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Primitive Neuroectodermal Tumor (PNET) is a soft tissue sarcoma classically described under small round blue cell tumors (SRBCT). There is considerable clinical and histologic overlap between this tumor and Ewing's sarcoma (ES). For many years, pathologists struggled to make a diagnostic distinction. Now with sophisticated molecular biological analysis, it turns out that both tumors share a common and unique chromosomal translocation. Most investigators now believe that Ewing's sarcoma and PNET are different morphological expressions of one tumor type. In general, Ewing's sarcoma arises within the bone while PNET arises within soft tissues. However, there are overlap cases of Ewing's sarcoma arising within soft tissue (Extraosseous Ewing's Sarcoma) and PNET arising within the bone. Under the microscope, the tumors share a considerable homology though there are usually more neuroendocrine features with PNET. Ewing's sarcoma is thought to be a more undifferentiated tumor. Though data is conflicting, some investigators believe ES to have a slightly better prognosis.

PNETs most commonly occur in buttocks and upper thighs and may be intimately associated with a large peripheral nerve such as the sciatic nerve.


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Peripheral neuroepithelioma
Peripheal neuroblastoma
Askin tumor (Thoracopulmonary PNET)
Extraosseous Ewing's sarcoma
INCIDENCE 1% of all sarcomas
AGE RANGE-MEDIAN 75% <35 years



Characteristic translocation shared with this tumor and Ewing's sarcoma of the bone-found in >90% of cases

Fusion gene designated EWS/FLI-1

Monoclonal antibodies to the fusion gene protein product are termed CD99

Visceral primitive peripheral neuroectodermal tumors: A clinicopathologic and molecular study

Maureen J. O'Sullivan, MD
Elizabeth J. Perlman, MD
Jaime Furman, MD
Peter A. Humphrey, MD, PhD
Louis P. Dehner, MD
John D. Pfeifer, MD, PhD

Hum Pathol 2001;32:1109-1115. Abstract quote

Ewing sarcoma–primitive neuroectodermal tumor (EWS/PNET) belongs to the group of pediatric small round blue cell tumors; although EWS/PNET is classically a tumor of the soft tissue or bone in children and young adults, individual cases have been described in patients of all ages. A group of chromosomal translocations involving the EWS gene and a member of the Ets transcription factor family of genes has been detected in EWS/PNET, and heterogeneity in the precise breakpoint of the translocation has been shown to generate a group of related fusion transcripts that may have prognostic significance. Within the last decade, the clinicopathologic spectrum of EWS/PNET has been markedly expanded by recognition that the tumor may also have a visceral origin.

To determine whether visceral EWS/PNET has the same pattern of genetic alterations and range of fusion transcripts as EWS/PNET of bone and soft tissue, we performed reverse-transcription polymerase chain reaction–based testing of formalin-fixed, paraffin-embedded tissue from a series of visceral tumors for which the diagnosis of EWS/PNET was well established.

Together with additional cases compiled from the literature, EWS-Fli1 (or a related fusion transcript) was present in 18 of 19 visceral EWS/PNET, with a distribution of transcript types not statistically different from EWS/PNET of soft tissue and bone (P > .05, 2 test).

These results firmly establish the genetic relationship between EWS/PNET of visceral sites, soft tissue, and bone.

Molecular diagnosis of Ewing sarcoma/primitive neuroectodermal tumor in routinely processed tissue: a comparison of two FISH strategies and RT-PCR in malignant round cell tumors.

Bridge RS, Rajaram V, Dehner LP, Pfeifer JD, Perry A.

1Department of Pathology and Immunology, Lauren V Ackerman Laboratory of Surgical Pathology, Barnes-Jewish and St Louis Children's Hospitals, Washington University Medical Center, St Louis, MO, USA.

Mod Pathol. 2006 Jan;19(1):1-8. Abstract quote

Ewing sarcoma/primitive neuroectodermal tumor (EWS/PNET) is a diagnostically challenging malignant round cell tumor with signature translocations involving the EWS gene. These translocations are detectable with both reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) in formalin-fixed paraffin-embedded tissue. However, RT-PCR is less sensitive in formalin-fixed paraffin-embedded than frozen tissue. Similarly, commercial FISH probes have recently become available, but have yet to be rigorously tested in the clinical setting.

