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Adenocarcinoma of unknown primary site

Adenocarcinoma of unknown primary site
Literature review current through: Jan 2024.
This topic last updated: Jan 31, 2024.

INTRODUCTION — Cancer of unknown primary site (CUP) is a relatively common clinical entity, accounting for approximately 2 percent of all invasive cancers [1]. CUP is diagnosed in patients who have metastatic cancer but who have no anatomic primary site identified by a comprehensive initial evaluation. Within this category, cancers from many primary sites with varying biology are represented. Improved diagnostic methods including molecular cancer classifier assays (MCCAs) and immunohistochemical (IHC) staining allow the site of tumor origin to be predicted in most patients with CUP. However, the anatomic primary site is usually not detected during the clinical course, so patients with CUP remain a clinically distinct group. (See "Overview of the classification and management of cancers of unknown primary site".)

Adenocarcinomas of unknown primary site comprise approximately 70 percent of CUPs. In autopsy series, although these cancers may arise from a wide variety of primary sites, the most frequently identified sites are lung, pancreas, hepatobiliary tree, and kidney, together accounting for approximately two-thirds of cases [2]. Adenocarcinomas of the breast and prostate are identified infrequently at autopsy, despite being the most common cancers in females and males, respectively. In 20 to 30 percent of patients, no primary site can be identified. However, it seems likely that very small primaries that would require multiple sections for microscopic identification may be missed at autopsy. Large autopsy series include patients who were not evaluated with modern imaging such as computed tomography (CT) and positron emission tomography (PET), and therefore published data may not accurately reflect contemporary patient population with adenocarcinoma of unknown primary site.

In patients with adenocarcinomas of unknown primary site, the focus is on identifying specific subsets in which disease-oriented therapy may be more effective than empiric therapy; this is based on a combination of clinical features, IHC results, and MCCA results.

The diagnosis and management of patients with adenocarcinoma of unknown primary site are reviewed here.

The diagnosis and management of the other CUPs are discussed separately:

(See "Overview of the classification and management of cancers of unknown primary site".)

(See "Poorly differentiated cancer from an unknown primary site".)

(See "Head and neck squamous cell carcinoma of unknown primary".)

(See "Neuroendocrine neoplasms of unknown primary site".)

(See "Squamous cell carcinoma of unknown primary site".)

(See "Axillary node metastases with occult primary breast cancer".)

CLINICAL PRESENTATION AND COURSE — The incidence of adenocarcinoma of unknown primary site increases with age. The clinical presentation is determined by the sites of metastatic tumor involvement, which are frequently multiple and often include the liver, lungs, lymph nodes, and bones. Many patients with adenocarcinoma of unknown primary site have widespread metastases and poor performance status at diagnosis. The prognosis for most of these patients is poor, although this is influenced by the type of adenocarcinoma, sites of metastases, extent of tumor burden, performance status, and disease management.

In an analysis of almost 19,000 patients with cancer of unknown primary site (CUP) from the Swedish Cancer Registry from 1987 to 2008, the median survival for those with adenocarcinoma (70 percent of the group) was three months, with a 17 percent one-year survival rate [3]. Another analysis from this cancer registry found an improvement over time in overall survival (OS) in patients with adenocarcinoma (median OS of approximately six months between 2001 and 2008 versus four months between 1987 and 1993) [4]. In both registry analyses, all patients with the diagnosis of CUP were included, regardless of performance status or treatment received.

Although there have been no randomized studies, substantial evidence supports a modest improvement in survival with empiric chemotherapy versus supportive care only. As opposed to the registry data, patients in empiric chemotherapy trials are restricted to those with a good performance status; in this population, empiric chemotherapy produced median survivals of 7 to 10 months in most phase II studies [5-9]. (See 'Empiric chemotherapy' below.)

However, several subsets of patients have a more favorable outlook, and initial evaluation should attempt to identify these patients. Additional diagnostic tests including improved immunohistochemical (IHC) stains and molecular cancer classifier assays (MCCAs) have improved the identification of the site of tumor origin, and improved the prognosis of selected patients when treated with site-specific therapy. Empiric chemotherapy also results in modest survival improvement (median survival, 9 to 11 months) for patients with good performance status. (See 'Initial evaluation of the tumor specimen' below and 'Specific patient subgroups' below and 'Approach to patients not included in specific subgroups' below.)

INITIAL CLINICAL EVALUATION — Most of the necessary clinical studies should have already been performed in the process of making the diagnosis of cancer of unknown primary site (CUP). These studies include a thorough history and physical examination, complete blood count, urinalysis, basic serum chemistries, and computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis. In males, assessment should incorporate a prostate examination and measurement of serum prostate-specific antigen (PSA). In females, the evaluation should include a pelvic examination and mammography. In addition, patients should have a focused clinical evaluation of any signs or symptoms suggestive of metastatic cancer.

In specific patient subgroups, several additional clinical studies are useful in identifying the anatomic primary site:

In females with a clinical presentation suggestive of metastatic breast cancer (eg, axillary adenopathy), breast MRI should be performed even if mammograms are normal. Immunohistochemical (IHC) staining of the biopsy specimen may detect the expression of breast cancer-specific markers, such as estrogen and progesterone receptors, mammaglobin, and gross cystic duct fluid protein. (See 'Females with axillary lymph node metastases' below.)

Colonoscopy should be performed in patients with intra-abdominal metastases who have histology typical of lower gastrointestinal cancer and either typical IHC staining (cytokeratin 20 [CK20]-positive, cytokeratin 7 [CK7]-negative, caudal-type homeobox transcription factor 2 [CDX-2]-positive) or a molecular cancer classifier assay (MCCA) diagnosis of a colorectal site of origin. (See 'Colon cancer profile' below.)

In males with clinical presentations suggestive of metastatic prostate cancer (eg, osteoblastic bone metastases), tissue staining for PSA is sometimes diagnostic even when serum PSA is not elevated.

Positron emission tomography (PET) is an additional standard diagnostic staging procedure that may be useful in certain presentations. In a number of retrospective series, PET identified a primary site in approximately 40 percent of patients [10,11]. However, in a single existing prospective study, PET was not superior compared with CT [12]. Therefore, the use of PET should be restricted to the evaluation of patients with specific clinical presentations (eg, those with squamous carcinoma in cervical lymph nodes or with a single metastasis). Although unrelated to the diagnostic evaluation, PET scans are also useful for monitoring response to treatment in patients with bone-predominant metastases.

