Botryoid embryonal rhabdomyosarcoma of Stensen's duct

Botryoid Embryonal of Stensen’s Duct

Rhabdomyosarcoma

Silloo B. Kapadia, MD, Rajiv Dhir, MD, Hiroaki Fujii, MD, Paul S. Dickman, Michael R. Wollman, MD, Jonas T Johnson, MD, and Leon Barnes, MD

(Editorial Comment: The authors present a clinically useful review of the various types of rhabdomyosarcoma.)

Rhabdomyosarcomas (RMS) are malignant mesenchymal tumors characterized by skeletal myogenic differentiation.*J They comprise 20% of all soft-tissue sarcomas and 75% of soft-tissue sarcomas occurring in children. Most patients with RMS are in their first or second decade of life, with only 12% being 215 years of age. 3,4 The most frequent sites of origin are the head and neck, the extremities, and the genitourinary tract.3v4 In the head and neck, the orbit is the most frequent site, followed by the nasopharynx, middle ear-mastoid region, and sinonasal tract. Tumors in these nonorbital sites have a propensity to invade the base of the skull with direct meningeal extension and are, therefore, collectively referred to as parameningeal sites.5-7 In about 25% of head and neck sarcomas, nonorbital, nonparameningeal sites, ie, the oral cavity, cheek, pharynx, larynx, parotid gland, scalp, and neck, may be involved.8-12 RMS in childhood is generally classified histologically into botryoid, embryonal, and Botryoid RMS is considalveolar types. 1,2~13~14 ered to be a variant of embryonal RMS. It has a characteristic grape-like configuration, both clinically and on gross examination, a predilection to occur in mucosa-lined structures and hollow viscera, and distinctive histological

MD,

features2 Recent data indicate that a diagnosis of botryoid RMS correlates with a favorable prognosis.14 RMS of the cheek, oral cavity, and parotid gland have been previously reported.8-12J5-1g To the best of our knowledge, however, RMS arising in Stensen’s duct has not been described. We report a case of primary botryoid embryonal RMS arising in Stensen’s duct without involvement of the parotid gland and discuss its management and histological differential diagnosis. CASE REPORT Clinical

Features

to a community A 15-year-old girl presented hospital in September 1993 with a “sore spot” and a small lump in her left cheek around the caruncle of Stensen’s duct of g-month’s duration. Oral examination showed a polypoid, grape-like, z-cm polypoid

mass protruding A biopsy

from the Stensen’s duct caruncle.

of the caruncle

was performed

nosed as embryonal rhabdomyosarcoma,

and diag-

botryoid

type. The patient was then referred for further evaluation and treatment to the Eye and Ear Institute, Pittsburgh, PA. Extensive systemic evaluation was performed, including computerized tomographic (CT) scans of the head, neck and chest. CT scans showed a nodular abnormality extending from the region of the buccinator muscle laterally along the course of the left parotid duct (Fig 1). It did not quite reach the accessory parotid duct, but there was a 1.5-cm nodular area just deep to the duct, which impinged on the masseter muscle. A fat

plane was seen between the nodular area and the masseter muscle. The mass was separate from the From the Departments of Pathology, Otolaryngology, and Pediatrics; Presbyterian-University Hospital, The Eye and Ear Institute, and Children’s Hospital, University of Pittsburgh, Pittsburgh, PA. Supported by the Pathology Education and Research Foundation, Department of Pathology, University of Pittsburgh, School of Medicine. Address reprint reauests to Silloo B. Kaoadia. MD. Department of Pathology, Presbyterian-University Hospi: tal. 200 Lothroo St. Pittsburah. PA 15213-2582. Copyright 0’1996 by W.BTSaunders Company 0196-0709/96/l 702-0010$5.00/O

parotid gland, which appeared normal. Small lymph nodes were noted along the spinal accessory chain,

but there was no involvement

of cervical lymph

nodes or bone erosion by tumor. On October 15, 1993, a left superficial parotidectomy, facial nerve dissection, and selective cervical lymph node dissection (Zones I, II, III) were performed. The patient was found to have localized disease, and the tumor was completely resected (group 1). She was then transferred to Children’s Hospital, Pittsburgh, PA, where further work-up

