Regional enteritis

Sarcomatoid carcinoma of the small bowel is rare; to our knowledge, 19 cases have been reported to date in the English literature under several names. We report an additional case occurring in the jejunum of a 55-year-old man. The tumor was a polypoid 7.5-cm mass, which infiltrated the full thickness of the intestinal wall and the serosa of an adhesed loop of small bowel. On microscopic examination, the neoplasm was composed of sheets of spindle cells; focally, an anaplastic component was present, including tumor giant cells with bizarre nuclei. On immunohistochemical stains, tumor cells were positive for cytokeratin 7, cytokeratin AE1/AE3, vimentin, and focally, epithelial membrane antigen. No staining for cytokeratin 20 was found. Sarcomatoid carcinoma must be kept in mind in the differential diagnosis of malignant spindle cell tumors of the small bowel. As consensus regarding the terminology of these rare tumors is being reached, immunohistochemical stains are essential for accurate diagnosis.

(Arch Pathol Lab Med. 2004;128:918-921)

Primary carcinoma of the small bowel is an uncommon tumor, with an incidence of 0.5 to 0.8 per 100 000 population per year.1,2 Although most cases are adenocarcinomas, rare cases of sarcomatoid carcinoma (SCA) are on record.2,3 As the name implies, SCA is a carcinoma containing mesenchymal-like spindle cell elements, thus mimicking sarcoma or a composite malignant tumor ("carcinosarcoma"). Sarcomatoid carcinomas have been described in various organ systems, including the respiratory and digestive systems, salivary and thyroid glands, breast, and skin.14

Gastrointestinal SCAs are unusual tumors that occur most frequently in the stomach, gallbladder, and esophagus.3 To the best of our knowledge, only 19 cases of small intestinal SCA have been reported in the English literature to date.2,5-12 Dikman and Toker7 in 1973 were the first to describe such a tumor in the small bowel and used the term enteroblastoma, which did not reflect the true nature of the tumor. As a result, other terms have been subsequently used, in parallel to those in other organs, including sarcomatoid carcinoma, carcinosarcoma, metaplastic carcinoma, and spindle cell carcinoma.

We describe herein a jejunal SCA occurring in a middle-aged African American man. This tumor showed the typical morphologic features of SCA, but had an unexpected immunohistochemical profile on stains for cytokeratins 7 and 20.

REPORT OF A CASE

A 55-year-old African American man with chronic hypertension and polysubstance abuse (cocaine and marijuana) was admitted with complaints of weakness and bright red blood per rectum. There was associated anorexia, a 9.1-kg weight loss, and fatigue. There had been no recent change in bowel habits. he was a heavy smoker (1-2 packs/d for 30 years) and had perforated diverticulitis 4 years before the current presentation, resulting in temporary colostomy placement. Physical examination revealed pale mucosa and mild hepatomegaly. Rectal examination revealed guaiac-positive stool. His blood investigations revealed the following values: hemoglobin, 5.2 g/dL; hematocrit, 18.8%; platelets, 722 × 10^sup 3^/ µL; serum iron, 6 µg/dL (1.1 µmol/L); sodium, 140 mEq/L; potassium, 4.7 mEq/L; chloride, 106 mEq/L; carbon dioxide, 27 mEq/L; total protein, 6.8 g/dL; albumin, 2.4 g/dL; total bilirubin, 0.6 mg/dL (10 µmol/L); alkaline phosphatase, 92 U/L; lactate dehydrogenase, 151 U/L; aspartate amino-transferase, 16 U/L; alanine aminotransferase, 8 U/L; [gamma]-glutamyltransferase, 28 U/L; and amylase 132 U/L. The patient was given multiple packed red cell transfusions.

Upper gastrointestinal series and follow-through showed midjejunal narrowing with mass effect in the left upper abdomen. Enteroscopy showed a 6- to 7-cm mass in the jejunum at 150 cm. Colonoscopy findings were normal, and an abdominal computed tomography scan showed mild hepatomegaly and masslike densities in the peritoneum, consistent with unopacified loops of small bowel. No liver masses were seen, and there was no retroperitoneal lymphadenopathy. Chest and brain computed tomographic scans and systemic examination showed no primary site other than the small intestine and did not reveal metastatic disease. A portion of jejunum with attached mesentery was removed, adhesions were lysed, a lateral enterotomy tube was placed, and a side-to-side small bowel anastomosis was performed. The tumor was completely excised. There was no evidence of metastatic disease, and no additional treatment was given. The patient developed extensive lung and brain metastases 8 months after diagnosis and died shortly thereafter. No autopsy was performed.

