—  SPECIALTY CONFERENCE  —

Surgical Pathology

Case 4 - Ectomesenchymoma

Cheryl M. Coffin
Primary Children's Medical Center
University of Utah
Salt Lake City


Click on each slide thumbnail image for an enlarged view
Clinical History
A 13-month old boy developed a left testicular mass over a period of a few weeks. An ultrasound showed irregularity and vascularity within the mass. Serum alpha-fetoprotein and human chorionic gonadotropin levels were normal. A CT scan of the chest, abdomen, and retroperitoneum showed no evidence of malignancy. A left radical orchiectomy was performed, and subsequently the patient underwent inguinal lymph node biopsy and staging bone marrow biopsies.


Case 4 - Slide 1
Click to view with ImageScope
Click to view with a Web-Based Viewer



Case 4 - Figure 1
The paratesticular ectomesenchymoma shows a proliferation of spindle and polygonal cells in sheets and fascicles.
Case 4 - Figure 2
The spindle cells are embedded in a myxoid and collagenized background and have elongated eosinophilic cytoplasmic extensions.
Case 4 - Figure 3
Mature ganglion cells with eosinophilic cytoplasm are intermingled with spindle cells.

Case 4 - Figure 4
The spindle cells have oval to elongated nuclei with granular chromatin, occasional prominent nucleoli and variable amounts of eosinophilic cytoplasm, with a focal strap-like configuration.
Case 4 - Figure 5
The mature ganglion cells are intermingled with spindle cells and in some areas the background resembles neuropil.
Case 4 - Figure 6 - MYOGENIN
Diffuse nuclear reactivity for myogenin is present in areas of rhabdomyoblastic differentiation.

Case 4 - Figure 7 - DESMIN
Diffuse cytoplasmic reactivity for desmin is present in areas of rhabdomyoblastic differentiation.
Case 4 - Figure 8 - SYNAPTOPHYSIN
Cytoplasmic reactivity for synaptophysin is present in ganglion cells N

Diagnosis:
Ectomesenchymoma

Gross Examination
The radical orchiectomy specimen weighed 11 g and contained a testicle measuring 3.7 x 2.7 x 2.5 cm with an attached spermatic cord measuring 3.5 cm in length and 0.5 cm in diameter. Sectioning revealed a firm, fibrous, white-tan paratesticular mass that compressed the adjacent testis and did not involve the epididymis or spermatic cord.

Histologic Findings
The paratesticular mass was composed predominantly of spindle cells intermingled with numerous large ganglion cells. The spindle cells were arranged in sheets and bundles and contained variable amounts of eosinophilic cytoplasm. The vesicular nuclei had fine chromatin and occasional prominent nucleoli, with some variability in nuclear size and staining. Mitoses were present, with a mitotic rate of approximately 18 per 10 high power fields. No zonal areas of necrosis were identified. In some areas the spindle cell proliferation was accompanied by an inflammatory infiltrate of lymphocytes, plasma cells, and occasional eosinophils. Occasional spindle cells had brightly eosinophilic cytoplasm with a strap-like configuration. Mature ganglion cells were irregularly dispersed throughout the lesion and had vesicular nuclei with a prominent nucleolus and amphophilic cytoplasm with variable amounts of Nissl substance. Occasional multinucleated ganglion cells were seen, and in some areas the ganglion cells were accompanied by spindle cells with delicate eosinophilic cytoplasm and buckled wavy nuclei with a neural or schwannian appearance. No immature neuroblasts or areas with an alveolar architecture were identified. In some areas the mesenchymal cells appeared less spindled and more plump and round to polygonal with more hyperchromatic nuclei. The epididymis, vas deferens, pampiniform plexus, and spermatic cord margin showed no evidence of malignancy. Testicular development was appropriate for age.

The inguinal lymph node and bone marrow showed no evidence of malignancy.

Immunohistochemical Findings
The spindle cells showed strong nuclear reactivity with myogenin and myo-D1 and strong cytoplasmic reactivity for muscle-specific actin and desmin. The ganglion cells displayed cytoplasmic reactivity for synaptophysin. An S100 protein stain revealed focal reactivity in areas with a schwannian stromatous appearance and weak cytoplasmic reactivity in ganglion cells.

