Cancer of Unknown Primary

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Chapter 34 Cancer of Unknown Primary

Aurelio Matamoros, Jr. , M.D. , Gauri R. Varadhachary, M.D.

Introduction^*

Cancer of unknown primary (CUP) is a designation given to a discordant group of metastatic carcinomas for which the primary site of origin cannot be identified despite a thorough diagnostic workup that includes a thorough medical history, complete physical examination to include breast and pelvic and rectal evaluations, complete blood count and biochemical analysis, urinalysis, prostate-specific antigen (PSA) in males, and histopathologic review of tissue specimens with immunohistochemistry. Computed tomography (CT) of the chest, abdomen, and pelvis; chest radiography; and mammography in females are performed as indicated.

Despite this workup, the attending physician will more than likely still be in a quandary as to the primary site that produced the aggressive metastatic disease. Needless to say, this scenario creates stress not only to the attending physician but also to the patient in trying to cope with the unknown.

Unproved theories regarding the localization of the primary CUP site include (1) the primary tumor has involuted and only the metastatic disease is evident and (2) metastatic disease is favored over the primary growth based on the phenotype and genotype of the tumor.¹

Epidemiology and Risk Factors

Worldwide, CUP is one of the 10 most frequent cancers constituting about 3% to 5% of all cancer cases.² In 2011, according to the American Cancer Society, there were an estimated 30,500 cases of “Other & unspecified primary sites” in the United States or approximately 2% of all cancer cases and an estimated 44,260 deaths.² At presentation, the median age is approximately 60 years and slightly more frequent in males.³

No risk factors have been identified for this heterogeneous group of neoplasms and no screening programs have been described.

Anatomy and Pathology

Because only carcinomas are included in the diagnosis of CUP, four main histologic types of CUP have been described: well to moderately differentiated adenocarcinomas (50%), undifferentiated or poorly differentiated carcinomas (30%), squamous cell carcinomas (15%), and undifferentiated neoplasms (5%). The latter group includes lymphomas, sarcomas, germ cell tumors, poorly differentiated carcinomas, neuroendocrine tumors, and embryonal malignancies that can be characterized by immunohistologichemistry.⁴ In children, CUPs represent less than 1% of solid tumors and the majority of these tumors are embryonal malignancies.²

Pathologic assessment is a must to characterize a CUP and is usually accomplished by histologic and cytopathologic evaluation. As an adjunct, electron microscopy is occasionally used to evaluate those CUPs that demonstrate indeterminate features that cannot be resolved with routine pathologic evaluation.

Serum tumor markers are mainly overexpressed glycoproteins that are released into the bloodstream by malignant tumors. The serum determination of these tumor markers can help to identify and diagnose, classify, and in patient follow-up, aid in assessment of response to therapy. However, these serum tumor markers have low sensitivity and low specificity, given that they are not expressed specifically by one organ.

The number of serum tumor markers is determined by the attending physician and include but are not limited to carcinoembryonic antigen (CEA), CA125, CA19-9, CDX2, CA15-3, CK-7, CK-20, thyroid transcription factor-1 (TTF-1), PSA, alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (β-HCG), estrogen receptors, and gross cystic disease fluid protein-15 (GCDFP-15). Some of these serum tumor markers can have elevated levels in benign disease such as CEA in inflammatory bowel disease and CA19-9 in pancreatitis.

More recently, molecular techniques have been used to aid in the determination of the site of origin of these CUPs. Tissue microarrays and transcriptional profiling (reverse transcriptase polymerase chain reaction [RT-PCR]) are examples of the available molecular technologies. Some of these molecular assays are commercialized and available by several vendors.

The chromosomal and molecular abnormalities identified in CUPs are beyond the scope of this chapter.

Key Points Anatomy and pathology

• Four main histologic types of CUP are described: well to moderately differentiated adenocarcinomas, poorly differentiated carcinomas, squamous cell carcinomas, and undifferentiated neoplasms

• CUPs’ metastatic disease can appear anywhere in the body.

Clinical Presentation

Patients with known primary malignancy have a neoplasm with a natural history and a predictable metastatic pattern that allows for staging. The opposite is true for CUPs, given that they are very aggressive and have an unpredictable metastatic pattern, and therefore, no formal staging can be made in certain patients.

The clinical presentation is due to the symptoms created by the rapid spread of metastases rather than the primary tumor. The presenting symptoms tend to be of short duration, and on physical examination, there may be visual and palpable masses. Constitutional symptoms can also be elicited during the initial evaluation.