Therefore, we have compared RT-PCR with FISH using 'home brew' fusion probes for Ewing sarcoma (EWS)-FLI1 and a commercial EWS break apart probe set in 67 archival round cell tumors, including 27 EWS/PNETs. Sensitivities and specificities for both FISH assays were 91 and 100%, respectively, whereas RT-PCR had a sensitivity of 54% and a specificity of 85%. The break apart strategy was easier to interpret than probe fusion approach.

We conclude that FISH is a more sensitive and reliable ancillary technique than RT-PCR for the diagnosis of EWS/PNET in formalin-fixed paraffin-embedded tissue, although the latter provides additional information regarding fusion transcript subtype and prognosis. The commercial break apart probe set is both readily available and easy to interpret, making it particularly attractive. Nonetheless, complex round cell tumors often benefit from molecular testing with multiple methods.


Ewing sarcoma family of tumors.

Khoury JD.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Adv Anat Pathol. 2005 Jul;12(4):212-20. Abstract quote  

The Ewing sarcoma family of tumors (ESFT) comprises morphologically heterogeneous tumors that are characterized by nonrandom chromosomal translocations involving the EWS gene and one of several members of the ETS family of transcription factors. The translocation t(11;22)(q24;q12) is the most common and leads to the formation of the EWS-FLI1 fusion protein, which contributes to ESFT pathogenesis by modulating the expression of target genes.

Tumors may be composed of small uniform cells with minimal morphologic evidence of differentiation, or they may be composed of larger, less uniform cells with varying degrees of neuroectodermal differentiation. CD99 expression is identified in nearly all ESFT and constitutes a useful positive marker when used as part of a panel of immunostains that can help rule out other differential diagnostic considerations. Molecular diagnostic tests commonly used to detect the presence of ESFT-specific translocations include RT-PCR and fluorescence in situ hybridization.

Current therapy for patients with ESFT includes chemotherapy and surgery with or without radiation therapy. At present, the most significant prognostic factor for patients with ESFT is whether the disease is localized or metastatic.
ASKIN TUMOR Thoracopulmonary PNET
Peripheral primitive neuroectodermal tumor/Ewing's sarcoma of the craniospinal vault: case reports and review.

Mobley BC, Roulston D, Shah GV, Bijwaard KE, McKeever PE.

Department of Pathology, Stanford University Medical Center, Stanford, CA 94035, USA.

Hum Pathol. 2006 Jul;37(7):845-53. Epub 2006 May 19. Abstract quote  

The peripheral primitive neuroectodermal tumor/Ewing's sarcoma family tumor (pPNET/ESFT) group includes small round cell tumors of the bone, soft tissue, and nerve with morphological attributes of the germinal neuroepithelium. Peripheral PNETs/ESFTs also occur within the craniospinal vault, a region including the central nervous system, the meninges, and the cranial and spinal nerve roots.

Gene rearrangements between the EWS gene on chromosome 22q12 and members of the ETS gene family are common in and specific to pPNETs/ESFTs. Another defining characteristic of pPNETs/ESFTs is their membranous expression of the MIC2 gene product. We describe 2 cases of pPNETs within the craniospinal vault. An intradural tumor arising from the nerve roots of the cauda equina was discovered in a 32-year-old man presenting with radiculopathic back pain and lower-extremity weakness. An intracranial pPNET that mimicked a meningioma was found in a 21-year-old man presenting with headache and visual disturbances. MIC2 gene product expression and EWS/ETS gene rearrangement were detected in both case patients.

The literature with regard to pPNETs/ESFTs arising within the craniospinal vault is reviewed.
Promoter hypermethylation profile of RASSF1A, FHIT, and sFRP1 in intracranial primitive neuroectodermal tumors.

Chang Q, Pang JC, Li KK, Poon WS, Zhou L, Ng HK.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.

Hum Pathol. 2005 Dec;36(12):1265-72. Abstract quote  

Medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumors (SPNETs) are histologically alike intracranial PNETs found in different anatomical locations of the brain. Current evidence suggests that hypermethylation of promoter CpG islands is a common epigenetic event in a variety of human cancers.