MATERIALS AND METHODS

Routine hematoxylin-eosin sections were prepared from formalin-fixed, paraffin-embedded tissue. sections were also stained with mucicarmine, periodic acid-Schiff diastase, and Alcian blue at pH 2.5. Immunohistochemical studies were performed by a standard streptavidin-biotin method. Antibodies included cytokeratin AEl/AE3 (monoclonal, dilution 1:5, Signet Pathology Systems, Dedham, Mass), cytokeratin (CK) 7 (monoclonal, dilution 1:25, Dako Corporation, Carpinteria, Calif), CK20, MIB-I, and CD30 (monoclonal, dilution 1:20, Dako), epithelial membrane antigen and CD117 (monoclonal, dilution 1:50, Dako), carcinoembryonic antigen (polyclonal, dilution 1:3000, Dako), vimentin (monoclonal, dilution 1:8, BioGenex, San Ramon, Calif), muscle cell actin (monoclonal, dilution 1:8, Enzo Diagnostics Inc, Farmingdale, NY), desmin (monoclonal, dilution 1:50, BioGenex), SlOO protein (monoclonal, dilution 1:12000, Dako), CD34 (monoclonal, dilution 1:10, BioGenex), and human chorionic gonadotropin (polyclonal, dilution 1:3200, Dako).

RESULTS

A convoluted segment of small intestine was received for examination. It measured 30 cm in length and 5 cm in widest diameter, showed multiple fibrous adhesions, and on opening contained a polypoid, fleshy, partially necrotic tumor measuring 7.5 × 6.3 × 2.5 cm. The tumor was centrally ulcerated and involved the bowel wall circumferentially to a depth of 2.5 cm. Serial sectioning revealed that the tumor infiltrated the full thickness of the wall, focally extending to the serosa of an adjacent, adherent loop of small bowel. The proximal and distal resection margins were free of tumor. No perforation was identified.

Microscopically, the tumor was composed of sheets of malignant spindle cells with oval vesicular nuclei, prominent nucleoli, and pale eosinophilic to clear cytoplasm (Figure 1). Focally, the rumor appeared anaplastic and contained sheets of mononuclear and multinucleated giant cells with bizarre nuclei and dense chromatin (Figure 2). Mitotic figures averaged 9 per 10 high-power fields. The surrounding stroma was scant with scattered inflammatory cells, including lymphocytes, histiocytes, and eosinophils. Tumor extended to the serosa and focally infiltrated the serosa of the adherent loop of small bowel. There was no evidence of lymphatic, vascular, or perineural invasion, and the surrounding lymph nodes were free of metastatic rumor (TNM stage pT4 pNO pMX). The segment of small bowel otherwise showed focal acute peritoneal reaction and serosal fibrous adhesions.

The histochemical stains (mucicarmine, Alcian blue, and periodic acid-Schiff diastase) failed to demonstrate mucin in tumor cells. On immunohistochemical stains, the tumor cells were strongly positive for cytokeratin AEl/AE3 and CK7, as well as vimentin (Figure 3, a). They were also focally positive for epithelial membrane antigen (Figure 3, b) and CD30, but negative for carcinoembryonic antigen, CK20, muscle cell actin, desmin, SlOO protein, CD34, CDl 17, and human chorionic gonadotropin. The MIB-I index averaged 25% to 30% positive cells.

