Case 2 -

Residual Olfactory Neuroblastoma Bruce M. Wenig, M.D. Mary S. Richardson, D.D.S., M.D.

History: A 56 year-old male presented with epistaxis. An intranasal mass was identified and a biopsy obtained. Gross findings: The preoperative CT scans shows a sinonasal mass in the midline which involves the superior nasal vault with probable erosion of the cribriform plate. A craniofacial resection was performed. At the time of surgery an en bloc resection was done that included the superior aspect of the nasal vault and portion of the medial aspect of the superior conchae. In the anterior aspect of the resection specimen a 1cm, soft, polypoid, yellowish-brown, glistening mass was noted. This mass was distinct from the surrounding pink-tan mucosal surfaces and was friable. The surgeon, in vivo, procured the surgical resection margins and submitted them for frozen section evaluation. Microscopic findings: The frozen section submitted for evaluation was from the "nasal septal" margin. On low power examination, the tissue examined was identifiable as respiratory tract mucosa with a dense fibrous connective tissue. Subjacent to the surface epithelium, within the fibrous connective tissue, scattered remnants of serous mucous glands are arranged in lobular units. Focal areas of the remaining excretory ducts show squamous metaplasia and marked atrophy of acinar units. Scattered aggregates of chronic inflammatory infiltrate are noted. On low power view there were also observed small aggregates of cells composed of small, blue cells which grew in tightly arranged nests. High power microscopy examination of these cells shows a fragmented eosinophilic cytoplasm. The nuclei were small with angular nuclear borders and the chromatin was finely granular. An occasional pyknotic nucleus was seen. Prominent nucleoli, obvious neurofibrillary background and mitotic figures are absent. The nests of cohesive cells did not have pseuorosettes (Homer-Wright) or true neural rosette (Flexner-Wintersteiner) formations. Intraoperative Diagnosis: The diagnosis rendered on this frozen section was "residual olfactory neuroblastoma present". Result: A subsequent "new" surgical margin was obtained which was negative for tumor. Diagnosis on Permanent Section: Residual olfactory neuroblastoma identified. The resection was completed with negative surgical margins on final pathologic examination. Discussion Intraoperative consultation for skull base surgery is uniquely challenging due to the diverse type of tissues present, the frequency (60%) of a pre-operative treatment modality (irradiation/chemotherapy), the regions' intricate anatomic relationships, and the lack of anatomic landmarks on tissue submitted for frozen section. Perhaps more than any other anatomic site in the head and neck, a close working relationship between the skull base surgical team and surgical pathologist must be in place. The surgical team is responsible for the manner of removal of the tissue as well as the orientation of the specimen. Methods used for orientation on small tissue fragments and the resection specimen should be established prior to surgery (ink vs. suture including drawings, if necessary). The skull base is the complex anatomic boundary through which vessels and nerves traverse between the extra cranial and intracranial tissues. Five bones compose the skull base of the cranium; the ethmoid, sphenoid, paratemporal, and parafrontal bones. In accordance with the divisions of the anatomic cranial fossa, the skull base is divided into the anterior, middle, and posterior regions. The important aspect of the normal anatomy of these three regions is found in the skull base apertures, presence of specialized tissues, and the relationships to sub-cranial structures. Skull base surgery is performed for a wide variety of tumors (Tables 1-3). Reported series show that over 80% of skull base resections are for malignant tumors. Despite the fact that the malignant lesions of the skull base are histologically a heterogeneous group, the results of their resections are usually reported together. Due to the relative rarity of these lesions, it is difficult for one institution to accumulate significant data for meaningful analysis of outcomes. Unfortunately, this makes interpretation of survival and controls statistically difficult. Moreover, most of the "large" series of patients (greater than 20 cases) are from craniofacial surgery (CFS), transcranial and transfacial