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Carcinomas of Unknown Primary are heterogeneous group of metastatic tumors accounting for 3-5 of all malignancies (1). CUPs are the carcinomas without identifiable primary lesion despite a thorough clinical and diagnostic workup (Table-1 from book).The cases of lymphomas, metastatic melanomas, and sarcomas are usually excluded from this category. With newer imaging techniques and diagnostic tools, the detection rates of occult primaries has immensely increased in last few decades and the incidences of true CUPs are decreasing (2).
Metastatic CUPs toliver, lung, pleura, bone and brain are usually taken as unfavorable subsets of CUPs because they usually have a dismal prognosis and remain untreatable. The favorable subset of CUPs include tumors with neuroendocrine traits, squamous cell carcinoma in head and neck region, axillary lymph nodal adenocarcinomas and peritoneal carcinomatosis (in women), blastic bony metastases in men, and midline malignancies in young men (probably representing extragonadal germ cell tumors) (3,4).The objective of diagnostic evaluation is usually to recognize this favorable subset for an early and timely diagnosis and proper management.
Metastatic CUPs primarily affecting liver is one of the most unfavorable presentations. Majority (60-80%) of these tumors is adenocarcinoma and fall outside the category of treatable tumors; therefore efforts to search for the primary are often fruitless, and even with best of diagnostic approach only 10-18 % of such CUPs reveal their primaries (5,6). The median survival of this subset is merely 6-9 months (3).
Expensive diagnostic work-up to find a sparse number of treatable primaries demonstrating favorable outcome is questionable and should be justified.
The goal of this study is toreviewthe current literature with the focus on CUPs presenting with liver metastases and to suggest a diagnostic algorithm to evaluate these tumors.
Hepatic metastasis is the second leading manifestation (after the nodal metastasis) of the CUPs , accounting for 25% of all cases (7). Median age of presentation is 61-65 years and there is male predilection (2:1) (8). Histologically, adenocarcinoma comprises majority(60-80% ) of such tumors followed by undifferentiated (4-26%), neuroendocrine (6-14%) and squamous cell carcinoma (2-6%) in descending order (3,5,8). Pulmonary, pancreatic and colorectal are the commonest identified primaries in this setting of CUPs. Concurrent metastasis to lymph nodes (46%), bones (37%) lungs (36%) also exist.
Mostly, the patients are asymptomatic, andthe tumor is accidentally detected during routine diagnostic work-up. However, some of the patients may present with diverse clinical symptoms. In a study with 49 patients with CUP to the liver, 62% of the patients showed signs of the disease(8). The symptoms are due to the metastases and their location. Patients with liver metastases can present with right upper quadrant or epigastric pain, abdominal swelling, jaundice and unspecific symptoms likeanorexia, weight loss or fatigue (3,4).
The etiopathogenesis of CUPs remains unclear and mysterious. The first and foremost question, "Why the primary tumor remains un-detectable?".
There are two proposed hypotheses to explain this enigma:
Theory of spontaneous tumor regression: primary tumor involuted and not detectable when metastasis becomes evident.
Phenotype and genotype of the primary tumor favors metastasis over local growth
In the first case the failure to grow is due to lack of sufficient angiogenesis to support a bigger tumor. A subpopulation of cells in the tumor can have some additional potential to migrate to distant organs, form metastases and find angiogenic factors in the new environment to grow and become an apparent mass (9,10). Additionally, When the tumor is still small and lives from the vasculature of the affected organ, the defense mechanisms of the host causes regression of the tapped vessels causing cell death and more cell turnover. This phenomenon leads to biologically more advanced tumor cells. The tumor cannot survive or grow unless it is able to induce angiogenesis (10).
In the second case the potential to metastasize is part of the biology of the tumor and is acquired early in tumor genesis. In breast cancer, the gene expression profile of the primary tumor showed to be able to predict with 90% accuracy metastases and relapse. Moreover the genotype of the metastases was extremely similar pattern to the primary tumor (9). Van't Veer et al. analyzed gene expression profiles with 'poor prognosis' signature, which could predict early metastasis to distant organs(11).
Rational of Searching Primary
If not already performed, a thorough medical history, examination, a full blood count, biochemistry and Î²-HCG, AFP, PSA in men are essential to have hints for the origin and to assess the health state of the patient.
After the clinical part, the effort specifying the exact type of cancer cells is important to separate subgroups with different outcomes. They can help deciding if additional diagnostic work-up is necessary.
The biopsy is a key step to find a possible primary tumor or to define the most probable tissue of origin to direct a possible therapy. Whenever possible a core biopsy is preferable over a fine needle biopsy. Light microscopy with hematoxylin and eosin stain and immunohistochemical stains help to identify the tumor lineage. Non-epithelial origins have to be excluded; they are managed with specific and very different treatment.
Once the epithelial pattern is recognized, the pathologist has to differentiate between:
Squamous cell carcinoma (SCC)
In little differentiated variants of neuroendocrine and squamous cell carcinomas electron microscopy will be necessary to detect the typical neurosecretory granules or desmosomes and prekeratin filaments (in SCC) (4,12). In CUP with liver metastases neuroendocrine carcinoma showed a three to fourfold longer median survival with 24 months versus 6.3 months median survival with other histologies, therefore it is important to perform all the necessary diagnostic work up to diagnose it (7).
To specify the type of carcinomas several immunohistochemical stains are available. CK7 and CK20 divide the carcinomas into different subgroups. Additionally, also more specific stains are available to restrict the most probable primary. See table 2.
