Peripheral Primitive Neuroectodermal Tumor Presenting With DiffuseCutaneous Involvement and 7;22 Translocation

Lynn M. Smith, MD,1,6* Roberta H. Adams, MD,2,6 Arthur R. Brothman, PhD,2,3,6

Sheryll L. Vanderhooft, MD,4,6 and Cheryl M. Coffin, MD5,6

We report an unusual case of peripheralprimitive neuroectodermal tumor (pPNET) in aninfant presenting with congenital cutaneousnodules and a t(7;22)(p21;q11.2). The biologicbehavior of the tumor diverged over time froma slowly growing tumor with multiple cutane-

ous nodules to a more aggressive neoplasmcharacterized by pulmonary metastases and asoft tissue mass showing additional cytogeneticalterations. Med. Pediatr. Oncol. 30:357–363,1998. © 1998 Wiley-Liss, Inc.

Key words: peripheral primitive neuroectodermal tumor; cytogenetics; pediatrics

INTRODUCTION

Peripheral primitive neuroectodermal tumor (pPNET)and Ewing sarcoma have the characteristic tumor-associated t(11;22) or t(21;22) in more than 90% ofcases. Recently, several cases with the variant t(7;22)have been reported, but clinical information regardingthis variant is very limited. We report the clinical, patho-logic, and cytogenetic findings in an unusual example ofpPNET characterized by presentation with multiple con-genital cutaneous nodules and a variant t(7;22).

CASE REPORTClinical

A full-term male infant presented at birth with a 1 cmblue nodule on his right hip. The remainder of his physi-cal examination was normal. The nodule doubled in sizeover the next 4 months. By 7 months of age, nine bluenodules had appeared, distributed over his extremities,trunk, and scalp, and ranging from 0.3 to 0.8 cm in di-ameter. At 8 months, the patient underwent a biopsy ofan enlarging nodule. The histopathology was interpretedas an immature peripheral nerve sheath neoplasm, andcareful clinical evaluation for a primary site was recom-mended. The patient was evaluated with a computed to-mographic (CT) scan of the chest, abdomen, and pelvisand 99mTc nuclear bone scan, and these radiographicstudies were interpreted as normal.

The patient returned at 23 months of age with a 6-month history of an enlarging mass in the right lumbarparaspinal region and multiple new blue cutaneous nod-ules (Fig. 1). Magnetic resonance imaging (MRI) of thespine revealed a 6 × 2 × 3 cmmass arising in the para-spinal musculature at the level of the kidneys. There wasno extension through the neural foramina (Fig. 2A,B). A

percutaneous needle biopsy revealed a poorly differenti-ated small cell tumor. A nodule on the left thigh wasbiopsied and showed histology similar to the paraspinalsoft tissue mass. Cytogenetics on both specimens re-vealed a t(7;22)(p21;q11.2) (Fig. 3). A diagnosis ofatypical pPNET was established. A bone scan was unre-markable, but a CT scan of the chest revealed multiplepulmonary nodules consistent with metastatic disease.Bone marrow aspiration and biopsy showed no evidencefor malignancy. In retrospect, CT scans performed at 8months of age showed a small calcified mass within theparaspinal musculature (Fig. 4A,B).

The patient’s management included induction chemo-therapy followed by surgical resection of the primarysite, two sequential peripheral stem cell transplants, andconsolidative irradiation to the primary tumor site. Thepatient has been in complete pathologic remission for 3months since completing therapy.

1Department of Radiation Oncology, University of Utah Health Sci-ences Center, Salt Lake City, Utah2Department of Pediatrics, University of Utah Health Sciences Center,Salt Lake City, Utah3Department of Genetics, University of Utah Health Sciences Center,Salt Lake City, Utah4Department of Dermatology, University of Utah Health SciencesCenter, Salt Lake City, Utah5Department of Pathology, University of Utah Health Sciences Center,Salt Lake City, Utah6Primary Children’s Medical Center, Salt Lake City, Utah

*Correspondence to: Lynn M. Smith, Department of Radiation Oncol-ogy, University of Utah Health Sciences Center, Salt Lake City, UT84132.

Received 22 July 1997; Accepted 27 January 1998

Medical and Pediatric Oncology 30:357–363 (1998)

© 1998 Wiley-Liss, Inc.