Cytogenetic Results
Chromosome analysis of tumor tissue with G-banding revealed a karyotype of 46, XY, inv(9)(p11q13). The inversion of chromosome 9 around the centromere in each metaphase cell was interpreted as a normal variant in the population, with no clinical significance.

Diagnosis
Ectomesenchymoma (biphenotypic sarcoma with spindle cell rhabdomyosarcoma and neural differentiation with ganglion cells).

Discussion
This represents an ectomesenchymoma of the paratesticular region. This tumor has also been called gangliorhabdomyosarcoma in the past. The current case essentially represents a spindle cell embryonal rhabdomyosarcoma that contains ganglion cells and some schwannian elements. This case was selected to review the clinicopathologic features of ectomesenchymoma with emphasis on differential diagnosis, especially with rhabdomyosarcoma, and to discuss the pathologic evaluation of a paratesticular mass in a pre-pubertal patient.

Paratesticular masses in pre-pubertal males are uncommon, and clinically a solid scrotal mass in a child is malignant until proven otherwise and warrants evaluation for both testicular and paratesticular malignancies. The clinical evaluation prior to surgery includes obtaining serum tumor markers such as beta human chorionic gonadotropin and alpha-fetoprotein levels and performing imaging studies of the scrotum. The surgical procedure is usually a radical inguinal orchiectomy, although testis-sparing surgery can be done for benign lesions. The most frequent paratesticular masses in prepubertal males are rhabdomyosarcoma and neuroblastoma, but a wide spectrum of benign, intermediate, and malignant tumors can occur in this region (Table 1).

The pathologic evaluation of a prepubertal paratesticular mass begins with a careful gross examination of the fresh specimen to gather information that will allow staging according to both TNM and rhabdomyosarcoma clinical group staging systems. The gross specimen should be weighed and measured and the type of specimen designated. The length of the spermatic cord, if present, should be measured. Specific information for documentation of the mass includes its location, size in three dimensions, appearance of external and cut surfaces, distance from soft tissue margins, and whether it appears solid or cystic and circumscribed or infiltrative. For radical inguinal orchiectomy specimens, histologic sampling includes sections of the mass, testis, epididymis, spermatic cord at approximately 1 cm from the testis and at the proximal cord margin (if any), and soft tissue margins if the tumor appears to be present at or close to the margin. In prepubertal patients it is important to obtain tissue for cytogenetic and potential molecular genetic studies, and in some cases material for flow cytometry may be useful.

Ectomesenchymoma has been defined as a malignant neoplasm that usually consists of rhabdomyosarcoma with a neural component. The name ectomesenchymoma has been used to designate a possible origin from ectomesenchyme, which is migratory neural clefts tissue that shows mesenchymal differentiation during embryogenesis. The neural component of most ectomesenchymomas consist of ganglion cells, but schwannian and neuroblastic elements may also be admixed.

Ectomesenchymoma is a rare tumor that was initially designated as "gangliorhabdomyosarcoma" in a case report by Holimon and colleagues in 1971. The term ectomesenchymoma was coined in the mid-1970s following description of additional cases. From then until the early 1990s a variety of case reports and small series of ectomesenchymoma were published that emphasized the mixed mesenchymal and neuroepithelial components. In these early reports, a wide spectrum of mesenchymal components were described in addition to rhabdomyosarcoma, including malignant peripheral nerve sheath tumor, liposarcoma, chondrosarcoma, and malignant fibrous histiocytoma, and neuroepithelial components included primitive neuroectodermal tumor, ganglioneuroblastoma, neuroblastoma, and melanocytic proliferations. From the mid-1990s to the present, the concept of ectomesenchymoma in children has changed because of its clinical and pathologic overlap with rhabdomyosarcoma and the clinicopathologic differences between ectomesenchymoma in children versus adults. In 2000, Boue and colleagues published a series of 15 ectomesenchymomas in children from the Intergroup Rhabdomyosarcoma Study Groups III and IV and reviewed 21 previously published cases. In this series and in a previous report in 1996 by Mouton and colleagues, the clinical and pathologic overlap with rhabdomyosarcoma was emphasized, with similarities in age at diagnosis, sex incidence, anatomic sites, and prognosis. Recently several cases of rhabdomyosarcoma have been reported that show ganglioneuromatous differentiation following treatment, a phenomenon that further emphasizes the potentially close relationship between rhabdomyosarcoma and ectomesenchymoma.

