Feb 15, 1991 - orbit with or without contiguous paranasal sinus involvement, nasal ... sphenoid sinus, middle ear, and soft tissues of the neck and preauricular ...
Juvenile (Embryonal and Alveolar) Rhabdomyosarcoma of the Head and Neck in Adults A Clinical, Pathologic, and Irnrnunohistochemical Study of 12 Cases Raouf E. Nakhleh, MD, Paul E. Swanson, MD, and Louis P. Dehner, MD Sites in the head and neck region (orbit, nasopharynx, nasal cavity, etc.) are among the most frequent locations for juvenile (embryonal and alveolar) rhabdomyosarcomas in patients younger than 15 years; however, comparable neoplasms in adults are very uncommon. A clinicopathologic and immunohistochemical study of 1 2 juvenile rhabdomyosarcomas in patients between the ages of 18 and 36 years is presented. There was a fema1e:male ratio of 2:1. The orbit with or without contiguous paranasal sinus involvement, nasal cavity, sphenoid sinus, middle ear, and soft tissues of the neck and preauricular region were the primary sites. Seven tumors involved a parameningeal site and eight cases were alveolar rhabdomyosarcomas which together contributed to the adverse outcome. Only two patients were long-term, disease-free survivors. Six patients have died of tumor and two others are alive with persistent disease. Immunohistochemical study in 11cases demonstrated reactivity for vimentin and muscle-specific actin (HHF-35) and desmin in ten cases. Juvenile rhabdomyosarcoma rarely presents in the head and neck of adults but should be considered in the differential diagnosis of a small cell neoplasm in patients during the third and fourth decades of life. Cancer 67:1019-1024.1991.
T
Of pleomorphic rhabdomyosarcoma from the diagnostic lexicon of soft tissue sarcomas has all but eliminated this histogenetic category of neoplasms in adults with some exceptions.'I2 On the other hand, in the pediatric age population, rhabdomyosarcoma of the embryonal and alveolar types is the most common mesenchymal malignancy with a predilection for the head and neck region and genitourinary t r a ~ t . In ~ - fact, ~ rhabdomyosarcoma is generally one of the initial diagnostic considerations in a child with proptosis, a mass in the middle ear or a polypoid lesion of HE VIRTUAL DISAPPEARANCE
From the Division of Surgical Pathology, University of Minnesota Medical School, Hospital and Clinics, Minneapolis. Minnesota, and Department of Pathology. Washington University School of Medicine and Barnes Hospital, St. Louis, Missouri. Address for reprints: Louis P. Dehner, MD, Division of Anatomic Pathology, Barnes Hospital, One Barnes Hospital Plaza, St. Louis, MO 6 3 1 10. Accepted for publication June 15, 1990.
the nasopharynx or nasal cavity with a biopsy specimen composed of small hyperchromatic cells. By contrast, a similarly appearing biopsy from these sites in an adult is more likely to represent a poorly differentiated carcinoma, malignant lymphoma, melanoma, neuroendocrine carcinoma, or a neuroectodermal tumor such as the esthesioneuroblastoma.' The current report documents our experience with 12 juvenile (embryonal and alveolar) rhabdomyosarcomas which presented in the head and neck of patients between the ages of 18 and 36 years. Although these neoplasms are very uncommon, nonetheless, there is a rationale for including rhabdomyosarcoma in the differential diagnosis of a poorly differentiated small cell tumor in patients during the third and fourth decades of life. Materials and Methods
Twelve cases coded as rhabdomyosarcoma of the head and neck region in patients 18 years or older at diagnosis
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were retrieved from the files of the Division of Surgical Pathology, University of Minnesota Hospital and Clinic (Minneapolis, MN). All cases were initially seen in consultation or were referred to the University of Minnesota for additional therapy. Clinical information was obtained from a review of the medical records of patients treated at the University of Minnesota or through contact with the referring physician. Histologic sections were available for review in the 12 cases and paraffin blocks were obtained in 11 cases for immunohistochemical studies. Immunohistochemical staining was performed on 4 pm of pasaffinized tissue sections that were dewaxed in Americlear (American Scientific Products, McGaw Park, IL) and absolute ethanol. Endogenous peroxidase was quenched by immersion in methanolic peroxide (0.6%) for 30 minutes. After rehydration through graded alcohols, distilled water, and phosphate-buffered saline (PBS, pH 7.4) sections were overlaid with monoclonal antibodies to vimentin (V9; BioGenex Laboratories, San Ramon, CA; diluted 1 :8), muscle-specific actin (HHF-35; Enzo Diagnostics, NY; 1: 2400), and desmin (DEB-5; BioGenex; 1 :4) and incubated for 18 hours at 4°C in moisture chambers. Sections were then developed with the avidin-biotin-peroxidase comusing plex (ABC) technique as described by Hsu et 3,3'-diaminobenzidine tetrahydrochloride (Sigma Chemicals, St. Louis, MO; 0.250 yg/dl with 0.03% hydrogen peroxide) as chromogen. The reaction product was enhanced by brief exposure to 0.125% osmium tetroxide. Sections were counterstained in Harris' hematoxylin, dehydrated, and coverslips were applied in a synthetic mounting medium. Positive controls consisted of neoplastic tissues known to contain the determinant of interest. Negative controls consisted of nonimmune mouse ascites fluid substituted for primary antibody.
