Diagnostic strategies for unknown primary cancer

Unknown primary cancer (UPC) is defined by the presence of metastatic disease for which a primary site is undetectable on presentation. Computed tomography scan of the body was performed routinely in search of the primary cancer and invasive procedures were pursued in selective cases. Magnetic resonance imaging of the breast enables identification of an occult breast primary tumor in ≤ 75% of women who present with adenocarcinoma in the axillary lymph nodes and can influence surgical management. Positron emission tomography scan also can be used in the diagnosis of UPCs, but its value is controversial. Cytokeratins 7 and 20 and thyroid transcription factor are some of the histochemical markers used in most patients who present with metastatic adenocarcinoma. Some of the newly discovered immunohistochemical markers further assist in narrowing the differential diagnosis. The role of molecular profiling to make the diagnosis, establish the prognosis, and assess the response to treatment in UPCs is evolving. The authors discuss the role of histochemical markers in the diagnosis of UPC and the most recent data regarding the use of imaging and invasive diagnostic modalities and gene expression profiles. Cancer 2004. © 2004 American Cancer Society.

[1]  A. D. De Schepper,et al.  Breast MR imaging in a patient with unilateral axillary lymphadenopathy and unknown primary malignancy , 2003, European Radiology.

[2]  S. Culine,et al.  Summary of the Standards, Options and Recommendations for the management of patients with carcinoma of unknown primary site (2002) , 2003, British Journal of Cancer.

[3]  L. J. Veer,et al.  Road map to metastasis , 2003, Nature Medicine.

[4]  C. Cordon-Cardo,et al.  A multigenic program mediating breast cancer metastasis to bone. , 2003, Cancer cell.

[5]  S. Wiseman,et al.  Thyroid transcription factor-1 expression prevalence and its clinical implications in non-small cell lung cancer: a high-throughput tissue microarray and immunohistochemistry study. , 2003, Human pathology.

[6]  E. Cagnano,et al.  Neuroendocrine (Merkel cell) carcinoma in regional lymph nodes without primary site. , 2003, The Israel Medical Association journal : IMAJ.

[7]  A. Folpe,et al.  Potential Utility of Uroplakin III, Thrombomodulin, High Molecular Weight Cytokeratin, and Cytokeratin 20 in Noninvasive, Invasive, and Metastatic Urothelial (Transitional Cell) Carcinomas , 2003, The American journal of surgical pathology.

[8]  R. Alsabeh,et al.  Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma. , 2002, Human pathology.

[9]  E. Wit,et al.  Identification from public data of molecular markers of adenocarcinoma characteristic of the site of origin. , 2002, Cancer research.

[10]  J. Johansen,et al.  Implication of 18F‐Fluoro‐2‐Deoxy‐D‐Glucose Positron Emission Tomography on Management of Carcinoma of Unknown Primary in the Head and Neck: A Danish Cohort Study , 2002, The Laryngoscope.

[11]  K. Naresh.  Do metastatic tumours from an unknown primary reflect angiogenic incompetence of the tumour at the primary site?--a hypothesis. , 2002, Medical hypotheses.

[12]  B. Addis,et al.  Immunohistochemistry in the distinction between malignant mesothelioma and pulmonary adenocarcinoma: a critical evaluation of new antibodies , 2002, Journal of clinical pathology.

[13]  M. Roh,et al.  Utility of thyroid transcription factor-1 and cytokeratin 20 in identifying the origin of metastatic carcinomas of cervical lymph nodes. , 2002, Journal of Korean medical science.

[14]  A. Vissink,et al.  Detection of unknown primary tumours and distant metastases in patients with cervical metastases: value of FDG-PET versus conventional modalities , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[15]  T. Poggio,et al.  Multiclass cancer diagnosis using tumor gene expression signatures , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Welsh,et al.  Molecular classification of human carcinomas by use of gene expression signatures. , 2001, Cancer research.

[17]  A. Maitra,et al.  Immunoreactivity for hepatocyte paraffin 1 antibody in hepatoid adenocarcinomas of the gastrointestinal tract. , 2001, American journal of clinical pathology.

[18]  D. Eisele,et al.  Oncologic Rationale for Bilateral Tonsillectomy in Head and Neck Squamous Cell Carcinoma of Unknown Primary Source , 2001, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[19]  R. Salgia,et al.  Use of cytokeratins 7 and 20 in determining the origin of metastatic carcinoma of unknown primary, with special emphasis on lung cancer , 2001, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[20]  U. Pietrzyk,et al.  2[18F]-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography is a Sensitive Tool for the Detection of Occult Primary Cancer (Carcinoma of Unknown Primary Syndrome) with Head and Neck Lymph Node Manifestation , 2000, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[21]  J. Olson,et al.  Magnetic Resonance Imaging Facilitates Breast Conservation for Occult Breast Cancer , 2000, Annals of Surgical Oncology.

[22]  M. Dietel,et al.  Uroplakin III is a highly specific and moderately sensitive immunohistochemical marker for primary and metastatic urothelial carcinomas. , 2000, American journal of clinical pathology.

