 diagnosed with RMS, age at diagnosis along with local tumor invasiveness, distant metastases, regional lymph node involvement, and histopathologic subtype were determined to be independent predictors of outcome.15 Identification of prognostic
factors is essential because it is through these findings that one may devise and revise appropriate treatment strategies. Although no discrete studies evaluating prognostic factors and therapeutic modalities in adults with RMS are reported in the literature, a wealth of information has been derived from the series of ongoing IRS1–3 in children. Begun in 1972, the stated goal of the studies was to improve the treatment outcome of children with RMS. Intergroup Rhabdomyosarcoma Study staging is based on the degree of tumor remaining after initial surgery and the histologic subtype, categorized as favorable or unfavorable.1–3,5 Each subsequent IRS trial contributed to a significant improvement in overall survival (OS) rate for children with RMS.1–3 Devising a comprehensive treatment plan for the patient in this case study was difficult because of the absence of literature concerning specific therapeutic modalities for adult patients with pleomorphic RMS. As with all tumors, 3 primary modalities must be considered: surgery, chemotherapy, and radiation therapy, either alone or combined. When therapeutic ambiguity exists, this institution’s tumor board recommends that patients be fully briefed on the paucity of available data and be presented the medical and radiation oncologists’ perspectives, along with the alternatives and the risks and benefits of each potential course of treatment. Ultimately, therapeutic decisions are made by the patients based on input from oncologists with surgical, medical, and radiation expertise. Wide en bloc excision with negative microscopic margins is the foundation of treatment for soft tissue extremity sarcomas and the single greatest contributor to outcome and OS.1–19 The postoperative extent of disease remaining in situ is such a profound prognostic indicator of outcome that RMS tumor staging systems, including those of the IRSs, are founded on surgicopathologic stratification.1–3 Historically, amputation was the treatment of choice for extremity sarcomas.20 A number of investigators have shown convincingly, however, that amputation with respect to OS has no inherent advantage and that wide excision plus adjuvant radiation is as effective as amputation or amputation plus chemotherapy.21–24 The implementation of this less draconian combination therapy benefits the patient through preservation of a functional extremity while not compromising survival. The issue of adjuvant radiation and chemotherapy for the patient in this report is less clearly defined. Were his histology consistent with juvenile RMS,
158 Jones et al / Pleomorphic Rhabdomyosarcoma
one could make a strong case for strict adherence to IRS III protocol. The patient, however, had a subtype not recognized under IRS protocol. From a broader context the question is, should adult pleomorphic RMS be considered primarily RMS and treated under IRS direction, or should it be ranked under the general classification of adult soft tissue sarcoma and treated as such? The answer is unclear at present. In considering the former, IRS III guidelines would categorize the patient in group I: complete removal of localized disease with negative regional nodes (if sampled).1 Within this group patients are subdivided based on “favorable” or “unfavorable” histology. For purposes of IRS classification we considered this patient’s pleomorphic RMS to fall more appropriately in the favorable category because it was not alveolar. Intergroup Rhabdomyosarcoma Study III showed that patients with favorable histology who received cyclic-sequential vincristine and actinomycin for 12 months had 5-year progression-free survival and survival rates of 83% and 93%, respectively.1 Radiation therapy is conspicuously absent from this regimen; IRS I showed it provided no benefit over chemotherapy alone.2 Radiation therapy, then, would be excluded from the patient’s treatment regimen based on IRS III results. Adult soft tissue sarcoma literature, however, suggests a very different approach. Although the many varieties of these mesenchymal soft tissue tumors arise from disparate cellular origins, they have one thing in common: as a group they tend to behave similarly,19 and as such they can often be treated similarly. For