Pathology

Skin biopsy obtained at the age of 8 months revealeda circumscribed, non-encapsulated dermal proliferationof round, polygonal, and spindle cells with scanty cyto-plasm and a vague nesting arrangement. No paciniancorpuscles or neuroid bundles were seen. The cellularproliferation involved the superficial and deep dermisand extended focally into the subcutaneous tissue. Mi-totic activity was low. No severe atypia or necrosis wasidentified. S-100 protein was strongly positive in the cy-toplasm of the tumor cells and Leu 7 was focally posi-tive, however, synatophysin and chromogranin werenegative excluding a neural phenotype such as neuro-blastoma. Other stains including leukocyte common an-tigen, CD1A, smooth muscle actin, factor VIII, CD31,CD34, and HMB 45 were negative, which helped to ex-clude the possibility of vascular, histiocytic, myofibro-blastic, pericytic, and nevoid proliferations. The primi-tive appearing tumor was given a diagnosis of immatureperipheral nerve sheath neoplasm of indeterminate bio-logic potential.

When the patient was 23 months of age, a biopsy of anew paraspinal soft tissue mass revealed a densely cel-lular neoplasm characterized by nests of cells with mod-

erate amounts of cytoplasm, regular ovoid nuclei withfine chromatin, and extremely rare mitoses. Dense fibro-sis between cellular foci without architectural or cyto-logic differentiation conferred a geographic architecturalpattern (Fig. 5A,B). Immunohistochemical stains showedstrong cytoplasmic staining for vimentin and 013 andfocal cytoplasmic staining for cytokeratin, Leu 7, andS-100 protein. Comparison with the previous skin biopsyshowed the paraspinal mass with similar except for amore prominent tightly nested small cell pattern withmore extensive stromal fibrosis in the paraspinal mass.Cytogenetics showed a t(7;22), which established a di-agnosis of pPNET. A biopsy of another cutaneous noduleconfirmed the histologic identity of the blue skin lesionsas pPNET as well.

Cytogenetics

Cytogenetic analyses were performed on the paraspi-nal mass and a cutaneous nodule biopsied at 23 monthsof age. G-banding was performed on short-term cultures.The paraspinal tumor specimen revealed an abnormalclone in 29% of the cells analyzed containing extra cop-ies of chromosomes 2, 8, 10, 12, and 15, an isochromo-some from the long arm of chromosome 1, and a

Fig. 1. Twenty-three-month-old boy with a paraspinal soft tissue mass and adjacent small blue cutaneous nodule.

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Fig. 2. Axial (A) and sagittal(B) MRI of the lumbar spine demonstrating an enhancing mass in the soft tissues of the right paraspinal muscles.

pPNET With Cutaneous Metastases and t(7;22) 359

t(7;22)(p21;q11.2). The breakpoint on chromosome 22was consistent with that observed in both Ewing sarcomaand pPNET. The cutaneous nodule revealed at(7;22)(p21;q11.2) as the only abnormality. Since thet(7;22) was the sole abnormality seen in the cutaneousnodule, it was interpreted as the most likely primaryclonal change in the tumor. The same balanced t(7;22)was documented in three subsequent cutaneous nodulesbiopsied after three cycles of chemotherapy.

DISCUSSION

The majority of tumors in the Ewing sarcoma familyexpress either a t(11;22)(q24;q12) or t(21;22)(q22;q12).A common feature of these translocations is the juxtapo-sition of the EWS gene located at 22q12 to a transcriptionfactor from the ETS family, FLI-1 or ERG [1–5]. Theresult of the gene fusion is a chimeric transcript whichacts as an aberrant transcription factor and promotes tu-morigenesis [6]. A third rare variant t(7;22)(p22;q12) hasbeen identified recently in this group of neoplasms. Thistranslocation juxtaposes the EWS gene on 22q12 withthe ETV1 gene, also a member of the ETS family oftranscription factors, located on 7p22 [7,8]. Although thet(11;22), t(21;22), and t(7;22) are detected in the majorityof patients with the Ewing sarcoma family of tumors,several reports have identified the EWS/FLI-1 fusiontranscript in non-Ewing tumors, such as rhabdomyosar-coma [9,10]. Therefore, while these translocations sug-gest the diagnosis for the Ewing family, histologic evalu-ation is necessary to confirm the diagnosis.