Ectomesenchymoma mainly affects infants and young children, with one-third of cases occurring in infancy and two-thirds in the first five years of life. Some series have suggested a slight male predominance. The most common sites are the paratesticular region and external genitalia, pelvis and abdomen, and head and neck. Syndromic associations have not been observed except for one case that occurred in a patient with linear epidermal nevi. Currently, ectomesenchymomas are treated according to Intergroup Rhabdomyosarcoma Study Protocols regardless of the neural component. In the past, 50% were fatal, but with current treatment, the outcome is similar rhabdomyosarcoma, based on the subtype of rhabdomyosarcoma, anatomic site, and patient age. Among paratesticular ectomesenchymomas, all cases with followup have been disease free at four years or longer, following diagnosis. Additional potential favorable prognostic features for ectomesenchymoma includes size less than 10 cm, absence of metastases, superficial location, and absence of a histologic component of alveolar rhabdomyosarcoma.

Pathologically, ectomesenchymomas range in size from 3 to 18 cm and most are greater than 5 cm in diameter. The multilobular, thinly encapsulated mass is tan and fleshy, with variable areas of necrosis and hemorrhage. Some may appear locally infiltrative. Histologically, the rhabdomyosarcomatous component is usually embryonal, with admixed ganglion cells, ganglioneuroma, or neuroblastoma. Occasionally areas resembling malignant peripheral nerve sheath tumor are seen. The ganglion cells are found individually scattered or clustered within the rhabdomyosarcomatous components. Histologic variants include areas of alveolar rhabdomyosarcoma, foci resembling peripheral primitive neuroectodermal tumor, and focal anaplasia. Necrosis is variable. The mitotic rate often exceeds 5 per 10 high power fields. Immunohistochemical analysis reveals muscle markers including myogenin, Myo-D1, desmin, and muscle-specific actin in the rhabdomyosarcomatous component and synaptophysin, chromogranin, and neuron-specific enolase in the ganglion cells. When schwannian foci are present, staining for S100 protein may be seen, although rhabdomyosarcomas may also show focal staining with this marker. Ectomesenchymomas are not reactive for CD99, neurofilament, or cytokeratin. Electron microscopy shows a combination of skeletal muscle differentiation and variable neural differentiation, including cytoplasmic processes with microtubules and dense core granules. No specific cytogenetic abnormalities have been reported for ectomesenchymoma. However, one case of intracranial ectomesenchymoma had a complex karyotypic abnormality, but without gene fusions associated with alveolar rhabdomyosarcoma or Ewing sarcoma, and similarities to malignant peripheral nerve sheath tumor was noted with gene expression microarray analyses. The MYCN amplification status for ectomesenchymoma is unknown.

The differential diagnosis includes rhabdomyosarcoma, Ewing sarcoma/PNET, neuroblastoma, other tumors with rhabdomyoblastic foci and other tumors that can contain ganglion cells (Table 2). Rare biphenotypic sarcomas with EWS/Fli-1 gene fusions with or without accompanying PAX 3/FKHR gene fusions have been reported, and these cases seem to differ histologically from most ectomesenchymomas.