surgical approaches. Some contain neoplasms involving almost exclusively the anterior and middle skull base regions. These two fore mentioned regions contain the osseous pathways (orbit and cranial foramina) of least resistance for tumor spread. A recent report from an international collaborative study comprised of 17 medical institutions looked retrospectively at 1,307 patients who had only malignant skull base tumors. The patients had undergone craniofacial resection from years 1956 to January of 2002. The median age was 54 years (range was 1:98 years). The male to female ratio was roughly 3:1, respectively. As might be expected, 86.9% of the patients with tumors of the skull base were those involving the anterior cranial fossa. The middle fossa was involved 9.7% and both fossae were involved in 3.4%. In this series, approximately 60% of the patients had received prior treatment (of the total patients 40% had prior surgery, 28% had prior radiation, and 11.6% had prior chemotherapy, and roughly 19% had been treated by more than one prior modality). The histologic types of tumors represented in this series are shown in Table 4. In this analysis, significant predictors of recurrence free survival and disease - specific survival were; (1) histologic type for the primary tumor, (2) extent of the intracranial extension, and (3) status of the final surgical resection margins (Table 5). Among the tumors occurring at the skull base, which are less frequently seen by the surgical pathologist, are small round cell tumors. The more common types of small round cell tumors seen at the skull base are olfactory neuroblastoma, rhabdomyosarcoma, sinonasal undifferentiated carcinoma, nasopharyngeal carcinoma, and lymphoma. Included in the key diagnostic elements needed in the overall evaluation of these tumors are: tumor growth patterns cellular composition and stromal components cytologic features immunohistochemical staining results and cytogenetic examination Indications for Intraoperative Consultation in Skull Base Surgery The indications for intraoperative consultation for skull base surgery may include: 1) determination of tumor type or process ( e.g. neoplastic vs. inflammatory) 2) evaluation of adequacy of surgical margins of resection 3) determination of presence of perineural invasion (pre-operative radiographic studies may suggest perineural invasion along cranial nerves) 4) evaluate viability or adequacy of tissue procurement for special studies (e.g. immunofluorescence, cytogenetics, lymphoma-flow cytometric analysis ) Surgeon's Expectation of the Intraoperative Assessment The surgeon's expectations in the intraoperative assessment of skull base surgery may include: 1) determining benign from malignant lesion 2) identify and specify location of neural invasion 3) determining the extent and location of perineural invasion in an oriented nerve (tagged by the surgeon to aid in embedding for appropriate evaluation of segment in question) 4) determining adequacy of surgical resection margin ( neural, soft tissue or mucosal) 5) determine the presence and adequacy of viable lesional tissue to obtain a definitive diagnosis or perform auxiliary studies Handling of Resected Tissue The handling of skull base resection specimens will vary according to the structures included within the extirpation. A detailed gross examination of the resection specimen is necessary for evaluating the boundaries of the surgical margins, locating the closest surgical margin, and locating anatomic landmarks to aid in reporting locations. Use of bone marrow smears to evaluate bony margins is usually inadequate and relegated to evaluation after decalcification on permanent section. Specimen should be inspected for location of closest surgical margin of excision and findings discussed with the surgeon and/or frozen section performed. Pitfalls in the Intraoperative Assessment From the above discussion, a few special considerations should be kept in mind when performing frozen sections for skull base surgeries. The vast majority of the patients have already been diagnosed. The collaborative study group findings confirmed that a significant number (60%) of patients who receive a skull base resection have been treated by prior surgery, irradiation, chemotherapy, or a combination of modalities. Regardless of the tumor type the following should be kept in mind at the time of resection: Freezing mucosal surfaces can be problematic under idea