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Results
Clinical Findings The principal clinical findings including age, primary site, and outcome have been summarized in Table 1. There were eight women and four men who ranged in age from 18 to 36 years (mean, 29 years) at the time of diagnosis. Nasal stuffiness, facial pain, proptosis, or a neck mass of 2 months' duration or less in most cases were the presenting manifestations. The orbit was primarily involved in four cases with contiguous extension into the ethmoid sinuses in three and the maxillary sinus in the fourth patient (Cases 1, 2, 6, 7; Table 1). Two tumors arose in the nasal cavity, and one had invaded the ipsilateral maxillary sinus (Cases 10 and 1 1; Table 1). The sphenoid sinus and middle ear were the remaining nonsoft tissue sites (Cases 3 and 4; Table 1). A lateral neck (three cases) and a preauricular (one case) mass were the primary soft tissue locations (Cases 5, 8, 9, 12; Table 1). Cervical lymphadenopathy which later proved to be metastatic disease on biopsy was noticed at presentation in four patients (Cases 7,8, 10, 1 1; Table 1). Within 2 months of diagnosis, a metastasis to the breast had developed in one patient (Case 10) which was confirmed on biopsy, Data about therapy were very limited other than general comments that surgery with chemotherapy and/or radiation was performed in nine patients. None of the patients had a radical resection. Excisional or incisional biopsy was the most frequent surgical procedure. A recent patient (Case 10) received doxorubicin, vincristine, and cyclophosphamide, and irradiation to the local area, but she is one of those with active disease. The eventual outcome was known for ten patients (Table 1). Two patients (Cases 3 and 9; Table 1) are known to be alive without evidence of disease at 5 and 8 years after diagnosis, respectively. Two other patients (Cases 10
TABLE1. Clinical and Pathologic Features of Juvenile Rhabdomyosarcoma in Adults Patient I 2 3 4 5 6 7 8 9 10 11
12
Age (yr)/sex
Location
29/F 32/F 20/M 19/F 32/F 22/M 29/F 20/M 21/M 36/F 26/F 18/F
Orbit, sinuses Orbit Middle ear Sphenoid sinus Soft tissues of preauricular region Orbit, paranasal sinus Orbit, paranasal sinus, lymph node Soft tissues of neck, lymph node Soft tissues of neck Nasal cavity, paranasal sinus, lymph node Nasal cavity, lymph node Soft tissues of neck
ABMT: autologous bone marrow transplantation; ANED: alive with no evidence of disease; AWD: alive with metastatic disease; CT: che-
Therapy
-
S, CT S, CT S, CT
-
S, CT, RT S, CT, RT S, RT S. CT S, CT S, CT, RT, ABMT
Follow-up (yr) 1.0 1.o 8.0 0.9 0.9
1.o
5.0
1.o
0.5 4.0
Status
Histologic type
DOD DOD ANED DOD DOD LFU LFU DOD ANED AWD AWD DOD
Embryonal Embryonal Embryonal Embryonal Alveolar Alveolar Alveolar Alveolar Alveolar Alveolar Alveolar Alveolar
motherapy; DOD: died of disease; LFU: lost to follow-up; RT: radiation therapy; S surgery.
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and 11; Table 1) have active disease at 6 months and 1 year, respectively. Six patients have died with metastatic tumor at 0.9 to 4.0 years (mean, 1.8 years); the lungs, lymph nodes, brain, and multiple intraabdominal organs were the major sites of metastasis.
