Metastatic Cancer With Unknown Primary Site

Practice Essentials

In metastatic cancer, the primary site of the cancer usually dictates the treatment, expected outcome, and overall prognosis. Consequently, in patients who present with metastatic cancer without a known primary site, the search for the primary site has high priority. Examination of an additional tissue sample very often proves helpful in this diagnostic process, and is often done if the initial biopsy result is equivocal.

Special stains and genomic and proteomic testing can be done with a clear plan of action. If those do not yield a diagnosis, the pattern of organ system involvement and the cytologic diagnosis may help in identifying the primary site. Clinical reassessment of the patient, including close questioning about signs and symptoms, may bring to light previously unreported issues that may help guide diagnosis. If a closed biopsy using ultrasound or CT guidance is equivocal, an open biopsy may sometimes be necessary. Liquid biopsy has overcome the many limitations of tumor biopsy, but its exact place in the spectrum of testing in cancer of unknown primary is still being studied.^[1]

Despite the increasing sophistication in the diagnostic workup for malignancies, detailed investigations fail to reveal a primary site of origin in a small percentage m of patients with metastatic cancer. This is often referred to as carcinoma of unknown primary origin (CUP) or occult primary malignancy.^[2]  In 15-25% of cases of CUP, the primary site cannot be identified even on postmortem examination. The diagnosis of CUP thus generates anxiety among patients and caregivers, who may feel that the evaluation has been incomplete.

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Pathophysiology

Cancers are thought to arise from a single cell that escapes the controls of normal cell replication, forms a tumor at the site of origin, and ultimately metastasizes to other organs. In some cases, the original tumor may remain small or undetectable at the time of metastasis, leading to the clinical presentation of cancer of unknown primary origin. Whether a specific genetic or mutational factor plays a role in cancer of unknown primary origin remains uncertain.

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Epidemiology

The exact incidence of cancer of unknown primary origin is not precisely known. It is almost certainly underreported, and its true incidence is most probably from 2% to 6% of all cancers diagnosed in the United States, and 2-9% of cancers diagnosed worldwide.

The American Cancer Society estimates that 31,480 persons (16,750 males; 14,730 females) will be diagnosed with cancers of unspecified primary sites in the United States in 2019.^[3]  This would suggest that cancer of unknown primary origin constitutes about 2% of all cancers diagnosed in the United States. However, deaths due to cancer of unknown primary site are estimated to be 45,140 in 2019 (24,240 males; 20,900 females).^[3]  This discrepancy between incidence and mortality is believed to be due to a lack of specificity in the listing of cause of death on death certificates.

Most series reporting on or reviewing cancer of unknown primary origin patient groups give an approximate equal incidence for men and women. The median age at presentation for both men and women ranges from 59-66 years.

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Prognosis

Median survival in patients with cancer of unknown primary origin ranges from 11 weeks to 11 months.^[4] The 5-year overall survival rate is about 11%. In those with multiple organ involvement and poor performance status, the median survival is only 3-4 months; the 1-year survival rate is less than 15%, with a 5-year survival of 5-10%. Factors associated with a poor prognosis include the following:

• Male sex
• Multiple brain metastases
• Pleural/lung involvement
• Liver involvement
• Adrenal involvement
• Adenocarcinoma histology

In contrast, lymph node involvement and neuroendocrine histology are associated with a longer survival.

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Patient Education

Communication between the clinician and the patient is paramount to optimal patient care. Patients and caregivers should be informed at each step of assessment and treatment. Patients should understand the goal of treatment, whether it is curative or palliative in nature. This should be defined upfront, although it can change as the patient responds or fails to respond to treatment

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History

The clinical presentation of cancer of unknown primary origin is extremely variable, and depends on the extent and type of organ involvement, However, because most of these patients have fairly advanced-stage disease, they typically present with the constitutional symptoms of malaise, weakness, fatigue, and weight loss.

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Physical Examination

Most patients with cancer of unknown primary origin present with multiple areas of involvement in multiple visceral sites, the most common being lung, bone, lymph nodes, and liver. A detailed physical examination should be conducted, and should include head and neck, rectal, testicular, pelvic, and breast examinations.

