Peripheral primitive neuroectodermal tumor of the small bowel mesentery: A case showing perforation...

Case Report

Peripheral primitive neuroectodermal tumor of the small bowelmesentery: A case showing perforation at onset

Yasushi Horie and Masako Kato

Department of Pathology, Tottori University Hospital, Yonago, Japan

CLINICAL SUMMARY

A 40-year-old man, who had been previously healthy, noticeda tumorous lesion in the lower abdomen in August 1995.Because of acute severe abdominal pain he was referred toTottori University Hospital in October 1995. Chest X-ray filmrevealed a free air sign beneath the diaphragm. At emer-gency surgery a large perforated mass was noted in thejejunal mesenteric region, 70 cm anal from the Treitz liga-ment. Partially, the tumor was strongly attached to the ilealwall. A thumb-sized disseminated focus was detected in theserosal part of the sigmoid colon. Several swollen mesentericlymph nodes were also observed. Partial resection of thesmall intestine (jejunum and ileum), regional mesentericlymph nodes and the serosal part of the sigmoid colon wasperformed. Postoperative laboratory examination revealed amild elevation (64 U/mL) of serum CA125 which is normallyless than 34 U/mL. However, serum levels of a-fetoprotein,carcinoembryonic antigen, CA19-9, CA50 and CA72-4 werenormal. Despite postoperative chemotherapy, the patientdied of massive intra-abdominal recurrence in March 1996.Autopsy was not performed.

PATHOLOGICAL FINDINGS

Macroscopically, a tumor measuring 11.0 ¥ 8.0 cm waslocated in the mesentery of the jejunum. A perforation wasseen in a 6.0 ¥ 5.5 cm ulceration in the jejunal mucosa. Thecut surface of the tumor demonstrated foci of massive necro-sis and the border was irregular in most areas. The tumordirectly invaded also the wall of the ileum without features ofulceration or perforation. The cut surface of the mass of thesigmoid colon serosa and mesenteric lymph nodes was solidand gray in color.

Microscopically, the tumor cells proliferated in the sub-serosal part of the jejunal mesentery (Fig. 1a) and focallyinvaded the mucosa of the jejunum (Fig. 1b). The lesion wascomposed of sheets of undifferentiated small round cells con-

Pathology International 2000; 50: 398–403

A case of peripheral primitive neuroectodermal tumor of thesmall bowel mesentery with an uncommon clinical onset isreported. A 40-year-old man was admitted to hospitalbecause of acute severe abdominal pain. Chest X-rayrevealed a free air sign beneath the diaphragm. At emer-gency surgery a mass measuring 11.0 ¥ 8.0 cm with perfo-ration was located in the jejunal mesenteric region.Histologically the resected lesion consisted of sheets ofundifferentiated small round cells forming abortive HomerWright rosettes. Some spindle-shaped cells showedperivascular pseudorosettes. Immunohistochemical studyrevealed that the tumor cells expressed positivity againstCD99 (MIC2), neuron-specific enolase, synaptophysin andvimentin. To the authors’ knowledge this is the first docu-mentation of peripheral primitive neuroectodermal tumor ofthe small bowel mesentery with perforation at onset.

Key words: acute abdomen, CD99, Homer Wright rosette,mesentery, perforation, peripheral primitive neuroectodermaltumor, perivascular pseudorosette, small intestine

Peripheral primitive neuroectodermal tumor (pPNET) is arare soft tissue neoplasm in children and young adults.1–7

Extra-osseous Ewing’s sarcoma, peripheral neuroepithe-lioma, Askin’s tumor of the thoracopulmonary wall andperipheral neuroblastoma are now considered to be a groupof the pPNET–Ewing’s sarcoma family. Histologically, it isoften difficult for pathologists to diagnose the pPNET accu-rately because it usually shows microscopic features of ‘smallround cell tumor’ that are seen in various neoplasms, includ-ing malignant lymphoma, leukemia (granulocytic sarcoma),rhabdomyosarcoma, undifferentiated carcinoma, small cellcarcinoma, conventional neuroblastoma and others. Herein,we report a case of pPNET arising from the small bowelmesentery with an uncommon clinical onset and discuss theclinicopathological characteristics.