[23]  J. Hainsworth,et al.  Overexpression of Her-2 in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  P. Johnstone,et al.  Tonsillectomy in diagnosis of the unknown primary tumor of the head and neck , 2000, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[25]  P. Watson,et al.  The potential role for prolactin-inducible protein (PIP) as a marker of human breast cancer micrometastasis , 1999, British Journal of Cancer.

[26]  J. Werner,et al.  [F-18 FDG PET for detection of occult primary tumor in patients with lymphatic metastases of the neck region]. , 1999, Laryngo- rhino- otologie.

[27]  M. Mandelkern,et al.  The role of positron emission tomography in occult primary head and neck cancers. , 1999, The cancer journal from Scientific American.

[28]  L. Friberg,et al.  18F-FDG whole body positron emission tomography (PET) in patients with unknown primary tumours (UPT). , 1999, European journal of cancer.

[29]  K. Hess,et al.  Unknown primary tumors metastatic to liver. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  N. Pavlidis,et al.  Bcl2 and p53 protein expression in metastatic carcinoma of unknown primary origin: biological and clinical implications. A Hellenic Co-operative Oncology Group study. , 1998, Anticancer research.

[31]  J. Roodenburg,et al.  Detection of unknown occult primary tumors using positron emission tomography , 1998, Cancer.

[32]  L. Schwartz,et al.  MR imaging of the breast in patients with occult primary breast carcinoma. , 1997, Radiology.

[33]  D. Peiffert,et al.  Cervical lymph node metastasis from an unknown primary: is a tonsillectomy necessary? , 1997, International journal of radiation oncology, biology, physics.

[34]  C. White,et al.  Search for a primary lung neoplasm in patients with brain metastasis: is the chest radiograph sufficient? , 1997, AJR. American journal of roentgenology.

[35]  K. Hess,et al.  Poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown origin: favorable subsets of patients with unknown-primary carcinoma? , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  J. Roodenburg,et al.  Detection of unknown primary head and neck tumors by positron emission tomography. , 1997, International journal of oral and maxillofacial surgery.

[37]  M. Dietel,et al.  Immunohistochemical differentiation of metastatic breast carcinomas from metastatic adenocarcinomas of other common primary sites , 1996, Histopathology.

[38]  R. Lauro,et al.  Surfactant proteins and thyroid transcription factor-1 in pulmonary and breast carcinomas. , 1996, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[39]  K R Hess,et al.  Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  D. Poller.  Prostate marker immunoreactivity in salivary gland neoplasms. , 1994, The American journal of surgical pathology.

[41]  R. Lenzi,et al.  The biology of unknown primary tumors. , 1993, Seminars in oncology.

[42]  J. Krieken.  Prostate Marker Immunoreactivity in Salivary Gland Neoplasms: A Rare Pitfall in Immunohistochemistry , 1993 .

[43]  J. V. van Krieken.  Prostate Marker Immunoreactivity in Salivary Gland Neoplasms: A Rare Pitfall in Immunohistochemistry , 1993, The American journal of surgical pathology.

[44]  R. Moll,et al.  Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. , 1992, The American journal of pathology.

[45]  R. Lauro,et al.  The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. , 1991, Development.

[46]  M. Merino,et al.  Value of gross cystic disease fluid protein-15 in distinguishing metastatic breast carcinomas among poorly differentiated neoplasms involving the ovary. , 1991, Human pathology.

[47]  M. Mattéi,et al.  Thyroid nuclear factor 1 (TTF‐1) contains a homeodomain and displays a novel DNA binding specificity. , 1990, The EMBO journal.

[48]  R. Moll,et al.  Identification of protein IT of the intestinal cytoskeleton as a novel type I cytokeratin with unusual properties and expression patterns , 1990, The Journal of cell biology.

[49]  M. Wick,et al.  Gross cystic disease fluid protein-15 as a marker for breast cancer: immunohistochemical analysis of 690 human neoplasms and comparison with alpha-lactalbumin. , 1989, Human pathology.

[50]  E. Levine,et al.  Computed tomography in the evaluation of metastatic adenocarcinoma from an unknown primary site. A retrospective study. , 1982, Radiology.

[51]  M. Koch,et al.  Carcinoembryonic antigen levels as an indicator of the primary site in metastatic disease of unknown origin , 1981, Cancer.

[52]  Alicia Samuels,et al.  Cancer Statistics, 2003 , 2003, CA: a cancer journal for clinicians.

[53]  A. Papadopoulou,et al.  Cytogenetic profile of unknown primary tumors: clues for their pathogenesis and clinical management. , 2003, Neoplasia.

[54]  J. Coebergh,et al.  Epidemiology of unknown primary tumours; incidence and population-based survival of 1285 patients in Southeast Netherlands, 1984-1992. , 2002, European journal of cancer.

[55]  E. Lander,et al.  Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[56]  R. Osamura,et al.  Immunohistochemical analysis of GCDFP-15 and GCDFP-24 in mammary and non-mammary tissue , 2000, Breast cancer.

[57]  R. Motzer,et al.  Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  J. Abbruzzese,et al.  p53 gene mutation spectrum in human unknown primary tumors. , 1993, Anticancer research.

[59]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.