Patients have early dissemination of their cancer without symptoms at the primary site. Nevertheless, clinical manifestations may suggest the primary site, as follows:

• Ascites should lead to evaluation for a gastrointestinal or an ovarian primary.
• An axillary mass in a woman should lead to evaluation for breast cancer^{[5, 6]}
• Cervical lymphadenopathy should lead to a thorough otolaryngologic examination^[7]
• Signs consistent with brain metastasis should lead to a search for a lung, breast, or kidney primary
• Apparent bone metastasis should lead to evaluation for prostate, breast, lung, renal, or thyroid primary
• A testicular mass should lead to measurement of tumor markers such as beta–human chorionic gonadotropin (beta-HCG) and alpha-fetoprotein (AFP)

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Approach Considerations

A minimal basic workup for cancer of unknown primary origin comprises basic blood and biochemical analyses along with computed tomography (CT) scans of the abdomen and pelvis.^[8] Further investigations are dictated by any positive findings on initial evaluation. Depending on the clinical situation, these may include studies such as chest CT, breast magnetic resonance imaging, or upper or lower endoscopy. In suspected head and neck malignancies, panendoscopy of the upper aerodigestive pathways should be performed, with blind biopsies of the lymphoid tissue in these areas. Diagnostic tonsillectomy may be warranted.

Intensive testing also adds to the morbidity for the weak and frail patient. A large negative cost-to-benefit ratio exists for an extensive unguided clinical evaluation, with one study quoting a 9.5% increase in 1-year survival at a cost of $2-8 million.^{[9, 10, 11]} When these investigations fail to reveal a potential primary lesion, a cancer of unknown primary origin is assumed. The goal of initial evaluation should be to detect the small subset of patients who warrant potentially curative management.

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Laboratory Studies

Lab studies for metastatic cancer with an unknown primary site should include the following:

• Complete blood cell count (iron deficiency anemia may point toward an occult gastrointestinal malignancy leading to chronic blood loss)
• Urinalysis (microscopic hematuria may be a sign of occult genitourinary malignancy)
• Liver and renal function tests
• Stool examination for occult blood
• Measurement of prostate-specific antigen (PSA) in men

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Imaging Studies

Imaging studies should include the following:

• Chest radiograph
• Computed tomography (CT) of abdomen and pelvis
• Mammography in women

Positron emission tomography with 18F-fluoro-2-deoxy-D-glucose (18F-FDG-PET) is increasingly being used in the evaluation of metastatic malignancies.^[12] This may be especially the case in suspected head and neck malignancies. However, this modality lacks specificity and may be useful only to identify promising sites for biopsy. Its high cost and false-positive rate of 20% limit its utility in cases of cancer of unknown primary origin. The combination of PE with CT may reduce the false-positive rate.^[13]

Depending on the clinical situation, further imaging studies may include CT of the chest or magnetic resonance imaging of the breasts.

The high level of inaccuracy of unguided radiographic studies raises the issue of cost effectiveness for intensive diagnostic workup of this disorder.

See the image below.

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CT scan of neck with contrast. The arrows indicate metastatic lymphadenopathy. Image courtesy of Head and Neck Cancer-Multidisciplinary Approach, Davi....

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Other Tests

The role of tumor markers, such as alpha-fetoprotein (AFP), beta–human chorionic gonadotropin (beta-HCG), cancer antigen 125 (CA125), CA 27.29, CA 19.9, and carcinoembryonic antigen (CEA), to establish a specific primary site or to identify patients who respond to chemotherapy remains unclear and should probably be limited to cases in which a particular primary site is favored. Most tumor markers are nonspecific and cannot be used to establish definitive diagnoses.^[14]

In a large prospective trial, molecular tumor profiling predicted a tissue of origin in the majority of patients with cancer of unknown primary (CUP). Patients who received assay-directed site-specific therapy had a median survival time of 12.5 months, which compares favorably with survival among patients treated with empiric CUP regimens. CUP patients who were predicted to have more responsive tumor types had longer survival than those with less responsive tumor types (14 vs 7 months).^[15]

For those tumors in which there is difficulty in making a diagnosis, several commercially available tests for genomic abnormalities and potential help with the diagnosis have been made available. These are often expensive, but at times are very helpful in identifying the primary site of the tumor. These tests include Pathwork, Cancer type Id, and micro-R.

