A 72-year-old white woman presented with fever, abdominal pain, and nausea. For the preceding 2 months, she had experienced abdominal pain and 2 episodes of bowel obstruction, which resolved with nasal gastric tube. Physical examination revealed decreased bowel sounds and bilateral lower quadrant tenderness with rebound, more prominent on the left than on the right side. A complete blood cell count showed the following values: hemoglobulin, 6.3 g/dL (63 g/L); platelets, 452 × 103/μL (452 × 109/L); and white blood cells, 19.6 × 103/μL (19.6 × 109/L) with 87% neutrophils. Stool was negative for occult blood. Chest radiograph was noncontributory. Small bowel series revealed gas and retained contrast. Abdominal computerized axial tomography and positron emission tomography showed an ulcerated 4.8 × 6.3-cm mass in the left lower quadrant. Past medical history was significant for remote right colonic adenocarcinoma with right hemicolectomy, mastectomy for breast carcinoma, thyroidectomy for adenoma 10 years previous, sigmoid diverticulitis with sigmoid resection, and multiple colonic adenomas with polypectomy 2 years previous. The significant family history included 1 sister with history of ovarian cancer, intestinal cancer, and breast malignancy.

Exploratory laporatomy was performed, and a tumor mass was found in the proximal ileum with a small perforation and surrounding abscess formation. The segment of ileum containing the tumor was resected with wide resection margins; the patient had complete recovery from surgery within 2 weeks. Grossly, a 4 × 5.5 × 2.2-cm, exophytic, firm, and ulcerated mass infiltrated the intestinal wall, extending to the serosa (Figure 1). The tumor was extensively necrotic and focally hemorrhagic. Microscopic examination revealed tumor infiltrating through the muscular bundles, with extensive necrosis and vascular invasion. The neoplastic cells were arranged in sheets and strands (Figure 2). On high magnification, the monotonous small anaplastic cells had indistinct borders with scant amophilic cytoplasm, a central round nucleus with inconspicuous nucleolus, coarsely granular chromatin, numerous mitoses, and single cell necrosis (Figure 3). Lymph nodes were negative for tumor. Immunohistochemical studies were performed on deparaffinized sections; the neoplastic cells were negative for lymphoid markers (CD45, CD3, CD20, CD79a), S100, low-molecular-weight cytokeratin (CAM 5.2), and TTF1 and were strongly positive for synaptophysin (Figure 4).

What is your diagnosis?

Primary tumors of the small intestine are comparatively rare; fewer than 2% of all gastrointestinal malignancies originate in the small bowel1; of the malignant tumors, approximately 30% to 50% are adenocarcinomas, 25% to 30% are carcinoid tumors, and 15% to 20% are lymphomas.2 Clinically, they share similar features, including abdominal pain, bleeding, obstruction, and occasional perforation in lymphoma and the highly aggressive tumor. The diagnosis of small intestinal tumors is frequently delayed because of the vague presentation, nonspecific signs and symptoms, and lack of accurate diagnostic studies.

Carcinoids were recognized as neuroendocrine-related tumors in the early 20th century; in recent years, it has become apparent that the term carcinoid represents a spectrum of neoplasms that originate from a variety of neuroendocrine cells,1 with the small cell neuroendocrine carcinoma being the most primitive subtype and the so-called classical carcinoid being the most differentiated one.

The peak incidence of carcinoid tumor is between the sixth and seventh decades of life. Of all the carcinoids in the gastrointestinal tract, small intestinal carcinoids account for 29%.3 

The vast majority of small intestinal neuroendocrine neoplasms are the classical carcinoids. Although the incidence is extremely rare, extrapulmonary small cell carcinomas, derived from undifferentiated intestinal neuroendocrine cells, have been documented in small intestine4,5; histologically, like their pulmonary counterpart, small cell carcinomas of small bowel are undifferentiated and composed of sheets and nests of densely packed round to ovoid cells with hyperchromatic nuclei, stippled nuclear chromatin, inconspicuous nucleoli, and scant cytoplasm; pleomorphism is minimal; numerous mitoses, apoptotic cells, foci of necrosis, and vascular invasion are usually obvious; ultrastructurally, membrane-bounded dense core granules are present; immunohistochemically, the neoplastic cells are positive for neuroendocrine markers.