Exhaustive imaging and endoscopic testing should not be performed, since these studies rarely detect the primary site in the asymptomatic patient, and confusion can result from false-positive results.

Traditional serum tumor markers (carcinoembryonic antigen [CEA], cancer antigen [CA] 19-9, CA 15-3, CA 125) are generally not useful as diagnostic or prognostic tests. However, they are commonly elevated and may be useful in following the response to therapy.

INITIAL EVALUATION OF THE TUMOR SPECIMEN

General approach — Cancer of unknown primary site (CUP) is, by definition, a metastatic tumor for which pretreatment evaluation does not reveal an anatomic primary site. In cases of suspected CUP, a biopsy of the most accessible site should be performed, preferably using a core needle or excisional biopsy to obtain sufficient tissue for all necessary studies. Adenocarcinoma can usually be distinguished from other histologies by light microscopic examination. Immunohistochemistry (IHC) and additional studies should be guided by the tumor histology, as described below. Treatment should then proceed based on results of these assessments (algorithm 1).

Light microscopy — The diagnosis of adenocarcinoma is usually based on the identification of glandular structures that are formed by the neoplastic cells. These features are shared by all adenocarcinomas, and the site of the primary tumor usually cannot be determined by light microscopy. Although certain morphologic features can be associated with a particular tumor type (eg, papillary features with ovarian cancer and signet ring cells with gastric cancer), they generally are not sufficiently specific to provide a definitive diagnosis.

The diagnosis of poorly differentiated adenocarcinoma is usually made when only minimal glandular formation is seen on histologic examination or in tumors that lack glandular differentiation but stain positively for mucin. Adenocarcinoma, poorly differentiated adenocarcinoma, and poorly differentiated carcinoma are histologic diagnoses that represent a spectrum of tumor differentiation rather than well-demarcated entities. Different pathologists may use somewhat different criteria for each of these diagnoses.

The light microscopic diagnosis of poorly differentiated adenocarcinoma should be interpreted with caution, since some of these patients have a distinctive tumor biology and responsiveness to systemic chemotherapy. For this reason, evaluation and treatment of patients with poorly differentiated adenocarcinoma of unknown primary site should follow the guidelines outlined for poorly differentiated carcinoma of unknown primary site, including the use of IHC staining, a molecular cancer classifier assay (MCCA), and electron microscopy (if necessary) to identify potentially chemotherapy-responsive cancer and rule out other tumor types such as hematologic malignancies, sarcomas, neuroendocrine carcinomas, or germ cell tumors. (See "Poorly differentiated cancer from an unknown primary site", section on 'Clinical evaluation'.)

Immunohistochemistry — In most instances, IHC is successful in defining the tumor lineage of poorly differentiated neoplasms (table 1). However, IHC allows the determination of the tissue of origin in only a minority of adenocarcinomas of unknown primary site [13]. In part, this is due to the atypical staining patterns present in many adenocarcinomas. However, selection of the appropriate IHC stains is also problematic. It is not possible to do all the IHC stains listed in the table (table 2) due to limitations of available tissue and expense; rather, the pathologist must select stains based on suggestive histologic or clinical findings [14].

In evaluating a CUP, most pathologists start with a panel of four IHC stains that form the basis of several potentially diagnostic patterns (cytokeratin 7 [CK7], cytokeratin 20 [CK20], thyroid transcription factor-1 [TTF-1], caudal-type homeobox transcription factor 2 [CDX-2]) to narrow the diagnostic possibilities, and add stains based on histology, clinical presentation, and results of the initial IHC panel [13]. With this approach, results are strongly suggestive of a single cancer type in only 33 percent of patients with CUP [15]. Even in these patients, clinicians have hesitated to use the IHC predictions to guide site-specific treatment, since the pathology reports are often somewhat equivocal, with phrases like "consistent with" or "favor," rather than a firm diagnosis.

In a few situations, IHC provides strong evidence regarding the primary site (table 1 and table 2) [16]:

Positive staining for prostate-specific antigen is quite specific for prostate cancer and should be included in the evaluation of males with adenocarcinoma of unknown primary site.

Positive staining for thyroglobulin in concert with TTF-1 is relatively specific for thyroid cancer.

Positive staining for CDX-2, or the combination of CK20-positive/CK7-negative, is highly suggestive of colorectal cancer [17].

Positive staining for CK7 and TTF-1, with negative staining for CK20, is highly suggestive of lung adenocarcinoma.

Positive staining for CK7, gross cystic fluid protein 15, and GATA-binding protein 3 (GATA3) is highly suggestive of breast adenocarcinoma.

Positive staining for renal cell carcinoma (RCC; also called renal cell carcinoma marker [RCC-Ma]) and paired box gene 8 (PAX8), with negative staining for CK20 is highly suggestive of RCC.

Positive staining for CK7, Wilms tumor 1 (WT-1), and PAX8 is highly suggestive of ovarian adenocarcinoma.

Positive staining for octamer-binding transcription factor 4 (OCT-4) and placental alkaline phosphatase is highly suggestive of germ cell carcinoma.

The pattern of staining with the cytokeratins CK20 and CK7 may be helpful in narrowing the diagnostic spectrum (table 3 and table 2). CK20 is a low molecular weight cytokeratin that is normally expressed in the lower gastrointestinal tract, urothelium, and in Merkel cells [17]. CK7 is expressed by cancers of the lung, ovary, endometrium, and breast, but not in cancers of the lower gastrointestinal tract. The CK20-positive/CK7-negative combination is the most specific, particularly if the CDX-2 stain is also positive, and allows a strong prediction of colorectal cancer in patients with compatible clinical and histologic features. In a study of 93 autopsy cases of adenocarcinoma of unknown primary site involving the liver, a CK20-positive/CK7-negative pattern correctly predicted a colorectal primary in 17 of 21 cases (81 percent) [17]. Other CK20/CK7 combinations were not specific enough for confident identification of a primary site.

