Cancer of Unknown Primary Origin - E. Briasoulis, N. Pavlidis : | 16/3/2009 5:35:05 šģ

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Cancer of Unknown Primary Origin
EVANGELOS BRIASOULIS, NICHOLAS PAVLIDIS
Department of Medicine/Oncology Unit, Ioannina University Hospital, Ioannina, Greecce

Key Words. Unkwon primary. Uknown origin. Occult cance. Carcinoma. Metastasis. Incidence. Diagnosis. Treatment

ABSTRACT
About 3% of all cancer patients suffer from cancer of unknown primary origin. These patients present with metastatic disease for which a primary site cannot be detected at the time of diagnosis. Sophisticated diagnostic techniques and operational procedures have failed to improve the diagnostic efficacy in this group of patients. Consequently, a limited diagnostic procedure with basic laboratory tests and imaging studies is sufficient for the diagnosis of this syndrome. The use of immunohistochemistry, as well as serum tumor markets of high specifity that may help to identify other tumors, is highly suggested. Although the prognosis for the majority of these patients still remains poor, several subsets of favorable outcome to treatment have been recognized. Nevertheless, promising in vitro data and new drugs on trials, paralleled with a better knowledge of the underlying pathogenetic molecular mechanisms, offer a more optimistic look to the future therapeutic management of these patients. The Oncologist 1997; 2: 142 - 152.

INTRODUCTION
Cancer of unknown primary origin (CUP) represents a group of heterogeneous tumors that share a unique clinical feature: “early” apparent metastatic disease with no identifiable site of origin at the time of presentation. Thus CUP patients present with usually widespread metastatic disease for which no primary site can be detected after a good medical history, detailed clinical examination, and extensive investigations. The primary site may either have a slow growth or may possibly become involute and therefore unlikely to manifest itself.
In spite of notable progress in imaging technology and immunohistochemistry and the introduction of serum tumor markers in the everyday clinical practice, CUP still imposes a diagnostic and therapeutic dilemma to the practicing oncologist - that is, how far to take the investigational procedures and how aggresseively to treat these patients who constitute a group of approximately 3% of all cancer patients.

DEFINITION
The definition as well as the nomenclature itself of cancer of unknown primary site or origin have been varied over time and from one series to another under the influence of inclusion criteria and the evolution of diagnostic tools used.
The common term for this group of diseases is “carcinoma of unknown primary” which underscorers the fact that the patients with metastatic disease in the absence of a discernible primary site. Historically, the simplest clinical definition has included all patients who presented with histologically confirmed metastatic carcinoma and in whom a complete medical history, careful physical examination, and chest radiography did not identify the primary site (1). However, today a basic blood and biochemistry survey, stool occult blood testing, urinalysis, histopathologic review of biopsy material with the use of immunohistochemistry, and computed tomography of abdomen and pelvis are needed to define this group of patients (2).

HISTOLOGIC CLASSIFICATION
According to routine light microscopy, cancers of unknown primary origin are divided into four major subtypes (3):
*Adenocarcinomas well to moderately differentiated
* Poorly differentiated carcinomas and adenocarcinoma.
* Squamous cell carcinomas.
* Undifferentiated neoplasms.
The majority of cases are adenocarcinomas, with poorly differentiated tumors being the next most frequent pathology (Table 1). Squamous cell carcinoma is a special minor subtype involving mainly the cervical nodes, and undifferentiated neoplasms are frequently reclassified to major histologic categories (i.e., carcinoma, lymphoma, melanoma, sarcoma) because of the improvements of the histopathology techniques.
Metastatic melanoma with an unknown primary and CCUP in children are usually discussed separately; metastatic melanoma with an unknown primary has the same propensities, biology, and survival as metastatic cutaneous melanoma (4,5). In childhood, embryonal malignancies make up the majority of the rare cases of disseminated malignancies without an identified primary site (6). Clinical characteristis of the major CUP histologic types are depicted in Table 2.

CLINICAL FEATURES
Epidemiology - Demographics
CUP comprises approximately 3% of juman cancer. The average annual age - adjusted incidence is 7 - 12 cases per 100.000 population per year (7), and as a cause of death it is reported to be the fourth most common among cancer - related deaths in developed countries (8,9). Demographics of CUP patients generally mirror those of the general cancer population, with a mean of 59 at diagnosis (range 20 - 89) (10) and a marginally higher frequency in males. Squamous cell carcinomas are twice as frequent in males in females, while there is a compensatory shift in the frequency of adenocarcinomas (7). In children, CUP represents <1% of diagnosed solid tumors (6).
It is remarkable that, regardless of the probable differences in the investigational stategies in several countries, no substantial difference in the prevalence of these tumors among cancer patients has been recorded worlwide (Table 3). The large variation of CUP prevalence reported in several studies actually represents referrals to hospital - based oncology units and depends on referral patterns, patient selection, and center specification (11, 12).