Chest x-ray, chest CT, abdomen and pelvis CT: Chest X ray or chest CT, abdomen and pelvis CT are currently part of the definition. They can show primaries and additional metastases. Due to the location, number and distribution of lesions it is possible to estimate better the prognosis of the disease. Metastasis in one or two sites only generally showed better prognosis(13,14). In case of bone lesions the radiologist can suggest Prostate-Specific Antigen (PSA) measurements in elderly males, germ cell tumor markers and testicular ultrasound in young males and mammography in females.
Testicular Ultrasound: Testicular Ultrasound should be recommended to young males presenting with large mediastinal masses, retroperitoneal masses or bone lesions.
Mammography: All women should get Mammography, especially if the patient presents with adenocarcinoma or axillary lymph nodes. In cases of uncertainties sonography of the breast can be added. If the mammogram and the sonogram are negative and there is still a strong suspicion of breast cancer an MR should be performed. MR proved to be more sensitive in finding clinically and mammographically occult cancers (15).
Whole Body MR: In the last years, whole-body MR was proposed to scan for metastases and primary tumors (16-22). It is tempting to use only one technique for the whole body, have a relatively short acquisition time, no radiation and moreover an extremely good soft tissue contrast. MR shows additional hepatic detection, but misses pulmonary lesions smaller than 6mm compared to CT(20). MR was shown to be better at revealing metastases in the spine, pelvis and femur bone, whereas Scintigraphy showed more malignant lesions in skull and ribs. There are a few more drawbacks for the whole-body MR. MR is significantly more expensive compared to CT and even more compared to sonography and conventional radiographs. Patients with metal implants cannot enter the magnetic field. Some patients suffer claustrophobia and MR machines are not yet available in smaller medical centers. In comparison to PET-CT MR showed to have a similar detection rate for different oncologic primaries and metastases, only for lymph node metastases the sensitivity of PET-CT showed to be superior(23) (ABSTRACT).
If the primary can be found in CUP cases with liver metastases, pathology and radiology have shown to play an important role, identifying the primary in 27% and 47.5% of the cases respectively (7).
Fluorine-18 Fludeoxyglucose Positron Emission Tomography PET: To date it is not recommended for all patients since it is not specific and it may be difficult to distinguish between malignancy and inflammation or even physiological activity in specific organs(24). Nevertheless, PET can add some information in selected cases such as cervical metastases of squamous cell cancer(25) or neuroendocrine carcinomas(3). In case of neuroendocrine carcinomas also somatostatin receptor scintigraphy can be performed.
Endoscopy: Fiberoptic laryngoscopy and nasopharyngoscopy are recommended only for suspected head and neck cancers. Endoscopy and bronchoscopy can be considered carefully in cases of probable head and neck or lung cancer and negative PET/CT. Panendoscopy showed to detect the primary lesion in only 9% of PET/CT negative cases (26).
All the diagnostic approaches have to be considered in the context that the patients with liver metastases have a dismal prognosis. Neuroendocrine histology is the only diagnosis, which predicts a three to fourfold longer survival and therefore it should be searched and excluded early. If there are concrete hints for other specific types of primary directed examinations can be conducted.
In all other cases any pathologic, radiologic and especially invasive examination should be considered very carefully. The examinations are time consuming and exhausting for the patients. The probability of finding the primary is scarce. Furthermore a directed therapy is not proven to prolong the patient's life enough to justify the inconveniences of strenuous diagnostic work-up.
Some clinical factors should be taken in account, such as young patient age and good performance status. Some studies suggest a survival benefit giving unspecific chemotherapy. In three different studies analizing CUP metastatic to the liver survival increased with chemotherapy from 1 month to 4 months, from 1 month to 7 months and from 4-5 months to 8-12 months, individually (6,7,27). In another study survival groups could not be compared because 96% of the patients were treated. Response or stabilization (complete reponse, partial response or stable disease) was reported in 30%(8). The question is left open, whether these effects are truly due to the therapy or to the fact that patients receiving chemotherapy are mostly younger and fitter.
Algorithm of Evaluation - our proposal
Thorough medical history, examination, a full blood count, biochemistry and Î²-HCG, AFP, PSA
Pathology: stains to exclude non-epithelial origin (lymphoma, melanoma, sarcoma)
Pathology: exclude neuroendocrine pattern
If there are concrete hints or symptoms for other specific types of primary directed examinations can be conducted, i.e. pathologic stains for CK7/20, gene expression profiles, radiologic examinations, invasive procedures.
If the patient is young and in good physical condition (high performance status), unspecific chemotherapy can be considered.
If a primary is found directed therapy is advisable. Supportive care and psychological support should be provided. Every patient should be discussed and followed in specialized centers by multidisciplinary teams.
The major goal for future management of CUP patients is to adapt the diagnostic approach to the improving diagnostic and therapeutic modalities. Only the necessary examinations should be performed. The therapy should be adapted to the clinical status, the age and most importantly to the wishes of the patient.
The radiologist is often the physician who detects the malignancy first and should report it promptly to the referring physician. It is the radiologist's duty to suggest the appropriate imaging modality and next steps to advance the search for the primary. Good consultation with the pathologist is essential, for the pathologist to know which patterns to look for in the tissue and for the radiologist the histological results give evidence of which could be the location of the primary. In centers where CUP patients are treated specialized teams should be formed with at least an oncologist, a radiologist and a pathologist keeping up to date with the current CUP guidelines and literature. All CUP cases should be discussed with these specialists.
PET-CT and MR have showed a lot of potential in the subset of CUP. They have been studied only in small groups or subgroups of CUP patients until the time being and therefore are only recommended in specific cases. Further definition of their role is required, especially in studies with bigger patient numbers.