The aim of this study was to investigate whether promoter hypermethylation of putative tumor suppressor genes was involved in both types of intracranial PNETs. We examined the methylation status at promoter regions of RASSF1A, FHIT, and sFRP1 by methylation-specific polymerase chain reaction in a cohort of 25 primary MBs, 9 primary SPNETs, and 3 MB and 2 SPNET cell lines. Our results revealed no promoter hypermethylation of RASSF1A, FHIT, and sFRP1 in 2 normal cerebellar and 5 normal cerebral tissue specimens examined. In contrast, promoter hypermethylation of RASSF1A was detected in 100% of primary MBs, 67% (6/9) of primary SPNETs, and all PNET cell lines. The frequency of promoter hypermethylation of RASSF1A was significantly lower in SPNETs than in MBs (Fisher exact test, P = .014). Treatment of RASSF1A-deficient PNET cell lines with 5-aza-2'deoxycytidine, a demethylating agent, restored RASSF1A expression, providing evidence that promoter hypermethylation contributes to transcriptional silencing. In addition, promoter hypermethylation of FHIT and sFRP1 was detected in 22% (2/9) and 11% (1/9) of SPNETs, respectively, but not in any MBs studied.

In conclusion, our study demonstrates that promoter hypermethylation of RASSF1A is a common event in intracranial PNETs, whereas FHIT and sFRP1 are epigenetically affected in a fraction of SPNETs.

Primitive neuroectodermal tumor of the cervix: A clinicopathologic and immunohistochemical study of two cases.

Malpica A, Moran CA.

Department of Pathology, M. D. Anderson Cancer Center, Houston, TX.

Ann Diagn Pathol 2002 Oct;6(5):281-7 Abstract quote

Two cases of primary primitive neuroectodermal tumors of the cervix are presented. The two female patients are 35 and 51 years of age who presented with abnormal uterine bleeding of several weeks' duration.

On gynecologic examination, a mass in the cervical area was palpated and a biopsy was obtained. The initial biopsy was interpreted as possible small cell carcinoma in both women. A radical hysterectomy was performed in both patients. Grossly, in both cases, the uterine cervix showed an ill-defined tumor involving the ectocervix and endocervix, measuring 3.0 and 4.0 cm in greatest dimension, respectively, and showing areas of necrosis and hemorrhage.

Histologic sections showed the presence of a malignant neoplasm arranged in cords and with a vague nesting pattern. Areas of hemorrhage and necrosis were also present. The neoplastic cells were characterized by having indistinct cell borders, small round to oval nuclei, and inconspicuous nucleoli. Mitotic figures were easily identified. In one patient, the tumor had metastasized to lymph nodes. Immunohistochemical studies revealed the neoplastic cells to be positive for antibodies for CD99 and focally for synaptophysin, while keratin, chromogranin, smooth muscle actin, desmin, and neurofilament protein were negative. Both patients received adjuvant chemotherapy and remain alive 5 and 18 months after initial diagnosis, respectively.

The present cases highlight the importance of keeping primitive neuroectodermal tumors in the differential diagnosis of small cell neoplasms of the uterine cervix.


Primary Peripheral PNET/Ewing's Sarcoma of the Dura: a Clinicopathologic Entity Distinct from Central PNET.

Dedeurwaerdere F, Giannini C, Sciot R, Rubin BP, Perilongo G, Borghi L, Ballotta ML, Cornips E, Demunter A, Maes B, Dei Tos AP.

Department of Pathology (FD, RS, AD, BM), Katholieke Universiteit Leuven, Leuven, Belgium.

Mod Pathol 2002 Jun;15(6):673-8 Abstract quote

We describe two cases of peripheral primitive neuroectodermal tumor-Ewing's sarcoma (PNET-ES) arising intracranially in the leptomeninges. Both tumors exhibited a primitive undifferentiated round-cell morphology.

Immunohistochemical stains revealed strong membrane expression of CD99 in both cases. A t(11;22)(q24;q12) could be demonstrated with reverse transcriptase-polymerase chain reaction in one case, whereas fluorescence in situ hybridization analysis performed in the second case showed a rearrangement of the EWS gene.

The occurrence of PNET-ES at this site is very unusual. Immunophenotypical as well as genetic analysis play a key role in the diagnosis and the distinction from central PNET.