conditions, however prior radiation, chemotherapy or both can significantly alter the microanatomy. The size of tissue fragments to be frozen is often problematic. The vast majority of these tissue fragments are small, often without normal anatomic landmarks or incomplete microanatomy borders. Interpreting tangentially cut tissue can be challenging to even the most experienced of pathologist. Proper orientation requires continual and exacting communication between the pathologist and the surgeon with frequent use of some sort of marking relationship on the specimen submitted. Useful information for the pathologist would include location (foramina) and request marking the area of concern to facilitate appropriate embedding. This is particularly important when segments of nerves are submitted for intraoperative consultation to be assessed for perineural invasion. In this setting, the neural margin of concern (designated by the surgeon) is cross-sectioned for circumferential evaluation and the remainder of the nerve is evaluated along the long axis. Pre-operative therapy may have an effect on the histomorphology of the tumor (e.g. cytodifferentiation). The prior diagnostic tissue whether inside the institution or outside should be reviewed prior to the resection. Knowledge of normal adjacent structures that may cause an interpretive error on frozen section. Olfactory Neuroblastoma (ONB) or Esthesioneuroblastoma Olfactory neuroblastoma is a malignant neoplasm which arises from the olfactory neuroepithelium found in the upper third of the nasal cavity. Three cell types are described within this specialized epithelium: bipolar sensory neurons; supporting cells; and reserve cells. The reserve cells are mitotically active and thought to be the putative cell of origin of this neoplasm. Clinical ONB occurs both in men and women alike, over a wide age range. Some studies have found a bimodal peak of occurrence at 15 and 50 years of age, however the vast majority of cases are seen in the third and fourth decades. Unilateral nasal obstruction, ocular disturbances, epistaxis, anosmia, headache, pain, excessive lacrimation, and ocular disturbances are common symptoms. The most common site of origin is the upper third of the nasal vault with frequent involvement of the ethmoid sinus and cribriform plate. There are no known etiologic factors for this tumor. Radiographic studies of ONB may show speckled calcification of the lesion. MRI may show enhancement with suggesting a vascular neoplasm. Pathology The gross examination usually shows a small mucosal-covered polypoid mass which is pink-red in appearance. The mass is frequently is unilateral. The microscopic features of ONB have been divided into four grades (Hyams Grading System - Table 6). The low power histomorphology of ONB includes highly vascularized stroma which is infiltrated by small blue cell in nested growth pattern. The cells have indistinct cytoplasmic borders and round, mildly vesicular, nuclei. Identification of mitotic figures and nucleoli are rare. A neurofibrillary background containing vague annular arrays of cells, called pseudorosettes (Homer Wright type), may be present. These tumors may also show divergent differentiation in the form of ganglion cells, melanocytic cells, aberrant glandular formations, and myogenic cells. This divergent differentiation certainly could have potential for diagnostic confusion, particularly when evaluating a frozen section. Immunohistochemical studies show the cell nests are rimmed by sustentacular (support) cells which stain positive for S100. Other positive immunohistochemical stains include neuron specific enolase (NSE), synaptophysin, infrequently chromogranin, and, very rarely (less than 20%), low molecular weight cytokeratin. Molecular studies initially had suggested ONB may be a member of the Ewing sarcoma/peripheral neuroectodermal tumor (PNET) family. The translocation common to the Ewing sarcoma/PNET group, EWS/FLI1, however has not been substantiated. Treatment and Prognosis The treatment sequence for olfactory neuroblastoma varies from center to center. The treatment for olfactory neuroblastoma includes complete surgical resection, if possible, with adjunctive radiotherapy. The stage of the olfactory neuroblastoma will dictate therapy but whether the tumor receives pre-operative therapy is variable Kadish et al, proposed a clinical staging system for this neoplasm which accesses the extension of tumor