These patients face a grim prognosis with reported survival rates of 6 to 10 months for those enrolled in clinical studies.²

However, those CUP patients not enrolled in clinical trials have reported life expectancies of 2 to 3 months.⁵ Given the diverse clinical presentation of these patients, it is best to classify them into favorable and unfavorable subsets, with the former having a better prognosis.⁶

The favorable subsets include

Figure 34-1 A 64-year-old man presented with a “lump” in the left axilla. Left axillary lymph node biopsy shows squamous cell carcinoma. Thorough workup failed to reveal site of origin. A, Coronal positron-emission tomography/computed tomography (PET/CT) scan shows increased activity in the left subpectoral nodes (arrow). B, Coronal PET/CT scan shows increased activity in the left axillary nodes (arrow). C, Axial PET/CT scan shows increased activity in the left subpectoral nodes (arrows).

Figure 34-2 A 54-year-old man presented with a “lump” in the left lower neck. Outside initial biopsy shows poorly differentiated adenocarcinoma. Further immunohistochemistry shows prostate origin. A, Coronal PET/CT shows increased activity in the left lower neck (top arrow), left axillary (middle arrow), and left subpectoral (bottom arrow) adenopathy. B, Coronal PET/CT scan shows increased activity in the retroperitoneum and pelvis (arrow). C, Axial PET/CT scan shows increased activity in the prostate gland (arrow). D, Bone scan shows diffuse metastatic disease.

Figure 34-3 A 65-year-old man presented with right groin mass at an outside institution. Biopsy was consistent with squamous cell carcinoma. Thorough workup failed to reveal primary site of origin. Contrast-enhanced pelvic CT scan shows a large, partially necrotic inguinal nodal mass (arrows).

The unfavorable subsets are

1. Adenocarcinoma primarily metastatic to the liver.

2. Adenocarcinoma with multiple metastases to the lungs (Figure 34-4).

3. Adenocarcinoma with mainly diffuse osseous metastatic disease.

4. Multiple cerebral metastases.

5. Malignant ascites with nonpapillary adenocarcinoma histology.

Figure 34-4 A 33-year-old woman presented with cough that did not resolve with conventional therapy. CT study of the chest was done to evaluate the lungs. Lung and left breast biopsies were consistent with poorly differentiated adenocarcinoma not specific for lung or breast primary. A, Contrast-enhanced chest CT scan shows pulmonary metastases (arrows) and a right pleural effusion. B, Contrast-enhanced chest CT scan shows mediastinal (long straight arrow) and hilar (short straight arrow) adenopathy, right pleural effusion (curved arrow), and collapse of the right lower lobe (arrowhead). C, Contrast-enhanced chest CT scan shows a small mass (arrow) in the inner lower quadrant of the left breast. D, Contrast-enhanced abdominal CT scan shows multiple liver metastases (arrows).

To complicate the clinical presentation, more than 50% of CUP patients present with multiple sites of metastatic disease and approximately 30% have three or more organs involved with metastatic disease. In comparison, in patients with known primary tumors, fewer than 15% have metastatic disease in three or more sites.^5,^7,⁸

Key Points Clinical presentation

• CUPs are very aggressive neoplasms with an unpredictable metastatic pattern.

• Clinical presentation is due to symptoms from the metastatic disease rather than the primary tumor.

• Prognosis is grim.

• Favorable and unfavorable subsets do exist.

Patterns of Tumor Spread

The most common sites for CUP metastatic disease are the liver, lungs, bones, and lymph nodes. However, when compared with tumors of known origin, CUPs typically present with unpredictable patterns of spread. For example, when pancreatic and hepatic carcinomas present as CUPs, there is a higher incidence of lung and osseous metastatic disease compared with a known primary originating in the pancreas and liver. Brain and osseous metastatic disease from a CUP originating in the gastrointestinal tract is more commonly seen than that from a known gastrointestinal primary carcinoma. Approximately 50% of pulmonary carcinomas have osseous metastatic disease, whereas CUPs of pulmonary origin have a lower incidence of osseous metastatic disease. Hepatic and pulmonary metastatic disease is seen more frequently in cases that present as a CUP from a prostatic carcinoma than from a known prostatic carcinoma.⁹^–¹²

Key Point Patterns of tumor spread

• At presentation, metastatic disease is the prevailing pattern, mainly lymphatic or hematogenous.