American Journal of Otolaryngology, Vol 17, No 2 (March-April), 1996: pp 127-l 32

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Fig 1. Axial CT scan showing along the course of the left parotid

a nodular duct.

abnormality

included ultrasound examination of the abdomen, chest radiographs, whole body bone imaging, and bone marrow aspirate and biopsy, the results of which were all negative for metastatic disease. She was registered on the current Intergroup Rhabdomyosarcoma Study (IRS IV) and was started on multiagent chemotherapy consisting of ifosfamide, etoposide, and vincristine with trimethoprin and sulphamethoxazole prophylaxis. In May 1994, she had completed 24 weeks of chemotherapy, and she remains clinically free of disease.

Pathological The buccal

Features

specimen was composed of a cuff of left mucosa, attached Stensen’s duct, superficial

ET AL

lobe of parotid gland and selective neck dissection (Zones I, II, III). Gross examination showed a polypoid, gray-white tumor protruding from Stensen’s duct onto the buccal surface. On opening Stensen’s duct there was a 2.0 x 2.0 X l.O-cm, polypoid, grape-like, gray-white mass that obstructed the lumen and involved the entire thickness of the duct wall (Fig 2). This mass was contiguous with a similar 1.5-cm, smooth, circumscribed, grape-like tumor nodule of the duct wall. The distal centimeter of the duct, parotid gland, and lymph nodes were uninvolved. Normal soft tissue surrounded the duct. The margins were uninvolved. Microscopically, botryoid RMS was seen in the biopsy sample of Stensen’s duct and the resected specimen. Polypoid tumor involved the duct caruncle from the external squamous epithelium to the pseudostratified columnar epithelium around the central duct lumen [Fig 3). The duct wall was infiltrated by tumor composed of hypercellular areas and less cellular fibromyxoid areas, and a prominent, densely cellular, subepithelial “cambium” layer of small spindled, straplike, or round tumor cells (Figs 4, and 5). The tumor cells had hyperchromatic nuclei with scant or moderate amounts of intensely eosinophilic cytoplasm. The short, spindled tumor cells had central elongated nuclei and tapered ends. The straplike tumor cells displayed rare delicate cytoplasmic cross striations (Fig 5). Mitoses were found in cellular areas. The distal Stensen’s duct, parotid gland, resection margins, and cervical lymph nodes were uninvolved. Immunohistochemistry performed on formalinfixed, paraffin-embedded sections of tumor showed evidence of striated muscle differentiation. There was strong, focal cytoplasmic reactivity of tumor cells for myoglobin and diffuse staining for desmin (Fig 5) and muscle-specific actin. The presence of cross striations was augmented by immunoperoxidase staining (Fig 5, inset). Tumor cells were nega-

Fig 2. Gross appearance of resected specimen showing grape-like, polypoid tumor within Stensen’s duct.

BOTRYOID

Fig 3. showing Stensen’s fication x

RHABDOMYOSARCOMA

Low magnification polypoid configuration duct (hematoxylin-eosin 20).

tive for cytokeratin (AEl/AE3, protein.

OF

of

STENSEN’S

129

DUCT

histological section of tumor involving stain; original magni-

CAM 5.2) and S-100

DISCUSSION The histological classification of RMS depends on the growth pattern, cellularity, degree of differentiation, and configuration of tumor ce11s.1-4J3J4In the head and neck, 85% of cases are reported to belong to the embryonal type (including botryoid RMS), 10% to 15% to the alveolar type, and less than 5% to the pleomorphic type.l However, according to the IRS Pathology Committee, pleomorphic RMS is not seen in soft-tissue sarcomas in children often enough to warrant designation as a specific subtype.14 Botryoid RMS is the subtype with the most

Fig 4. Photomicrograph of botryoid embryonal RMS showing subepithelial cambium layer and myxoid stroma. Inset shows higher magnification of tumor cells displaying nuclear atypia (hematoxylin-eosin stain; original magnification x 150, inset x400).