None of these IHC results have been prospectively evaluated for accuracy in identifying the primary site in patients with CUP. Likewise, no studies have adequately addressed the question of whether treatment based on these IHC "diagnoses" improves the outcome for these patients. However, the good correlation between IHC and MCCA diagnoses when a single primary site is suggested by IHC supports the accuracy of these IHC diagnoses. (See 'Molecular cancer classifier assays' below.)

Further evaluation — After initial clinical and pathologic evaluation, groups of patients who fit into favorable subsets requiring specific therapy can be identified. Due to improvements in diagnosis, primarily using IHC and MCCA, the number of these treatable groups has increased, and now comprises 30 to 35 percent of all patients with adenocarcinoma of unknown primary site. (See 'Specific patient subgroups' below.)

The remaining 65 to 70 percent of patients do not fit into these specific subgroups (although some have a primary site suggested by IHC). In these patients, the tissue of origin can usually be identified using an MCCA, and opportunities for targeted therapy can be suggested by comprehensive molecular profiling. (See 'Molecular cancer classifier assays' below and 'Comprehensive molecular profiling' below.)

SPECIFIC PATIENT SUBGROUPS — The diverse group of patients with adenocarcinoma of unknown primary site contains several subgroups, defined by clinical and/or pathologic features, for which specific therapy is available. All patients who fit into one of these subgroups should receive specific therapy.

Females with peritoneal carcinomatosis — In females, adenocarcinoma causing diffuse peritoneal involvement without an obvious primary tumor usually originates in the ovary or in extraovarian tissues with similar histogenesis. Disease-directed therapy can result in a relatively favorable outlook in these patients compared with adenocarcinoma of unknown primary site of nonovarian origin. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)

Pathology and pathogenesis – In some cases, these tumors arise from the peritoneal surface or fallopian tubes, which share a common histogenesis with ovarian tissues. Many have morphologic features that are typical for epithelial ovarian carcinoma, such as papillary configuration or psammoma bodies. In such cases, this syndrome has various terms such as primary peritoneal carcinoma, serous carcinoma of the peritoneum, or multifocal extraovarian serous carcinoma. However, some patients may present with a poorly differentiated adenocarcinoma that does not exhibit a papillary configuration (analogous to poorly differentiated epithelial ovarian carcinomas); they should be approached similarly to those with typical serous histology. Both immunohistochemistry (IHC) and molecular cancer classifier assays (MCCAs) often corroborate this diagnosis. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology", section on 'Microscopic pathology'.)

Primary peritoneal carcinoma may share a common biology with ovarian carcinoma, a concept that is supported by the following observations:

Females at high risk for ovarian cancer may also develop primary peritoneal carcinoma. For example, these cancers occur more commonly in females with breast cancer susceptibility gene 1 (BRCA1) mutations and occasionally in those from families at high risk for ovarian cancer who have undergone prophylactic oophorectomy. (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer" and "Screening for ovarian cancer".)

The clinical features of primary peritoneal carcinomas are often typical of advanced ovarian cancer, with tumor involvement limited to the peritoneal surfaces and elevated serum concentrations of cancer antigen (CA) 125. (See "Screening for ovarian cancer".)

Management – Management of females with peritoneal carcinomatosis of unknown primary site may include a multimodality approach that includes surgical debulking and systemic chemotherapy:

Surgical cytoreduction should be considered in patients with bulky disease. In patients with epithelial ovarian cancer, debulking may provide the best chance for long-term remission, although the optimal timing is controversial [18]. (See "Cancer of the ovary, fallopian tube, and peritoneum: Surgical cytoreduction".)

Patients with peritoneal carcinomatosis of unknown primary site often respond well to chemotherapy regimens that are effective in the treatment of advanced epithelial ovarian cancer. Several studies have documented high initial response rates similar to those seen in patients with advanced ovarian carcinoma [19-23]. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)

Females with axillary lymph node metastases — Breast cancer should be suspected in females (and, rarely, in males) who have an adenocarcinoma of unknown primary site and axillary lymphadenopathy. Multiple series have demonstrated that females presenting with axillary lymphadenopathy have a much better prognosis than those with adenocarcinoma of other unknown primary sites. (See "Axillary node metastases with occult primary breast cancer", section on 'Initial diagnostic workup' and "Axillary node metastases with occult primary breast cancer", section on 'Prognosis'.)

To support a diagnosis of breast cancer, IHC staining (for estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 [HER2], and other breast cancer-specific markers such as GATA-binding protein 3 [GATA3] and gross cystic duct fluid protein 15) should be obtained on the biopsy material in such patients. Even with physical examination and mammography, bilateral breast magnetic resonance imaging (MRI) is successful in identifying a primary site in the majority of such cases. (See "Axillary node metastases with occult primary breast cancer", section on 'Breast MRI'.)

If a focal breast lesion is identified, further diagnostic evaluation should follow standard guidelines for suspected breast cancer. (See "Diagnostic evaluation of suspected breast cancer" and "Clinical features, diagnosis, and staging of newly diagnosed breast cancer".)

Females with adenocarcinoma or poorly differentiated carcinoma in axillary nodes, compatible IHC staining, and no metastatic sites other than the axillary lymph nodes may have potentially curable breast cancer. These patients are treated according to guidelines for stage II breast cancer. (See "Axillary node metastases with occult primary breast cancer", section on 'Locoregional treatment' and "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer".)

If metastatic sites in addition to axillary lymph nodes are present, such patients may have metastatic breast cancer. These patients should receive systemic therapy according to guidelines for the treatment of metastatic breast cancer. (See "Axillary node metastases with occult primary breast cancer", section on 'Metastatic disease' and "Overview of the approach to metastatic breast cancer".)

Males with skeletal metastases and elevated prostate-specific antigen — When bone metastases are the first manifestation of metastatic adenocarcinoma, the most common primary tumor sites are the lung, prostate, and less often, liver, kidney, thyroid, and colon [24].

Metastatic prostate cancer should be suspected in males with adenocarcinoma predominantly involving bone, particularly if the metastases are osteoblastic or sclerotic. Elevated serum levels of prostate-specific antigen (PSA) or tumor staining with PSA provides confirmatory evidence of prostate cancer, and such patients should be treated using guidelines for metastatic prostate cancer. Occasional patients have a significantly elevated serum PSA or tumor staining for PSA, but a clinical presentation that is atypical for prostate cancer (eg, metastases to the lung or mediastinal or upper abdominal lymph nodes, without concomitant involvement of bone or pelvic lymph nodes) [25,26]. Such patients, in the absence of data supporting another primary, should also be considered for treatment for metastatic prostate cancer. (See "Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis".)