Am J Surg Pathol 2001;25:133-146

146 cases from the National Wilms' Tumor Study Group (NWTSG) Pathology Center

Primitive neural tumors with varying amounts of rosettes and neuropil; however, a large proportion of cases displayed unusual features such as spindle cells, ganglion cells, clear cell sarcoma-like foci, rhabdoid cells, epithelioid cells, and organoid foci

Wide age spectrum, ranging from 1 month to 72 years (median, 18 years)

EWS/FLI1 fusion analysis using reverse transcriptase-polymerase chain reaction found only 13 of the 45 were fusion-positive-no correlation between fusion status and histology, presence of rosettes, ultrastructural features, or cytokeratin positivity

CD99 staining had been performed on 69 cases and showed membranous staining in 65
CD99-negative cases were usually fusion-negative (six of seven cases), and all three chromogranin-positive cases were fusion-negative

Tumor staging, performed on 72 clearly defined and quantifiable cases by using NWTSG criteria:
Aggressive tumors
Six were Stage 1
16 Stage 2
31 Stage 3
19 Stage 4 lesions

Generally aggressive, high-grade lesions that may present in a wide age range and are difficult to characterize without immunohistochemistry and cytogenetics/molecular biology

Immunohistochemistry of primary malignant neuroepithelial tumors of the kidney: a potential source of confusion? A study of 30 cases from the National Wilms Tumor Study Pathology Center.

Department of Pathology, Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.

Hum Pathol. 2007 Feb;38(2):205-11. Epub 2006 Nov 28. Abstract quote

Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET) is a rare primary tumor of the kidney with morphologic features similar to those of other primitive tumors. Previous studies have shown that these tumors frequently stain positively with immunostains against CD99 and FLI-1 and negatively with stains against WT-1, suggesting that these markers may be used for the distinction between Wilms tumor and pPNET.

We present 30 cases of primary malignant neuroepithelial tumor with immunohistochemical profiles and reverse transcriptase polymerase chain reaction (RT-PCR) analysis and show that immunophenotypic overlap exists between Wilms tumor and pPNET. A subset of 30 neuroepithelial tumors from the National Wilms Tumor Study originally categorized as putative pPNETs of the kidney was stained with FLI-1, WT-1, and thyroid transcription factor-1. Bicolor fluorescence in situ hybridization studies were performed on 19 of the cases. Other data on these tumors were available from a previous study (Am J Surg Pathol 2001;25:133). Of 7 primary tumors that had the EWS/FLI-1 fusion transcript by RT-PCR, 6 exhibited strong immunopositivity for FLI-1. Nine that were negative by RT-PCR stained positively with the FLI-1 stain. Five fusion-negative cases stained with both FLI-1 and WT-1. Three fusion-negative cases were negative for FLI-1 but positive for WT-1. Five fusion-negative cases were negative for both FLI-1 and WT-1. Of the 30 cases, 29 were positive for CD99. Seven cases that were negative for the EWS-FLI-1 fusion by RT-PCR were positive by fluorescence in situ hybridization. All cases were negative for thyroid transcription factor-1.

Reliance upon immunohistochemistry as the sole means of ancillary diagnosis in renal pPNET can lead to confusing results.

We recommend molecular fusion studies for clarification of primitive renal tumors with unexpected immunophenotypic results.
Primary Ewing's Sarcoma/Primitive Neuroectodermal Tumor of the Kidney
A Clinicopathologic and Immunohistochemical Analysis of 11 Cases

Rafael E. Jimenez, M.D.; Andrew L. Folpe, M.D.; Rosanna L. Lapham, M.D.; Jae Y. Ro, M.D.; Patricia A. O'Shea, M.D.; Sharon W. Weiss, M.D.; Mahul B. Amin, M.D.

From the Departments of Pathology and Laboratory Medicine (R.E.J., A.L.F., P.A.O., S.W.W., M.B.A.), Emory University School of Medicine, Atlanta, Georgia; and the M.D. Anderson Cancer Center (R.L.L., J.Y.R.), Houston, Texas, U.S.A.


Am J Surg Pathol 2002;26:320-327 Abstract quote

Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is an extraordinarily rare primary tumor in the kidney and can be mistaken for a variety of other round cell tumors, including blastema-predominant Wilms' tumor (WT). Approximately 90% of ES/PNET have a specific t(11;22), which results in a chimeric EWS-FLI-1 protein. Immunohistochemistry for the carboxy-terminus of FLI-1 is sensitive and highly specific for the diagnosis of ES/PNET. WT-1, the WT-associated tumor suppressor gene, is overexpressed in WT but not in ES/PNET. No study has examined FLI-1 or WT-1 expression in renal ES/PNET.