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. The histologic-prognostic subtypes have been defined in the International Classification of Rhabdomyosarcoma (Table 3). In addition to the botryoid, spindle cell, embryonal, and alveolar variants of rhabdomyosarcoma in the International Classification of Rhabdomyosarcoma, the World Health Organization Classification also includes pleomorphic rhabdomyosarcoma, which is principally a neoplasm of adulthood. Embryonal rhabdomyosarcoma most often occurs in the head and neck and genitourinary tract and has a predilection for the first decade, while alveolar rhabdomyosarcoma has a predilection for the extremities and occurs most often in the second decade of life. Embryonal rhabdomyosarcoma, not otherwise specified, accounts for nearly half of rhabdomyosarcomas and displays a range of morphology from primitive mesenchymal cells to highly differentiated neoplastic muscle cells with rhabdomyoblastic, strap-cell, and myotube configurations. At the less differentiated end of the spectrum, the cells are fusiform or stellate with scant cytoplasm and minimal nuclear or cytoplasmic maturation. Botryoid embryonal rhabdomyosarcoma accounts for 5% of rhabdomyosarcomas and is distinguished by a cambial layer of condensed tumor cells beneath an epithelial surface, with variable differentiation, cellularity, and degree of myogenesis. Spindle cell embryonal rhabdomyosarcoma accounts for 3% of rhabdomyosarcomas and consists of elongated spindle cells with a fascicular, storiform or whorled pattern, and variable collagen between tumor cells. Alveolar rhabdomyosarcoma accounts for 31% of rhabdomyosarcomas and classically displays anastomosing fibrovascular septa lined by round tumor cells with fine nuclear chromatin and variable amounts of myogenic cytoplasm. The solid and microalveolar variants of alveolar rhabdomyosarcoma create challenges in recognition. Anaplastic features characterized by nuclear cytomegaly, hyperchromasia, and atypical mitotic figures may be seen in all histologic subtypes of rhabdomyosarcoma and appear to confer unfavorable prognostic features. Several cases of rhabdomyosarcoma have been reported that have displayed differentiation to ganglion cells or ganglioneuroma following treatment. These observations further suggest that ectomesenchymoma may represent a histologic variant of rhabdomyosarcoma with divergent differentiation, similar to other neoplasms that may display divergent differentiation. The immunohistochemical profile of rhabdomyosarcoma includes reactivity for myogenin, myo-D1, muscle-specific actin, and desmin. The most specific and sensitive markers are myogenin and myo-D1, and alveolar rhabdomyosarcoma tends to display more extensive nuclear staining for these two markers, while embryonal rhabdomyosarcoma and its variants generally display more focal reactivity. Recently, comparative expression of specific protein subsets has been reported for rhabdomyosarcoma, with AP-2 beta and p-cadherin in alveolar rhabdomyosarcoma and EGFR and fibrillin 2 in embryonal rhabdomyosarcoma. Cytogenetic and molecular genetic abnormalities in rhabdomyosarcomas have been studied extensively (Table 5). Although it was initially thought that nearly all alveolar rhabdomyosarcomas harbored translocations involving PAX and FKHR genes, it is now recognized that at least 20% of alveolar rhabdomyosarcomas lack the PAX-FKHR gene fusion. Although a variety of genetic abnormalities have been described for embryonal rhabdomyosarcoma, a consistent and diagnostically useful genetic abnormality has yet to be identified.

Ewing sarcoma is the second most common childhood soft tissue sarcoma after rhabdomyosarcoma. Ewing sarcoma/PNET is a member of a family of tumors with EWS gene rearrangements. Pathologically, the round to ovoid tumor cells with minimal cytoplasm are arranged in sheets, nests, festoons, filigree, or a trabeculae with or without pseudorosette formation. Histologic variants include spindled, hyalinizing, sclerosing, clear cell, anaplastic, and adamantinoma-like Ewing sarcoma. Rare cases have been reported that contain ganglion cells before or after treatment, and in such cases with genetic analysis, the translocation between chromosomes 11 and 22 has been present. Immunohistochemically Ewing sarcomas are typically reactive for CD99, Fli-1 (approximately 70% of cases), vimentin, and neuron-specific enolase, with variable reactivity for synaptophysin, leu-7, and cytokeratin. Occasional cases display desmin reactivity. The most common translocations in Ewing sarcoma involve t(11;22) with EWS/Fli-1 or t(21;22) with EWS/ERG. Other rare translocations involving EWS and ETS family genes have been reported. Recently several cases of childhood sarcomas with morphologic features of Ewing sarcoma, but lacking an EWS gene rearrangement and containing a t(4;19) with a CIC/DUX4 gene fusion have been reported. The gene fusion product in these cases includes ETS family genes that might result in the development of Ewing sarcoma via a different mechanism than the EWS/ETS chimeric tumors.

