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Carcinomas of Unknown Primary are heterogenous group of metastatic tumours accounting for 3-5 of all malignances ( 1 ) . CUPs are the carcinomas without identifiable primary lesion despite a thorough clinical and diagnostic workup ( Table-1 from book ) .The instances of lymphomas, metastatic melanomas, and sarcomas are normally excluded from this class. With newer imaging techniques and diagnostic tools, the sensing rates of supernatural primaries has vastly increased in last few decennaries and the incidences of true CUPs are diminishing ( 2 ) .

Metastatic CUPs toliver, lung, pleura, bone and encephalon are normally taken as unfavourable subsets of CUPs because they normally have a blue forecast and remain untreatable. The favourable subset of CUPs include tumours with neuroendocrine traits, squamous cell carcinoma in caput and cervix part, alar lymph nodal glandular cancer and peritoneal carcinomatosis ( in adult females ) , blastic bony metastases in work forces, and midplane malignances in immature work forces ( likely stand foring extragonadal source cell tumours ) ( 3,4 ) .The aim of diagnostic rating is normally to acknowledge this favourable subset for an early and timely diagnosing and proper direction.

Metastatic CUPs chiefly impacting liver is one of the most unfavourable presentations. Majority ( 60-80 % ) of these tumours is adenocarcinoma and autumn outside the class of treatable tumours ; hence attempts to seek for the primary are frequently bootless, and even with best of diagnostic attack merely 10-18 % of such CUPs reveal their primaries ( 5,6 ) . The average endurance of this subset is simply 6-9 months ( 3 ) .

Expensive diagnostic work-up to happen a thin figure of treatable primaries showing favourable result is questionable and should be justified.

The end of this survey is toreviewthe current literature with the focal point on CUPs showing with liver metastases and to propose a diagnostic algorithm to measure these tumours.



Hepatic metastasis is the 2nd prima manifestation ( after the nodal metastasis ) of the CUPs, accounting for 25 % of all instances ( 7 ) . Median age of presentation is 61-65 old ages and there is male preference ( 2:1 ) ( 8 ) . Histologically, glandular cancer comprises bulk ( 60-80 % ) of such tumours followed by uniform ( 4-26 % ) , neuroendocrine ( 6-14 % ) and squamous cell carcinoma ( 2-6 % ) in falling order ( 3,5,8 ) . Pulmonary, pancreatic and colorectal are the commonest identified primaries in this scene of CUPs. Concurrent metastasis to lymph nodes ( 46 % ) , castanetss ( 37 % ) lungs ( 36 % ) besides exist.

Clinical Presentation

Largely, the patients are symptomless, andthe tumour is by chance detected during everyday diagnostic work-up. However, some of the patients may show with diverse clinical symptoms. In a survey with 49 patients with CUP to the liver, 62 % of the patients showed marks of the disease ( 8 ) . The symptoms are due to the metastases and their location. Patients with liver metastases can show with right upper quarter-circle or epigastric hurting, abdominal puffiness, icterus and broad symptoms likeanorexia, weight loss or weariness ( 3,4 ) .


The etiopathogenesis of CUPs remains ill-defined and cryptic. The first and first inquiry, “ Why the primary tumour remains un-detectable? “ .

There are two proposed hypotheses to explicate this mystery:

Theory of self-generated tumour arrested development: primary tumour involuted and non noticeable when metastasis becomes apparent.

Phenotype and genotype of the primary tumour favours metastasis over local growing

In the first instance the failure to turn is due to miss of sufficient angiogenesis to back up a bigger tumour. A subpopulation of cells in the tumour can hold some extra potency to migrate to distant variety meats, signifier metastases and happen angiogenic factors in the new environment to turn and go an evident mass ( 9,10 ) . Additionally, When the tumour is still little and lives from the vasculature of the affected organ, the defence mechanisms of the host causes arrested development of the tapped vass doing cell decease and more cell turnover. This phenomenon leads to biologically more advanced tumour cells. The tumour can non last or turn unless it is able to bring on angiogenesis ( 10 ) .