The clinicopathologic features of 11 renal ES/PNET were studied along with immunohistochemistry for cytokeratin, desmin, CD99, FLI-1, and WT-1. WT were also immunostained for CD99 (5 cases), FLI-1 (10 cases), and WT-1 (9 cases). The patients (6 men, 5 women) ranged from 18 to 49 years of age (mean, 34 yr). The mean tumor size was 11.8 ± 3.8 cm (mean ± standard deviation). Presenting symptoms included abdominal/flank pain and/or hematuria. Grossly, all tumors showed necrosis and hemorrhage, and 4 had cystic change. Microscopically, all tumors showed vaguely lobular growth, primitive round cells, and variable rosette formation. Epithelial, myogenous, or cartilaginous differentiation was not seen. Immunohistochemical results on the renal ES/PNET were cytokeratin (2/8 focal), desmin (0/9), CD99 (8/8), FLI-1 (5/8), and WT-1 (0/8). In comparison, the WT only rarely expressed CD99 (1/5) and did not express FLI-1 (0/10), but were usually WT-1-positive (7/9). Follow-up on 8 cases (mean, 28 mo; range, 6–64 mo) showed 4 lung and pleural metastases, 1 bone metastasis, liver metastasis, 2 local recurrences, and 5 deaths from disease (median time to death, 16.8 mo). No case had distant metastatic disease at presentation. Adjuvant therapy included chemotherapy (8 cases), radiation (3 cases), and bone marrow transplantation (1 case).

Our study affirms a unique proclivity of renal ES/PNET for young adults and that it is a highly aggressive neoplasm, with rapid death in many cases, usually after the development of treatment-resistant lung metastases. These tumors must be distinguished from blastema-predominant WT and other primitive renal tumors that require different therapy. FLI-1 and WT-1 immunohistochemistry may be valuable in this differential diagnosis, given the known immunophenotypic overlap between ES/PNET and blastema-predominant WT with regard to CD99, cytokeratin, and desmin. The accurate distinction between these two entities has clear prognostic and therapeutic implications.


Arch Pathol Lab Med 2001;125:397–399

An 18-year-old man presented with hemoptysis
Chest radiographs revealed a right middle lobe mass, and bronchoscopy showed an endobronchial tumor

The lesion was resected by middle lobectomy
After 2 years, a local recurrence was treated by pneumonectomy
The patient died after surgery


Primary neuroectodermal tumors of the ovary. A report of 25 cases.

Kleinman GM, Young RH, Scully RE.

Department of Pathology, Harvard Medical School, Boston, Massachusetts.

Am J Surg Pathol 1993 Aug;17(8):764-78 Abstract quote

Twenty-five primary ovarian neuroectodermal tumors occurred in females from 6 to 69 (average, 23) years of age; they had the usual presenting symptoms of abdominal swelling or pain.

The tumors, which varied from cystic to solid, ranged from 4 to 20 cm (average, 14 cm) in diameter. Microscopic examination revealed three histologic categories--differentiated, primitive, and anaplastic--with the tumors in the first group having a better prognosis than those in the other two groups. Five of the six differentiated gliomas were pure ependymomas, and one was an ependymoma with an astrocytoma component; none contained teratomatous elements. Two patients with stage I tumors were alive 4 and 5 years postoperatively. The one patient with stage IIA tumor was free of disease at 3 years; one of the two patients with a stage III tumor died of tumor after 5 years, and one had two recurrences but was alive and well at 5 years. Twelve tumors were primitive, resembling medulloepithelioma, ependymoblastoma, neuroblastoma or medulloblastoma. Seven tumors had teratomatous foci of other types, including three dermoid cysts. Three patients with stage I tumors were alive at 7 months, 3 years, and 9 years postoperatively; six of seven patients with stage III tumors died of tumor 2 to 20 months postoperatively, and one was alive with disease at 1 year. Seven tumors were anaplastic, resembling glioblastoma. All contained foci of squamous epithelium. One patient with stage IA tumor died of tumor at 2 years, but two were free of tumor after 3 and 4 years. One patient with a stage IIA tumor died of disease after 5 years; another was alive with tumor at 1 year. One patient with a stage III tumor died after 4 months.

The differential diagnosis of neuroectodermal tumors of the ovary includes many primary and metastatic ovarian neoplasms of diverse types, and distinction among them is important. Neuroectodermal tumors should be considered when examining unusual ovarian tumors, particularly if the patient is young.