Metastatic prostate cancer is amenable to treatment with a range of therapies that differ from those used for metastatic adenocarcinoma of other primary sites; therefore, identification of these patients is important in guiding appropriate therapy. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer".)

Patients with specific tumor profiles

Colon cancer profile — Systemic treatment for patients with metastatic colorectal cancer has resulted in a substantial improvement in overall survival. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach".)

Accurate recognition of patients with adenocarcinoma of unknown primary site who are likely to respond to similar treatments is therefore increasingly important. A "colon cancer profile" has been described and includes:

Predominant metastatic sites in the liver and/or peritoneum

Adenocarcinoma with histology typical of gastrointestinal origin

Typical IHC staining pattern including cytokeratin 20 (CK20) positive/cytokeratin 7 (CK7) negative and caudal-type homeobox transcription factor 2 (CDX-2) positive

Patients with this profile respond well to chemotherapy with regimens developed for patients with metastatic colorectal carcinoma (eg, FOLFOX/bevacizumab) [27,28].

Increasing evidence also supports the use of site-specific treatment in cancer of unknown primary site (CUP) patients who have a colorectal tissue of origin identified by MCCA. In two retrospective series, patients with CUP who had a colorectal site of origin predicted by MCCA and received standard regimens for advanced colon cancer had median survival >20 months [29,30]. In both series, approximately 45 percent of patients predicted to have colorectal cancer by MCCA had atypical IHC staining, and would not have been identified by standard pathologic evaluation. Although prospective data are needed, the survival documented in these retrospective studies, which is similar to patients with advanced colon cancer, suggests accurate identification by molecular profiling.

Tumors with a colon cancer profile should also be tested for high microsatellite instability (MSI-H) and high tumor mutational burden (TMB) to assess treatment eligibility for checkpoint inhibitor immunotherapy. The approach to such testing is discussed separately. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Assessing mismatch repair'.)

Lung adenocarcinoma profile — Lung cancer is one of the most common cancers represented among patients with adenocarcinoma of unknown primary site. In one autopsy series, lung primary sites were found in approximately 20 percent of patients with CUP [2]. In another study of 252 patients with CUP whose biopsies were tested with MCCA, 28 patients (11 percent) were predicted to have a lung primary site [31].

The recognition of patients with CUP from a lung tissue of origin is important because it influences therapy. The treatment of non-small cell lung cancer (NSCLC) has evolved with the addition of immunotherapy, molecular targeted therapies, and maintenance therapy, among other approaches, but none of these specific therapies are included in the empiric chemotherapy options for CUP. (See "Overview of the initial treatment and prognosis of lung cancer".)

Patients with CUP and a lung adenocarcinoma profile often exhibit the following features:

Mediastinal and/or hilar adenopathy, often accompanied by metastases at other sites

Typical IHC staining pattern (TTF-1-positive, CK7-positive, CK20-negative, thyroglobulin-negative

MCCA prediction of lung tissue of origin [32-35]

In patients with lung adenocarcinoma identified by MCCA, standard first-line NSCLC chemotherapy produced median survival of 16 months [31]. However, no prospective studies have applied contemporary NSCLC treatment in its entirety to patients with CUP. While awaiting further data, patients with CUP and a lung adenocarcinoma profile can be treated using the same approach for advanced NSCLC. (See "Overview of the initial treatment and prognosis of lung cancer".)

Treatment selection can also be guided by early initial testing for programmed cell death ligand 1 (PD-L1) as well as critical driver mutations such as epidermal growth factor receptor (EGFR), the anaplastic lymphoma kinase (ALK) fusion oncogene, and other targetable mutations. (See "Overview of the initial treatment of advanced non-small cell lung cancer", section on 'Driver mutation present'.)

Renal cell carcinoma profile — Renal cell carcinoma (RCC) accounts for approximately 5 percent of CUP in autopsy series and in MCCA series [31].

Treatment options for advanced RCC include immunotherapy, vascular endothelial growth factor receptor (VEGFR) inhibitors, and mTOR inhibitors, as well as immunotherapy. None of these agents are included in the empiric chemotherapy regimens options for CUP, which have no activity in the treatment of RCC. (See "Systemic therapy of advanced clear cell renal carcinoma".)

Although patients may have diverse clinical presentations, the diagnosis of advanced RCC can often be suspected based on pathologic findings, which can include:

Clear cell or papillary histology

IHC staining for RCC marker, CD10, and PAX8

MCCA diagnosis of a kidney site of origin [35]

In a typical IHC evaluation of a CUP biopsy, renal-specific stains are not included unless the diagnosis is suspected, so the recognition of these patients can be missed.

The efficacy of treatment for patients with CUP predicted to have advanced RCC by IHC and/or MCCA has not been extensively evaluated, but data from observational studies are encouraging [36,37]. As examples:

In one retrospective series, 10 patients with CUP predicted to have RCC by histology and IHC were treated with targeted RCC-specific therapy [36]. None of the patients had detectable kidney lesions, and over half (60 percent) were in the poor risk category. In all patients, the objective response rate (ORR) was 40 percent. Among those with intermediate-risk disease, median overall survival (OS) was 18.5 months.

Site-specific RCC treatment based on MCCA prediction has also been reported. In another retrospective series, 24 patients with CUP were predicted to have RCC by MCCA, including papillary histology in 11 patients [37]. Among the 20 patients treated with VEGFR inhibitors or mTOR inhibitors, the ORR was 19 percent and median OS was 16 months.

Although further data are necessary, patients with CUP identified as having an RCC profile can be treated using the same approach for advanced or metastatic RCC. (See "Systemic therapy of advanced clear cell renal carcinoma" and "The treatment of advanced non-clear cell renal carcinoma".)

Thyroid carcinoma profile — Although rare, follicular/papillary thyroid carcinoma can present as a CUP. The thyroid carcinoma profile includes:

Metastases in cervical or mediastinal lymph nodes, lungs, or bones

Tumor IHC staining for thyroglobulin

Elevated serum thyroglobulin levels

The treatment of patients with CUP identified as having a thyroid carcinoma profile should follow guidelines for metastatic follicular/papillary thyroid cancer. (See "Follicular thyroid cancer (including oncocytic carcinoma of the thyroid)", section on 'Treatment' and "Differentiated thyroid cancer: Overview of management".)