Staging Evaluation

To stage a malignancy, the tumor needs to be identified for the tumor-node-metastasis (TNM) system. However, in only approximately 11% to 20% are the CUPs identified after a thorough clinical workup.^13,¹⁴ The postmortem tumor identification yield has been reported to be higher at approximately 51% to 79%.^10,^12,¹⁵ CUPs do not allow for the typical staging of tumors, given their diverse clinical presentation, different subtypes, different histologies, and metastatic patterns. The best approach for optimal patient management is to identify the subset to which that patient best fits.

Imaging

Part of the routine evaluation of CUPs is the plain radiographic imaging of the chest, because the lungs are frequently involved with these tumors. The histologic diagnosis will dictate the extent of imaging that needs to be performed to hopefully identify the site of the CUP and, at the same time, limit the discomfort and distress to the patient and the overall expense. Usually CTs of the chest, abdomen, and pelvis are obtained as a baseline. A mammogram is ordered based on the clinical evaluation. Bone scintigraphy and brain imaging by either CT or magnetic resonance imaging (MRI) is performed based on symptomatology. MRIs of body parts or cavities may yield further information regarding the site of the CUP. Positron-emission tomography (PET) and PET/CT are now more frequently used to help identify not only the location of the CUP but also other metastatic sites not identified by CT or MRI. Endoscopy with or without imaging and neck CT or MRI is done as clinically indicated, such as in those patients with a diagnosis of squamous cell carcinoma and metastatic cervical adenopathy. An octreotide scan is appropriate for those patients with neuroendocrine carcinoma.

The use of ultrasound is mainly for evaluation of lymph nodes and to provide biopsy guidance for lymph node or suspicious soft tissues, either superficial or moderately deep structures such as liver, testicular, breast, and renal lesions.

An example of tailored imaging in a favorable subset would be that of a female with axillary adenopathy but with a nondiagnostic mammographic study. This patient would benefit from an MRI evaluation of the breasts, in which there is a reported higher detection rate of 70% to 86%.¹⁶^–¹⁸

A testicular sonogram may help to identify a neoplasm in a male with midline adenopathy.

Although an optional imaging study, PET and PET/CT are being more frequently used to identify not only the tumor but also any unrecognized metastatic disease. These imaging modalities utilize 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)–PET and provide functional results, with PET/CT providing better anatomic information, a disadvantage for FDG-PET only. In a study reported by Kolesnikov-Gauthier and coworkers,¹⁹ CUP patients underwent FDG per imaging. The primary tumor site was identified in 6 of the 24 patients and all known metastatic sites were visualized.

An excellent paper by Seve and colleagues ²⁰ reviewed 10 published studies (1998-2006) involving a combined total of 221 CUP patients. This review included a heterogeneous patient population, study design, and diagnostic workup; however, 94% of these patients had a single metastatic site. Each study evaluated the role of FDG-PET in identifying the unknown primary cancer site. FDG-PET detected the primary tumor sites in 41% of these patients. Previously unrecognized metastases were detected in 37% of patients. Of the detected tumors, 59% were in the lungs. A false-positive rate of 58% was noted in those tumors of the lower digestive tract and likely due to the inherent bowel activity. The clinical management was changed in approximately 35% of these patients. Specific chemotherapy was given to those patients (53%) with lung and pancreatic cancers. Specific therapy (12%) was given for breast, ovarian, and prostate cancers, and 14% of these patients underwent potential curative surgery.

Based on FDG-PET, the clinical management of metastatic cervical lymph adenopathy was altered in 25% of patients as reported by Johansen and associates.²¹

FDG-PET/CT has the advantage of providing anatomic location as well as the location(s) of metabolic activity and may be the modality of choice in the future for evaluation of CUP patients based on the information that is garnered; it also may be less expensive than the thorough diagnostic imaging studies that are currently utilized. In addition, with new radiopharmaceuticals, better results could be obtained.

In a systematic review and meta-analysis of 11 published studies with a cohort of 433 patients with CUP, Kwee and Kwee ²² reported a primary tumor detection rate of 37% and a pooled sensitivity and specificity of 84% and 84%, respectively. Across the studies, the sensitivity was heterogeneous and the specificity was homogeneous. Another review article on the clinical utility of FDG-PET/CT is presented and compared with other imaging modalities.²³ It also addresses the potential role for radiation therapy planning and for monitoring response or lack of response to therapy.

Key Points Imaging and imaging evaluation

• Clinical problem is to identify the primary tumor, mainly using CT of the chest, abdomen, and pelvis. A mammogram, breast MRI, or bone scan is ordered as indicated. CT or brain MRI is used if the patient is symptomatic.

• PET/CT may become a more global evaluation of a CUP patient and forego all or some other forms of imaging.