Genomic testing is becoming less expensive, and multiple tests have been claimed to be very effective in finding the primary site of the tumor. Additionally, test results are accompanied by listings of the therapeutic drugs available for the cancer and the therapies that are in clinical trials. All this information must be taken into consideration by the clinician, and the case should be managed on the basis of a thorough synthesis of the data provided and the clinical relevance of the results.

At this time, the National Comprehensive Cancer Network (NCCN) does not recommend gene signature profiling for tissue of origin for standard management of CUP. The NCCN advises that although these tests may offer diagnostic benefit, they do not necessarily provide clinical benefit.^[16]

A 2013 technology assessment by the Agency for Healthcare Research and Quality (AHRQ) on commercially available genetic tests reported that the accuracy of the tests is 85-88%, but their accuracy in CUP cases is not easily determined, because in most cases the actual tissue of origin is not identified. The assessment concluded that the available evidence was insufficient to determine whether these tests affect clinician decisions or alter patient survival, and recommended that future studies addressing the clinical value of these tests be carried out by groups who have no evident conflict of interest.^[17]

In a study by Hainsworth et al, a 92-gene reverse transcriptase polymerase chain reaction (RT-PCR) cancer classification assay predicted the tissue of origin in 247 of 252 assays (98%). Of the 289 patients enrolled in the study, 12.5% had insufficient tissue for the assay and 10% of patients were not treatment candidates by the time the results became available.^[18]

A randomized clinical trial by Hayashi et al compared site-specific therapy directed by gene expression profiling with empirical chemotherapy (carboplatin and paclitaxel) in 101 previously untreated patients with CUP. One-year survival was not significantly different with site-specific treatment than with empirical chemotherapy (44.0% versus 54.9%, respectively ( P = 0.264). However, prediction of the original site seemed to have prognostic value; survival was slightly better for tumor types predicted to be more responsive.^[19]

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Procedures

Often the diagnostic procedure of choice is a biopsy of the metastatic site and a careful evaluation of the pathology, which leads the clinician to a cost-effective diagnostic evaluation of the disease.

Depending on the clinical situation, upper or lower endoscopy may be warranted. In suspected head and neck malignancies, panendoscopy of the upper aerodigestive pathways should be performed, with blind biopsies of the lymphoid tissue in these areas, as indicated. Diagnostic tonsillectomy may be warranted.

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Histologic Findings

The pathologist has an indispensable role in the evaluation of cancer of unknown primary origin. The help of a pathologist familiar with cancer of unknown primary origin is essential. Tumors provided for pathological review should come from tissue that has whenever possible been excised if such tissue is available and accessible. Needle biopsy specimens may provide insufficient tissue for diagnosis or provide tissue that has been too damaged or distorted by the biopsy procedure for accurate diagnosis.^[20]

Various immunoperoxidase stains are available for providing a differential diagnosis for cancer of unknown primary origin. An experienced and knowledgeable pathologist will be familiar with appropriate DNA microarray techniques and proteonomic studies to establish a definitive diagnosis. The pathologist typically puts the tissue specimen through 1-4 steps, depending on the need. These studies include light microscopy, immunohistochemical stains,^[21] electron microscopy, and chromosomal analysis including cytogenetics.^[22] Deatils are as follows:

• Light microscopy: After initial light microscopic evaluation, most tumors are classifiable as epithelial cancers, lymphomas, sarcomas, melanomas, or germ cell tumors. When cytologic distinguishing features are limited, the tumor may be classified as undifferentiated or poorly differentiated carcinoma.
• Immunohistochemistry: These tests help define tumor lineage by using peroxidase-labeled antibody against specific tumor antigens. These include stains for keratin, leukocyte common antigen and S-100 (expressed in melanomas), thyroid transcription factor  thyroid transcription factor–1 (TTF-1; for lung and thyroid cancer), prostate-specific antigen (PSA), human chorionic gonadotropin (hCG; for germ cell tumors), alpha-fetoprotein (AFP; for germ-cell tumors and hepatomas); and estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) for breast cancer.
• Electron microscopy: This study has limited utility in identification of the primary site of cancer of unknown primary origin but may rarely be used in poorly differentiated tumors.
• Chromosomal studies: In cases of cancer of unknown primary origin with suspected occult nasopharyngeal carcinoma, DNA amplification of Epstein-Barr virus (EBV) in tissue may clinch the diagnosis.^[23] The presence of iso-chromosome 12p, i(12p), a specific chromosomal marker characteristic of germ cell tumors, can help diagnose extragonadal germ cell tumors in patients with cancer of unknown primary origin.^{[24, 25]}

The majority of cancers of unknown primary origin are adenocarcinomas or undifferentiated tumors (up to 58% in some studies). Less commonly, squamous cell carcinoma, melanoma, sarcoma, and neuroendocrine tumors can also present as metastasis with an unknown primary site of origin.^[26] Most studies exclude sarcomas and melanomas from their analysis.