extremity soft tissue tumors the literature is unequivocal: postoperative radiation therapy with or without adjuvant chemotherapy in the treatment of high-grade extremity sarcomas is clearly indicated21–26 and may be justified for low-grade lesions as well.19 Data continue to show that grade is more important on multivariate analysis than size with respect to local recurrence (LR),27 so radiotherapy should also be considered for small high-grade lesions, especially if resected with close margins. Radiation therapy in conjunction with limb-sparing surgery has proven to be a worthy alternative to amputation with respect to OS, and for this reason the rate of amputations in the United States for extremity sarcomas has decreased to less than 10%.26,28 Similarly, recent data from the National Cancer Institute show that external-beam radiation therapy significantly reduces the rate of LR in patients with high- and low-grade extremity tumors.26 Marcus et al19 reviewed the long-term outcome of 87
patients with low-grade soft tissue sarcoma and showed, too, that the absence of adjuvant radiation and positive margins were notable indicators of LR. In a study of Ewing’s sarcoma, alveolar RMS, and non-RMS soft tissue sarcoma of the hands and feet, Johnstone et al22 also showed that excellent local control with preservation of limb function is possible with combined modality therapy. Although minimization of LR is desirable, the impact of LR on OS is obscure. The rate of distant metastases and OS have not been shown to be affected by radiation therapy.19,26 Two retrospective studies show compromised OS in patients experiencing LR29,30 and thus suggest an association of LR with increased tumor dissemination. It is unclear, however, whether this observation is a reflection of the disposition of an inherently more virulent tumor in general.21,31,32 This position is supported by the work of Trovik et al33 who showed that, as a group, patients with LR but without concurrent metastasis have a similar prognosis as those who remain LRfree, suggesting a noncausal relationship between LR and metastasis. The role of adjuvant chemotherapy in the treatment of adult pleomorphic RMS and extremity soft tissue sarcomas is equivocal. As discussed, IRS III data showed a clear survival advantage in pediatric patients treated with vincristine and actinomycin who underwent complete resection of their juvenile RMS with no residual margins and no positive lymph nodes.1 Several small studies during the late 1980s to early 1990s showed a trend toward improved disease-free survival with adjuvant chemotherapy, although none was statistically significant.34 These findings prompted formal review of the data, and in 1997 data from a meta-analysis by Tierney et al35 presented at the Connective Tissue Oncology Society annual meeting did indeed show statistically improved distant-metastasis–free survival, overall disease-free survival, and OS.34 Most recently, a small randomized study reported by the Italian Cooperative Group and presented in abstract form at the 1997 Annual Society of Clinical Oncology showed a survival advantage for soft tissue extremity sarcomas.36 This study used a more current chemotherapeutic regimen of epirubicin and ifosfamide; final results are eagerly awaited. Thus, although controversy remains concerning the use of adjuvant chemotherapy in patients with soft tissue sarcoma, recent data suggest that all patients with extremity sarcoma should receive adjuvant chemotherapy.
The Journal of Hand Surgery / Vol. 27A No. 1 January 2002 159
References 1. Crist W, Gehan EA, Ragab AH, et al. The third intergroup rhabdomyosarcoma study. J Clin Oncol 1995;13:610 – 630. 2. Maurer HM, Beltangady M, Gehan EA, et al. The intergroup rhabdomyosarcoma study-I: a final report. Cancer 1988;61:209 –220. 3. Maurer HM, Gehan EA, Beltangady M, et al. The intergroup rhabdomyosarcoma study-II. Cancer 1993;71:1904 – 1922. 4. LaQuaglia MP. Extremity rhabdomyosarcoma: biological principles, staging, and treatment. Semin Surg Oncol 1993; 9:510 –519. 5. Pappo AS, Shapiro DN, Crist WM, Maurer HM. Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 1995;13:2123–2139. 6. Pappo AS, Shapiro DN, Crist WM. Rhabdomyosarcoma: biology and treatment. Pediatr Oncol 1997;44:953–972. 7. De Jong ASH, Van Kessel-Van Vark M, Albus-Lutter CE. Pleomorphic rhabdomyosarcoma in adults: immunohistochemistry as a tool for its diagnosis. Hum Pathol 1987;18: 298 –303. 