Adenocarcinoma of unknown primary in a single site — In occasional patients, only a single metastatic lesion is identified after a complete staging evaluation. Such single lesions have been described in a variety of sites including lymph nodes, brain, lung, adrenal gland, liver, and bone. The possibility of an unusual primary site (eg, apocrine, eccrine, or sebaceous carcinoma) mimicking a metastatic lesion should be considered, but can usually be excluded on the basis of clinical or pathologic features.

In most of these patients, other metastatic sites become evident within a relatively short time. A positron emission tomography (PET) scan may be helpful to rule out additional unrecognized sites of metastatic disease prior to definitive local therapy [38]. (See 'Initial clinical evaluation' above.)

If no evidence of additional disease is found, resection of the solitary lesion should be considered. If resection is not feasible because of the location of the metastatic lesion, definitive local radiation therapy should be administered. Local treatment sometimes results in long disease-free intervals.

The benefit of surgical resection of more than one metastatic lesion in patients with CUP is not well documented. Since this approach is recommended in highly selected patients with several tumor types (eg, renal carcinoma, colon cancer with liver metastases, non-small cell lung cancer), it may also be reasonable in occasional patients with CUP.

In some instances (eg, after resection of a solitary brain metastasis), local radiation therapy may also be appropriate to maximize the chance of local control [39,40]. (See "Overview of the treatment of brain metastases".)

The role of adjuvant chemotherapy in this setting is undefined. However, a primary site can now be predicted in many of these patients using IHC and MCCA. Adjuvant therapy is reasonable to consider if indicated in the management of the tumor type predicted. When a primary site cannot be predicted, empiric chemotherapy may be useful in patients with poorly differentiated carcinoma. (See 'Empiric chemotherapy' below.)

APPROACH TO PATIENTS NOT INCLUDED IN SPECIFIC SUBGROUPS — A majority of patients (65 to 70 percent) with adenocarcinoma of unknown primary site do not fit into any of the clinical subgroups outlined above. These patients have traditionally received empiric chemotherapy with regimens designed to have efficacy in a broad spectrum of cancer types. However, the role of molecular cancer classifier assays (MCCAs) and comprehensive molecular profiling in the treatment of these patients is evolving. Patients are encouraged to enroll in clinical trials, where available, since the cancer of unknown primary site (CUP) population continues to have a poor prognosis with standard treatments. (See 'Molecular cancer classifier assays' below and 'Comprehensive molecular profiling' below and 'Empiric chemotherapy' below.)

Local therapy may be appropriate if only a single focus of disease is identified. (See 'Adenocarcinoma of unknown primary in a single site' above.)

Choice of treatment approach — For patients who do not fit into any of the clinical subgroups outlined above and do not have an immunohistochemistry (IHC) profile highly suggesting the primary site, we perform an MCCA to classify CUPs based on primary tumor sites and identify those patients with tumors that are either sensitive or resistant to standard treatment approaches.

Molecular cancer classifier assays — MCCAs can accurately identify the tissue of origin and subsequently guide site-specific therapy in patients with CUP. The diagnostic efficacy of MCCAs is based on distinct gene expression profiles present in different normal body tissues. When cancers arise from normal tissues, the distinct gene expression profiles are usually retained, at least in part, by the neoplastic cells, allowing identification of the tumor site of origin (eg, primary site). Several MCCAs, using either reverse transcription polymerase chain reaction (RT-PCR) or gene microarray technology, are commercially available and provide results with a clinical turnaround time of approximately one to two weeks [32,33,41]. Based on clinical validation studies, MCCAs can correctly identify the primary site in 85 to 95 percent of metastatic cancers from various known primary sites [32,33,41] and in the large majority of CUP [5,15,16,42].

MCCA-directed site-specific therapy has been compared with empiric chemotherapy, with mixed results [43]. Some data have suggested improved overall survival (OS) for site-specific treatment relative to empiric chemotherapy, particularly in those with "treatment-sensitive" tumor types, where site-specific therapy is quite effective [31,44], which includes approximately one-third of patients with CUP.

In contrast, randomized studies have demonstrated similar outcomes between the two treatment approaches [44,45]. In these studies, the majority of patients had "treatment-resistant" tumor types, where site-specific therapy is relatively ineffective. Therefore, further randomized studies are needed to evaluate the benefit of site-specific treatment versus empiric chemotherapy, specifically in those with treatment-sensitive tumor types. Defining treatment-sensitive tumor types may evolve over time with the use of easily accessible molecular testing, more precise delineation of CUP subsets, and continued improvements of treatment efficacy in many types of advanced cancer. (See 'Cancers with predicted treatment sensitivity' below and 'Cancers with predicted treatment resistance or no primary site identified' below.)

Cancers with predicted treatment sensitivity — In patients with potentially treatment-sensitive tumor types detected by IHC and/or MCCA (eg, kidney cancer, colorectal cancer, non-small cell lung cancer [NSCLC], breast cancer, melanoma, ovarian cancer, bladder cancer, and others), we use site-specific therapy, which includes (1) use of site-specific first-line and subsequent-line chemotherapy, (2) molecular testing for specific molecular alterations pertinent to the specific tumor type (eg, human epidermal growth factor receptor 2 [HER2] testing for breast cancer), with targeted therapy for appropriate subsets, and (3) use of immunotherapy if indicated for the tumor type identified.

Comprehensive molecular profiling may also be offered to select patients to identify actionable molecular alterations, a technique also used to identify active therapies in those with treatment-resistant tumors. However, the routine use of MCCA and comprehensive molecular profiling in guiding treatment for CUP is not yet considered definitive by the National Comprehensive Cancer Network (NCCN), and these tests are not included in the NCCN treatment guidelines. (See 'Comprehensive molecular profiling' below.)