In the approximately 30% of cancers of unknown primary origin in which a full workup establishes a clear pathological diagnosis, the most common epithelial malignancies are lung (15%), pancreas (13%), colon/rectum (6%), kidney (5%), and breast (4%). Sarcomas, melanomas, and lymphomas each contribute 6-8%. The remaining primary tumors are those of stomach (4%), ovary (3%), liver (3%), esophagus (3%), prostate (2%), and a variety of other malignancies (22%).

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Staging

Patients with cancer of unknown primary origin are presumed to all have stage IV disease at the time of initial presentation.

See Cancer of Unknown Primary Staging for more information.

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Immunohistochemistry-Based Classification

Guidelines from the European Society for Medical Oncology (ESMO) recommend selected marker assays as part of the basic immunohistochemical workup of cancers of unknown primary.^[8] See the table below.

Table. Immunohistochemical markers for cancers of unknown primary

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See Table

It is important to note that immunostains are not diagnostic but only supportive of the diagnosis. In some cases, these markers can yield misleading information. In this situation, molecular testing might at times clarify the situation.

New IHC markers can provide a more accurate diagnosis; for example, CDH17 may be a more sensitive marker for gastric cancer than CK20 and CDX2.^[27] Nonetheless, due to tumor heterogeneity, both false positive and false negative IHC staining patterns can be found; for example, TTF1 or CDX2 is absent in a minority of lung and colon cancers.^[28]

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Medical Care

The treatment of cancer of unknown primary origin continues to evolve.^{[29, 30]} The most common scenario is a patient with progressive, metastatic adenocarcinoma with multiple organ involvement.^[31] The treatment of this group of patients remains suboptimal.

Some favorable subsets have been identified that respond well to certain specific treatment strategies. These are discussed below.

See Cancer of Unknown Primary Treatment Protocols for summarized information.

Metastasis to cervical lymph nodes

A histologic diagnosis of metastatic carcinoma in the cervical nodes warrants a careful evaluation of the upper aerodigestive tract, including direct visualization of the hypopharynx, nasopharynx, larynx, and upper esophagus. Histologically, most of these tumors are squamous cell carcinomas, but adenocarcinoma, melanoma, or anaplastic tumors can also be seen in this location. In patients with squamous or undifferentiated carcinoma, tonsillectomy should be considered.^[32] Cervical adenopathy can be the primary disease manifestation in 2-5% of patients with primary squamous cell carcinoma of the head and neck region.

In the absence of localization of a primary site, aggressive local therapy is indicated. This may involve any of the following:

• Radical radiation therapy with curative intent to the neck and possible site of origin
• Preoperative radiation therapy followed by radical neck dissection
• Radical neck dissection
• Radical neck dissection followed by radiation to possible sites of origin

Five-year survival rates as high as 30-50% have been achieved with this approach.

The role of chemotherapy is debated. One randomized study showed an improved response rate and median survival with cisplatin and 5-fluorouracil—based chemotherapy when compared to radiation alone. A single adenocarcinoma-involved lymph node in either the cervical or inguinal areas with no evidence of disease elsewhere may be managed with surgical excision alone and watchful expectation.^[33] Radiation therapy to the involved and local fields may be provided as well. Combination therapy may be superior to monotherapy, with 5-year survival rates of 35% reported.

Patients with cervical node metastases from squamous cell carcinoma of unknown primary have an overall survival comparable to that of patients with known primary. In a retrospective study of 89 patients cancer of unknown primary treated with curative intent at a single institution, Mistry et al showed that the overall 5-year and 8-year survival rates were 55% and 51%, respectively. All patients were treated with surgery, and 70 patients received more than 40 Gy postoperative radiotherapy.^[34]

Isolated axillary adenopathy in women

Metastatic adenocarcinoma presenting as isolated axillary lymphadenopathy in women is usually a manifestation of an occult breast primary cancer.^[5] Mastectomy specimens in this subset of patients have shown a previously undiagnosed breast primary tumor in 40-70% cases. Immunohistochemical stains for estrogen and progesterone receptor should be performed in this setting, as they may aid in diagnosis.

