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Davor
Tomas, Mladen Belicza, Bozo Kruslin, Ljudevit Jurak University
Department of Pathology, Sestre milosrdnice University Hospital,
Vinogradska 29, 10000 Zagreb, Croatia
Mario Ledinsky, University Department of Surgery, Sestre
milosrdnice University Hospital, Zagreb, Croatia
Correspondence to: Bozo Kruslin M.D., Ph.D. Ljudevit Jurak
University Department of Pathology, Sestre milosrdnice University
Hospital Vinogradska 29, 10000 Zagreb, Croatia.
bkruslin@kbsm.hr
Telephone: +385-1-3787-177
Fax: +385-1-3787-244
Received: 2003-12-11
Accepted: 2004-01-30
Abstract
AIM: Metastases from lung cancer to gastrointestinal tract
are not rare at postmortem studies but the development of clinically
significant symptoms from the gastrointestinal metastases is very
unusual.
METHODS: Formalin-fixed, paraffin-embedded tissues were cut
into 5 mm thick sections and routinely stained with hematoxylin and
eosin. Some slides were also stained with Alcian-PAS. Antibodies
used were primary antibodies to pancytokeratin, cytokeratin 7,
cytokeratin 20, epithelial membrane antigen, vimentin, smooth muscle
actin and CD-117.
RESULTS: We observed three patients who presented with
multiple metastases from large cell bronchial carcinoma to small
intestine. Two of them had abdominal symptoms (sudden onset of
abdominal pain, constipation and vomiting) and in one case the tumor
was incidentally found during autopsy. Microscopically, all tumors
showed a same histological pattern and consisted almost exclusively
of strands and sheets of poorly cohesive, polymorphic giant cells
with scanty, delicate stromas. Few smaller polygonal anaplastic
cells dispersed between polymorphic giant cells, were also observed.
Immunohistochemistry showed positive staining of the tumor cells
with cytokeratin and vimentin. Microscopically and
immunohistochemically all metastases had a similar pattern to
primary anaplastic carcinoma of the small intestine.
CONCLUSION: In patients with small intestine tumors showing
anaplastic features, especially with multiple tumors, metastases
from large cell bronchial carcinoma should be first excluded,
because it seems that they are more common than expected.
© 2005 The WJG Press and Elsevier Inc. All rights reserved.
Key words: Small intestine tumors; Bronchial carcinomas;
Large cell carcinoma; Tumor metastases
Tomas D, Ledinsky M, Belicza M, Kruslin B. Multiple metastases to
the small bowel from large cell bronchial carcinomas. World J
Gastroenterol 2005;
11(9): 1399-1402
http://www.wjgnet.com/1007-9327/11/1399.asp
INTRODUCTION
Metastases from lung cancer to gastrointestinal tract are not rare
at postmortem studies but the development of clinically significant
symptoms from the gastrointestinal metastases is very unusual. Small
bowel metastases from lung carcinoma are also not uncommon and may
be seen more frequently as patients live longer after their
diagnosis of cancer. Small bowel metastases must be considered in
any patient with both lung carcinoma and abdominal pain, and should
be expected in patients with both lung carcinoma and acute abdomen.
The major manifestations are gastrointestinal hemorrhage (occult or
massive), ileus, intussusceptions, and perforation[1-7].
On the other hand, primary malignant tumors of the small intestine
are rare, especially anaplastic carcinoma. Very few of these
malignant neoplasms have been reported in the literature. The major
manifestations are the same as in metastatic tumors[8-15].
We described three patients with large cell bronchial carcinoma
having multiple metastases to small intestine. Diagnosis of primary
large cell bronchial carcinoma was confirmed by cytological or
pathohistological examination in all patients.
Case reports
Patient 1
A 64-year-old man who was previously diagnosed having large cell
bronchial carcinoma by cytology presented with sudden onset of
abdominal pain, constipation and vomiting. Two years earlier the
patient was treated with four cycles of chemotherapy and TCT.