Neuroblastoma is a tumor of the sympathetic nervous system and is the most common extracranial tumor of childhood. The pathologic spectrum ranges from undifferentiated neuroblastoma to fully differentiated ganglioneuroblastoma and is summarized in the International Neuroblastoma Pathology Classification. Classic neuroblastoma contains abundant, small, undifferentiated, poorly differentiated, and differentiating neuroblastic cells in varying proportions in a scant schwannian stroma with occasional cells that demonstrate differentiating toward ganglion cells. Mitoses, karyorrhexis, rosette formation, neuropil, and ganglion cells are variable. Half of patients are less than 2 years old at initial diagnosis, and more than 95% of cases occur in the first decade of life. Primary sites include the adrenal gland in 40% of neuroblastic tumors, followed by the abdominal, thoracic, cervical, and pelvic sympathetic ganglia. Ganglioneuroblastoma has areas resembling classic neuroblastoma or differentiating neuroblastoma and also displays a schwannian stroma that occupies more than 50% of the tumor. Two subtypes of ganglioneuroblastoma have different prognostic significance. Intermixed ganglioneuroblastoma contains microscopic foci of neuroblastic elements in an expanding schwannian stroma without grossly visible nodule formation and is a favorable histologic-prognostic subtype. Nodular ganglioneuroblastoma contains one or more visible neuroblastic nodules, coexisting with either intermixed ganglioneuroblastoma or ganglioneuroma, and is an unfavorable pathologic prognostic subtype. Ganglioneuroma is the benign and most differentiated member of the neuroblastic tumor family and consists of mature ganglion cells in a benign schwannian background with only rare differentiating neuroblasts identified in the maturing subtype of ganglioneuroma. The immunohistochemical profile of neuroblastoma includes reactivity for neuron-specific enolase, synaptophysin, chromogranin, leu-7, PGP 9.5, NB84, and other neural antigens. Neuroblastoma lacks expression of CD99 and muscle markers such as myogenin and myo-D1. Amplification of the MYCN proto-oncogene is present in more than 25% of neuroblastomas and is a poor prognostic indicator that correlates with higher stage, lower survival, advancing age, and high mitotic-karyorrhectic index. Abnormalities of ploidy and deletion of chromosomes 1p and 11q have been reported in neuroblastoma and are additional prognostic indicators. A biologic and clinical classification of neuroblastoma subdivides the tumor into low, intermediate, and high-risk groups based on a variety of prognostic indicators.

Other tumors that can occur in the paratesticular region in prepubertal males include malignant rhabdoid tumor, desmoplastic small round cell tumor, Wilms tumor (either arising in a renal heterotopia or by extension or metastasis), melanotic neuroectodermal tumor of infancy, giant cell fibroblastoma, fibrous hamartoma of infancy, angiomyofibroblastoma, and calcifying fibrous pseudotumor. For most of these lesions, the differential diagnosis with rhabdomyosarcoma and ectomesenchymoma is quite straightforward based on standard histologic features.

Although ectomesenchymoma is a rare tumor and data is limited, the available information suggests that childhood ectomesenchymoma that are composed of rhabdomyosarcoma with neuroblastic components may better be regarded as a variant of rhabdomyosarcoma than as a separate entity.

Take Home Messages
  • Paratesticular masses in prepubertal males are malignant until proven otherwise and preoperative evaluation of serum tumor markers, such beta human chorionic gonadotropin and alpha-fetoprotein levels is important.

  • The pathologic evaluation of a prepubertal paratesticular mass should be approached with the assumption that the lesion is malignant and staging information should be obtained, with histologic sampling of the mass, testis, epididymis, spermatic cord at 1 cm from the testis, and the proximal spermatic cord margin and soft tissue margins.