• The vast majority of these patients will be managed by the medical oncologist with radiation therapy as needed. To define the burden and location of disease, a surgeon may be needed for a biopsy.

• There is no set staging or TNM system available because the primary tumor is occult.

Key Points The radiology report

• The locations of metastatic disease should be identified.

• More isolated lesions should be identified and used as index lesions.

• Describe all soft tissue, osseous sites of disease to include any lymphadenopathy.

• Suggest possible primary tumor etiology, if possible, based on radiographic pattern of metastatic disease.

• Suggest alternative imaging modalities that may help in evaluating the possible primary tumor or to manage potential complications such as spinal cord involvement.

Role of Molecular Profiling to Determine Tissue of Origin

Molecular profiling of CUP cancers offers a promising technique to determine the tissue of origin (ToO) with a possible impact on therapy. Several studies demonstrated the feasibility of using gene expression profiling with DNA microarray to classify uncertain tumors based on their ToO, identifying gene subsets whose expression typify each cancer class. These studies achieved accuracy in identifying the tissue of origin in 78% to 89% of tumors.²⁴^–²⁹

Two main strategies have been used to identify ToO: the DNA microarray platforms and the quantitative reverse transcription real-time polymerase chain reaction (qRT-PCR) assays and in both strategies, messenger RNA (mRNA) is extracted from fresh frozen or formalin-fixed paraffin-embedded (FFPE) tumor tissue. The multigene expression pattern of a CUP cancer is compared with known primary cancers and a tissue of origin assignment is given based on the molecular signature it most closely resembles. Currently, three assays are commercially available in the United States to evaluate tissue of origin in CUP patients. Small independent feasibility studies in CUP patients have suggested that this approach has some merit, although these trials are difficult to interpret because there is no primary cancer. Additional trials evaluating clinical effectiveness and pharmacoeconomics are warranted.

At this time, although a molecular profiling test will not obviate the need for thorough clinical investigation and routine pathologic evaluation, it may facilitate more focused testing, which may eventually result in reduced cost and improved outcome. This will be more important as specific targeted therapies emerge for known cancers, which can then be applied to CUP subsets.

General Considerations

The median survival duration of patients with disseminated CUP is approximately 6 to 10 months. Patients with favorable prognosis do better because they have a cancer biology that is either more indolent or more responsive to therapies. Prognostic factors include performance status, locations of and number of metastases, response to chemotherapy, and serum lactate dehydrogenase level (LDH). Culine and coworkers ³⁰ developed and retrospectively validated a prognostic model that uses performance status and serum LDH, allowing patients to be assigned to one of two subgroups with divergent outcomes. Further prospective trials using this prognostic model are warranted. Management of some of the favorable subsets and of disseminated CUP outside of favorable subset is discussed later.

Prognostically Favorable Subsets of Cancers of Unknown Primary: Treatment Considerations

These subgroups are important to note because therapies can significantly affect survival.

1. Isolated axillary adenopathy with adenocarcinoma or carcinoma in women. Women with isolated axillary adenopathy and adenocarcinoma or carcinoma are often treated for stage II or III breast cancer and are candidates for breast MRI if their mammography and sonography results are negative (as discussed previously). Beside breast markers on immunohistochemisty including mammoglobin and GCDFP-15, estrogen and progesterone receptors and HER2 neu are warranted to determine the appropriate treatment. If the clinical and imaging presentation suggests breast cancer, neoadjuvant or adjuvant chemotherapy and axillary lymph node dissection and radiation therapy (and hormonal therapy if appropriate) is the standard therapy.

2. Peritoneal carcinomatosis suggestive of primary peritoneal carcinoma in women. The term primary peritoneal papillary serous carcinoma (PPSC) refers to CUP with carcinomatosis and the pathologic and laboratory (elevated CA125 antigen) characteristics of a müllerian cancer without an obvious ovarian primary identified on transvaginal sonography or laparotomy. Patients with PPSC are candidates for cytoreductive surgery followed by adjuvant taxane- and platinum-based chemotherapy and suggest median progression-free and overall survival durations of 7 and 15 months or longer, respectively (median follow-up 60 mo).

3. Cervical adenopathy with squamous cell carcinoma. Patients with cervical adenopathy with squamous cell carcinoma should undergo triple endoscopy with biopsies of inconspicuous sites, bilateral tonsillectomy, and CT or PET/CT of the neck and chest to search for the primary and determine the stage of the tumor. Patients with early-stage disease are candidates for node dissection and radiation therapy, which can result in long-term survival. The utility of chemotherapy in these patients is unknown, although chemoradiation therapy or induction chemotherapy is often used and is beneficial in bulky N2 and N3 disease.