Disturbances persisted for two days before admission. Physical
examination revealed diffuse pain on deep abdominal palpation and
weakness of intestinal passage. Blood examination showed
leukocytosis, anemia and slightly elevated glucose. Lung radiography
was done and showed no signs of bronchial carcinoma or mediastinal
lymph node enlargement. The patient was treated with a nasogastrical
probe, infusion of physiological solution and intravenous
metoklopramid and trospij application. Abdominal
ultrasonography showed subileus of small intestine. After
ultrasonography the patient underwent abdominal computed tomography
scan that confirmed subileus and revealed few solid tumors in
jejunum. Liver, spleen, gallbladder, pancreas and abdominal lymph
nodes had no signs of tumor infiltration. Five days after admission,
surgical resection of 30 cm of small intestine with adjacent
mesenterium and regional lymph nodes was performed. During surgery,
three intraluminal cherry-like tumors and four knots in mesenterial
fat were palpable. The knots were gummy. No other signs of tumor
expansion were found. The patient had no complication during the
postoperative course and was discharged ten days after surgery with
suggested oncological examination and treatment. No additional
therapy was performed as suggested by oncologists. One year after
surgery the patient was still alive and showed no signs of tumor
spread.
Patient 2
A 63-year-old woman who had large cell bronchial carcinoma confirmed
by small biopsy with metastases in suprarenal glands, liver and
brain. Diagnosis was made eight months ago and the patient underwent
chemotherapy and TCT. The patient presented with sudden onset of
abdominal pain and vomiting. Disturbances started one day before
admission. The physical examination revealed hardness of abdominal
wall and diffuse pain on abdominal palpation. Intestinal passage was
weak. Blood examination showed leukocytosis and anemia. Abdominal
radiography and ultrasonography showed perforations of small
intestine with free air in peritoneum. The patient underwent urgent
surgery and 27 cm of small intestine with adjacent mesenterium was
resected. During surgery, two tumors which penetrated the wall of
small intestine, were seen. The patient had no complication during
the postoperative course and was discharged nine days after surgery
with suggested continuation of oncological treatment. Two months
after surgery the patient died at home. Autopsy was not performed.
Patient 3
A 60-year-old woman presented with sudden onset of psychical
disorientation and back pain extending to the left leg. Head
computed tomography scan excluded brain damage, but lung radiography
revealed tumorous infiltration in the right upper lung lobe. The
patient was hospitalized and additional examinations showed
increased body temperature, leukocytosis, anemia, slight hypoxemia
and sinus tachycardia. Bone radiography showed no sign of
metastases. The patient was treated with analgetics, sedatives,
antibiotics, antiarrhythmic drugs and infusion of physiological
solution. Two days after admission, the patient became unconscious
and died. Autopsy revealed nonhemorrhagic brain infarct located in
parietal right region as a cause of death. Pathological examination
confirmed large (eight centimeter in diameter) neoplastic process in
right upper bronchus and found metastasis in left adrenal gland.
During the resection of small intestine, a pathologist revealed four
whitish tumors in the wall. Tumors measured between 1 and 2
centimeters in diameter and intestinal wall between tumors had no
sign of tumor involvement. On the cut surface, tumors were partially
necrotic, soft and did not penetrate intestinal wall.
MATERIALS AND METHODS
Formalin-fixed, paraffin-embedded tissues were cut into 5 mm thick
sections and routinely stained with hematoxylin and eosin. Some
slides were also stained with Alcian-PAS. Deparaffinization and
immunohistochemical staining were performed following microwave
streptavidin immunoperoxidase (MSIP) protocol on a DAKO TechMateTM
Horizon automated immunostainer. We used primary antibodies to
pancytokeratin, cytokeratin 7, cytokeratin 20, epithelial membrane
antigen, vimentin, smooth muscle actin and CD-117 (purchased from
DAKO, Copenhagen, Denmark). Dilution of all antibodies was “ready
to use”.
RESULTS
Patient 1
Pathologic examination revealed three separate polypoid tumors in
intestinal lumen, the distance between tumors was at least 3 cm
(Figure 1). Intestinal wall between tumors had no sign of tumor
spread or infiltration. The tumors had a maximum diameter between
1.5 and 4 cm and showed an expansive growth. In the adjacent
mesenteric fat tissue four knots were found. One knot was measured 8
cm and the other three were up to 1 cm. On the cut surface, tumors
and knots were whitish, flashy and soft.