In the 2nd instance the potency to metastasise is portion of the biological science of the tumour and is acquired early in tumour generation. In chest malignant neoplastic disease, the cistron look profile of the primary tumour showed to be able to foretell with 90 % truth metastases and backsliding. Furthermore the genotype of the metastases was highly similar form to the primary tumour ( 9 ) . Va n’t Veer et Al. analyzed cistron look profiles with ‘poor forecast ‘ signature, which could foretell early metastasis to distant variety meats ( 11 ) .


Gene look

Rational of Searching Primary

If non already performed, a thorough medical history, scrutiny, a full blood count, biochemistry and I?-HCG, AFP, PSA in work forces are indispensable to hold intimations for the beginning and to measure the wellness province of the patient.


After the clinical portion, the attempt stipulating the exact type of malignant neoplastic disease cells is of import to divide subgroups with different results. They can assist make up one’s minding if extra diagnostic work-up is necessary.

The biopsy is a cardinal measure to happen a possible primary tumour or to specify the most likely tissue of beginning to direct a possible therapy. Whenever possible a nucleus biopsy is preferred over a all right needle biopsy. Light microscopy with hematoxylin and eosin discoloration and immunohistochemical discolorations help to place the tumour line of descent. Non-epithelial beginnings have to be excluded ; they are managed with specific and really different intervention.

Once the epithelial form is recognized, the diagnostician has to distinguish between:



Neuroendocrine and

Squamous cell carcinoma ( SCC )

In little differentiated discrepancies of neuroendocrine and squamous cell carcinomas negatron microscopy will be necessary to observe the typical neurosecretory granules or desmosomes and prekeratin fibrils ( in SCC ) ( 4,12 ) . In CUP with liver metastases neuroendocrine carcinoma showed a three to fourfold longer average endurance with 24 months versus 6.3 months average endurance with other histologies, therefore it is of import to execute all the necessary diagnostic work up to name it ( 7 ) .

To stipulate the type of carcinomas several immunohistochemical discolorations are available. CK7 and CK20 divide the carcinomas into different subgroups. Additionally, besides more specific discolorations are available to curtail the most likely primary. See table 2.


Chest X ray, thorax CT, venters and pelvis CT: Chest X beam or thorax CT, venters and pelvic girdle CT are presently portion of the definition. They can demo primaries and extra metastases. Due to the location, figure and distribution of lesions it is possible to gauge better the forecast of the disease. Metastasis in one or two sites merely by and large showed better forecast ( 13,14 ) . In instance of bone lesions the radiotherapist can propose Prostate-Specific Antigen ( PSA ) measurings in aged males, source cell tumour markers and testicular ultrasound in immature males and mammography in females.

Testicular Ultrasound: Testicular Ultrasound should be recommended to immature males showing with big mediastinal multitudes, retroperitoneal multitudes or bone lesions.

Mammography: All adult females should acquire Mammography, particularly if the patient presents with glandular cancer or alar lymph nodes. In instances of uncertainnesss echography of the chest can be added. If the mammogram and the echogram are negative and there is still a strong intuition of chest malignant neoplastic disease an MR should be performed. MR proved to be more sensitive in happening clinically and mammographically occult malignant neoplastic diseases ( 15 ) .

Whole Body MR: In the last old ages, whole-body MR was proposed to scan for metastases and primary tumours ( 16-22 ) . It is alluring to utilize merely one technique for the whole organic structure, have a comparatively short acquisition clip, no radiation and moreover an highly good soft tissue contrast. MR shows extra hepatic sensing, but misses pneumonic lesions smaller than 6mm compared to CT ( 20 ) . MR was shown to be better at uncovering metastases in the spinal column, pelvic girdle and thighbone 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 radiogram. Patients with metal implants can non come in the magnetic field. Some patients suffer claustrophobia and MR machines are non yet available in smaller medical centres. In comparing to PET-CT MR showed to hold a similar sensing rate for different oncologic primaries and metastases, merely for lymph node metastases the sensitiveness of PET-CT showed to be superior ( 23 ) ( ABSTRACT ) .

If the primary can be found in CUP instances with liver metastases, pathology and radiology have shown to play an of import function, placing the primary in 27 % and 47.5 % of the instances severally ( 7 ) .