4. Low-grade neuroendocrine carcinoma. It is important to differentiate between low-grade and high-grade neuroendocrine CUP. High-grade neuroendocrine cancers have a high mitotic index (Ki-67), necrosis, and hemorrhage on pathologic evaluation. Patients with low-grade neuroendocrine carcinoma may present with an indolent disease course; thus, treatment decisions are based on symptoms and tumor bulk. Current therapies include treatment with somatostatin analogues alone for hormone-related symptoms and locoregional therapies including bland or chemoembolization or SIR Spheres microspheres. Systemic therapy including anti–vascular endothelial growth factor (VEGF) therapies and mammalian target of rapamycin (mTOR) inhibitors are showing promise in these tumors and are indicated in patients with symptomatic or progressive disease.

5. Solitary metastases. Patients with solitary metastatic disease most often present with nodal, liver, bone, or brain metastasis. Some of these are candidates for aggressive management, which can result in prolonged disease-free survival and even a cure. Immunohistochemical studies, pattern of spread, age, gender, and risk factors help determine the best therapy for these patients. In selected patients, neoadjuvant chemotherapy is used to treat micrometastatic disease and downstage the cancer to maximize the potential for a margin-negative resection as well as study its biology. We do not advocate that all patients with solitary metastatic CUP follow this approach, and this is not intended to define the standard of care in this setting.

Prognostically Unfavorable Subsets, Disseminated Cancer of Unknown Primary: Treatment Considerations

Often, these patients have bulky liver metastases, non-PPSC peritoneal carcinomatosis, and bone or adrenal metastases. Non-PPSC peritoneal carcinomatosis has a large differential diagnosis including gastric, appendiceal, colon, and pancreatic cancer and cholangiocarcinoma. Imaging, endoscopy, and pathologic evaluation including immunohistochemistry can help suggest best-therapy options. For example, in patients with carcinomatosis and an immunohistochemical profile favoring colon cancer (CK7-negative/CK 20-positive and CDX-2-positive) using a colon cancer regimen is a reasonable treatment approach, although data comparing response rates and survival using this approach to conventional “CUP” regimens are lacking.

Key Points Treatment

• Mainstay of therapy for the CUP patients is chemotherapy with multiple drugs that are available.

• Chemotherapy is best if targeted to the suspected type of tumor with use of immunohistochemistry and molecular profiles and especially the favorable subsets.

Detecting Recurrences and Complications

Traditionally, cisplatin-based combination chemotherapy regimens have been used to treat CUP patients. In a phase II study by Greco and colleagues,³¹ 55 CUP patients (51 of whom were chemotherapy-naïve) were treated with paclitaxel, carboplatin, and oral etoposide every 3 weeks. The overall response rate was 47%, and the median overall survival was 13.4 months. Briasoulis and associates³² reported similar results in 77 CUP patients treated with paclitaxel and carboplatin (without etoposide). Patients with nodal or pleural disease and peritoneal carcinomatosis had a higher response rate (than did patients with visceral disseminated disease) and overall survival durations of 13 and 15 months, respectively. More recent studies have incorporated newer agents, such as gemcitabine, irinotecan, and targeted agents. In a phase II randomized trial by Culine and coworkers,³³ 80 patients were randomly assigned to receive gemcitabine plus cisplatin or irinotecan plus cisplatin. Seventy-eight patients were assessable for effectiveness and toxicity. Objective responses were observed in 21 patients (55%) in the gemcitabine and cisplatin arm and 15 (38%) in the irinotecan and cisplatin arm. The median survival durations were 8 and 6 months in the gemcitabine and cisplatin and irinotecan and cisplatin arms, respectively (median follow-up 22 mo).

Key Points Detecting recurrences and complications

• The response to therapy is for control, prolonged disease-free survival, and occasional cure. Recurrence is guided by the clinical examination and appropriate imaging studies.

• Given the use of multiple chemotherapeutic agents, the complications are varied based on the agent(s) used and their specific toxicities to organs and systems in the body.

Preliminary data on combination targeted therapy are available. Hainsworth and colleagues ³⁴ determined the effectiveness of bevacizumab and erlotinib in 51 patients, 25% of who were chemotherapy naïve with advanced bone or liver metastases and 75% of who had been treated with one or two chemotherapy regimens. Responses were noted in 4 patients (8%), and 30 patients (59%) experienced stable disease or a minor response. The median overall survival duration was 8.9 months, with 42% of patients alive at 1 year.