beyond the nasal cavity (see Table 7). The five-year survival for a stage I is 57-88%, stage B 58-60%, and stage C 0-50%. Late recurrences (20 years), primarily local recurrence, and metastases do occur (lymph nodes 10-30%, distant metastasis lung and bone) making five-year survival less significant. The prognostic value of histomorphologic features in olfactory neuroblastoma is uncertain. Hyams et al, introduced a four tiered histologic grading system which in the initial series correlated with patient outcome, however clinical usefulness of this grading system remains uncertain. Rhabdomyosarcoma (RMS) Rhabdomyosarcoma (RMS) is a soft tissue sarcoma demonstrating skeletal muscle differentiation, which is a significant disease of childhood and adolescence. It is the most common sarcoma of childhood and comprises about 4-8% of all pediatric cancers. The tumor is included within the rubric of "small round cell tumors". Clinical The origin of approximately 40% of all RMS is in the head and neck, and of these, up to 90% occur in children. Moreover, this sarcoma accounts for up to 25% of all head and neck sarcomas. Sites of origin within the head and neck include orbit, nasopharynx, nose, and paranasal sinuses, middle ear, and temporal bone. Although very rare, when RMS occurs in the head and neck in an adult the sinonasal tract is the most common site. Both genders are nearly equally affected with only a slight male predominance. Patients with sinonasal tract and nasopharyngeal RMS present with sinusitis, nasal obstruction, epistaxis, pain, otalgia, headaches, and facial swelling. Pathology The RMS frequently appears as a submucosal nodule or polyp which, in the sinonasal tract, clinically mimics a sinonasal papilloma or inflammatory polyp. On cut surface, the lesion is a soft, gelatinous and tan-white mass capable of attaining considerable size. The World Health Organization divides RMS into six histologic types: sarcoma botryoides; embryonal; alveolar; pleomorphic; spindle cell; and RMS with ganglionic differentiation (ectomesenchyoma). The embryonal type is the most common histologic type (80-85% of head and neck cases), but the proportion of alveolar tumors (10-15% of head and neck cases) increases with age (at the time of diagnosis). This histologic classification of these tumors is clinically relevant because alveolar RMS is associated with significantly decreased survival as compared with the other histologic types. Histomorphology of each histologic type is slightly different with a few key features: embryonal type: cells are small, often spindled with eccentrically located eosinophilic cytoplasm or small lymphocyte-like cells in a fibrillary or myxoid background; botryoid type: is a variant of embryonal differing only by the gross appearance and the occasional presence of a "cambium" layer (condensed tumor cells seen usually subjacent to the surface); spindle cell type: highly differentiated form of embryonal type composed of spindle cells which recapitulate the later stages of muscle development; alveolar type: small, hyperchromatic lymphocyte-like cells with a thin eccentrically located rim of eosinophilic cytoplasm, fibrous trabeculae containing "free floating" tumor cells within the spaces. Tumors may have large multinucleated cells; pleomorphic type: is composed of numerous large pleomorphic rhabdomyoblasts with deeply eosinophilic cytoplasm; ectomesenchymoma : is a very rare form of this sarcoma which usually contains ganglion cells. Among the special studies techniques that facilitate information necessary for the diagnosis and prognosis of RMS are immunohistochemical stains and cytogenetics. Useful immunohistochemical stains for this sarcoma are the cytoplasmic stains, desmin, muscle specific actin, and the nuclear stains, myogenin and myo-D1. Cytogenetics can confirm the alveolar subtype which has translocations involving chromosomes 2 and 13 or chromosomes 1 and 13. These chromosomal translocations create chimeric genes PAX3-FKHR t (2; 13) and PAX7-FKHR t (1; 13) which have prognostic significance. The alveolar RMS of the head and neck are usually PAX3-FKHR type which portends a poorer prognosis (widespread disease). Treatment and Prognosis Remarkable advances in the treatment of RMS have occurred in the last three decades. The Intergroup Rhabdomyosarcoma Study Group (IRSG) have developed multimodality therapy (chemotherapy, radiotherapy and surgery), surgicopathologic criteria for clinical