Several attempts have been made to improve treatment outcome in CUP by using site-specific therapy, guided by MCCA predictions. Site-specific treatment and empiric chemotherapy have been directly compared in two randomized trials:

In a phase III trial (GEFCAPI 04), 243 treatment-naïve patients with CUP were randomly assigned to receive either empiric chemotherapy with gemcitabine plus cisplatin or site-specific treatment directed by MCCA results [44]. Among a subset of 60 patients with cancer types considered unlikely to respond to empiric gemcitabine plus cisplatin and thus more likely to respond to site-specific treatment (eg, kidney, colorectal, sarcoma, liver, neuroendocrine, breast, melanoma, salivary gland), 37 received site-specific treatment whereas 23 received empiric chemotherapy. In this small cohort, the one- and two-year OS rates favored patients receiving site-specific therapies (one-year OS 39 versus 30 percent; two-year OS 24 versus 10 percent). For the entire group of 243 patients, median OS (10 versus 10.7 months; hazard ratio [HR] 0.92, 95% CI 0.69-1.23) and progression-free survival (PFS; 5.3 versus 4.6 months; HR 0.95, 95% CI 0.72-1.25) were comparable between empiric chemotherapy and site-specific therapy.

In a smaller, randomized phase II trial, 101 patients with CUP were randomized to receive either empiric paclitaxel/carboplatin or site-specific therapy directed by an MCCA [45]. In this group, only 17 patients (17 percent) had carcinomas predicted by MCCA to be sensitive to treatment. OS (9.8 versus 12.5 months) and PFS (5.1 versus 4.8 months) were similar between the two treatment groups. However, the study results were potentially biased by the inclusion of patients with lymphoma (26 patients [20 percent]), which is typically detected on standard pathologic examination; inclusion of these patients in a study designed to evaluate those with CUP suggests problems either with the standard pathology or with the MCCA.

Observational studies (both prospective and retrospective) suggest that site-specific treatment improves outcome in specific tumor types, including colorectal cancer, renal cancer, and poorly differentiated neoplasms [16,29,30,37,46-49]. As an example, in a prospective nonrandomized phase II trial, 194 patients with CUP received site-specific therapy based on MCCA predictions (CancerTYPE ID) [31]. Median OS for the entire group was 12.5 months, which is longer than the OS observed with empiric chemotherapy in separate studies (median 9 to 11 months). In addition, patients with potentially responsive tumor types did better with site-specific treatment than did those with less responsive types (median 13.4 versus 7.6 months).

Cancers with predicted treatment resistance or no primary site identified — In patients predicted to have a tumor type relatively resistant to treatment as detected by IHC and/or MCCA (eg, pancreatic, biliary, gastric, liver cancer, and others) or those in whom no primary tumor site is identified, empiric chemotherapy provides treatment results equivalent to site-specific therapy, although both approaches have relatively poor efficacy. Several two-drug empiric combinations are reasonable choices for initial therapy, such as paclitaxel plus carboplatin, gemcitabine plus cisplatin (or carboplatin), and gemcitabine plus irinotecan. (See 'Empiric chemotherapy' below.)

With the evolution of cancer therapy, empiric chemotherapy has become less attractive in the diverse CUP population. Treatment now differs markedly based on the site of tumor origin and often involves the identification of defined molecular targets, none of which are included in the empiric chemotherapy regimens for CUP. As a result, there is developing interest in using other molecular profiling techniques to identify and offer therapy directed at the tumor of origin in patients with CUP. (See 'Comprehensive molecular profiling' below.)

As an example, patients with advanced NSCLC are treated using checkpoint inhibitor immunotherapy (alone or in combination with chemotherapy) as well as therapies targeting molecular alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and c-ROS oncogene 1 (ROS1). Prior to these newer therapies, most were initially treated with paclitaxel/platinum, a commonly used CUP regimen [50,51]. Similar situations exist in the treatment of other cancer sites including advanced colorectal, kidney, breast, and gastric cancers. Further details on the specific treatment of these cancers are discussed separately. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer" and "Systemic therapy for metastatic colorectal cancer: General principles" and "Systemic therapy of advanced clear cell renal carcinoma" and "Overview of the approach to metastatic breast cancer" and "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer".)

Comprehensive molecular profiling — We offer comprehensive molecular profiling of CUP. Molecular alterations predictive of activity of targeted agents or immunotherapy are present in a sizable minority of these patients. Such treatment should be offered, either as first-line, when other treatment options are unlikely to be beneficial, or as subsequent treatment.

Comprehensive molecular profiling involves assaying a broad group of genes for the purpose of identifying potentially actionable oncogenic molecular alterations (eg, HER2, EGFR, BRAF, others), which in one study, were identified in approximately 20 percent of patients with CUP [52].

Comprehensive molecular profiling therefore differs from an MCCA, which measures differential expressions of normal genes to enable identification of a tissue of origin. Similar to MCCAs, data suggest comprehensive molecular profiling using a next-generation sequencing (NGS) panel may also be able to predict tissue of origin, but further clinical validation is necessary [53].

Data supporting the use of comprehensive molecular profiling are rapidly evolving. Increased use of comprehensive profiling has allowed for the evaluation of established targeted agents in a wide variety of cancer types that are rare or have a low incidence of the critical molecular alterations. As expected, active targeted agents have efficacy across a variety of tumor types, as long as the critical molecular alteration is present [54,55]. Examples include BRAF, EGFR, HER2, TRK, high microsatellite instability (MSI-H), and high tumor mutational burden (TMB). However, activity of the same targeted agent can vary widely in different tumor types, for reasons that are incompletely understood [56,57]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors" and "TRK fusion-positive cancers and TRK inhibitor therapy".)

Available evidence suggests that comprehensive molecular profiling of patients with CUP could identify a substantial number of potentially actionable molecular abnormalities [58]. To date, most comprehensive molecular profiling studies in CUP have been performed on tissue biopsies, but blood-based liquid biopsies (circulating tumor DNA) are becoming important and may eventually replace tissue testing [59].

In a group of 200 patients with CUP (125 with adenocarcinoma, 75 with carcinoma), 38 patients (18 percent) had molecular alterations for which targeted agents are approved in other indications (HER2, BRAF, EGFR, ALK, rearranged during transfection proto-oncogene [RET], breast cancer susceptibility gene [BRCA], ROS1) [52]. The rare TRK mutation (not assessed in this group of patients with CUP) is another tumor-agnostic targetable alteration responsive to available treatment [60]. At present, the efficacy of targeted therapy in patients with CUP is documented only by a few case reports [34,61-67], so the impact of these actionable mutations on treatment cannot be fully assessed.