Correspondence: Yasushi Horie, MD, Department of Pathology,Tottori University Hospital, 36-1 Nishimachi, Yonago, Tottori 683-8504, Japan. Email: yhorie-ttr@umin.ac.jp

Received 16 September 1999. Accepted for publication 27December 1999.

Peripheral primitive neuroectodermal tumor 399

taining round or oval nuclei (Fig. 2a). Some intermingledspindle-shaped cells were often arranged radially to thelumen of the vessel, showing perivascular pseudorosettes(Fig. 2b). Most cells had inconspicuous nucleoli, but somehad a single prominent nucleolus (Fig. 3a). Abortive HomerWright rosettes were occasionally observed (Fig. 3b), while

Flexner–Wintersteiner rosettes were absent. Mild desmo-plastic stromal changes were present in the lesion. Mitoticfigures counted approximately 25 per 10 high-powered fields.The histology of metastatic lesions of the regional mesentericlymph nodes and the serosal part of the sigmoid colon wasthe same as that of the primary jejunal lesion. Periodic

a b

Figure 1 Low-power microscopy of the tumor of the small bowel mesentery. The tumor cells invade (a) the subserosal part and (b) the ulcer-ated mucosal part.

ab

Figure 2 (a) The tumor is composed of sheets of undifferentiated small round cells. (b) Spindle-shaped tumor cells show a perivascularpseudorosette in this field.

acid–Schiff reaction with and without diastase pretreatmentrevealed that the cytoplasmic glycogen was not detected inthe tumor cells. Grimelius and Masson–Fontana stainingshowed no cytoplasmic reactivity. Naphthol AS-D chloroac-etate esterase staining showed negativity. Silver impregna-tion stain showed mild to moderate amounts of delicatereticulin fibers among the tumor cells.

Immunohistochemically, 10% formalin-fixed, paraffin-embedded specimens were examined by the envisionmethod (Dakopatts, Glöstrup, Denmark; Table 1). Most

tumor cells were positive for CD99 (MIC2) (Fig. 4) andneuron-specific enolase, while some cells were also positivefor synaptophysin and vimentin. The tumor cells were negative for chromogranin-A, neurofilament, carcinoembry-onic antigen, cytokeratin (AE1/AE3), epithelial membraneantigen, antihuman epithelial antigen (BER-EP4), antihumanmesothelial cell (HBME1), CA125, CA19-9, CD45 (leukocytecommon antigen), CD20 (L26), CD79a, CD3, CD45RO(UCHL-1), CD30 (Ber-H2), CD34, desmin, a-smooth muscleactin, muscle actin (HHF35) or S-100 protein.

Based on these findings the lesion was diagnosed asperipheral primitive neuroectodermal tumor of the smallbowel mesentery.

DISCUSSION

Clinically, peripheral primitive neuroectodermal tumor(pPNET) may occur anywhere in the body.1–13 Kushner et al.

400 Y. Horie and M. Kato

a

b

Figure 3 High-power microscopy of the tumor cells. (a) Smallround tumor cells in the subserosal part. (b) Some small round tumorcells forming abortive Homer Wright rosettes.

Figure 4 Immunostaining reveals that the cytoplasm of the tumorcells is positive for CD99 (MIC2).