Figure
1 Polypoid
tumor in intestinal lumen. On the cut surface the tumor was whitish,
flashy and soft.
Microscopically all tumors showed a same
histological pattern and consisted almost exclusively of strands and
sheets of poorly cohesive, polymorphic giant cells with scanty,
delicate stromas (Figure 2). Few smaller polygonal anaplastic cells
dispersed between polymorphic giant cells, were also observed. Tumor
giant cells were anaplastic with abundant light eosinophilic
cytoplasms. The nuclei were pleomorphic with distinct nuclear
membranes, irregular chromatin clumping and pushed to the edge of
cells. Each nucleus contained one or more prominent nucleoli.
Smaller polygonal cells had same nuclei and the only difference
between two cell types was the cytoplasm size and shape. Mitotic
index was high with typical and atypical mitotic figures. Mucosal
ulceration, focal necrosis and hemorrhage were found. Diffuse and
slight infiltration with mononuclear and polymorph cells was also
seen in all tumors and metastases. Tumors infiltrated submucosa but
muscular part of intestinal wall was not affected. Two mesenterial
knots were built of the same tumorous tissue and the other two were
built of lymph nodes without signs of tumor infiltration. The
surgical margins were free of tumor. Special stain (Alcian-PAS)
demonstrated no intracellular or extracellular mucin.
Immunohistochemically, tumor cells at both sites, intestinal and
lymph nodes, were focally positive for pancytokeratin (Figure 3),
cytokeratin 7, cytokeratin 20 and epithelial membrane antigen and
diffusingly positive for vimentin (Figure 4). Smooth muscle actin
and CD-117 were negative.
The diagnosis of primary anaplastic
carcinoma of small bowel was suggested. However, careful clinical
check-up was recommended in order to exclude primary giant cell
bronchial cancer. Few weeks after diagnosis was established, we got
some additional information about the patient. Two years earlier,
the patient was treated for pulmonary carcinoma with four cycles of
chemotherapy and TCT (cytological diagnosis was large cell pulmonary
carcinoma). Lung radiography was done before surgical resection of
small intestine and showed no signs of bronchial carcinoma or
mediastinal lymph node enlargement. These data suggested the
diagnosis of metastatic large cell bronchial carcinoma.
Figure
2
Tumor consisted almost exclusively of strands and sheets
of poorly cohesive, polymorphic giant cells with scanty, delicate
stromas (hematoxylin-eosin ×400).
Figure
3 Focal positivity for pancytokeratin in tumor cells(MSIP ×400).
Figure
4
Diffuse intense staining for vimentin in tumor cells (MSIP
×400).
Patient 2
Pathologic examination revealed two separate whitish tumors in
intestinal wall, the distance between tumors was 22 cm. Intestinal
wall between tumors had no sign of tumor involvement. The tumors had
a maximum diameter 1.5 and 2.5 cm and were partially necrotic,
flashy and soft on the cut surface with obvious affection of
intestinal serosa. Microscopically both tumors showed a same
histological pattern as described previously. Tumors penetrated
intestinal serosa and spread to adjacent fat tissues. No tumor was
found at the surgical margins. Imunohistochemically tumor cells were
focally positive for pancytokeratin and diffusely positive for
vimentin. We compared these microscopic findings with findings in
first patient and asked additional data about the patient.
Additional data showed the existence of an extended large cell
bronchial carcinoma and diagnosis of metastatic large bronchial
carcinoma was made.
Patient 3
Microscopically all four tumors (lung, adrenal glands and
four intestinal tumors) showed a same histological pattern that was
previously described and were similar to those found in large cell
bronchial carcinoma.
DISCUSSION
Primary malignant tumors of the small intestine are rare and
easy to be misdiagnosed because of their low morbidity and
nonspecific clinical manifestations[15].
Metastases in small intestine are also rare, especially multiple
ones. Primary and metastatic tumors share the same clinical
manifestations and diagnostic problems[1-3,5,15].