groupings. These groupings are according to local extension of disease, regional and distant metastases, and amount of residual tumor remaining after resection. For RMS of the head and neck region in children the 5-year overall survival rate is 74-77%. The 5-year disease-free survival in this group is 58-74%. In the head and neck , RMS is further classified by the site which include orbital ( most common site), parameningeal (middle-ear temporal bone, external auditory canal, nasopharynx, nasal cavity, paranasal sinuses and infratemporal fossa) and other head and neck sites( scalp, neck, parotid, oral cavity, oropharynx and larynx). The various head and neck sites correlate with prognosis and, therefore, have been incorporated into the staging system. The five year survival for the various head and neck subsites are: orbital- 92%, parameningeal-69% and other head and neck sites-81%. When all body sites are viewed collectively the 5 year survival is 63%. Therapy (cytotoxic drugs) induced changes, usually cytodifferentiation, in the RMS have been noted at least since 1984 (Molenaar) and observed in both recurrences and second-look tumor resections. Awareness of the possibility of increased cytodifferentiation occurring within RMSs prior to the surgical management which may require intraoperative surgical margin assessment may be crucial to the success of the procedure (Table 8). When evaluating for therapy-related changes, the initial pre-treatment and post-therapeutic surgical pathology specimens should be reviewed. Cytodifferentiation is characterized by a variety of changes that closely resemble skeletal muscle including, polygonal rhabdomyoblasts with prominent eosinophilic cytoplasm, strap cells with abundant eosinophilic cytoplasm or spindle cells resembling smooth muscle cells. In areas showing cytodifferentiation, the overall cellularity of the specimen is decreased and the mitotic activity is low. These cytodifferentiated tumor cells still express myoid markers. Sometimes distinguishing cytodifferentiated tumor from skeletal muscle regeneration is problematic. In reported series, embryonal type of RMS most frequently had extensive cytodifferentiation. Cytodifferentiation caused by cytotoxic drugs is associated with reduced proliferation and chemoresistance. The finding of cytodifferentiation should be included in the final pathology report findings. Sinonasal Undifferentiated Carcinoma (SNUC) SNUC is a rare, extremely aggressive epithelial tumor. This malignant tumor is thought to be derived from Schneiderian epithelium lining the nasal cavity and paranasal sinuses. Clinical The demographics reported for this neoplasm are mixed however it appears the tumor has a slight male predominance. SNUCs occur in a wide range of ages (20-81yrs) with the median around the sixth decade. At presentation, these tumors are usually destructive bulky lesions invading the nasal cavity, multiple paranasal sinuses, and extending into the periorbital tissues or central nervous system. The tumor usually does not involve the nasopharynx unless there is secondary extension, which is rare. The patients frequently have had symptoms for 3-4 months which include epistaxis, headaches, nasal obstruction, cranial nerve palsies, weight loss and visual disturbances. Exposure to nickel and cigarette smoking have been suggested as possible etiologic factors to this tumor. The median survival in some series is 18 months. Because of the dismal survival it is necessary to distinguish this tumor from ONB and nasopharyngeal carcinoma (Table 9). Pathology The histomorphology of SNUC is characterized by a markedly cellular proliferation of hyperchromatic cells with inconspicuous nucleoli and a high nuclear-to-cytoplasmic ratio. Trabecular, sheet like, ribbon and organoid growth patterns have been described. The tumor cells are round with oval hyperchromatic nuclei and a brisk mitotic index (>10MF/10HPF). Areas of confluent necrosis, neurotropism and vascular invasion are common. Pseudorosettes, neurofibrillary material, glandular foci and squamous differentiation are not features of SNUC. These tumors on ultrastructure show sparse neurosecretory granules. Ninety percent of SNUCs are positive for cytokeratin, showing some neuron specific enolase (NSE) staining and approximately 65% stain positively with epithelial membrane antigen (EMA). Occasionally, an overlying component of dysplastic mucosa can be identified. Sites for metastases