Fig 5. Strong immunoreactivity of tumor cells desmin highlights the subepithelial cambium layer botryoid embryonal RMS. Inset shows augmentation cross striations in rhabdomyoblast (immunoperoxidase stain; original magnification x150, inset x400).

for of of

favorable survival.14 It is a distinctive variant of embryonal RMS (5% of cases) that presents in sites such as the vagina, vulva, and upper aerodigestive tract in children aged 2 to 5 years.1-4 As in our case, the tumor has a typical “bunch of grapes” appearance and is characterized histologically by a myxoid stroma in which there are hypocellular and hypercellular areas of small round, spindled, or straplike tumor cells showing immature rhabdomyoblastic differentiation. The subepithelial condensation of tumor cells is called a “cambium layer,” analogous to the zone of maximum growth in a tree.2 The histological differential diagnosis of embryonal RMS includes non-neoplastic inflammatory lesions, fetal rhabdomyomas,20-25 and small cell or spindle cell malignant tumors. In the upper aerodigestive tract, botryoid embryonal RMS may be mistaken for reactive stromal atypia in sinonasal polyps and polypoid granulation tissue (eg, aural polyps).l However, close scrutiny of botryoid RMS shows areas of increased cellularity, mitoses, a cambium layer, focal cross striations, and marked nuclear atypia. Furthermore, the typical histological background of sinonasal polyps, such as a thickened epithelial basement membrane, eosinophils, chronic inflammatory cells and distended mucous glands, is absent in RMS. In difficult cases, the diagnosis of RMS can be confirmed by the demonstration of immunoreactivity of tumor cells for desmin,26 whereas stromal atypical cells would be expected to be negative.

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Fetal rhabdomyoma (F-RM) is a benign mesenchymal tumor that has clinical and histological features overlapping those of embryonal RMS.Zo-24 Both neoplasms are common in childhood, often occur in the head and neck, and exhibit immature skeletal muscle differentiation.lJ Dehner et a120first drew attention to F-RM as a slow-growing, circumscribed, solitary mass often located in the superficial soft tissue in the postauricular area of infants or children. Mucosal F-RM may be polypoid but lacks the “bunch of grapes” appearance typical of botryoid RIMS. On microscopic examination, F-RM classically have a myxoid stroma in which bland, primitive spindle cells and fetal-type rhabdomyoblasts lacking nuclear atypia are haphazardly arranged. Kapadia et a121 have shown that some F-RM, located in facial soft tissue or mucosal sites of the head and neck in children or adults, show a wider spectrum of maturation, intermediate between that of classic F-RM and adult rhabdomyoma. These “intermediate” F-RM have been referred to by others as “cellular” F-RM24 or “juvenile” rhabdomyomas,25 and like the classic F-RM, are differentiated from RMS by the lack of marked nuclear atypia or infiltrating borders.2l21 F-RM rarely show tumor necrosis or mitotic activity, features common in RMS, but the mere presence of necrosis or mitoses cannot be used as criteria of malignancy.2* In one study of 24 cases of F-RM, mitoses were absent in 19 tumors, and in 5 cases, there were 1 to 14 mitoses per 50 high-power fields; however, the clinical course was benign with no evidence of malignant potential.21 In addition to the skeletal muscle phenotype of F-RM, Kapadia et al found unexpected focal staining of tumor cells for smooth muscle actin (SMA), S-100 protein, and glial fibrillary acidic protein. 21 None of the F-RM was positive for cytokeratin. RMS is distinguished from other malignant small cell tumors, such as Ewing’s group, lymphoma, olfactory neuroblastoma, carcinoma, plasmacytoma, and melanoma, by the presence of rhabdomyoblastic differentiation on light microscopy, or with ancillary methods, such as immunohistochemistry or electron microscopy.14,26-31 RMS is positive for desmin and muscle specific actin in 75% to 90% of cases and for myoglobin in only 20% to 50%.1,2J4,26j2g Al-