Fluorine-18 Fludeoxyglucose Positron Emission Tomography PET: To day of the month it is non recommended for all patients since it is non specific and it may be hard to separate between malignance and redness or even physiological activity in specific variety meats ( 24 ) . Nevertheless, PET can add some information in selected instances such as cervical metastases of squamous cell malignant neoplastic disease ( 25 ) or neuroendocrine carcinomas ( 3 ) . In instance of neuroendocrine carcinomas besides somatostatin receptor scintigraphy can be performed.

Endoscopy: Fiber-optic laryngoscopy and nasopharyngoscopy are recommended merely for suspected caput and cervix malignant neoplastic diseases. Endoscopy and bronchoscopy can be considered carefully in instances of likely caput and cervix or lung malignant neoplastic disease and negative PET/CT. Panendoscopy showed to observe the primary lesion in merely 9 % of PET/CT negative instances ( 26 ) .

Diagnostic attack

All the diagnostic attacks have to be considered in the context that the patients with liver metastases have a blue forecast. Neuroendocrine histology is the lone diagnosing, which predicts a three to fourfold longer endurance and therefore it should be searched and excluded early. If there are concrete intimations for other specific types of primary directed scrutinies can be conducted.

In all other instances any pathologic, radiologic and particularly invasive scrutiny should be considered really carefully. The scrutinies are clip devouring and wash uping for the patients. The chance of happening the primary is scarce. Furthermore a directed therapy is non proven to protract the patient ‘s life plenty to warrant the incommodiousnesss of strenuous diagnostic work-up.

Some clinical factors should be taken in history, such as immature patient age and good public presentation position. Some surveies suggest a survival benefit giving broad chemotherapy. In three different surveies analizing CUP metastatic to the liver endurance increased with chemotherapy from 1 month to 4 months, from 1 month to 7 months and from 4-5 months to 8-12 months, separately ( 6,7,27 ) . In another survey endurance groups could non be compared because 96 % of the patients were treated. Response or stabilisation ( complete reponse, partial response or stable disease ) was reported in 30 % ( 8 ) . The inquiry is left unfastened, whether these effects are genuinely due to the therapy or to the fact that patients having chemotherapy are largely younger and fitter.

Algorithm of Evaluation – our proposal

Thorough medical history, scrutiny, a full blood count, biochemistry and I?-HCG, AFP, PSA


Pathology: discolorations to except non-epithelial beginning ( lymphoma, melanoma, sarcoma )

Pathology: exclude neuroendocrine form

If there are concrete intimations or symptoms for other specific types of primary directed scrutinies can be conducted, i.e. pathologic discolorations for CK7/20, cistron look profiles, radiologic scrutinies, invasive processs.

If the patient is immature and in good physical status ( high public presentation position ) , broad chemotherapy can be considered.

If a primary is found directed therapy is advisable. Supportive attention and psychological support should be provided. Every patient should be discussed and followed in specialised centres by multidisciplinary squads.


The major end for future direction of CUP patients is to accommodate the diagnostic attack to the bettering diagnostic and curative modes. Merely the necessary scrutinies should be performed. The therapy should be adapted to the clinical position, the age and most significantly to the wants of the patient.

The radiotherapist is frequently the doctor who detects the malignance foremost and should describe it quickly to the mentioning doctor. It is the radiotherapist ‘s responsibility to propose the appropriate imagination mode and following stairss to progress the hunt for the primary. Good audience with the diagnostician is indispensable, for the diagnostician to cognize which patterns to look for in the tissue and for the radiotherapist the histological consequences give grounds of which could be the location of the primary. In centres where CUP patients are treated specialised squads should be formed with at least an oncologist, a radiotherapist and a diagnostician maintaining up to day of the month with the current CUP guidelines and literature. All CUP instances should be discussed with these specializers.

PET-CT and MR have showed a batch of possible in the subset of CUP. They have been studied merely in little groups or subgroups of CUP patients until the clip being and hence are merely recommended in specific instances. Further definition of their function is required, particularly in surveies with bigger patient Numberss.

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