Modified radical mastectomy with axillary node dissection has been advocated. A study with 42 patients, however, showed improved survival with systemic chemotherapy and improved local control with breast and axillary radiation. When these patients are treated with local excision or as having primary breast cancer, 50% of patients achieve 2-10 year survival. Currently, management is based on the guidelines for stage II breast cancer.

Peritoneal carcinomatosis in women

Women with peritoneal carcinomatosis with adenocarcinoma have similarities with patients with ovarian cancer. They often have papillary histology with elevation of CA-125 and a good response to platinum-based chemotherapy, but a primary tumor is not revealed on exploratory laparotomy.

Metastatic melanoma to a single nodal site

Five percent of patients with malignant melanoma may present with nodal metastasis in the absence of a documented primary site. They should be treated with radical lymph node dissection. Survival, surprisingly, is slightly better than that for stage II melanoma in patients with a known primary site.

Poorly differentiated and undifferentiated carcinoma

One third of patients with cancer of unknown primary origin have poorly or undifferentiated carcinoma. A subpopulation of these can be potentially curable. This subgroup includes patients with lymphomas, germ cell tumors, or neuroendocrine tumors. The features that point toward a treatment-responsive tumor include the following:

• Patient younger than 50 years
• Midline distribution, with elevated levels of beta-HCG or AFP
• Beta-HCG/AFP positive on immunohistochemistry
• Neuroendocrine granules
• Rapid tumor growth
• Iso-chromosome 12p in midline tumors

Platinum-based combination chemotherapy regimens specific for germ cell tumors have been employed in these patients with a response rate of 63%, a complete response rate of 26%, and a 10-year survival rates of 16%.

Poorly differentiated neuroendocrine carcinomas

These tumors are characterized by positive histochemical stains for chromogranin or neuron-specific enolase. These patients often present with extensive liver or bone metastases. In a series of 29 patients, 19 were treated with intensive cisplatin-based chemotherapy, and 6 others received doxorubicin-based combinations. Complete responses were achieved in 6 patients, and 4 of these patients were alive 19-100 months after diagnosis.^[26]

Inguinal node metastasis

Metastatic carcinoma in inguinal nodes from an unknown site can be found in 1-3.5% of patients. Squamous cell histology in this area is usually metastatic from the genital/anorectal area. The anorectal area should be carefully inspected in both sexes. Vulvar, vaginal, and cervical examination in women and penile examination in men is warranted. Treatment can involve groin dissection alone or with radiation and chemotherapy. In some patients, local excision with or without radiation may be adequate.^[35]

Cancer of unknown primary origin in unselected patients

The results from the favorable patient subsets do not apply to most of the patients with cancer of unknown primary origin (CUP). The most effective chemotherapy regimens for this group of patients involve combination therapy with a platinum compound (cisplatin or carboplatin) and a taxane (preferably paclitaxel). This combination gives a response rate of about 12-26% and a median survival of 5-7 months. Triple drug therapy does not appear to offer any additional benefit.

Docetaxel and carboplatin chemotherapy was found to be convenient, safe and effective outpatient palliative treatment for CUP. In a phase II cycle, Pentheroudakis et al treated 47 patients with CUP with sequential 30-minute infusions of docetaxel 75 mg/m² and carboplatin area under the concentration time-curve (AUC) of 5 (30 min each) every 3 weeks.  A median of six cycles were given, response rate was 32% (46% for favorable risk, 17% for unfavorable risk), and granulocyte colony stimulating factor support was used in a third of the patients. Toxicity was mild including grade 3-4 neutropenia (26%), febrile neutropenia (7%), and severe nonhematologic side effects in fewer than 8% of patients. Median time to progression and overall survival were 5.5 and 16.2 months, respectively. (Survival in the favorable risk was 22.6 months; visceral metastases had poor median survival 5.3 months.)^[36]

Patients in whom combination therapy fails may benefit from single-agent treatment with gemcitabine with median time to progression of 5 months. A phase II clinical trial with bevacizumab and erlotinib reported a median survival of 7-8 months with 33% of patients alive at 1 year.^[37]