Natural History
Early dissemination, clinical absence of primary tumor, unpredictable metastatic pattern, and aggressivences constitute the fundamental characteristics of these tumors (Table 4). Understandably, apart from this general approach, a precise natural history of this heterogeneous cluster of neoplasms cannot easily be stablished. Early dissemination is reflected in the clinical absence of symptoms related to a primary tumor and even more in the relative failure of autopsy to localize the site of tumor origin. Several studies report that autopsy has failed to identify the primary site in 15% - 25% of CUP cases (13, 14). Between the identified occult primaries, ling and pancreas constitute the majority, while other common malignancies represent smaller proportions (1, 2, 14 - 19) (Fig. 1). CUP has a tendency toward a metastatic pattern different from that expected for the primary neoplasm if eventually found. For example, while bone metastases are usual in breast or prostate cancer, as a manifestation of CUP they are usually attributed to lung, liver, or renal occult primary (20). Similarly, occult prostate cancer manifests with liver and lung secondaries, while the usual natural history of this cancer is most commonly to develop bone metastases (17). Obviously, this unpredictability complicates the search for a primary site. Apart from having the propensity for early dissemination, these tumors can be characterized as particularly aggressive ones. The very shor elapsed time between first symptoms and diagnosis is an indication of the speed of tumor increase (21).
The clinical presentation in cases of CUP depens on the predominant site of metastatic involvement. Regarding the organ sites affected most patiens (60%) have more than two sites affected at presentation (2), with lymph nodes being the most frequently involved. Liver, lung, bone, and pleura constitute common metastatic sites, whereas relatively high frequencies of odd localizations of metastases have been observed (14, 22, 23). General deterioration and weight loss are the most common symptoms, while digestive and respiratory symptoms, liver enlargement, ascites, skin nodules, and bone pains suggest the sites of predominant metastatic involvement.

Prognosis
The overall prognosis in patients with CUP is poor, with a mean survival of five to ten months (10, 11). Fewer than 25% of patients srurvive up to one year, but survival differs among clinicohistological subgroups (Table 2). Significant prognostic factors recognized in CUP are: histopathology, organs involved, tumor burden, gender and perfomance status (Table 5). The prognostic significance of histological type can be attributed to the chemosensitivity of the underlying occult primary in each category. In poorly differentiated carcinomas, several tumors chemosensitive in origin may be included, whereas adenocarcinomas usually represent chemotherapy - resistant primaries.
Lymph node metastatic topography deserves separate mention, since several distinct subgroups of prognostic significance have been recognized. Cervical nodes with squamous cell cancer, acillary nodes with adenocarcinomas in females, and lymph nodes with undifferentiated carcinomas constitute presentations of a favorable prognosis. Supraclavicular lymph node involvement has been defined as a bad prognostic factor.

DIAGNOSIS
Pursuing the Anatomical Location, or Searching for Clues to Treatable Tumors?
The search for the indentification of the occult primary has always challenged clinicians. The argument in favor of pursuing the anatomical location of the primary is the belief that localizing the primary might result in a more specific and effective treatment. In a minority of CUP patients, a primary site of origin can indeed be identified after extensive diagnostic evaluation, but exhaustive investigations have been criticized because of a low yield and a lack of influence on patiens prognosis (14). Such a strategy has never been found to have any therapeutic implications or to be of survival benefit to the patient. On the contrary, it costs the patient a longer hospital stay, with the experience of painful and distressing investigations and the health care system an unaccceptable cost - effectiveness ratio (24). Although the phenomenon of performing all available sophisticated tests on these patients in the everyday clinical practice is not uncommon, practicing oncologists have always been skeptical about performing speculative low - yield investigations (15). Moreover, a limited diagnostic approach with patient - benefit orientations has now been justifiably proposed (2).
Regarding the identification of treatable subgroups, a careful consideration of the clinical presentation of the disease with an optimal re - evaluation of the biopsy specimen provides the best clue. Immunohistochemistry and, in exceptional cases, molecular genetic and cytogenetic studies may help the diagnosis (25, 26). This way, the well - recognized clinicopathological subsets of treatable and potentially curable timors can easily be identified, and any histological misclassifications can be clarified (27). Such a strategy that can lead to optional management of treatable tumors underlines the necessity for the collaboration and interaction between clinician and pathologist.