Pathologic and immunohistochernicaI Findings Eight of 12 tumors had an alveolar pattern, whereas the remaining four neoplasms were embryonal rhabdomyosarcomas. The alveolar rhabdomyosarcomas were composed of polygonal to round cells with hyperchromatic nuclei and variably eosinophilic cytoplasm. The cells were arranged in cohesive clusters or noncohesive aggregates with alveolar qualities (Fig. 1). A solid pattern of mononuclear cells without alveolar characteristics was present focally in six of eight tumors. Some degree of pleomorphism was noted in all cases, but was more apparent in the loosely cellular areas where tumor giant cells were evident in six cases (Fig. 1, inset). Mitotic activity was readily identified in all tumors. Confluent zones of necrosis were present in three cases. In contrast to the alveolar rhabdomyosarcomas, the embryonal neoplasms were composed of smaller, more compactly arranged cells with ovoid to spindle-shaped nuclei and delicate cytoplasmic processes when present (Fig. 2). A myxoid stroma was a uniform feature of the background, and a fibrous stroma separated groups of tumor cells. None of the excisions showed a convincing botryoid pattern of cellular condensation beneath an ep-
FIG. 1. Alveolar rhabdomyosarcoma of the orbit and sinus (Patient 6 ) showing the characteristic loosely arranged cells in alveolar spaces. Inset Occasional multinucleated tumor cells were present (H & E, X 125, X320).
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ithelial surface. Spindle cell features predominated in two tumors. Nuclear pleomorphism was less pronounced than in the alveolar rhabdomyosarcomas. Neither classic strap cells nor cross-striations were identified in these four neoplasms, nor in the alveolar rhabdomyosarcomas. The 11 cases were immunoreactive for both vimentin and muscle-specific actin; the former was diffusely expressed in all tumor cells and the latter stained cells focally (Fig. 3). Desmin reactivity produced globular cytoplasmic staining in ten of 11 cases (Fig. 3). There was an overlapping distribution of immunoreactive cells between the desmin and muscle-specific actin.
Discussion Age at presentation and the anatomic site of the presumed primary tumor are important factors which are considered by the pathologist in the formulation of a differential diagnosis when the biopsy is an undifferentiated or poorly differentiated neoplasm. If the patient is younger than 15 years with a “small round cell tumor,” rhabdomyosarcoma is one of a limited number of neoplasms with this morphologic appearance. The pediatric experience with rhabdomyosarcoma has been extensively evaluated as part of the Intergroup Rhabdomyosarcoma Study (IRS). In the final report on the treatment of 686 patients who were enrolled in IRSI, 37% of tumors presented in the orbit, one of the parameningeal sites (nasopharynx, nasal cavity, paranasal sinuses, and pterygopalatine and intratemporal fossae) or
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FIG. 2. Embryonal rhabdomyosarcoma of the sphenoid sinus (Patient 4)showing spindle to ovoid hyperchromatic cells in a myxoid background (H & E, X 125).
FIG.3. Alveolar rhabdomyosarcoma showing the immunoreactivity for vimentin (left), muscle specific actin (center), and desmin (right) (immunoperoxidase, X320, X320, X320).
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other head and neck locations; those rhabdomyosarcomas of childhood with an embryonal histologic type and in one of the nonparameningeal locations in the head and neck region have a favorable prognosis particularly in the case of orbital tumors (89%) and somewhat less so for other head and neck (55%) and parameningeal sites (47%).” An alveolar pattern of rhabdomyosarcoma has been consistently correlated with an adverse outcome regardless of the primary location and clinical Rhabdomyosarcoma in patients older than 20 years are relatively uncommon and according to Enzinger and Weiss, are rare after the age of 45 years; a review of the experience at the Armed Forces Institute of Pathology of 558 rhabdomyosarcomas in a 10-year period indicated that 15% of cases were diagnosed in patients older than 20 years of age.’ Lloyd et identified 82 cases of “embryonal rhabdomyosarcoma” including the alveolar type in patients who were age 20 years or older at diagnosis; a final group of 54 cases were analyzed in their study and only four (7%) of the 54 tumors arose in the head and neck region. The total number of rhabdomyosarcomas in the period from 1950through 1978 was not given by Lloyd et ~ 1 . in’ ~order to ascertain the percentage of rhabdomyosarcomas occurring in adults. We likewise did not determine the total number of rhabdomyosarcomas which were accessed during the period when the 12 rhabdomyosarcomas of the head and neck were examined. Due to the fact that each one of these cases was submitted in consultation and thus represented a skewed population, such a figure would distort the true incidence. It is difficult to argue with the impression from the literature and our own experience that rhabdomyosarcomas are rare in the head and neck of adults. I4-l9 Among our 12 cases, the alveolar rhabdomyosarcoma was the predominant histologic subtype in eight patients and also seven patients had one of the parameningeal sites involved at the time of diagnosis. Three of the orbital neoplasms (Cases 1, 6, 7) had extension into the contiguous paranasal sinus. Whether each of these neoplasms had arisen in the paranasal sinus and secondarily invaded the orbit was an equally plausible scenario; however, the imaging studies were interpreted otherwise. Unfortunately, two of the three patients were lost to clinical followup (Cases 6 and 7), but lymph node metastases were evident at the time of diagnosis in one case (Case 7). Both an alveolar histologic type and/or a parameningeal location of the tumor was present in 1 1 of 12 cases. Interestingly, the one “favorable” case of an embryonal rhabdomyosarcoma of the orbit (Case 2) died of metastatic disease within a year of the diagnosis. Among the four adults with rhabdomyosarcoma of the head and neck in the series of Lloyd el aI.,l3 none survived beyond 2 years. The experience with rhabdomyosarcoma in large series
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like those of the IRS, Armed Forces Institute of Pathology, and others is that the alveolar type emerges as the predominant variant in older children, adolescents and adults so that our experience is consistent with those earlier observations.’,12,20 This finding proves to be unfortunate in terms of prognosis, but offers a special challenge in pathologic diagnosis. A round cell neoplasm in a nasal, orbital, or lymph node biopsy specimen from an adult is unlikely to suggest the immediate possibility of a rhabdomyosarcoma. However, the patients in our series were age 36 years or younger at diagnosis so that the relatively young age of these adults may serve as a clue. In general, squamous cell carcinoma, malignant lymphoma, and melanoma of the head and neck region present in the fifth decade or later, but there are the younger exceptions as there are the older exceptions for rhabdomyosarcoma.” Other than the age at diagnosis, the clinical behavior and pathologic findings were entirely consistent with the pediatric experience of the IRS.’o,2ZEmbryonal and alveolar rhabdomyosarcomas in children must be differentiated from neuroblastoma, primitive neuroectodermal tumor, Ewing’s sarcoma, and malignant lymphoma-leukemia.23In addition to electron microscopic study, immunohistochemical analysis with a panel of select antibodies has become the technique to solve the diagnostic enigma. These latter studies were performed in 1 1 of the 12 cases in the current series with uniform immunoreactivity for vimentin and muscle-specific antigen (HHF35).24-25 Vimentin is a sensitive marker for mesenchymal tissues but is not specific for rhabdomyosarcoma, whereas muscle-specific antigen is very sensitive for the myogenic phenotype but does not differentiate skeletal from smooth m u s ~ l eThe . ~ intermediate ~ ~ ~ ~ filament, desmin, is more specific for myogenic differentiation, but it is less sensitive than muscle specific a c t i r ~ . ~Ten ’ . ~ ~of the 1 1 cases showed focal globular cytoplasmic reactivity for desmin. To screen for the other potential “small cell neoplasms,” cytokeratin, leukocyte common antigen, neuron-specific enolase, and possibly synaptophysin are appropriate markers.23 In virtually all respects, the rhabdomyosarcomas of the head and neck region in the 12 patients who are the subjects of this report behaved as their pediatric counterparts. Since alveolar rhabdomyosarcoma is encountered more often in older children and adolescents, it is not surprising that this tumor type occurred in a majority of our cases. The approach to the pathologic diagnosis for these tumors is identical to the one which is applied to rhabdomyosarcomas in children. However, one is less likely to consider the diagnosis in an adult. REFERENCES I . Enzinger FM, Weiss SW. Soft Tissue Tumors, ed. 2. St. Louis: CV Mosby, 1988; 448-488. 2. DeJong ASH, Vark VKV, Albus-Lutter CE. Pleomorphic rhab-