Comprehensive molecular profiling may also identify patients with CUP who may benefit from immune checkpoint inhibitors. While the use of immune checkpoint inhibitors is largely untested in patients with CUP, the efficacy of these agents seems likely. Cancer types known to be responsive to these agents (lung, urothelial, renal) are well represented in the CUP population. Molecular alterations predictive of response to immune checkpoint inhibitors, including MSI-H, high TMB, and programmed cell death ligand 1 (PD-L1) amplification or overexpression [68-70], have been identified in CUP [71-73]. High TMB (≥20 mutations/mb) is relatively common in CUP, occurring in 8 percent of adenocarcinomas, 11 percent of carcinomas, and 23 percent of squamous carcinomas [71]. PD-L1 is also overexpressed in patients with CUP; staining in tumor-infiltrating lymphocytes was seen in 63 percent, and staining of cancer cells was observed in 21 percent of patients with CUP [72]. MSI-H and PD-L1 amplification are less common (1 to 2 percent) [73]. (See "Principles of cancer immunotherapy".)

Although comprehensive molecular profiling identifies an actionable molecular alteration in a sizable minority of patients with CUP, optimal use of these data in guiding therapy may also require additional information, including identification of the likely primary site. Few targeted drugs are recommended for first-line, single-agent treatment in any solid tumor type. Combination chemotherapy continues to play an integral role in the treatment of many cancers. One would not recommend the same chemotherapy for patients with breast versus colon cancer, nor would one treat patients with either of these cancer types with first-line, single-agent, targeted therapy. Likewise, initial treatment with BRAF-targeted therapy would be inappropriate in a patient with a BRAF V600E mutation if the primary site was known to be colorectal.

Empiric chemotherapy — Empiric chemotherapy has historically been the standard initial therapy for patients with CUP and still remains part of the treatment approach in these patients. However, for those who have actionable targets identified on comprehensive molecular profiling, incorporation of targeted therapy or immunotherapy (either as single agents or in combination with chemotherapy) may be offered. (See 'Comprehensive molecular profiling' above.)

Patients with poor performance status are much less likely to benefit from chemotherapy, and optimal management in these patients may be limited to supportive measures.

Choice of chemotherapy

Initial therapy – Several two-drug combinations have similar activity and are reasonable choices for initial therapy. These combinations include paclitaxel plus carboplatin, gemcitabine plus cisplatin (or carboplatin), and gemcitabine plus irinotecan [5-9]. These regimens produce response rates of 25 to 45 percent, with a median OS ranging between approximately 7 and 10 months.

As an example, a combined analysis of five single-arm phase II trials included a total of 396 treatment-naïve patients with CUP treated with empiric chemotherapy. Using this approach, the combined objective response rate (ORR) was 30 percent, median PFS was nine months, and two-year OS was 19 percent [5].

Subsequent therapy – A few subsequent-line empiric regimens have been evaluated in phase II trials, usually following initial therapy with taxane/platinum combinations [74-76]. Modest activity was seen with oxaliplatin/capecitabine (ORR 19 percent; median OS 9.7 months) [74], gemcitabine/irinotecan (ORR 10 percent; median OS 4.5 months) [76], bevacizumab/erlotinib (ORR 10 percent; median OS 7.4 months) [75], and nivolumab (ORR 22 percent; median OS 16 months) [77]. There are limited data to support the benefit for single-agent chemotherapy.

Prognostic factors — Retrospective analyses have identified clinical and pathologic features that are associated with a favorable response to treatment using empiric chemotherapy in patients with CUP [78-84]. Many of these features are related to tumor grade or extent of disease and are prognostic factors for many types of advanced cancer.

These include the following:

Tumor location in lymph nodes or soft tissue. Patients with involvement of the liver or bones have a relatively poor prognosis.

Fewer sites of metastatic disease.

Female sex.

Poorly differentiated carcinoma histology.

Good performance status.

Normal serum lactate dehydrogenase (LDH) level.

Normal serum albumin.

Normal lymphocyte count.

In one prognostic factor analysis that included 150 patients with CUP who were seen at a single institution over a 10-year period, the performance status and serum LDH could be used to separate patients into good- and poor-risk categories. The median survival durations for good- and poor-risk patients were 11.7 and 3.9 months, and one-year survival rates were 45 and 11 percent, respectively [83].

A multivariate analysis of prognostic factors based on a series of 317 consecutive patients found that a normal serum albumin and the absence of liver metastases identified a favorable subset of patients (median survival 371 days, versus 103 days in patients with a low serum albumin and/or liver metastases) [84]. In the same report, the favorable prognosis associated with the combination of a normal serum albumin and the absence of liver metastases was validated in a second cohort of 124 patients with CUP.

Prognostic factors have not been studied in patients receiving site-specific therapy, and they may differ from those recognized in previous studies. In addition, it is likely that molecular tumor prognostic factors of greater clinical value will be identified (eg, actionable mutations, alterations predicting response to immune checkpoint inhibitors). (See 'Cancers with predicted treatment sensitivity' above.)

SUMMARY AND RECOMMENDATIONS

Definition and epidemiology – Cancer of unknown primary site (CUP) is diagnosed in patients who have metastatic cancer but have no anatomic primary site identified by a comprehensive initial evaluation. CUPs account for approximately 2 percent of all invasive cancers. Adenocarcinomas of unknown primary site comprise approximately 70 percent of CUPs. (See 'Introduction' above.)

Initial clinical evaluation – In order to make the diagnosis of CUP, the following evaluation should be obtained, yet fail to identify the anatomic primary site (see 'Initial clinical evaluation' above):

History and physical examination

Complete blood count

Urinalysis

Basic serum chemistries

Computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis

In males, a prostate examination and measurement of serum prostate-specific antigen (PSA)

In females, a pelvic examination and mammography

Pathologic evaluation – Once the diagnosis of CUP is established, additional evaluation may be warranted based on the findings of clinical and pathologic assessment. (See 'Initial evaluation of the tumor specimen' above.)

Histologic characteristics of a biopsy specimen usually allow for classification of the lineage of a CUP (ie, carcinoma versus sarcoma, lymphoma, melanoma). (See 'Light microscopy' above.)