Proposed Diagnostic Strategy
As a rule a reasonable diagnostic approach to CUP patients is to avoid excessive diagnostic procedures without compromising clinically useful diagnostic efficacy.
Based on the initial clinical presentation and pathology report, the diagnostic strategy for a probable CUP should be divided into the standard and optional diagnostic procedures (Table 6).
The standard diagnostic procedure for the majority of these patients is proposed to include the histopathologic review of biopsy material with the use of immunohistochemistry, full blood count, routine biochemistry, fecal occult blood testing, urine testing, chest radiography, and computed tomography of abdomen and pelvis. It must be emphasized that immunohistochemistry staining for common leukocyte antigen, CEA, cytokeratin and vementin is considered today a routine pathology procedure for these tumors. For the subgroups of the cervical node epidermoid carcinomas and the axillary adenocarcinomas in females, more specific initial investigational procedures are advisable; those include ENT panendoscopy and head and neck CT scanning in cases of cervical lymph nodes, and mammography in axillary lymph node metastasesin women. Other recommended optional investigations are the high specificity afetoprotein (AFP), b-human chrionic gonadotropin (b-HCG), and prostate-specific antigen (PSA) serum tumor markers in men to exclude extragonadal germ cell tumor or prostate, cancer, and symptoms - or signs - oriented endoscopies. Surgical diagnostic procedures have not gained a wide acceptance.

Evaluation of Diagnostic Methods
Physical Examination
The physical examination must always be a thorough one and should include head and neck, thyroid, and rectal examination. In women, breast and pelvis, and in men, prostate and testicles examination should never be overlooked,

Imaging Studies
Although chest radiography has always been a prerequisite for the diagnosis of CUP, its usefulness in the differential diagnosis between primaty and secondary disease in lungs has been disputed [17].
Computed tomography is considered today one of the most valuable imaging tests in CUP cases. It has a clearly proven impact on CUP diagnosis, offering an additional diagnostic accuracy of 20% in cases previously characterized as CUP [28]. CT scan also helps the evaluation of tumor mass and provides guidance to biopsy procedure.
Most barium studies have failed to contribute to the detection of the primary [17] and to the overall management and survival improvement [15], so should only rarely if ever be used. Mammography has been proposed as a basic test in women with metastatic adenocarcinomas in axillaty lymph nodes [29], but its sensitivity in this context was found to be low [30].

Endoscopy
Endoscopies should always be symptoms - or signs-oriented investigational procedures in CUP cases.
ENT panendoscopy with fine-needle aspiration has been proposed as the initial diagnostic approach in cases of cervical node involvement [31]. Fiber optic bronchoscopy is advisable in cases of radiographic indications or symptoms, given the high frequency of the lung as the occult primary and the failure of radiography to differentiate primary and secondary tumor in the CUP setting [17]. Proctoscopy and colposcopy seem to be of practical interest in cases of inguinal lymph node involvement [32].

Surgery
Surgery as a diagnostic procedure has a definite role in biopsy sampling [33]. In cases of women with adenocarcinomas of the peritoneum, cytoreductive laparotomy has a therapeutic rather than a diagnostic benefit [34,35].

Pathology
Histopathology is the cornestone in the diagnostic procedure of CUP. A good biopsy specimen is of great importance, especially in cases of poorly differentiated tumors, and for the application of special pathology techniques that can improve the diagnosis of chemosensitive tumors which are subject to misdiagnosis. By definition, conventional light microscopy cannot indentify the site of origin [36] or define any prognostic characteristics of responsiveness to chemosensitivity [37]. Identifying the primary site is not an easy task for conventional histopathology, especially in metastatic adenocarcinoma cases. Interestingly, a correct diagnosis of only 48% was achieved by pathologists when they were shown 100 metastatic adenocarcinomas of known primary origin which were presented as unknowns with the provision of minimal essential clinical data. A higher accuracy was achieved for prostate, ovarian, and breast carcinomas, and a lower accuracy for the upper gastrointestinal tract, biliary tract, and pancreatic adenocarcinoma [38].
Immunohistochemistry is the most useful diagnostic tool and the central axis of the initial basic investigation, especially in cases of poorly differentiated carcinomas [36, 39]. Immunoperoxidase staining has now become widely available and can be reliably applied on routinely fixed paraffinembedded biopsy materials. It uses specific monoclonal or polyclonal antibodies directed against a wide range of antigens: specific mambrane antigens, cytoskeleton proteins, secreted proteins, enzymes, hormonal receptors, and other cell elements. Immunocytochemistry can also be applied on cytological preparations in cases of maligant perfusions [40]. Today, with the help of a wide range of immunohistochemistry markers, the misdiagnosis of other malignancies such as lymphomas, extragonadal germ cell tumors, maligant melanomas, and undifferentiated sarcomas as CUP is rather rare. Nevertheless, it should always be kept in mind that regardless of the relatively high specificity of several immunoperoxidase markers, false positive as well as false negative staining may be expected. Differences in fixation techniques and in the kind of antigen used are responsible for the observed differences in sensitivity and specificity [36].
The clinical importance of immunoperoxidase staining in the differential diagnosis of poorly differentiated CUP has recently been evaluated. At the Vanderbilt Center, a series of biopsy samples of 87 cases diagnosed before the immunohistochemistry period (1978-1983) were re-evaluated with the use of immunoperoxidase staining techniques. Different diagnoses resulted in 16% of the cases: eight malignant melanomas, four lymphomas, one prostate cancer, and one yolk sack tumor [41].