COMMENT

Sarcomatoid carcinoma of the small bowel is rare; 19 cases have been reported in the literature to date (Table). These neoplasms primarily affected middle-aged to older patients, with a mean age at presentation of 57 years. The youngest described patient was 35 years old,2 while the male-female ratio was 1.5:1. No definite risk factors have been identified, but long-standing regional enteritis has been implicated in 2 cases.7,11 Small intestinal SCA primarily occurs in the ileum (11 cases) and jejunum (8 cases), with the duodenum being the site in 1 case.2,5-12 Tumors may be polypoid or endophytic with central ulceration,3 average 7 cm in greatest dimension (range, 3-16 cm), and are frequently necrotic and hemorrhagic. Although SCAs are typically single tumors, 2 patients had multifocal primary tumors.6

On routine histologie examination, SCA may appear biphasic or monophasic. A mixture of epithelial-looking and mesenchymal-like cells characterizes the typical biphasic pattern.4 The former may be arranged in glandlike structures or in clusters and sheets of oval to polygonal cells containing variable amounts of lightly to deeply eosinophilic cytoplasm and round to oval vesicular nuclei with or without prominent nucleoli. In 1 reported case, the epithelial-looking cells showed a prominent trabecular pattern suggestive of neuroendocrine ("carcinoidal") differentiation.7 The mesenchymal-like component of SCA consists of spindle cells with tapering cytoplasm, bipolar vesicular nuclei, and often prominent central nucleoli. These are arranged in sheets, fascicles, or haphazardly. This component may appear anaplastic with bizarre tumor giant cells, including multinucleated "osteoclast-like" giant cells. Anaplastic cells may predominate to the exclusion of the spindle cell component. Such tumors have been called pleomorphic giant cell carcinoma.'' The mesenchymal-like component may also contain heterologous elements, including gemistocyte-like cells,6 syncytiotrophoblast-like cells," and rhabdomyoblasts, some with prominent cross striations/" Monophasic tumors, such as the one we describe herein, show a predominance of the mesenchymallike component, with minimal to absent epithelioid areas. The stromal background often shows a mixed inflammatory infiltrate.

On histochemical stains, most small bowel SCAs were negative for mucin; however, Robey-Cafferty et al2 demonstrated positivity for intracellular mucin in all 6 cases they reported. Immunohistochemically, epithelial-looking and mesenchymal-like components show positivity for cytokeratins (75% of cases examined).11 Other markers of epithelial differentiation (epithelial membrane antigen, carcinoembryonic antigen, and Leu-Mi) may be positive.3,4 Both components often show focal or diffuse positivity for vimentin (90% of cases examined).4 Tumors may also show focal positivity for the neuroendocrine markers chromogranin and neuron-specific enolase.6 One tumor showed prominent carcinoidal features/ but no immunohistochemical stains were performed. Another contained syncytiotrophoblast-like cells, which were focally positive for [alpha]-fetoprotein and human chorionic gonadotropin.11 The tumor we describe herein demonstrated an unexpected staining pattern with CK7 and CK20, that is, it was strongly positive for CK7 and negative for CK20. Typically, small intestinal and colorectal adenocarcinomas are positive for CK20 and negative for CK7, while nongastrointestinal carcinomas (such as lung, breast, ovarian, and endometrial carcinomas) are CK7 positive and CK20 negative.13 The cytokeratin pattern of staining in our case raised the possibility of metastatic carcinoma. This patient's smoking history put him at risk for lung cancer, but the initial chest computed tomographic scan failed to reveal any lung mass. Interestingly, our tumor also demonstrated focal positivity for CD30, an antigen associated with Hodgkin disease, anaplastic large cell lymphoma, and embryonal carcinoma.

Several theories have been proposed to explain the histologie features of SCA, including the following: (1) a "collision tumor" hypothesis that suggests separate but simultaneous proliferation of malignant epithelium and mesenchyme, (2) a "stromal induction/metaplasia/fusion" theory that suggests that carcinomas induce sarcomatous transformation of adjacent stroma (or vice versa) or epithelial and stromal cell fusion inducing malignancy in adjacent connective tissue, and (3) a theory of a "totipotential stem cell" capable of epithelial and mesenchymal differentiation.4 Over the years, there has been growing consensus that SCAs are clonal tumors with divergent differentiation. This is based on their ultrastructural, cell culture, and immunohistochemical features. Sarcomatoid carcinoma is now the most universally accepted term and is recommended for routine use in diagnostic surgical reports. This will improve clinician-pathologist communication and should, in the future, allow in-depth analysis of clinicopathologic data and development of more effective treatment protocols.