include bone, brain, liver and regional lymph nodes. Treatment and Prognosis The treatment for SNUC is multimodality therapy which includes radiotherapy and surgical resection. SNUC however is a highly aggressive tumor that usually cannot be completely removed by surgery. It is not particularly responsive to irradiation either. Reported survival intervals have ranged from 3 months to 18 months. There have been some reports of slight increase in survival with triple therapy. Nasopharyngeal Carcinoma (NPC) Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma which is derived from the surface epithelium of the nasopharynx. Clinical This particular tumor is primarily a tumor of adults between the ages of 30 and 50 years of age. Irrespective of geographic location there is a 2:1 male predominance. NPC is rare tumor in the United States (0.25%) but is quite common in Southern China and in Africa (Sudan , Tunisia , Uganda , Kenya , and Nigeria ) where the tumor is more common in children. The etiology of this malignancy is multifactorial but the tumor is well-known for its association with the Epstein-Barr virus which can be demonstrated in all histologic subtypes of NPC. Patients may be asymptomatic except for a neck mass in the posterior triangle of the neck. Cranial nerve deficits, epistaxis, chronic serous otitis media, and nasal obstruction are frequently present on initial examination. In contrast to other squamous cell carcinomas of the head and neck, these patients do not have a significant risk for second primary tumors. Pathology The gross appearance of NPC is usually a slight bulge under an intact overlying mucosa. The most common location for NPC to arise is within the lateral wall of the nasopharynx at the fossa of Rosenmüller, just behind the pharyngeal opening of the Eustachian tube. The histologic features are that of a squamous cell carcinoma with varying degree of differentiation. The tumors are divided into squamous cell carcinoma, differentiating non-keratinizing carcinoma, and undifferentiated carcinoma. The first resembles any squamous cell carcinoma seen at any other body site with prominent keratin formation. Differentiated non-keratinizing carcinoma shows no evidence of keratinization but grows in a sheet like pattern. This histologic subtype has been said to resemble transitional cell carcinoma of the bladder. Undifferentiated carcinoma is composed of loosely cohesive cells with indistinct borders, large vesicular nuclei, often infiltrated by lymphocytes. Nonkeratinizing type of NPC can be so undifferentiated as to raise the possibility of lymphoma. The classification by the World Health Organization divides NPC into two broad categories, the keratinizing squamous cell carcinoma and non-keratinizing carcinoma. The nonkeratinizing carcinoma group is further subdivided into differentiated non-keratinizing carcinoma and undifferentiated carcinoma. The non-keratinizing carcinomas are the most common form of NPC in endemic regions (China ). Treatment and Prognosis Due to the infiltrative nature of NPC and close anatomic proximity of vital structures, irradiation is the therapy of choice. Local and regional disease can be adequately managed by radiotherapy, while the role of chemotherapy is usually reserved for disseminated disease. Surgery is reserved solely for radioresistant tumors. Mucosal Melanoma (MM) Mucosal melanomas (MM) are malignant neoplasms demonstrating melanocytic differentiation derived from the neural-crest. Clinical Mucosal melanomas have a much worse prognosis when compared to their cutaneous counterparts. The head and neck region is the most common site for MM (55%). The occurrence of MM in the oral and sinonasal regions is about equal, 48% and 52%, respectively. With the sinonasal group, the nasal cavity is dominant (82%) with the sinuses representing about 16% of tumors. Within the nasal cavity the most frequently involved areas are the anterior septum, inferior turbinate, and middle turbinate. Among the paranasal sinuses the maxillary antrum and ethmoid sinuses are frequent sites of occurrence. There is no sex predilection and over 75% of the patients are over fifty years of age. Tumor thickness parameters used for cutaneous melanomas do not apply to mucosal melanoma. Pathology Grossly, these tumors can appear as an ulcerated polypoid structure with brown to pink coloration. The varied histologic appearance of melanomas is notorious. The appearance may range from