Molecular Profiling of a Tumor of Unknown Origin
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《新英格兰医药杂志》
To the Editor: A 26-year-old woman had had abdominal pain since the beginning of her pregnancy. Endoscopy of the esophagus, stomach, and duodenum and abdominal ultrasonography showed only gastroesophageal reflux. Two months later, physical examination revealed a palpable left supraclavicular lymph node and hepatomegaly. Repeated abdominal ultrasonography showed multiple hepatic metastases.
The patient underwent an exploratory laparotomy during the 34th week of gestation, during which her baby was delivered by cesarean section; the infant was subsequently admitted to the neonatology unit. During the surgery, no primary tumor was identified. Hepatic biopsy showed a metastatic, well-differentiated mucinous adenocarcinoma. Mammography, breast ultrasonography, and colonoscopy revealed no abnormalities, and 18F-fluorodeoxyglucose–labeled positron-emission tomography showed uptake lesions on the peritoneum and on the cervical, left supraclavicular, paraesophageal, and retroperitoneal lymph nodes, beyond the massive liver invasion. Magnetic resonance imaging (MRI) revealed multiple lumbar and thoracic vertebral metastases. Serum tumor markers were as follows: carcinoembryonic antigen, 10.6 ng per milliliter (normal range, 0 to 2.5); cancer antigen 15-3, 33.9 U per milliliter (normal range, 0 to 33); alpha-fetoprotein, 49.3 ng per milliliter (normal range, 0 to 9.8); neuron-specific enolase, 41.4 ng per milliliter (normal range, 0 to 18); cancer antigen 19-9, less than 0.6 U per milliliter (normal range, 0 to 26); and -human chorionic gonadotropin, less than 0.1 ng per milliliter (normal range, 0 to 0.1).
Immunohistochemical analysis of the biopsy specimen revealed that three markers were positive: carcinoembryonic antigen, cytokeratin 19, and cytokeratin 7. The following markers were negative: estrogen receptor, progesterone receptor, vimentin, thyroid transcription factor 1, cancer antigen 125, cytokeratin 20, thyroglobulin, and alpha-fetoprotein. The immunohistochemical report suggested a primary tumor of upper gastrointestinal origin.
Molecular profiling was performed with the use of the CupPrint test (Agendia). On the basis of a gene-expression database of 643 cases of cancer, a k–nearest neighbor algorithm was developed for the discrimination of 51 tumor types, k being 5 in this case. (The nearest neighbor algorithm reports the 5 nearest neighbors to the sample size being analyzed.) This top-5 grouping indicated that the tumor had an upper gastrointestinal origin. The final weighted prediction from this grouping pointed to the gallbladder as the primary origin.
MRI cholangiopancreatography revealed an oval, polypoid image inside the gallbladder (Figure 1). Multiple liver metastases were reconfirmed, the largest of which was in contact with the gallbladder wall. This finding also suggested that the gallbladder was the probable primary site. In such cases, microarray profiling can be useful in determining the origin of an unknown primary tumor.1,2,3,4
Figure 1. MRI Cholangiopancreatogram Showing a Polypoid Tumor in the Gallbladder (Arrow).
Gustavo Ismael, M.D.
Evandro de Azambuja, M.D.
Ahmad Awada, M.D., Ph.D.
Jules Bordet Institute
1000 Brussels, Belgium
gustavo.ismael@bordet.be
References
Su AI, Welsh JB, Sapinoso LM, et al. Molecular classification of human carcinomas by use of gene expression signatures. Cancer Res 2001;61:7388-7393.
Ramaswamy S, Tamayo P, Rifkin R, et al. Multiclass cancer diagnosis using tumor gene expression signatures. Proc Natl Acad Sci U S A 2001;98:15149-15154.
Erlander M, Moore M, Cotter P, et al. Molecular classification of carcinoma of unknown primary by gene expression profiling from formalin-fixed paraffin-embedded tissues. J Clin Oncol 2004;22:Suppl 14:846s-846s.
Tothill RW, Kowalczyk A, Rischin D, et al. An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin. Cancer Res 2005;65:4031-4040.
The patient underwent an exploratory laparotomy during the 34th week of gestation, during which her baby was delivered by cesarean section; the infant was subsequently admitted to the neonatology unit. During the surgery, no primary tumor was identified. Hepatic biopsy showed a metastatic, well-differentiated mucinous adenocarcinoma. Mammography, breast ultrasonography, and colonoscopy revealed no abnormalities, and 18F-fluorodeoxyglucose–labeled positron-emission tomography showed uptake lesions on the peritoneum and on the cervical, left supraclavicular, paraesophageal, and retroperitoneal lymph nodes, beyond the massive liver invasion. Magnetic resonance imaging (MRI) revealed multiple lumbar and thoracic vertebral metastases. Serum tumor markers were as follows: carcinoembryonic antigen, 10.6 ng per milliliter (normal range, 0 to 2.5); cancer antigen 15-3, 33.9 U per milliliter (normal range, 0 to 33); alpha-fetoprotein, 49.3 ng per milliliter (normal range, 0 to 9.8); neuron-specific enolase, 41.4 ng per milliliter (normal range, 0 to 18); cancer antigen 19-9, less than 0.6 U per milliliter (normal range, 0 to 26); and -human chorionic gonadotropin, less than 0.1 ng per milliliter (normal range, 0 to 0.1).
Immunohistochemical analysis of the biopsy specimen revealed that three markers were positive: carcinoembryonic antigen, cytokeratin 19, and cytokeratin 7. The following markers were negative: estrogen receptor, progesterone receptor, vimentin, thyroid transcription factor 1, cancer antigen 125, cytokeratin 20, thyroglobulin, and alpha-fetoprotein. The immunohistochemical report suggested a primary tumor of upper gastrointestinal origin.
Molecular profiling was performed with the use of the CupPrint test (Agendia). On the basis of a gene-expression database of 643 cases of cancer, a k–nearest neighbor algorithm was developed for the discrimination of 51 tumor types, k being 5 in this case. (The nearest neighbor algorithm reports the 5 nearest neighbors to the sample size being analyzed.) This top-5 grouping indicated that the tumor had an upper gastrointestinal origin. The final weighted prediction from this grouping pointed to the gallbladder as the primary origin.
MRI cholangiopancreatography revealed an oval, polypoid image inside the gallbladder (Figure 1). Multiple liver metastases were reconfirmed, the largest of which was in contact with the gallbladder wall. This finding also suggested that the gallbladder was the probable primary site. In such cases, microarray profiling can be useful in determining the origin of an unknown primary tumor.1,2,3,4
Figure 1. MRI Cholangiopancreatogram Showing a Polypoid Tumor in the Gallbladder (Arrow).
Gustavo Ismael, M.D.
Evandro de Azambuja, M.D.
Ahmad Awada, M.D., Ph.D.
Jules Bordet Institute
1000 Brussels, Belgium
gustavo.ismael@bordet.be
References
Su AI, Welsh JB, Sapinoso LM, et al. Molecular classification of human carcinomas by use of gene expression signatures. Cancer Res 2001;61:7388-7393.
Ramaswamy S, Tamayo P, Rifkin R, et al. Multiclass cancer diagnosis using tumor gene expression signatures. Proc Natl Acad Sci U S A 2001;98:15149-15154.
Erlander M, Moore M, Cotter P, et al. Molecular classification of carcinoma of unknown primary by gene expression profiling from formalin-fixed paraffin-embedded tissues. J Clin Oncol 2004;22:Suppl 14:846s-846s.
Tothill RW, Kowalczyk A, Rischin D, et al. An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin. Cancer Res 2005;65:4031-4040.