Differential diagnoses of malignant small bowel spindle cell tumors must include primary and metastatic gastrointestinal stromal tumors and sarcomas. Gastrointestinal stroma tumors consist of proliferating spindle cells, with or without an epithelioid pattern. They are negative for cytokeratins and positive for CDl 17 (a stem cell factor receptor) and CD34. None of the reported cases of SCA (including our own) have shown positivity for these markers. Leiomyosarcoma, the most frequent primary sarcoma of small bowel,1 is characterized by the proliferation of intersecting bundles of malignant spindle cells. If poorly differentiated, it may be histologically indistinguishable from SCA. Immunohistochemistry distinguishes the two. Leiomyosarcoma is positive for muscle-specific actin and desmin, while SCA is generally not.1 Leiomyosarcoma may rarely appear epithelioid or show cytokeratin and epithelial membrane antigen positivity, necessitating electron microscopy for ultimate distinction.14

Small intestinal carcinomas have a poor prognosis (37%-63% survival at 5 years).1 Sarcomatoid carcinoma, however, has a far worse prognosis. Most patients have large tumors (T4) with extensive local disease at the time of diagnosis. Of the 20 cases reported (including our own), 70% of patients died of disease within 2 months to 3 years of diagnosis, and 79% had metastatic or recurrent disease at death. Surgical resection remains the mainstay of treatment, as patients show poor response to chemotherapy and radiation treatment.

References

1. Hamilton SR, Aaltonen LA, eds. Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC Press; 2000. World Health Organization Classification of Tumours; vol 1.

2. Robey-Cafferty SS, Suva EC, Cleary KR. Anaplastic and sarcomatoid carcinoma of the small intestine. Hum Pathol. 1989:20:858-863.

3. lezzoni IC, Mills SE. Sarcomatoid carcinomas (carcinosarcomas) of the gastrointestinal tract: a review. Semin Diagn Pathol. 1993:2:176-187.

4. Cuarino M, Tricomi P, Giordano F, et al. Sarcomatoid carcinomas: pathological and histopathogenetic considerations. Pathology. 1996:28:298-305.

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6. Bak M, Teglbjaerg PS. Pleomorphic (giant cell) carcinoma of the intestine: an immunohistochemical and electron microscopic study. Cancer. 1989;65: 2557-2564.

7. Dikman SH, Toker C. Enteroblastoma complicating regional enteritis. Gastroenterology. 1973:65:562-566.

8. FukudaT, KamishimaT, Ohnishi Y, etal. Sarcomatoid carcinoma of the small intestine: histologie, immunohistochemical and ultrastructural features of three cases and its differential diagnosis. Pathol Int. 1996;56:682-688.

9. Jones EA, Flejou |F, Molas C, et al. Pleomorphic carcinoma of the small bowel: limitations of immunohistochemical specificity. Pathol Res Pract. 1991; 187:235-250.

10. Lam KY, Leung CY, ho JWC. Sarcomatoid carcinoma of the small intestine. Aust N Z J Surg. 1996:66:636-639.

11. Radi MF, Gray GF, Scott HW. Carcinosarcoma of ileum in regional enteritis. Hum Pathol. 1985:15:385-387.

12. Tsukadaira A, Koizumi T, Okubo Y, et al. Small-intestinal sarcomatoid carcinoma with superior vena cava syndrome. J Gastroenterol. 2002:37:471-475.

13. Rubin BP, Skarin AT, Pisick E, et al. Use of cytokeratins 7 and 20 in determining the origin of metastatic carcinoma of unknown primary, with special emphasis on lung cancer. Eur 1 Cancer Prev. 2001 ;10:77-82.

14. Weiss SW, Goldblum JR. Leiomyosarcoma. In: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St Louis, Mo: The CV Mosby Co; 2001:727-748.

Michelle Reid-Nicholson, MD; Muhammed Idrees, MD; Giorgio Perino, MD; Prodromos Hytiroglou, MD

Accepted lor publication April 8, 2004.

From The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, The Mount Sinai Medical Center, New York, NY (Drs Reid-Nicholson, ldrees, and Hytiroglou); and the Pathology and Laboratory Medicine Service, VA Medical Center, Bronx, NY (Dr Perino).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Michelle Reid-Nicholson, MD, The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, The Mount Sinai Medical Center, One Gustave L. Levy Pl, Box 1194, New York, NY 10029 (e-mail: michelle.reid-nicholson@mssm.edu).

Copyright College of American Pathologists Aug 2004
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