Primitive Neuroectodermal Tumors of the Pancreas: A Report of Seven Cases of a Rare Neoplasm

Saeid Movahedi-Lankarani, M.D.; Ralph H. Hruban, M.D.; William H. Westra, M.D.; David S. Klimstra, M.D.
Am J Surg Pathol 2002; 26(8):1040-1047 Abstract quote

Primitive neuroectodermal tumors (PNETs) have rarely been described in solid organs.

We report a series of seven PNETs of the pancreas. The clinical, gross, microscopic, and immunohistochemical features of these seven PNETs of the pancreas are described, as are the genetic analyses in five cases. The patients ranged in age from 6 to 25 years (mean 18 years). Four of the patients were male. All of the patients presented with jaundice and/or abdominal pain. All of the tumors were located in the head of the pancreas, and they ranged in size from 3.5 to 9.0 cm. Light microscopy revealed the typical morphologic features of PNETs. By immunohistochemistry the neoplastic cells in all seven cases expressed O13 (CD99, p30/32MIC2). In five of six tested cases, the neoplastic cells also expressed cytokeratin. All of the tumors expressed neural-neuroendocrine markers. Two of the three cases examined ultrastructurally showed prominent epithelial features. There was cytogenetic or molecular genetic evidence of the t(11;22)(q24;q12) in four of five cases examined. Clinical follow-up was available in five cases. Two of the patients were alive with no evidence of disease at 33 and 43 months. One patient was alive with disease at 27 months. One patient died of postoperative complications. Another patient died of disease 4 years after diagnosis. PNET can sometimes arise as a primary neoplasm of the pancreas.

Like PNETs arising in more conventional sites, pancreatic PNETs occur in the pediatric and adolescent population, show the characteristic staining with O13, and typically harbor the t(11;22)(q24;q12) chromosomal translocation. PNETs should be included in the differential diagnosis of poorly differentiated small round cell tumors of the pancreas. Moreover, they should not be confused with pancreatic endocrine tumors, which also demonstrate dual epithelial and neuroendocrine differentiation by immunohistochemistry and express O13 in 30% of cases.



Sheets or lobules of small round cells with dark staining, round to oval nuclei

Indistinct cytoplasm

Occasional rosette formation
Homer-Wright rosette (central solid core of neurofibrillary material)
Flexner-Wintersteiner (central lumen or vesicle)


Peripheral medulloepithelioma: an immunohistochemical, ultrastructural, and cytogenetic study of a rare, chemotherapy-sensitive, pediatric tumor.

Donner LR, Teshima I.


Am J Surg Pathol. 2003 Jul;27(7):1008-12 Abstract quote

A case of peripheral medulloepithelioma, a rapidly growing tumor involving the pelvic cavity of a 12-year-old girl, is presented. The diagnosis was supported by expression of vimentin, nestin, alpha-internexin, neurofilaments, and microtubule-associated protein 5 and by characteristic ultrastructure that included absence of cilia or microvilli.

Trisomy of chromosomes 2 and 8 was the only detectable chromosomal abnormality. Combination chemotherapy resulted in complete remission.

Because some of these rare tumors are sensitive to chemotherapy, their recognition and separation from other neuroectodermal tumors are advisable for better understanding of their biology and determination of optimal treatment.


Intercellular junctions in Ewing sarcoma/primitive neuroectodermal tumor: additional evidence of epithelial differentiation.

Schuetz AN, Rubin BP, Goldblum JR, Shehata B, Weiss SW, Liu W, Wick MR, Folpe AL.

1Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.

Mod Pathol. 2005 Nov;18(11):1403-10 Abstract quote.  

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) has recently been shown to frequently express cytokeratins, suggesting partial epithelial differentiation. Older ultrastructural studies have documented primitive cell-cell junctions in ES/PNET, reportedly resembling poorly formed desmosomes. Recently, paraffin-reactive antibodies have become available to proteins found in a variety of intercellular junctions indicative of epithelial differentiation, including tight junctions, desmosomes and adherens junctions.