We report an infant who presented with disseminatedcongenital cutaneous nodules. Although the clinical his-tory was suggestive of stage IVS neuroblastoma, a pri-mary site could not be identified and biopsy of a cuta-neous nodule suggested an immature peripheral nervesheath neoplasm. Due to the benign histologic appear-ance of the tumor the patient was observed. The diagno-sis of pPNET was established months later when an as-sociated soft tissue mass became clinically evident andwas biopsied. The presence of immunoreactivity for 013and the presence of the t(7;22) supported the histologicdiagnosis of pPNET.

The translocation breakpoint in our patient (7p21 and22q11.2) is similar to that reported by Jeon et al. [7](7p22 and 22q12). Identification of the EWS and ETV1fusion transcript would provide definitive evidence thatthe breakpoint in our patient is the same as the t(7;22)recently described. Chimeric transcripts which resultfrom the fusion of the EWS gene and ETS family oftranscriptional activators may have important prognosticsignificance. At least 14 chimeric transcripts have beenreported for the EWS-FLI-1 and EWS-ERG transcripttypes, of which the fusion of EWS exon 7 to FLI-1 exon6 may portend a better relapse-free survival [11,12]. Theoutcome for patients with the EWS-ETV1 transcript hasnot been specifically reported; however, a case reportwhich identified a t(7;22) in an extremity Ewing sarcomaof a 12-year-old female suggested a poor outcome as thepatient relapsed soon after the completion of therapy anddied shortly thereafter [8].

The clinical course in our patient is unusual in that

Fig. 3. Partial karyotypes from three metaphase cells showing the t(7;22). The normal chromosome is depicted on the left of each pair and thederivative chromosome on the right. An ideogram showing the respective breakpoints on each chromosome is shown to the right of thekaryotype.

360 Smith et al.

cutaneous dissemination was present at birth before asoft tissue mass was evident. The cutaneous nodules ap-peared to follow an indolent course characterized byclinical and pathological evidence of involution without

treatment. Rare case reports of pPNET with the skin asthe primary site of disease suggest that cutaneous pPNETis associated with a prolonged clinical course with ex-cellent outcome using surgery alone [13–15]. Cutaneous

Fig. 4. A: CT scan of the abdomen demonstrating the paraspinal soft tissue mass at the age of 8 months.B: CT scan of the abdomendemonstrating interval growth of the paraspinal soft tissue mass at the age of 23 months.

pPNET With Cutaneous Metastases and t(7;22) 361

dissemination of pPNET in a neonate is rare, but a recentcase report, in which the cutaneous lesions underwentspontaneous regression without treatment, suggests thatmetastases to the skin may be associated with a favorableprognosis [16]. On the other hand, our patient developeda rapidly enlarging soft tissue mass which was accom-panied by the development of pulmonary metastases,

long after the cutaneous nodules were established. Pul-monary metastases have uniformly been associated witha poor outcome despite aggressive multimodal manage-ment. This divergent behavior in the tumor biology maybe a result of the accumulation of multiple cytogeneticabnormalities in the soft tissue mass over time, leading toa more aggressive neoplasm. This hypothesis is sup-

Fig. 5. A: The paraspinal mass displays sheets of round cells in a desmoplastic stroma, with a geographic pattern (hematoxylin-eosin, ×100).B: The tumor cells have round to oval nuclei, small nucleoli, and a small amount of pale cytoplasm (hematoxylin-eosin, ×400).

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ported by the finding of the t(7;22) as the sole karyotypicchange in the cutaneous nodules, in contrast with the softtissue mass, which expressed additional karyotypicchanges, including an isochromosome from the long armof 1 and extra copies of chromosomes 2, 8, 10, 12, and15. This might indicate that the soft tissue tumor evolvedover time to a more malignant phenotype and the abnor-mal clone which spread to the lung has a different bio-logic behavior than the cutaneous nodules. Alternatively,these additional cytogenetic changes may simply repre-sent clonal evolution of generalized chromosome insta-bility following alteration of an unidentified gene pro-viding selection for metastases.

CONCLUSION

In summary, we present an unusual case of pPNETpresenting as disseminated cutaneous metastases in aninfant and characterized by a t(7;22). The biologic be-havior of the tumor diverged over time from a slowlygrowing tumor with multiple cutaneous nodules to amore aggressive neoplasm characterized by pulmonarymetastases and the presence of additional cytogeneticalterations. Whether the t(7;22) is associated with a dis-tinctive clinical presentation of pPNET in the skin and aprolonged evolution to a more aggressive neoplasm is anintriguing possibility which merits further consideration.

