Abnormal uterine bleeding. (Pathologic Quiz Case).

A 38-year-old woman presented to the emergency department with acute (<24 hours) vaginal bleeding requiring transfusion of 2 units of packed red blood cells. On physical examination, the patient was noted to have a large cervical mass. Past medical history was significant for menorrhagia status post-endometrial ablation and submucosal myomectomy 1 year earlier. Since that time, the patient's menstrual history had been unremarkable. Laboratory values included hemoglobin, 103 g/L; hematocrit, 0.33; white blood cell count, 7.6 x [10.sup.9]/L; and platelets, 173 x [10.sup.9]/L. Computed tomography (Figure 1) revealed a 7 x 6 x 6-cm, circumscribed cervical mass, thought to be a leiomyoma, which extended into the pelvic sidewall. Several attempted biopsies were nondiagnostic. The patient then underwent an exploratory laparotomy. On examination of the frozen section biopsy specimen, the mass was diagnosed as a poorly differentiated carcinoma, possibly small cell carcinoma. Based on this diagnosis and the tumor size, the mass was considered nonresectable. Pelvic and periaortic lymph node sampling at this time was negative for metastases. The patient was started on vincristine, adriamycin, and cyclophosphamide, alternating with ifosfamide, MESNA, and etoposide. The tumor proved markedly responsive to chemotherapy, decreasing approximately 10% after only 1 treatment cycle. Following 2 additional cycles of chemotherapy, the patient underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Surgical staging revealed stage IB disease; 4 additional cycles of chemotherapy followed surgical resection. The patient achieved full remission.

[FIGURE 1 OMITTED]

Grossly, the surgical specimen contained a 6.5 x 6.0-cm, soft, cervical mass with a yellow-tan, focally hemorrhagic cut surface. An incidental 3.5-cm leiomyoma was also identified in the right cornu of the uterus. Microscopically, the cervical neoplasm was composed of solid nests of small round to oval cells with vesicular nuclei and scant cytoplasm (Figure 2). No gland formation, rosettes, or trabecular pattern was identified.

[FIGURE 2 OMITTED]

What is your diagnosis?

Extraosseous Ewing sarcoma (EES) belongs to the family of primitive peripheral neuroectodermal tumors. These 2 lesions are thought to represent a single spectrum of disease characterized by small round cells with hyperchromatic nuclei and scant cytoplasm. (1,2) Like Ewing sarcoma (ES) of the bone, EES/peripheral neuroectodermal tumor occurs in children to young adults, usually between 15 and 30 years of age. It is slightly more common in males. (1,2) Typically arising in the trunk, extremities, paravertebral region, and the retroperitoneum, these tumors often present as a rapidly enlarging solitary mass. (2) Pain at the site of origin may be the initial symptom that brings the tumor to medical attention. (1)

Diagnosis of this tumor is based on light microscopy, immunohistochemistry, cytogenetic/molecular techniques, and/or electron microscopy. By light microscopy, EES is composed of diffuse sheets of small round cells with vesicular nuclei, a high nuclear-cytoplasmic ratio, inconspicuous nucleoli, and pale, ill-defined, scant cytoplasm. (2) The immunohistochemical profile of ES includes strong reactivity to the cell surface glycoprotein CD99 antigen, encoded by the pseudoautosomal MIC-2 gene. (3) MIC-2 immunoreactivity is seen in up to 98% of tumors in the ES family, but the specificity of this stain for this group of tumors is much lower. (4) This case stained diffusely positive for CD99 and focally positive for neuronspecific enolase. Cytokeratin, common leukocyte antigen, chromogranin, and synaptophysin stains were negative. Cytogenetics can confirm the diagnosis of ES by demonstrating a t(11:22)(q24,q12) translocation. (5) This finding correlates with the EWS/FLI1 fusion transcript that can be detected by reverse-transcriptase polymerase chain reaction or fluorescent in situ hybridization. (3) Ultrastructurally, the tumor cells lack cell projections, contain few cytoplasmic organelles, and exhibit rare neurosecretory granules. (1-3) The majority of these tumors contain large pools of glycogen in their cytoplasm. Prior to the widespread use of immunohistochemistry, periodic acid-Schiff staining of this glycogen was supportive evidence for the diagnosis of ES.

The differential diagnosis of a small round cell tumor of the cervix includes neuroendocrine neoplasms, carcinoid, endometrial carcinoma, malignant melanoma, malignant lymphoma, endometrial stromal sarcoma, and metastatic carcinoma. Differentiation of these lesions can be made with the aid of immunohistochemistry, as well as cytogenetic and molecular techniques. Accurate diagnosis of EES is important for establishing a prognosis and treatment planning.

The prognosis of EES is generally good; approximately 70% of patients survive 5 years or more. (2) This is largely due to the addition of chemotherapy in the treatment regimen. Management consists of chemotherapy and radical surgical excision, with possible adjuvant radiation therapy. (1)

Primary ES of the cervix is an unusual but previously described entity. (6,7) All cases of primary EES of the cervix have presented as abnormal uterine bleeding. (6,7) The biologic behavior of primary EES of the cervix is unknown. These lesions demonstrate the immunohistochemical, cytogenetic, and molecular profiles of EES in other sites. (6) In turn, prognostic factors may be similar. Our patient remains healthy and disease-free more than 5 years after therapy.

References

(1.) Enzinger EM, Weiss SW. Soft Tissue Tumors. 3rd ed. St Louis, Mo: Mosby-Year Book Inc; 1995:952-961.

(2.) Shimada H, Newton WA Jr, Soule EH, et al. Pathologic features of extraosseous Ewing's sarcoma: a report from the Intergroup Rhabdomyosarcoma Study. Hum Pathol. 1988;19:442-453.

(3.) Scotlandi K, Serra M, Manara MC, et al. Immunostaining of the [p.sup.30/32] MIC2 antigen and molecular detection of EWS rearrangement for the diagnosis of Ewing's sarcoma and peripheral neuroectodermal tumor. Hum Pathol. 1996;27: 408-416.

(4.) Fellinger EJ, Garin-Chesa P, Glasser DB, et al. Comparison of cell surface antigen HBA71 ([p.sup.30/32] MIC2), neuron specific enolase, and vimentin in the immunohistochemical analysis of Ewing's sarcoma of bone. Am J Surg Pathol. 1992; 16:746-755.

(5.) Turc-Carcel C, Aurias A, Mugmerat F, et al. Chromosomes in Ewing's sarcoma, I: an evaluation of 85 cases of remarkable consistency of t(11;22)(q24; q12). Cancer Genet Cytogenet. 1988;32:229-238.

(6.) Cenacchi G, Pasquinelli G, Montanaro L, et al. Primary endocervical extraosseous Ewing's sarcoma/PNET. Int J Gynecol Pathol. 1998;17:83-88.

(7.) Satro S, Yajima A, Kimura N, Nanniki T, Furuhashi N, Sakura H. Peripheral neuroepithelioma (peripheral primitive neuroectodermal tumor) of the cervix. Tohoku J Exp Med. 1996;180:187-195.

Accepted for publication February 9, 2001.

From the Department of Pathology, University of Michigan Hospitals, Ann Arbor, Mich.

Reprints: Augusto F. G. Paulino, MD, Department of Pathology, University of Michigan Hospitals, 1500 E Medical Center Dr, Rm 2G332, Ann Arbor, MI 48109 (e-mail: [e-mail]).