We examined intercellular junction protein expression in a large number of genetically confirmed ES/PNET. Formalin-fixed, paraffin-embedded sections from 23 primary and seven recurrent or metastatic cases of genetically confirmed ES/PNET were immunostained for claudin-1 and occludin (tight junction structural proteins), zonula occludens-1 (ZO-1, tight junction linker protein), desmoglein 1/2 (desmosomal adherens protein), desmoplakin (desmosomal structural protein) and E-cadherin (epithelial adherens junction protein), using steam heat-induced epitope retrieval and the Dako Envision system. Cases with >5% positive cells were scored as 'positive'. Normal colonic epithelium and skin served as external positive controls. Claudin-1 was expressed by 19 of 30 specimens (63%), ZO-1 was expressed by 15 of 29 specimens (51%), and occludin was expressed by three of 28 specimens (11%). In 28 specimens all three tight junction markers were evaluable. In all, 15 samples (54%) expressed only one tight junction marker, and 10 samples (36%) expressed two tight junction markers. No case expressed all three tight junction markers. Desmoglein was expressed in one of 30 (3%) samples. Desmoplakin was expressed in two of 28 (7%) samples. E-cadherin was negative in all cases.

Our data suggest that many of the previously described cell-cell junctions in ES/PNET are poorly formed tight junctions, given the high frequency of claudin-1 and ZO-1 expression. This may underestimate the true frequency of tight junction protein expression in ES/PNET, as there are at least 20 different claudins and other ZO proteins. These tight junctions are almost certainly abnormal, given the absence of occludin expression in most cases. Desmosomal and adherens junction protein expression was rare to absent.

Our findings provide additional evidence that ES/PNET frequently show partial epithelial differentiation.
Morphologic and Immunophenotypic Diversity in Ewing Family Tumors: A Study of 66 Genetically Confirmed Cases.

Folpe AL, Goldblum JR, Rubin BP, Shehata BM, Liu W, Dei Tos AP, Weiss SW.

From the *Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA; daggerDepartment of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH; double daggerDepartment of Pathology, University of Washington Medical Center, Seattle, WA; and section signDepartment of Pathology, Regional Hospital, Treviso, Italy.
Am J Surg Pathol. 2005 Aug;29(8):1025-1033. Abstract quote  

More than 85% of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), or "Ewing family of tumors" (EFTs), have the translocation, t (11;22) (q24;q12), with others having variant translocations. Identification of these by cytogenetic and/or molecular genetic techniques is specific for EFT and is increasingly recognized as the "gold standard" for diagnosis. However, these techniques are not universally available.

We therefore studied a large group of genetically confirmed EFTs to more completely understand the morphologic and immunophenotypic spectrum of this rare sarcoma. Sixty-six cytogenetically, FISH or RT-PCR proven-EFTs were retrieved. In 56 cases, immunohistochemistry (IHC) was performed for pan-cytokeratins (PanCK), high molecular weight cytokeratins (HMWCK), desmin (DES), CD99, CD117, and FLI1 protein using heat-induced epitope retrieval and the Dako Envision system.

The cases arose chiefly in children and young adults (median 18 years; range, 3-65 years) of both sexes (male, 32; female, 31; unknown, 3) in a variety of bone (N = 39) and soft tissue (N = 27) sites. Histologically, 46 cases (73%) showed only typical features of ES, 9 cases (16%) showed features of PNET, 3 cases (5%) showed "adamantinoma-like" features, 3 cases (5%) corresponded to "atypical Ewing sarcoma," 3 cases (5%) showed principally intersecting fascicles of spindled cells, and 2 cases had abundant hyalinized matrix. IHC results were as follows: PanCK (18 of 56, 32%), HMWCK (3 of 55, 5%), DES (1 of 56, 2%), CD99 (52 of 52, 100%), CD117 (13 of 54, 24%), and FLI1 (44 of 47, 94%). HMWCK was expressed only in "adamantinoma-like" EFTs, none of which expressed DES.

In conclusion, most, but not all, EFTs can be accurately diagnosed using time-honored morphologic criteria and ancillary immunohistochemistry. However, genetic confirmation remains essential for the diagnosis of unusual morphologic variants of EFT, including "adamantinoma-like," spindled, sclerosing, and clear cell/anaplastic variants. Therefore, to exclude or confirm the diagnosis of Ewing's sarcoma in round cell sarcomas having a variety of patterns but not specifically conforming to a tumor of known lineage (eg, rhabdomyosarcoma), cytogenetics, and/or molecular analysis is required.