Advanced Diagnostic Tests
Electron microscopy can be a useful diagnostic tool in 15% of undifferentiated CUP not otherwise identified by light microscopy, offering an additional accutacy in one-third of these cases [42-44]. It is a well-reputed diagnostic method for the poorly differentiated neuroendocrine tumors and amelanotic melanomas recognizing core granules, electron - dense secretory granules, and premelanosomes. It can also contribute to the diagnosis of dedifferentiated squamous cell tumors (desmosomes attached to tonofilaments), adenocarcinomas (acinar spaces, tight junctions, and microacini) and sarcomas (myofibrils, dilated rough endoplasmic reticulum, extracellular osteoid). Disadvantages of electron microscopy are the special handling procedure, the experienced personnel, and the expensive equipment required,
Molecular genetic and cytogenetic studies can offer today additional diagnostic information toward the identification of special tumor types that have specific genetic markers [45-47]. Fluorescence in situ hybridization (FISH) using the chromosomal marker i(12p) [48], which is highly nonrandom for germ cell tumors, has been proven an excellent diagnostic tool in atypical extragonadal germ cell tumors presenting as undifferentiated CUP [25]. Genetic analysis can also contribute to the diagnosis of a number of tumors with specific chromosomal aberrations, usually seen in soft tissue sarcomas and lymphomas [49]. Nasopharyngeal undifferentiated carcinomas can be distinguished from dedifferentiated epidermoid tumors by detection of EBV genome with PCR analysis [50].

Serum Tumor Markers
Males should always have the high-specificity tumor markers b-HCG, AFP, and PSA tested to exclude treatable extragonadal germ cell tumors and prostate cancer amenable to endocrine treatment. In children, testing for urinary catecholamines can produce valuable diagnostic clues, as high urine levels are diagnostic of neuroblastoma. In all other cases, routine evaluation of current, commonly used serum tumor markers have not been proven of any prognostic of diagnostic assistance, and a non-specific multiple overexpression in the majority of CUP patients has been observed [51] (Fig. 2).

Treatment
A reasonable treatment approach for CUP patients is to individualize the treatment, taking into consideration the most appropriate modality for each case, whether locoregional, systemic, curative, palliative, or supportive.

Locoregional Treatment
Being by definition a metastatic disease, CUP leaves only limited room for locoregional treatment practises, radiotherapy, and surgery.
Locoregional treatment of curative orientation should be considered in cases of isolated axillary node metastases in females [52, 53] and squamuos cell metastases in cervical nodes, especially in

Systemic Treatment
Although curative in few cases of CUP, chemotherapy constitutes the mainstream of treatment practises for the majority of patients with this systemic metastatic disease.

Potentially Curable CUP Subgroups
Notable advances have been made over the past decade in the treatment of poorly differentiated CUP. Although it has been proposed by some investigators that these tumors should be challenged as a whole with cisplatin-based combination regimens with the intent of achieving long-lasting responses in a number of patients [57], several subgroups of CUP have been identified as potentially curable.
The better-defined, potentially curable subpopulation is young adults, primarily males, with poorly differentiated carcinomas having as dominant tumor sites the mediastinum, retroperitoneum, lungs, or peripheral lymph nodes. In these patients, a 16% actuarial 10-year survival has been achieved [58, 59]. It has recently been shown by molecular and cytogenetic studies that response to cisplatin therapy in those patients correlated with the finding of i(12p) in tumor, a specific chromosomal marker characterizing germ cell tumors [25].
Another well-documented subset of patients with favorable response to platinum-based chemotherapy and improved prognosis is women with peritoneal carcinomatosis [34, 35]. Patients with advanced lymph node metastases from an epidermoid carcinoma have also been shown to achieve long-term survival when treated with platinum-based combination chemotherapy [60]. Cure is also possible for the rare cases of children with CUP if treated with chemotherapy regimens effective against embryonal malignancies [6].
An indicative synopsis of effective treatment approaches in patients with CUP is presented in Table 2.