  • The most common sarcomas of childhood and adolescents are rhabdomyosarcoma, Ewing sarcoma/PNET, synovial sarcoma, and malignant peripheral nerve sheath tumor. These can usually be distinguished with a combination of conventional histopathology, immunohistochemistry, and cytogenetic or molecular diagnostic tests.

References
  1. Agarwal PK, Palmer JS. Testicular and paratesticular neoplasms in prepubertal males. J Urol. 2006;176:875-81.

  2. Asmar L, Gehan EA, Newton WA, et al. Agreement among and within groups of pathologists in the classification of rhabdomyosarcoma and related childhood sarcomas. Report of an international study of four pathology classifications. Cancer. 1994;74:2579-88.

  3. Bechtold RE, Sumner TE. Case of the month: ectomesenchymoma (malignant testicular tumor). J Ultrasound Med. 1984;3:R20, R22.

  4. Boue DR, Parham DM, Webber B, et al. Clinicopathologic study of ectomesenchymomas from Intergroup Rhabdomyosarcoma Study Groups III and IV. Pediatr Dev Pathol. 2000;3:290-300.

  5. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003;3:203-16.

  6. Brodeur GM, Maris JM, Yamashiro DJ, et al. Biology and genetics of human neuroblastomas. J Pediatr Hematol Oncol. 1997;19:93-101.

  7. Cavazzana AO, Schmidt D, Ninfo V, et al. Spindle cell rhabdomyosarcoma. A prognostically favorable variant of rhabdomyosarcoma. Am J Surg Pathol. 1992;16:229-35.

  8. Cecchetto G, Grotto P, De Bernardi B, et al. Paratesticular rhabdomyosarcoma in childhood: experience of the Italian Cooperative Study. Tumori. 1988;74:645-7.

  9. Coffin CM. The new International Rhabdomyosarcoma Classification, its progenitors, and considerations beyond morphology. Advances in Anatomic Pathology. 1997;4:1-16.

  10. Coffin CM, Lowichik A, Zhou H. Treatment effects in pediatric soft tissue and bone tumors: practical considerations for the pathologist. Am J Clin Pathol. 2005;123:75-90.

  11. Collini P, Mezzelani A, Modena P, et al. Evidence of neural differentiation in a case of post-therapy primitive neuroectodermal tumor/Ewing sarcoma of bone. Am J Surg Pathol. 2003;27:1161-6.

  12. Cozzutto C, Comelli A, Bandelloni R. Ectomesenchymoma. Report of two cases. Virchows Arch A Pathol Anat Histopathol. 1982;398:185-95.

  13. Edwards V, Tse G, Doucet J, et al. Rhabdomyosarcoma metastasizing as a malignant ectomesenchymoma. Ultrastruct Pathol. 1999;23:267-73.

  14. Holimon JL, Rosenblum WI. "Gangliorhabdomyosarcoma": a tumor of ectomesenchyme. Case report. J Neurosurg. 1971;34:417-22.

  15. Johnson DE, McHugh TA, Jaffe N. Paratesticular rhabdomyosarcoma in childhood. J Urol. 1982;128:1275-6.

  16. Karcioglu Z, Someren A, Mathes SJ. Ectomesenchymoma. A malignant tumor of migratory neural crest (ectomesenchyme) remnants showing ganglionic, schwannian, melanocytic and rhabdomyoblastic differentiation. Cancer. 1977;39:2486-96.

  17. Kawamoto EH, Weidner N, Agostini RM, Jr., et al. Malignant ectomesenchymoma of soft tissue. Report of two cases and review of the literature. Cancer. 1987;59:1791-802.

  18. Kawamura-Saito M, Yamazaki Y, Kaneko K, et al. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet. 2006;15:2125-37.

  19. Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005;12:212-20.

  20. Kleinschmidt-Demasters BK, Lovell MA, Donson AM, et al. Molecular array analyses of 51 pediatric tumors shows overlap between malignant intracranial ectomesenchymoma and MPNST but not medulloblastoma or atypical teratoid rhabdoid tumor. Acta Neuropathol (Berl). 2007;113:695-703.