spindle-shaped cells to epithelioid cells with eosinophilic cytoplasm and prominent eosinophilic nucleoli. Prominent vascular network may be present. Approximately one-third of these melanomas will have pigmentation. Treatment and Prognosis Complete surgical resection is the treatment of choice. MM of the sinonasal tract is extremely aggressive with a local recurrence rate of 60-80%. The five-year survival.is a dismal 10% . Table 1. Anterior skull base lesions Meningoencephaloceles Mucoceles Benign tumor and tumor-like condition Polyps Inverted papilloma Giant cell granuloma Malignant tumors from paranasal sinuses and nasal cavity Carcinomas Esthesioneuroblastoma Lymphoma Plasmacytoma Melanoma Malignant fibrous histiocytoma Langerhans' cell histiocytosis Sarcoma Modified from Surgery of the Skull Base, Donald PJ ed.Philadelphia, Lippincott-Raven, 1998, pp. 89. Table 2. Central skull base lesions Epidermoid cyst Cholesterol cyst Peripheral nerve sheath tumors Schwannoma Neurofibroma Meningioma Chordoma Chondrosarcoma Carcinoma of nasopharynx invading skull base Metastases Multiple myeloma, including plasmacytoma Modified from Surgery of the Skull Base, Donald PJ ed.Philadelphia, Lippincott-Raven, 1998, pp. 92. Table 3. Posterior skull base lesions Cerebellopontine angle lesions Jugular fossa tumors Foramen magnum lesions Acoustic neurinoma Meningioma Tumors Malignant lesions Carcinoma Endolymphatic sac tumor Facial nerve neurinoma Epidermoid cyst Arachnoid cyst Vascular lesions Metastatic disease Ependymoma originating in fourth ventricle of cerebellum Glomus jugulare tumor Neurogenic tumors Chondrosarcoma Meningioma Intradural extramedullary Meningioma Neurogenic tumors Extradural Bone lesions Metastases Chordoma Inflammatory and miscellaneous lesions Rheumatoid arthritis Synovial cyst Modified from Surgery of the Skull Base, Donald PJ ed.Philadelphia, Lippincott-Raven, 1998, pp. 98. Table 4. Collaborate Study Group Malignant Tumors Squamous cell carcinoma 375 (28.8) Adenocarcinoma 210 (16.1) Esthesioneuroblastoma 151 (11.6) Malignant salivary tumors 124 (9.5) Skin malignancies 120 (9.1) High grade sarcoma 93 (7.1) Other malignancies 89 (6.8) Melanoma 53 (4.1) Low grade sarcoma 53 (4.1) Undifferentiated or anaplastic tumors 39 (3.0) Table 5. Margins Collaborative Study Group Craniofacial Resection Margins of surgical resection No. of Patients (%) Close 191 (14.6) Negative 710 (54.3) Positive 221 (17.0) Data not reported 185 (14.1) Modified from Cancer 2003;98:1179-1187. Table 6. Hyams' Grading System for Olfactory Neuroblastoma Feature Grade I Grade II Grade III Grade IV Architecture Lobular Lobular ± Lobular ± Lobular Mitotic activity Absent Present Prominent Marked Nuclear pleomorphism Absent Moderate Prominent Marked Fibrillary matrix Prominent Present Minimal Absent Rosettes ± HW ± HW Flexner Absent Necrosis Absent Absent ± Present Common Hyams VJ, Batsakis JG, Michaels L. Tumors of the Upper Respiratory Tract and Ear. 2nd Ser. Fasc 25, Atlas of Tumor Pathology, Washington , DC : Armed Forces Institute of Pathology, 1988. Table 7. Kadish Staging of Olfactory Neuroblastomas Stage Description A Disease confined to nasal cavity B Disease confined to the nasal cavity and one or more paranasal sinuses C Disease extending beyond the nasal cavity or paranasal sinus Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. A clinical analysis of 17 cases. Cancer 37:1571-1576, 1976. Table 8. Therapy related changes in RMS Series and Cases with Cytodifferentiation/Total Cases Histologic Type Molenaar 1984 d'Amore 1994 Heyn 1997 Coffin 1997 Total % Embryonal (all types) 6/7 4/4 (3H&N) 27/27 7/8 (1H&N) 96% "Solid" 3/4 0 0 0 75% Alveolar 1/4 0 1/1 4/8 (2H&N) 46% Total 10/15 4/4 28/28 11/16 84% Modified from Advances in Anatomic Pathology, 7(6):348, 2000 Table 9. Immunohistochemical staining of common small round cell tumors Neoplasm Myogenin CK EMA LCA Synaptophysin HMB-45 Desmin Vim CD99 SNUC - + + - - - - - - ONB - +/- - - + - - - - NPC - + + - - - - - - Lymphoma - - - + - - - + +/- Melanoma - - - - - + - + - RMS + - - - - - + + - CK, cytokeratin; EMA, epithelial membrane antigen; LCA, leukocyte common antigen. SNUC, sinonasal undifferentiated carcinoma; ONB, olfactory neuroblastoma; NPC, nasopharyngeal carcinoma; RMS - rhabdomyosarcoma References Intraoperative Consultation Acs G, Baloch ZW, LiVolsi VA. Intraoperative consultation. An historical perspective. 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