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ET AL

though myoglobin is a specific marker for striated muscle, it is the least sensitive and, therefore, of little use in diagnosis of RMS. Exceptionally, RMS may also express unexpected reactivity for cytokeratin, S-100 protein, or SMA.26-28,30 Therefore, caution should be exercised in interpretation of immunohistochemical stains. The diagnostic ultrastructural features of RMS include cytoplasmic arrangements of thick and thin filaments with Z-band material forming sarcomeres, or amorphous masses of Z-band material with thin, intermediate, or thick filaments radiating from them, thick filaments lined by ribosomes, or combinations of these findings.14 Generally, embryonal RMS and its botryoid variant do not pose diagnostic problems, because they are composed predominantly of spindled cells, rather than round cells. In diagnostically difficult cases, primitive RMS can be diagnosed on the ultrastructural demonstration of features that are compatible with presumptive myogenous differentiation.31 Cytogenetic study provides useful information in characterizing some of the small cell tumors.32z33Recent studies have shown a nonrandom chromosomal translocation, t(2;13) (q35; q14), to occur as a specific abnormality in alveolar RMS,32 and t(11;22) (q24;q12) has been observed in Ewing’s sarcoma and related tumors, including olfactory neuroblastoma.33 A loss of heterozygosity on the short arm of chromosome 11 has been found in some cases of embryonal RMS. 34However, the presence of genomic deletions on the short arm of chromosome 11 is not specific for embryonal RMS and is shared by a number of other small cell pediatric neoplasms, including Wilms tumor and neuroblastoma.34 Major advancements in the management of RMS in the last two decades with the introduction of aggressive multimodality treatment regimens, including multiagent chemotherapy (vincristine, dactinomycin, and cyclophosphamide), radiation therapy, and surgery have markedly improved surviva1.3,4~8~g,35According to the IRS, survival and prognosis depend on the anatomic site (orbit > nonparameningeal sites > parameningeal sites), histological type (botryoid > embryonal > alveolar type) and stage of disease. 3,4 Clinical and/or imaging evaluation of regional lymph nodes should be

BOTRYOID

RHABDOMYOSARCOMA

OF STENSEN’S

DUCT

performed pretreatment and preoperatively by a responsible surgeon and is an important part of pretreatment staging. Aggressive regional lymph node sampling is the most appropriate method of evaluation for most sites, although prophylactic radical regional node dissection, as employed for some other malignancies, is not necessary in childhood RMS. Wharam et aPg have recently shown that tumors of nonorbital, nonparameningeal sites of the head and neck, such as the oral cavity, parotid, cheek, scalp, and larynx, have a favorable prognosis, except for tumors presenting in the neck. The IRS-I study has shown that localized tumors completely resected (Clinical Group I) have a 5-year survival of 83%, compared with 70% for Group II (regional disease, grossly resected), 52% for Group III (incomplete resection or biopsy of primary with gross residual disease), and 20% for Group IV or disseminated disease.3 Chemotherapy is the backbone for all clinical groups of patients with RMS. It has been shown that of patients with clinical group I tumors treated postoperatively with radiotherapy to the primary site, 65% survived at 3 years versus 87% of those who had received a course of combination chemotherapy.36 Since that time, surgical resection followed by chemotherapy has been the mainstay of therapy for clinical group I patients. Radiation therapy was shown in the IRS I study8.g to be unnecessary in the management of totally resected nonalveolar histology RMS. As a result, since the IRS I study, radiation therapy is no longer recommended therapy for clinical group I nonalveolar RMS. In the IRS III, patients with clinical group I disease had a 5-year progression-free survival of 84%. This, however, included patients with paratesticular and orbital primaries, two groups with a known favorable outlook (personal communication, H.M. Maurer, MD). The most effective treatment for localized RMS has been repeated courses of vincristine, actinomycin, and cyclophosphamide (VAC).3,4 However, a failure rate of 16% must be considered unacceptable. In an attempt to further improve outcome, new chemotherapy agents and combinations will be required. Two such agents, ifosfamide and etoposide (VP-16), have shown promise in phase II trials of pretreated recurrent RMS.37 Based on this encouraging data,