REFERENCES

1. Delattre O, Zucman J, Melot T, et al.: The Ewing family of tu-mors—A subgroup of small round-cell tumors defined by specificchimeric transcripts. N Engl J Med 331:294–299, 1994.

2. Giovannini M, Biegel JA, Serra M, et al.: EWS-erg and EWS-fli1fusion transcripts in Ewing’s sarcoma and primitive neurocecto-dermal tumors and variant translocations. J Clin Invest 94:489–496, 1994.

3. May WA, Gishizky ML, Lessnick SL, et al.: Ewing sarcoma 11;22translocation produces a chimeric transcription factor that requiresthe DNA-binding domain encoded by FLI1 for transformation.Proc Natl Acad Sci USA 90:5752–5756, 1993.

4. Sorensen PH, Lessnick SL, Lopez-Terrada D, et al.: A secondEwing’s sarcoma translocation, t(21;22), fuses the EWS gene toanother ETS-family transcription factor, Erg. Nat Genet 6:146–151, 1994.

5. Turc-Carel C, Philip I, Berger M-P, et al.: Chromosome study ofEwing’s sarcoma cell lines. Consistency of a reciprocal translo-cation t(11;22)(q24;q12). Cancer Genet Cytogenet 12:1–19, 1984.

6. Ladanyi M: The emerging molecular genetics of sarcoma trans-locations. Diagn Mol Pathol 4:162–173, 1995.

7. Jeon I-S, Davis JN, Braun BS, et al.: A variant Ewing’s sarcomatranslocation (7;22) fuses the EWS gene to the ETS gene ETV1.Oncogene 10:1229–1234, 1995.

8. Squire J, Zielenska M, Thorner P, et al.: Variant translocations ofchromosome 22 in Ewing’s sarcoma. Genes Chromosom Cancer8:190–194, 1993.

9. Sorensen PH, Shimada H, Liu XF, et al.: Biphenotypic sarcomaswith myogenic and neural differentiation express the Ewing’s sar-coma EWS/FLI1 fusion gene. Cancer Res 55:1385–1392, 1995.

10. Thorner P, Squire J, Chilton-MacNeill, et al.: Is the EWS/FLI1fusion transcript specific for Ewing sarcoma and peripheral primi-tive neuroectodermal tumor? Am J Pathol 148:1125–1138, 1996.

11. Zoubek A, Pfleiderer C, Salzer-Kuntschik M, et al.: Variability ofEWS chimaeric transcripts in Ewing tumours: A comparison ofclinical and molecular data. Br J Cancer 70:908–913, 1994.

12. Zoubek A, Dockhorn-Dworniczak B, Delattre O, et al.: Does ex-pression of different EWS chimeric transcripts define clinicallydistinct risk groups of Ewing tumor patients? J Clin Oncol 14:1245–1251, 1996.

13. Lee CS, Southey MC, Slater H, et al.: Primary cutaneous Ewing’ssarcoma/peripheral primitive neuroectodermal tumors in child-hood. Diagn Mol Pathol 4:174–181, 1995.

14. Patterson JW, Maygarden SJ: Extraskeletal Ewing’s sarcoma withcutaneous involvement. J Cutan Pathol 13:46–58, 1986.

15. Peters MS, Reiman HM, Muller SA: Cutaneous extraskeletal Ew-ing’s sarcoma. J Cutan Pathol 12:476–485, 1985.

16. Paley C, Valderrama E, Garcia M, et al.: Congenital peripheralneuroectodermal tumor presenting as disseminated cutaneous dis-ease (abstract). J Pediatr Hematol Oncol 18:447, 1996.

COMMENT

The initial presentation of the patient described bySmith and colleagues is arresting. An infant presenting atbirth with a ‘‘1 cm blue nodule’’ would certainly makeone think of stage 4-S neuroblastoma. The fact that thischild developed a pPNET should alert all those caring forchildren to this alternate diagnosis, especially when the

clinical evolution is not that expected with neuroblas-toma stage 4-S. pPNET has an ominous prognosis, andrequires aggressive management.

Giulio J. D’Angio, MD

Editor-in-Chief

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