Although small cell lung carcinoma is a highly aggressive tumor, the accumulated data indicate that the natural history of extrapulmonary small cell carcinomas is related to their primary sites. Those that originate in more cephalad portions of the airway system (trachea and larynx) resemble bronchogenic small cell carcinoma in their aggressive behavior, with rapid local progression and early regional lymph node and distant spread. It is thought that extrapulmonary small cell carcinomas resemble bronchogenic small cell carcinomas in their responsiveness to radiation and chemotherapy.6 Small cell carcinomas of the gastrointestinal tract may have a natural history different from their pulmonary counterpart.7 Inadequate information exists for a general recommendation for the treatment of extrapulmonary small cell carcinomas. Surgery has resulted in prolonged disease-free survival in some patients with gastric and colonic small cell carcinomas.6,8 Radiation and chemotherapy may also provide temporary remission in some cases.

The biological behavior of small cell carcinoma in small intestine has not been clearly defined because of the rare incidence. Recently a small intestinal small cell neuroendocrine carcinoma was reported with satisfactory outcome after the patient was treated with aggressive surgery.4 In the case presented here, despite its large size (>5 cm), aggressive features of transmural invasion, an undifferentiated growth pattern, and high grade of histological index, no metastases were identified on regular image studies, and lymph nodes were negative for metastases.

Differentiating small cell neuroendocrine carcinoma from classical carcinoids of midgut usually poses few diagnostic difficulties; typically, classical carcinoids show a characteristic growth pattern, rare mitosis, and lack of necrosis. Small intestinal metastases of lung primary small cell carcinoma that may microscopically and clinically mimic that of small intestine have been reported, and perforation has been documented for such incidence9; differentiating from metastases of lung primary small cell carcinoma can be achieved with the presence of corresponding lung primary malignancy and by immunohistochemical staining with TTF1 (a marker specific for tumors of lung and thyroid, and occasionally some extrapulmonary small cells). By regular histology, it may be challenging to differentiate small cell carcinoma from lymphoma; in contrast to lymphoma, small cell carcinoma is negative for lymphoid markers and positive for neuroendocrine markers.

Gill
,
S. S.
,
D. M.
Heuman
, and
A. A.
Mihas
.
Small intestinal neoplasms.
J Clin Gastroenterol
2001
.
33
:
267
282
.
North
,
J. H.
and
M. S.
Pack
.
Malignant tumors of the small intestine: a review of 144 cases.
Am Surg
2000
.
66
:
46
51
.
Modlin
,
I. M.
and
A.
Sandor
.
An analysis of 8305 cases of carcinoid tumors.
Cancer
1997
.
79
:
813
829
.
Testini
,
M.
,
F.
Cirillo
, and
S.
Miniello
.
et al
.
Diffuse neuroendocrine tumor of the small bowel: an exceptional case with long survival and literature review.
Int Surg
2002
.
87
:
1
5
.
Doertenbach
,
J. G.
and
C.
Gustmann
.
Multiple synchronous small intestine carcinomas, a rare case observation.
Langenbecks Arch Chir
1996
.
381
:
218
220
.
Remick
,
S. C.
and
J. C.
Ruckdeschel
.
Extrapulmonary and pulmonary small-cell carcinoma: tumor biology, therapy, and outcome.
Med Pediatr Oncol
1992
.
20
:
89
99
.
Remick
,
S. C.
,
G. R.
Hafez
, and
P. P.
Carbone
.
Extrapulmonary small-cell carcinoma: a review of the literature with emphasis on therapy and outcome.
Medicine (Baltimore)
1987
.
66
:
457
471
.
Richardson
,
R. L.
and
L. H.
Weiland
.
Undifferentiated small cell carcinomas in extrapulmonary sites.
Semin Oncol
1982
.
9
:
484
496
.
McNeill
,
P. M.
,
L. D.
Wagman
, and
J. P.
Neifeld
.
Small bowel metastases from primary carcinoma of the lung.
Cancer
1987
.
59
:
1486
1489
.

Author notes

Corresponding author: Guang-Qian Xiao, MD, PhD, Department of Pathology, Box 1194, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574 ([email protected])