Adenocarcinoma: Supportive, Palliative or Investigational Treatment Approach?
Unfortunately, the favorable subsets of CUP constitute a minority. The large majority of adenocarcinomas of unknown primary origin (ACUP) still remain resistant to clinically established chemotherapy. The regimens used so far have been empirical and of palliative orientation [61], and the observed responses in most retrospective studies were moderate, with no definite impact on survival [58]. Four randomized trials and more than a dozen non-randomized ones with combinations of several chemotherapy agents published during the last 20 years yielded on average a crude response rate of 25% [62]. The conclusion of almost all of these studies was pessimistic [63-67] - poor responses and no significant impact on survival. Our experience with a carboplatin - based combination regimen in a phase II trial gave comparable results with other regimens and no long-term disease-free survivors. Because of the lack of any effective treatment, therapeutic trials are much needed in this category of patients to improve the hope of cure and the ability to palliate. ACUP patients should either be treated in an investigational setting with agents holding clinical promises, or they should be given low-toxicity treatment of palliative orientantion or even supportive care only. Quality of life is a major point in these cases and should be taken very seriously into consideration because of the poor performance status and prognosis of these patients.

Future Treatment Perspectives
Some interesting in vitro data have been published recently regarding chemosensitivity of ACUP [68]. Two hundred seventy-eight agents were tested in 313 freshly explanted tumor specimens of ACUP in a tumor-cloning system. The higher response rates (>20%) were observed for paclitaxel, actinomycin - D, methotrexate, vinblastine, and melphalan, while most of the compounds clinically characterized inactive in ACUP were shown less active in vitro as well. Interestingly enough, and in support of the in vitro finding of paclitaxel chemosensitivity, we have observed that CUP highly overexpress the p53 protein [69], and there is now evidence of activity of taxoids in tumors with aberrant p53 function [70, 71]. These new data may be seen as a potential therapeutic promise, and further clinical development of these agents in the ACUP setting is warranted.

Search for Genetic Identity - Biological Profile
Regardless of being a relatively common clinical entity and in spite of its obvious biological significance, CUP has attracted only limited research attention to date. The reason is probably the relatively short life of a well-recognized clinical entity with a grim prognosis.
The search for genetic damage has taken a central role in cancer research in the last decade [72]. In clinical practise, it already offers a useful diagnostic and prognostic tool, while at the same time opening wide horizons to a deeper understanding of carcinogenesis, identification of malignant diseases, and search of new treatment targets. Regarding CUP, such studies are very limited. They aim not only to identify special tumor types but also mostly to recognize a common identity in these tumors, if any. Consistent structural anomalies involving chromosome 1 have been observed in a small number of CUP cases including deletions, duplication, and the presence of a homogeneous staining region [73, 74]. Abnormalities in chromosome 1 have generally been reported in several malignant diseases [47, 75], but most importantly they have been associated with advanced malignancy [76]. It has been supported that some oncosuppressor gene may be located in the short that some chromosome 1 whose aberration might lead to the expression of a metastatic phenotype [77].
It has been proposed that CUP progresses to malignancy via a unique (type II) series of molecular and accelerated biochemical events, and that the cellular interactions with the host are different from malignancies where the primary is known [78]. A unique biological profile is also suggested by our observations that show an extremely high overexpression of several tumor markers [51] and oncoproteins in these tumors [69, 79] (Fig. 3). Nevertheless, no pattern of expression of these biological markers was found, and neither prognostic nor diagnostic significance was proven. The research for the genetic identity and the biological profile of these tumors remains an open challenge to the investigators.

Conclusions
The heterogeneous-in-origin tumors that present clinically as CUP share common clinical features of early metastatic dissemination from an occult primary. A limited diagnostic evaluation toward the detection of the primary tumor and a thorough clinicopathological evaluation for clues to identify the well - recognized, treatable subgroups are recommended. As a significant therapeutic improvement has not been achieved for the majority of patients with metastatic adenocarcinomas, innovative treatment approaches with the introduction of new classes of drugs into trials are warranted. Findings suggestive of a unique biological profile of CUP have recently been evidenced and justify further research for the genetic and biologic identity of these aggressive tumors that express an absolute metastatic phenotype.

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