8. Gaffney EF, Dervan PA, Fletcher CDM. Pleomorphic rhabdomyosarcoma in adulthood. Analysis of 11 cases with definition of diagnostic criteria. Am J Surg Pathol 1993;17:601– 609. 9. Hollowood K, Fletcher CDM. Rhabdomyosarcoma in adults. Semin Diagn Pathol 1994;11:47–57. 10. Stout AP. Rhabdomyosarcoma of the skeletal muscles. Ann Surg 1946;123:447– 472. 11. Miettinen M. Rhabdomyosarcoma in patients older than 40 years of age. Cancer 1988;62:2060 –2065. 12. Molenaar WM, Oosterhuis AM, Ramaekers FCS. The rarity of rhabdomyosarcomas in the adult. A morphologic and immunohistochemical study. Pathol Res Pract 1985;80: 400 – 404. 13. Kodet R, Newton WA Jr, Hamoudi AB, Asmar L, Jacobs DL, Maurer HM. Childhood rhabdomyosarcoma with anaplastic (pleomorphic) features. A report of the Intergroup Rhabdomyosarcoma Study. Am J Surg Pathol 1993;17: 443– 453. 14. Erlandson RA. The ultrastructural distinction between rhabdomyosarcoma and other undifferentiated “sarcomas.” Ultrastruct Pathol 1987;11:83–101. 15. LaQuaglia MP, Heller G, Ghavimi F, et al. The effect of age at diagnosis on outcome in rhabdomyosarcoma. Cancer 1994;73:109 –117. 16. Brennan MF. The management of soft tissue sarcomas. Br J Surg 1984;71:964 –967. 17. Collin C, Hajdu SI, Godbold J, Friedrich C, Brennan MF. Localized operable soft tissue sarcoma of the upper extremity. Ann Surg 1987;205:331–339. 18. LaQuaglia MP, Ghavimi F, Penenberg D, et al. Factors predictive of mortality in pediatric extremity rhabdomyosarcoma. J Pediatr Surg 1990;25:238 –244. 19. Marcus SG, Merino MJ, Glatstein E, et al. Long-term outcome in 87 patients with low-grade soft-tissue sarcoma. Arch Surg 1993;128:1336 –1343. 20. Stinson SF, DeLaney TF, Greenberg J, et al. Acute and long-term effects on limb function of combined modality
21. 22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
limb sparing therapy for extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys 1991;21:1493–1499. Brennan MF, Hilaris B, Shiu MH, et al. Local recurrence in adult soft tissue sarcoma. Arch Surg 1987;122:1289 –1293. Johnstone PA, Wexler LH, Venzon DJ, et al. Sarcomas of the hand and foot: analysis of local control and functional result with combined modality therapy in extremity preservation. Int J Radiat Oncol Biol Phys 1994;29:735–745. Lindberg RD, Martin RG, Romsdahl MM, Barkley HT Jr. Conservative surgery and postoperative radiotherapy in 300 adults with soft-tissue sarcomas. Cancer 1981;47:2391–2397. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities. Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305–315. Suit HD, Russell WO, Martin RG. Sarcoma of soft tissue: clinical and histopathologic parameters and response to treatment. Cancer 1975;35:1478 –1483. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197–203. Coindre JM, Terrier P, Bui NB, et al. Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 1996;14:869 – 877. Lawrence W Jr, Donegan WL, Natarajan N, Mettlin C, Beart R, Winchester D. Adult soft tissue sarcomas: a pattern of care survey of the American College of Surgeons. Ann Surg 1987;205:349 –359. Collin CF, Friedrich C, Godbold J, Hajdu S, Brennan MF. Prognostic factors for local recurrence and survival in patients with localized extremity soft-tissue sarcoma. Semin Surg Oncol 1988;4:30 –37. Stotter AT, A’Hern RP, Fisher C, Mott AF, Fallowfield ME, Westbury G. The influence of local recurrence of extremity soft tissue sarcoma on metastasis and survival. Cancer 1990;65:1119 –1129. Gustafson P, Ro¨o¨ser B, Rydholm A. Is local recurrence of minor importance for metastases in soft tissue sarcoma? Cancer 1991;67:2083–2086. Ro¨o¨ser B, Gustafson P, Rydholm A. Is there no influence of local control on the rate of metastases in high-grade soft tissue sarcoma? Cancer 1990;65:1727–1729. Trovik C, Gustafson P, Bauer H, et al. Consequences of local recurrence of soft tissue sarcoma: 205 patients from the Scandinavian Sarcoma Group Register. Acta Orthop Scand 2000;71:488 – 495. Benjamin RS. Evidence for using adjuvant chemotherapy as standard treatment of soft tissue sarcoma. Semin Radiat Oncol 1999;4:349 –351. Tierney J, Stewart L, Parmar M, et al. Adjuvant chemotherapy for localized respectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 1997;350: 1647–1654. Frustaci S, Gherlinzoni F, DePaoli A, et al. Preliminary results of an adjuvant randomized trial on high risk extremity soft tissue sarcomas (STS): the interim analysis. Proc Am Soc Clin Oncol 1997;16:496a (abstr).