All our patients had multiple metastases and all tumors were
predominantly composeed of large anaplastic cells, which expressed
both epithelial and mesenchymal immunohistochemical markers. In the
first case we were not completely sure that the tumor was metastatic
because polypoid growth pattern, multiple tumors and affection of
mesenterial lymph nodes were not characteristic for metastatic
tumors. Incomplete clinical data and lung radiography that was done
before surgery failed to confirm the metastasis of lung cancer. The
next two cases showing similar features more commonly favor
metastatic tumors from primary lung cancer. Lung cancer is most
commonly metastatic to mediastinal lymph nodes, pleura, liver, bone,
brain and adrenals, but some authors proved that symptomatic small
bowel metastases could occur early in the course of the disease[2,7].
Previous reports of such metastases of the small bowel have
documented a very poor prognosis for such patients[1-7].
Diagnostic problems might appear due to the lack of appropriate
clinical data or when primary tumor was unknown because clinical
symptoms, microscopic pattern and immunohistochemical profile of
large cell bronchial carcinoma metastases were similar to primary
anaplastic carcinoma of the small intestine. Predominant sites of
anaplastic carcinoma (so called pleomorphic carcinoma, sarcomatoid
carcinoma, giant cell carcinoma or carcinosarcoma) are lung,
pancreas, thyroid and gallbladder. It is very uncommon in small
intestine. According to the predominance of cell type, these tumors
could be subdivided in three types: giant (gemistocytic) cell type,
spindle cell type or mixed type[8-14].
Bak et al.[9].
reported four cases of giant cell carcinoma, two in small intestine
(tumors were multiple) and two in large bowel (in one case tumor was
multiple), and concluded on the basis of the same light and electron
microscopy, nuclear characteristics and identical
immunohistochemical reaction that the distinction among three cell
types was the shape and amount of cytoplasm and believed that
gemistocytic cells evolved from smaller polygonal cells.
Gemistocytic cells were identical to the giant cells of pulmonary
giant cell carcinoma. The size of gemistocytic cells varied and
larger cells had two or more nuclei. All the three cell types were
imunohistochemically positive for epithelial (cytokeratin,
epithelial membrane antigen) and mesenchymal markers (vimentin).
Some of these tumors were also positive for neuroendocrine markers
(neuron specific enolase, chromogranin)[8,9,11,12].
The WHO classification of lung cancer recognizes spindle cell
carcinoma and giant cell carcinoma as separate neoplasms related to
squamous cell carcinomas and large cell carcinomas, but some authors
included these group tumors with adenocarcinomatous foci and
considered all giant cell carcinomas to be poorly differentiated
adenocarcinomas[9].
Indeed the foci of squamous cell carcinoma or adenocarcinoma were
found in 10% and 45% of pleomorphic carcinomas, respectively, and
produced an additional uncertainty as to the distinctive nature of
this tumor type[16].
In adenocarcinomas of the lungs, pancreas and thyroid, focal giant
cell formation was sometimes seen but these cells retained some
characteristics of their origin and had no typical gemistocytic
morphology[9].
Przygodzki et al.[16].
tested the hypothesis that pleomorphic carcinomas (giant and spindle
cell) were one entity separated from squamocellular carcinomas or
adenocarcinomas by evaluating the mutational spectrum seen in these
tumor types. They compared the mutation type and the rate of K-ras-2
and p53 genes in pleomorphic and squamocellular adenocarcinoma and
revealed significant differences in the pattern and frequency of
genetic mutations between all three types of tumors and according to
these findings separate histopathologic classification of these
tumors were recommended. Before these findings, Agrawal et al.[8].
also proved that pleomorphic carcinomas had no connections with
squamocellular adenocarcinomas and thought that some of the
histological, immunohistochemical and ultrastructural
differentiation characteristics were similar with carcinoid tumors
and considered that these tumors were poorly differentiated variants
of neuroendocrine carcinomas. Despite the name and origin,
anaplastic carcinoma is a rare variant of small intestinal carcinoma
with an aggressive clinical course and poor outcome and must be
distinguished from large cell bronchial carcinoma metastases, which
may be the first sign of lung malignancy[11-15].
In conclusion, multiple metastatic intestinal tumors from primary
large cell bronchial carcinoma are more common than generally
believed. Therefore in patients with small intestine tumors with
anaplastic features, especially in patients with multiple tumors,
metastases from large cell bronchial carcinoma must be excluded
because they might be more common than expected.
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