Peripheral primitive neuroectodermal tumor 401

reviewed 54 cases of extracranial pPNET encountered atMemorial Sloan-Kettering Cancer Center over a 20-yearperiod and found that the primary sites were thoracopul-monary (25 cases), pelvis (12 cases), retroperitoneum orabdomen (10 cases), limb (five cases), neck (one case) andunknown (one case).4 Isolated cases of pPNET have beenreported in various visceral sites, including the pancreas,8

heart,10 kidney,11 ovary,12 uterus, testis, urinary bladder andparotid gland.13 However, we were unable to find any previ-ous case of pPNET of the mesentery with a perforation onsetin the English literature. Despite combined therapy withsurgery, chemotherapy and irradiation, the prognosis ofpPNET is poor. Kushner et al. indicated that only 25% ofpatients with tumors greater than 5 cm were alive at 24months.4

Histologically, pPNET is composed of undifferentiatedsmall round cells that may form Homer Wright orFlexner–Wintersteiner rosettes and perivascular pseudo-rosettes.1 The lesion may contain areas with a resemblanceto carcinoid tumor, small cell undifferentiated carcinoma,fibrosarcoma or malignant peripheral nerve sheath tumor.There are also examples of pPNET containing glial, ependy-mal, cartilaginous and epithelial elements. Ultrastructurally,the tumor cells possess elongated interdigitating cellprocesses and contain neurosecretory granules, measuring50–100 nm, and occasionally contain microtubules.1,9

Immunohistochemically, most authors agree that CD99(MIC2), which recognizes a 30/32 kDa surface glycoprotein,is a useful tool in diagnosing pPNET.14–19 More than 90% ofpPNET cases demonstrate this marker. Pathologists shouldremember, however, that the CD99 expression may be seenin several tumors such as malignant lymphoma, leukemiaand small cell carcinoma.20–22 Riopel et al. reported that CD99expression was not uncommon in pediatric malignant lym-phoma and leukemia, and that especially the incidence washigh in malignant lymphoma and leukemia of T-cell lineage.20

Menasce et al. indicated that four (15%) of 26 granulocyticsarcomas were positive for CD99.21 Lumadue et al. reportedthat two (6.1%) of 33 small cell carcinomas were stained positively.22

A karyotypic analysis for t(11;22)(q24;q12) is now consid-ered to be the most objective diagnostic tool for pPNET.11,12,17

This translocation was seen in more than 87% of thepPNET–Ewing’s sarcoma family. Moreover, recent studieshave revealed that reverse transcription–polymerase chainreaction facilitated the detection of EWS/FLI-1 chimericmRNA originating from the t(11;22)(q24;q12) translocation ofthe pPNET–Ewing’s sarcoma family.12

The differential diagnosis of the present lesion includedmalignant lymphoma, leukemia (granulocytic sarcoma), rhab-domyosarcoma, leiomyosarcoma, gastrointestinal stromaltumor, desmoplastic small round cell tumor, malignant

Table 1 Immunohistochemical findings of the tumor of the small bowel mesentery

Antibody Clone Dilution Source Reactivity

CD99 (MIC2) HO36-1.1 Prediluted YLEM, Rome, Italy +++Neuron-specific enolase Polyclonal Prediluted Nichirei, Tokyo, Japan +++Synaptophysin SY38 1 : 10 Dakopatts, Glöstrup, Denmark ++Vimentin V9 Prediluted Nichirei +Chromogranin-A Polyclonal Prediluted Dakopatts –Neurofilament 2F11 Prediluted Nichirei –Carcinoembryonic antigen COL-1 Prediluted Nichirei –Cytokeratin AE1/AE3 1 : 50 Dakopatts –Epithelial membrane antigen E29 Prediluted Nichirei –Antihuman epithelial antigen BER-EP4 1 : 50 Dakopatts –Antihuman mesothelial cell HBME1 1 : 50 Dakopatts –CA125 OC125 Prediluted Japan Tanner, Kobe, Japan –CA19-9 1116NS-19-9 Prediluted Japan Tanner –CD45 (Leukocyte common antigen) 1.22/4.14 Prediluted Nichirei –CD20 L26 Prediluted Dakopatts –CD79a JCB117 1 : 50 Dakopatts –CD3 PS1 1 : 50 Nichirei –CD45RO UCHL-1 1 : 100 Nichirei –CD30 Ber-H2 1 : 20 Dakopatts –CD34 NU-4A1 1 : 100 Nichirei –Myoglobin Polyclonal Prediluted Immunon, Pittsburgh, USA –Desmin ZC18 Prediluted Nichirei –a-Smooth muscle actin 1A4 1 : 50 Dakopatts –Muscle actin HHF35 Prediluted Dakopatts –S-100 protein Polyclonal Prediluted Nichirei –