Cell surface glycoprotein

Several antibodies to CD99 have been identified including:

>95% sensitivity for PNET/ES

Keratin Positive

Am J Surg Pathol 2000;24:1657-1662
FLI-1 protein is overepxressed as a result of the translocation

Some cases of PNET are negative in spite of CD99 positivity

NSE Positive
Negative Key is negative coexpression of cytokeratin and desmin



Ewing's sarcoma family of tumor arising in the adrenal gland—Possible diagnostic pitfall in pediatric pathology: Histologic, immunohistochemical, ultrastructural, and molecular study

Keisuke Kato, MD
Yoshikazu Kato, MD
Rieko Ijiri, MD
Kazuaki Misugi, MD, PhD
Ikuko Nanba, MT
Jun-Ichi Nagai, MT
Noriyuki Nagahara, MD, PhD
Hisato Kigasawa, MD
Yasunori Toyoda, MD
Toshiji Nishi, MD
Yukichi Tanaka, MD, PhD

Hum Pathol 2001;32:1012-1016 Abstract quote

We present an adrenal Ewing's sarcoma family of tumor (ESFT) arising in an 11-year-old Japanese boy. Although intensive chemoradiotherapy and radical surgery were performed, the patient died of obstinate disease 1 year and 3 months after the initial presentation. The primary site (adrenal gland) with radiologic findings (with foci of calcification), high titer of serum neuron specific enolase, and sheets of monotonous primitive rounded cells on histology mostly favored neuroblastoma. However, a diagnosis of ESFT was confirmed by immunohistochemical profile, including MIC2-positivity and molecular study disclosing EWS-FLI1 chimera gene verified by direct sequencing.

Recognition of adrenal ESFT and use of newly developed diagnostic techniques are required for differential diagnosis of undifferentiated small round cell tumor of the adrenal gland.

CD56 positive small round cell tumors. Differential diagnosis of hematological, neurogenic, and myogenic neoplasms.

Liu Q, Ohshima K, Sumie A, Suzushima H, Iwasaki H, Kikuchi M.

Department of Pathology, School of Medicine, Fukuoka University, Nanakuma 7-45-1, Jonanku, Fukuoka 814-01, Japan.

Virchows Arch 2001 Mar;438(3):271-9 Abstract quote

CD56-positive nasal and nasal-type natural killer (NK)/T-cell lymphoma is now a well-defined disease entity. Rare cases of blastic NK-cell lymphoma positive for CD56 have been recently reported. However, CD56 expression is also identified in several types of non-hematopoietic small round cell tumors in which lymphoma is included as a differential consideration.

Here, we present nine cases of CD56+ small round cell tumors of histological origin unrelated to nasal NK/T-cell lymphoma. Eight of the nine cases presented as solid tumors of the sinonasal region. Clinical, histological, ultrastructural, and immunohistochemical examination and gene analysis for T-cell receptor (TcR) and immunoglobulin heavy chain (IgH) genes and in situ hybridization (ISH) for Epstein-Barr virus (EBV) were performed. Two cases presented with features consistent with blastic NK-cell lymphoma or lymphoblastic lymphoma of NK-cell phenotype. These cases showed features of lymphoblastic lymphoma, phenotypes of sCD3-, cCD3+, CD45+, CD56+, TdT+, and human leukocyte antigen (HLA)-DR+, germline of IgH and TcR genes, and EBV negative reactivity. One case had myeloid/NK-precursor acute leukemia/lymphoma with a phenotype of CD13+, CD33+, CD34+, CD56+, and MPO-. Three cases were neurogenic, including one case of olfactory neuroblastoma and two of primitive neuroectodermal tumors (PNET). It was difficult to differentiate CD56+ PNET from blastic NK-cell lymphoma, especially when only paraffin-embedded sections were available. Myogenic markers, such as HHF35, alpha-sarcomeric actin, and desmin, were positive in three cases of rhabdomyosarcomas.

Our findings suggest that as CD56 is used more routinely as a marker in immunohistochemical staining, the differential diagnosis of extranodal lymphohematological malignancies and small round cell tumors will become more complicated.


Metastasis Lung
Regional Lymph nodes
Treatment Combination chemotherapy, surgery, and radiation therapy
Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study.

Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE.

City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA 91010, USA.
J Clin Oncol. 2004 Jul 15;22(14):2873-6. Abstract quote  

PURPOSE: One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes.

METHODS: Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m(2), cyclophosphamide 1,200 mg/m(2), and either doxorubicin 75 mg/m(2) or dactinomycin 1.25 mg/m(2). Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m(2)/d for 5 days and etoposide 100 mg/m(2)/d for 5 days.

RESULTS: Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms.

CONCLUSION: Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.

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Ewing's Sarcoma

Sarcoma and soft tissue tumors

Small round blue cell tumor

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