  21. Kodet R, Kasthuri N, Marsden HB, et al. Gangliorhabdomyosarcoma: a histopathological and immunohistochemical study of three cases. Histopathology. 1986;10:181-93.

  22. Leuschner I, Newton WA, Jr., Schmidt D, et al. Spindle cell variants of embryonal rhabdomyosarcoma in the paratesticular region. A report of the Intergroup Rhabdomyosarcoma Study. Am J Surg Pathol. 1993;17:221-30.

  23. Maeda G, Masui F, Yokoyama R, et al. Ganglion cells in Ewing's sarcoma following chemotherapy: a case report. Pathol Int. 1998;48:475-80.

  24. Morotti RA, Nicol KK, Parham DM, et al. An immunohistochemical algorithm to facilitate diagnosis and subtyping of rhabdomyosarcoma: the Children's Oncology Group experience. Am J Surg Pathol. 2006;30:962-8.

  25. Mouton SC, Rosenberg HS, Cohen MC, et al. Malignant ectomesenchymoma in childhood. Pediatr Pathol Lab Med. 1996;16:607-24.

  26. Naka A, Matsumoto S, Shirai T, et al. Ganglioneuroblastoma associated with malignant mesenchymoma. Cancer. 1975;36:1050-6.

  27. Newton WA, Jr., Gehan EA, Webber BL, et al. Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification--an Intergroup Rhabdomyosarcoma Study. Cancer. 1995;76:1073-85.

  28. Parham DM, Hijazi Y, Steinberg SM, et al. Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol. 1999;30:911-8.

  29. Parham DM, Qualman SJ, Teot L, et al. Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Am J Surg Pathol. 2007;31:895-901.

  30. Qualman SJ, Bowen J, Fitzgibbons PL, et al. Protocol for the examination of specimens from patients with neuroblastoma and related neuroblastic tumors. Arch Pathol Lab Med. 2005;129:874-83.

  31. Qualman SJ, Bowen J, Parham DM, et al. Protocol for the examination of specimens from patients (children and young adults) with rhabdomyosarcoma. Arch Pathol Lab Med. 2003;127:1290-7.

  32. Qualman SJ, Coffin CM, Newton WA, et al. Intergroup Rhabdomyosarcoma Study: update for pathologists. Pediatr Dev Pathol. 1998;1:550-61.

  33. Raney RB, Jr., Hays DM, Lawrence W, Jr., et al. Paratesticular rhabdomyosarcoma in childhood. Cancer. 1978;42:729-36.

  34. Richkind KE, Romansky SG, Finklestein JZ. t(4;19)(q35;q13.1): a recurrent change in primitive mesenchymal tumors? Cancer Genet Cytogenet. 1996;87:71-4.

  35. Sebire NJ, Ramsay AD, Malone M, et al. Extensive posttreatment ganglioneuromatous differentiation of rhabdomyosarcoma: malignant ectomesenchymoma in an infant. Pediatr Dev Pathol. 2003;6:94-6.

  36. Shimada H, Ambros IM, Dehner LP, et al. Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Cancer. 1999;86:349-63.

  37. Shimada H, Ambros IM, Dehner LP, et al. The International Neuroblastoma Pathology Classification (the Shimada system). Cancer. 1999;86:364-72.

  38. Shimada H, Umehara S, Monobe Y, et al. International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer. 2001;92:2451-61.

  39. Wachtel M, Runge T, Leuschner I, et al. Subtype and prognostic classification of rhabdomyosarcoma by immunohistochemistry. J Clin Oncol. 2006;24:816-22.

  40. Weissferdt A, Neuling K, English M, et al. Peripheral primitive neuroectodermal tumor with postchemotherapy neuroblastoma-like differentiation. Pediatr Dev Pathol. 2006;9:229-33.

  41. Williams S, Parham DM, Jenkins JJ, 3rd. Peripheral neuroepithelioma with ganglion cells: report of two cases and review of the literature. Pediatr Dev Pathol. 1999;2:42-9.