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the IRS III was devised as a randomized trial comparing standard VAC therapy with two experimental treatment arms. One experimental arm will test repeated courses of vincristine, actinomycin, and ifosfamide (VAI) and the other will employ repeated courses of vincristine, ifosfamide, and etoposide (VIE). Treatment duration for the three regimens will be 56 weeks. It is hoped that either or both of these newer combinations will be superior to VAC and improve progression-free survival and overall survival for patients with Stage I (Group I) disease. In summary, we have described the clinical and pathological features of an unusual case of botryoid embryonal RMS arising in Stensen’s duct with a discussion of its management and histological differential diagnosis. REFERENCES 1. Barnes L: Tumors and tumorlike lesions of the soft tissues, in Barnes L (ed): Surgical Pathology of the Head and Neck. New York, NY, Dekker, 1985, pp 725-880 2. Enzinger FW, Weiss SW (eds): Soft Tissue Tumors (ed 2). St Louis, MO, Mosby, 1988, pp 448-488 3. Maurer HM, Beltangady M, Gehan EA, et al: The Intergroup Rhabdomyosarcoma Study-I: A final report. Cancer 61:209-220, 1988 4. Maurer HM, Gehan EA, Beltangady M, et al: The Intergroup Rbabdomyosarcoma Study-II. Cancer 71:19041922,1993 5. Anderson GJ, Tom LWC, Womer RB, et al: Rhabdomyosarcoma of the head and neck in children. Arch Otolaryngol Head Neck Surg 116:428-431,199O 6. Coene IJ, Schouwenburg PF, Voute PA, et al: Rhabdomyosarcoma of the head and neck in children. Clin Gtolaryngol 17:291-296,1992 7. Dohar JE, Marentette LJ, Adams GL: Rhabdomyosarcoma of the infratemporal fossa: Diagnostic dilemmas and surgical management. Am J Otolaryngol 12:146-149, 1991 8. Wharam MD, Foulkes MA, Lawrence W, et al: Soft tissue sarcoma of the head and neck in childhood: Nonorbital and nonparameningeal sites: A report of the Intergroup Rhabdomyosarcoma Study [IRS)-I. Cancer 53:10161019,1984 9. Wharam MD, Beltangady MS, Heyn RM, et al: Pediatric orofacial and laryngopharyngeal rhabdomyosarcoma. An Intergroup Rhabdomyosarcoma Study Report. Arch Otolaryngol Head Neck Surg 113:1225-1227, 1987 10. Yoshihara T, Nabeshima M, Ishii T: Embryonal rhabdomyosarcoma arising in the buccal mucosa: A case report with immunohistochemical and electron microscopic findings. Int J Ped Otorhinolaryngol 28:247-255, 1994 11. Bras J, Batsakis JG, Luna MA: Rhabdomyosarcoma of the oral soft tissues. Oral Surg Oral Med Oral Path01 64:585-596,1987 12. Peters E, Cohen M, Altini M, Murray J: Rhabdomyosarcoma of the oral and paraoral region. Cancer 63:963966,1989 13. Newton WA, Soule EH, Hamoudi AB, et al: Histopathology of childhood sarcomas, Intergroup Rhabdomyosar-

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