Histologic examination cannot distinguish among various adenocarcinomas, but immunohistochemical (IHC) staining strongly suggests the primary site in approximately one-third of patients. (See 'Immunohistochemistry' above.)

Specific treatable subgroups – Patients with adenocarcinoma of unknown primary site should be evaluated to determine whether their clinical features and pathology classify them as belonging to any of the following subsets (table 4) for which individualized therapy is appropriate (algorithm 1) (see 'Specific patient subgroups' above):

Females with peritoneal carcinomatosis – Females with adenocarcinoma of unknown primary and peritoneal carcinomatosis and consistent pathology should be treated like those with ovarian carcinoma. This approach may include both surgical debulking and systemic chemotherapy. (See 'Females with peritoneal carcinomatosis' above and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer" and "Cancer of the ovary, fallopian tube, and peritoneum: Surgical cytoreduction".)

Females with axillary lymphadenopathy – Females presenting with adenocarcinoma of unknown primary and axillary lymphadenopathy should be treated as if they have primary breast cancer, as long as the pathology and clinical presentation are consistent with that diagnosis. (See 'Females with axillary lymph node metastases' above and "Axillary node metastases with occult primary breast cancer".)

Males with skeletal metastases and elevated PSA – Males with metastatic adenocarcinoma and skeletal metastases and elevated serum levels of PSA and/or tumor staining with PSA should be treated for advanced prostate cancer. (See 'Males with skeletal metastases and elevated prostate-specific antigen' above and "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer".)

Colon cancer profile – Patients who present with a colon cancer profile (ie, predominant metastatic sites in the liver and/or peritoneum, an adenocarcinoma with histology typical of gastrointestinal origin, and typical immunohistochemical staining pattern [cytokeratin 20 [CK20]-positive/cytokeratin 7 [CK7]-negative, or caudal-type homeobox transcription factor 2 [CDX-2]-positive]) should be treated as if they have metastatic colorectal cancer. Treatment for colorectal cancer should also be offered for patients with a colorectal tissue of origin predicted by a molecular cancer classifier assay (MCCA). (See 'Colon cancer profile' above and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach".)

Lung adenocarcinoma profile – Patients who present with a lung adenocarcinoma profile (ie, mediastinal and/or hilar adenopathy often accompanied by metastases at other sites; typical IHC staining pattern [TTF-1-positive, CK7-positive, CK20-negative]; MCCA prediction of non-small cell lung cancer [NSCLC]) should be treated using the same approach for advanced NSCLC. (See 'Lung adenocarcinoma profile' above and "Overview of the initial treatment of advanced non-small cell lung cancer".)

Renal cell carcinoma profile – Patients who present with a renal cell carcinoma (RCC) profile (ie, clear cell or papillary histology; typical IHC staining [RCC marker, CD10, PAX8]; MCCA prediction of RCC) should be treated using the same approach for advanced or metastatic RCC. (See 'Renal cell carcinoma profile' above and "Systemic therapy of advanced clear cell renal carcinoma" and "The treatment of advanced non-clear cell renal carcinoma".)

Thyroid carcinoma profile – Patients who present with a thyroid carcinoma profile (ie, metastases in cervical or mediastinal lymph nodes, bones, or lungs; elevated serum thyroglobulin levels, IHC staining for thyroglobulin) should be treated using the same approach for metastatic follicular/papillary thyroid carcinoma. (See 'Thyroid carcinoma profile' above and "Follicular thyroid cancer (including oncocytic carcinoma of the thyroid)", section on 'Treatment' and "Differentiated thyroid cancer: Overview of management".)

Disease at a single site – Patients with a single metastatic focus of adenocarcinoma who do not fit any of the patterns above should be carefully evaluated to exclude any other sites of disease involvement. If no other site of disease involvement can be identified, we offer definitive local therapy, consisting of either surgical resection or radiation therapy. Although most patients will develop disseminated disease relatively rapidly, this approach is associated with prolonged survival in some cases. (See 'Adenocarcinoma of unknown primary in a single site' above.)

Patients not in specific treatable subgroups – In patients who do not fit into a specific subset, we attempt to identify the tissue of origin using an MCCA or IHC stains. The approach to treatment depends on whether a treatment-sensitive or treatment-resistant tissue of origin is identified (algorithm 1). (See 'Approach to patients not included in specific subgroups' above and 'Molecular cancer classifier assays' above.)

Treatment-sensitive tumor types – In patients predicted to have potentially treatment-sensitive tumor types by IHC and/or MCCA (eg, kidney cancer, colorectal cancer, non-small cell lung cancer [NSCLC], breast cancer, melanoma, ovarian cancer, bladder cancer, and others), we use site-specific therapy, which includes use of site-specific first-line and subsequent-line chemotherapy, molecular testing for specific molecular alterations pertinent to the specific tumor type (eg, human epidermal growth factor receptor 2 [HER2] testing for breast cancer), with targeted therapy for appropriate subsets, and use of immunotherapy if indicated for the tumor type identified. The support for these recommendations is not yet considered definitive by the National Comprehensive Cancer Network (NCCN). (See 'Choice of treatment approach' above and 'Cancers with predicted treatment sensitivity' above.)

Treatment-resistant tumor types – In patients predicted to have a treatment-resistant tumor type by IHC and/or MCCA (eg, pancreatic, biliary, gastric, liver cancer, and others) or who do not have a specific tumor type identified, empiric chemotherapy provides treatment results equivalent to site-specific therapy (both treatments relatively poor). Several two-drug empiric combinations are reasonable choices for initial therapy, such as paclitaxel plus carboplatin, gemcitabine plus cisplatin (or carboplatin), and gemcitabine plus irinotecan. (See 'Approach to patients not included in specific subgroups' above and 'Cancers with predicted treatment resistance or no primary site identified' above.)

We also offer comprehensive molecular profiling of CUP biopsy specimens. Molecular alterations predictive of activity of targeted agents or immunotherapy are present in a sizable minority of these patients. Such treatment should be offered, either as first-line, when other treatment options are unlikely to be beneficial, or as subsequent treatment. (See 'Comprehensive molecular profiling' above.)

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Topic 4877 Version 43.0

References

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