–, Negative staining; +, positive cells in 1–33%; ++, positive cells in 34–66%; +++, positive cells in 67–100% of total tumor cell population.

mesothelioma, undifferentiated carcinoma, small cell carci-noma and conventional neuroblastoma. For the distinction,we thoroughly examined the lesion by the histological, histo-chemical and immunohistochemical methods, because wewere unable to perform ultrastructural and karyotypic analy-ses. Malignant lymphoma and leukemia (granulocyticsarcoma) were excluded because the present tumor cellswere negative for lymphoid cell markers (CD45, CD20,CD79a, CD3, CD45RO and CD30) and showed negativity in naphthol AS-D chloroacetate esterase staining. Rhab-domyosarcoma was excluded because the present cellslacked cytoplasmic glycogen accumulation and were negativefor myogenic cell marker (myoglobin, desmin and muscleactin). Both leiomyosarcoma and gastrointestinal stromaltumor were ruled out because of the lack of smooth musclecell markers (desmin, a-smooth muscle actin and muscleactin) and CD34. Desmoplastic small round cell tumor, malignant mesothelioma and undifferentiated carcinomawere denied because the present cells were negative formesothelial and epithelial markers (cytokeratin, carcinoem-bryonic antigen, epithelial membrane antigen, BER-EP4,HBME1, CA125 and CA19-9). Small cell carcinoma wasexcluded because the cytoplasm of the present cells wasapparently larger than that of small cell carcinoma. Conven-tional neuroblastoma was denied because the present cellswere positive for CD99. Regarding the primary site of thetumor, the majority of the mass was confined in the subserosalregion of the jejunum and the direct invasion to the ileal wallwas also present, while the grade of involvement to themucosal part of the jejunum was relatively limited despite thelarge size of the tumor (11.0 ¥ 8.0 cm). Therefore, the presenttumor was finally diagnosed as pPNET of the jejunal mesen-tery.

In conclusion, we have documented the first case ofpPNET arising from the small bowel mesentery with perfora-tion at onset. The perforation was considered to be caused bymassive invasion of the tumor cells with prominent tumornecrosis and/or local ischemic changes. It is important forboth surgeons and pathologists to remember that intra-abdominal pPNET may present with acute abdomen.

REFERENCES

1 Enzinger FM, Weiss SW. Primitive neuroectodermal tumors andrelated lesions. In: Soft Tissue Tumors, 3rd edn. Mosby, NewYork, 1995; 929–964.

2 Llombart-Bosch A, Lacombe MJ, Peydro-Olaya A, Perez-Bacete M, Contesso G. Malignant peripheral neuroectodermaltumours of bone other than Askin’s neoplasm: Characterizationof 14 new cases with immunohistochemistry and electronmicroscopy. Virchows Arch. 1988; 412: 421–430.

3 Marina NM, Etcubanas E, Parham DM, Bowman LC, Green A.Peripheral primitive neuroectodermal tumor (peripheral neu-

roepithelioma) in children. A review of the St. Jude experienceand controversies in diagnosis and management. Cancer 1989;64: 1952–1960.

4 Kushner BH, Hajdu SI, Gulati SC, Erlandson RA, Exelby PR,Lieberman PH. Extracranial primitive neuroectodermal tumors.The Memorial Sloan-Kettering Cancer Center experience.Cancer 1991; 67: 1825–1829.

5 Ushigome S, Shimada T, Nikaido T et al. Primitive neuroecto-dermal tumors of bone and soft tissue with reference to histo-logic differentiation in primary or metastatic foci. Acta Pathol.Jpn. 1992; 42: 483–493.

6 Shishikura A, Ushigome S, Shimada T. Primitive neuroectoder-mal tumors of bone and soft tissue: Histological subclassifica-tion and clinicopathologic correlations. Acta Pathol. Jpn. 1993;43: 176–186.