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domyosarcoma in adults: Immunohistochemistry as a tool for its diagnosis. Hum Pathol 1987; 18:298-303. 3. Masson JK, Soule EH. Embryonal rhabdomyosarcoma ofthe head and neck: Report on 88 cases. A m JSurg 1965: 110585-596. 4. Dito WR, Batsakis JG. Rhabdomyosarcoma of the head and neck: An appraisal of the biologic behavior in 170 cases. Arch Surg 1962: 84: 582-588. 5. Malogalowkin MH, Ortega JA. Rhabdomyosarcoma of childhood. Pediatr Annu 1988; 17:251-268. 6. Newman AN, Rxe DH. Rhabdomyosarcoma ofthe head and neck. Laryngoscope 1984; 94:234-239. 7. Raney RB Jr, Hays DM, Tefft M?Triche TJ. Rhabdomyosarcoma and the undifferentiated sarcomas. In: Pizzo PA, Poplack DG, eds. Principles and Practices of Pediatric Oncology. Philadelphia: JB Lippincott, 1989; 635-658. 8. Wick MR, Stanley SJ, Swanson PE. Immunohistochemical diagnosis of sinonasal melanoma, carcinoma and neuroblastoma with monoclonal antibodies HMB-45 and anti-synaptophysin. Arch Pathol Lab Med 1988; I12:616-620. 9. Hsu SM, Raine L, Fanger H. The use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 1985; 19577-580. 10. Maurer HM, Beltangady M, Gehan EA et al. The Intergroup Rhabdomyosarcoma Study: I. A final report. Cancer 1988; 61:209-220. 1 1. Newton WA Jr, Soule EH, Hamoudi AB et al. Histopathology of childhood sarcoma: Intergroup Rhabdomyosarcoma Studies I and 11. Clinicopathologic correlation. J Clin Oncol 1988; 6:67-75. 12. Shimada H, Newton WA Jr, Soule EH, Beltangady MS, Maurer HM. Pathology of fatal rhabdomyosarcoma: Report from Intergroup Rhabdomyosarcoma Study (IRS-I and IRS-11). Cancer 1987: 59:459465. 13. Lloyd RV, Hajdu SI, Knapper WH. Embryonal rhabdomyosarcoma in adults. Cancer 1983; 5137-565. 14. Singhal RM, Bahadur S, Bhatia R. Rhabdomyosarcoma of the head and neck. JLaryngolO101 1987; 101:971-974. 15. Peters E, Cohen M, Altini M, Murray J. Rhabdomyosarcoma of the oral and paraoral region. Cancer 1989; 63:963-966. 16. Grieman RB, Katsikeris NF, Symington JM. Rhabdomyosarcoma
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of the maxillary sinus: Review of the literature and report of a case. J OralMaxillofac Surg 1988; 46:1090-1096. 17. Bras J, Batsakis JG, Luna MA. Rhabdomyosarcoma of the oral soft tissues. Oral Surg 1988: 645855596, 18. Sadeghi EM, Gingrass DJ, Sunvilla EJ, Anderson T, Tong TT. Embryonal rhabdomyosarcoma. Int J Oral Maxi//ofhc Surg 1988; 17: 198-200. 19. Balazs M, Egerszegi P. Laryngeal botryoid rhabdomyosarcoma in an adult: Report of a case with electron microscopic study. Pathol Res Pract 1989; 184:643-649. 20. Gonzalez-Crussi F, Black-Schaffer S. Rhabdomyosarcoma of infancy and childhood: Problem of morphologic classification. A m J Surg Pathol 1979: 3: 157-171. 2 1. Million RR, Cassisi NJ, Clark JR. Cancer of the head and neck. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, ed. 3. Philadelphia: JB Lippincott, 1989; 488590. 22. Sutow WW, Lindberg RD, Gehan EA. Three-year relapse-free survival rates in childhood rhabdomyosarcoma of the head and neck: Report from the Intergroup Rhabdomyosarcoma Study. Cancer 1982; 49:22 17-2221. 23. Dehner LP. A contemporary view of neoplasms in children. The pathologist’s perspective. Pediatr Clin North Am 1989; 36:113-137. 24. Tsukada T, McNutt MA, Ross R, Gown AM. HHF-35. A muscle actin-specific monoclonal antibody: 11. Reactivity in normal, reactive and neoplastic human tissues. Am J Pathol 1987; 127:389-402. 25. Schmidt RA, Cone R, Haas JE, Gown AM. Diagnosis of rhabdomyosarcomas with HHF-35: A monoclonal antibody directed against muscle actins. A m J Paihol 1988; 131:19-28. 26. Molenaar WM, Oosterhuis JW, Oosterhuis AM, Ramaekers FCS. Mesenchymal and muscle-specific intermediate filaments (vimentin and desmin) in relation to differentiation in childhood rhabdomyosarcomas. Hum Paihol 1985: 162338-843. 27. Miettinen M. Antibody specific to muscle actins in the diagnosis and classification of soft tissue tumors. Am JPathol 1988: 130:205-215. 28. Altmannsberger M, Weber K, Droste R, Osborn M. Desmin is a specific marker for rhabdomyosarcomas of human and rat origin. A m J Pathol 1985: I18:85-95. 29. Troung LD, Rangdaeng S, Cagle P, Ro JY, Hawkins H, Font RL. The diagnostic utility of desmin: A study of 584 cases and review of the literature. Am J Clin Pathol 1990; 93:305-3 14.