A subsequent trial found that empiric treatment with paclitaxel, carboplatin, bevacizumab, and erlotinib is effective and well tolerated as first-line treatment for patients with CUP. Major responses to treatment occurred in 32 of 60 patients (53%), and an additional 18 patients had stable disease. The median progression-free survival time was 8 months, with 38% of patients progression free at 1 year; the 2-year overall survival rate was 27%.^[38]

Future directions

Newer agents, such as sorafenib, bevacizumab, antineoplaston, CS-1008 (humanized anti-CD-5 antibody), BMS-690514, and ZD1839, are currently being tested in various clinical trials. Also, combinations of older drugs such as capecitabine, carboplatin with weekly paclitaxel, and oxaliplatin with capecitabine are being evaluated in this group of patients.

Insights into the molecular biology of CUP are needed for the development of targeted therapeutic approaches to the treatment of these patients.

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Guidelines Summary

Clinical guidelines on the diagnosis and management of cancers of unknown primary (CUP±en published by the following organizations:

• National Comprehensive Cancer Network (NCCN)
• European Society for Medical Oncology (ESMO)
• Sociedad Espanola de Oncologia Medica (SEOM)

Immunohistochemistry (IHC) tests

The National Comprehensive Cancer Network (NCCN) guidelines recommends immunohistochemistry (IHC) tests to assist in localizing a primary tumor but cautions that they lack uniform specificity and sensitivity and some markers are found on multiple tumors. Large series of markers should be avoided. An undifferentiated panel for determining the most likely cell lineage includes the following^[16] :

• Pan-keratin (AE1/AE3 and CAM5.2):  Carcinoma
• CK5/6, p63/p40:  Squamous cell carcinoma (SCC)
• S100, SOX10: Melanoma
• LCA± CD20± CD3± : Lymphoma
• OCT3/4± SALL4±: Germ cell tumor
• WT1, calretinin, mesothelin, D2-40: Mesothelial tumor

Guidelines from the European Society for Medical Oncology (ESMO) note that IHC staining patterns are capable of identifying the site of origin in <  30% of all CUPs. In patients with poorly differentiated cancers or small biopsy specimens/malignant effusions, IHC staining may not be useful or feasible. ESMO recommend selected marker assays as part of the basic immunohistochemical workup of cancers of unknown primary.^[8]  See the table below.

Table. Immunohistochemical markers for cancers of unknown primary

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See Table

The Sociedad Espanola de Oncologia Medica (SEOM) guidelines find IHC testing is cost-effective and recommend it be carried out in all CUPs using a stepwise algorithm. Initial testing may include CKAE1-AE3 (Carcinoma), CLA (Lymphoma), S100, HMB-45, Melan-A (Melanoma), S100, Vimentin (Sarcoma).^[28]  

The 20 cytokeratin (CK) subtypes are typically expressed in carcinomas. A CK7 plus CK20 staining pattern can point toward additional IHC staining and specific, clinical tests. For example, a CUP having a IHC profile such as CK7+ CK20− TTF1+ suggests lung cancer and bronchoscopy should be performed, whereas CK 7−, CK20+ and CDX2+ suggest colorectal cancer and colonoscopy should be considered.^[28]

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Medication Summary

The goals of pharmacotherapy are to induce remission, prevent complications, and reduce morbidity. See Medical Care.

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Paclitaxel (Abraxane, Taxol)

• Dosing, Interactions, etc.

Clinical Context:  Mechanisms of action are tubulin polymerization and microtubule stabilization, which in turn inhibits mitosis and may result in breakage of chromosomes.

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Carboplatin (Paraplatin)

• Dosing, Interactions, etc.

Clinical Context:  Analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA crosslinks and inhibition of DNA replication. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of the cell cycle, but cell is most vulnerable to action of these drugs in G1 and S phase.

Has same efficacy as cisplatin but with better toxicity profile. Main advantages over cisplatin include less nephrotoxicity and ototoxicity not requiring extensive prehydration, less likely to induce nausea and vomiting, but more likely to induce myelotoxicity.

Dose is based on the following formula: total dose (mg) = (target AUC) x (GFR+25) where AUC (area under plasma concentration-time curve) is expressed in mg/mL/min and GFR (glomerular filtration rate) is expressed in mL/min.

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Class Summary

These agents inhibit cell growth and differentiation.

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