7 Dehner LP. Primitive neuroectodermal tumor and Ewing’ssarcoma. Am. J. Surg. Pathol. 1993; 17: 1–13.

8 Danner DB, Hruban RH, Pitt HA, Hayashi R, Griffin CA,Perlman EJ. Primitive neuroectodermal tumor arising in thepancreas. Mod. Pathol. 1994; 7: 200–204.

9 Papierz W, Alwasiak J, Kolasa P et al. Primitive neuroectoder-mal tumors: Ultrastructural and immunohistochemical studies.Ultrastruct. Pathol. 1995; 19: 147–166.

10 Charney DA, Charney JM, Ghali VS, Teplitz C. Primitive neu-roectodermal tumor of the myocardium: A case report, review ofthe literature, immunohistochemical, and ultrastructural study.Hum. Pathol. 1996; 27: 1365–1369.

11 Marley EF, Liapis H, Humphrey PA et al. Primitive neuroecto-dermal tumor of the kidney. Another enigma: A pathologic,immunohistochemical, and molecular diagnostic study. Am. J.Surg. Pathol. 1997; 21: 354–359.

12 Kawaguchi S, Fukuda T, Miyamoto S et al. Peripheral primitiveneuroectodermal tumor of the ovary confirmed by CD99immunostaining, karyotypic analysis, and RT-PCR forEWS/FLI-1 chimeric mRNA. Am. J. Surg. Pathol. 1998; 22:1417–1422.

13 Deb RA, Desai SB, Amonkar PP, Aiyer PM, Borges AM. Primaryprimitive neuroectodermal tumour of the parotid gland.Histopathology 1998; 33: 375–378.

14 Ambros IM, Ambros PF, Strehl S, Kovar H, Gadner H, Salzer-Kuntschik M. MIC2 is a specific marker for Ewing’s sarcoma andperipheral primitive neuroectodermal tumors. Cancer 1991; 67:1886–1893.

15 Pappo AS, Douglass EC, Meyer WH, Marina N, Parham DM.Use of HBA 71 and anti-b2-microglobulin to distinguish periphe-ral neuroepithelioma from neuroblastoma. Hum. Pathol. 1993;24: 880–885.

16 Weidner N, Tjoe J. Immunohistochemical profile of monoclonalantibody O13: Antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing’s sarcoma and peripheral neuroepithelioma. Am. J. Surg. Pathol. 1994; 18:486–494.

17 Scotlandi K, Serra M, Manara MC et al. Immunostaining of the p30/32MIC2 antigen and molecular detection of EWSrearrangements for the diagnosis of Ewing’s sarcoma andperipheral neuroectodermal tumor. Hum. Pathol. 1996; 27:408–416.

18 Shanfeld RL, Edelman J, Willis JE, Tuason L, Goldblum JR.Immunohistochemical analysis of neural markers in peripheralprimitive neuroectodermal tumors (pPNET) without light micro-scopic evidence of neural differentiation. Appl. Immunohis-tochem. 1997; 5: 78–86.

19 Halliday BE, Slagel DD, Elsheikh TE, Silverman JF. Diagnosticutility of MIC-2 immunohistochemical staining in the differentialdiagnosis of small blue cell tumors. Diagn. Cytopathol. 1998;19: 410–416.

402 Y. Horie and M. Kato

Peripheral primitive neuroectodermal tumor 403

20 Riopel M, Dickman PS, Link MP, Perlman EJ. MIC2 analysis inpediatric lymphomas and leukemias. Hum. Pathol. 1994; 25:396–399.

21 Menasce LP, Banerjee SS, Beckett E, Harris M. Extra-medullary myeloid tumour (granulocytic sarcoma) is often mis-

diagnosed: A study of 26 cases. Histopathology 1999; 34:391–398.

22 Lumadue JA, Askin FB, Perlman EJ. MIC2 analysis of small cellcarcinoma. Am. J. Clin. Pathol. 1994; 102: 692–694.