Carcinomas of Unknown Primary Presenting as Isolated Brain Metastases
In up to 15% of patients presenting with brain metastases, the primary site remains unknown (68,69). The important factor in treating patients with brain lesions is to distinguish patients with metastatic disease from those with primary brain tumors. Once this distinction has been made, patients with single metastatic lesions should be considered for surgery, and those with multiple lesions should receive radiotherapy. In a recent small prospective study, patients with CUP who had single brain metastases treated with gross total resection and subsequent whole-brain radiotherapy (WBRT) had a median survival of 13 months. Patients with CUP who had multiple brain metastases and who underwent either WBRT alone or gross resection of symptomatic lesions followed by adjuvant WBRT had a median survival of only 6 to 8 months (69). Stereotactic brain radiation is often used in the CUP setting using the same principles as for brain metastases from known primary cancers.
Carcinomas of Unknown Primary Presenting as Metastatic Cervical Adenopathy
In this subgroup, patients present with high-to-midcervical or -supraclavicular adenopathy; on histopathology, these tumors are squamous cell or PDCs. For squamous cell carcinoma, the primary site is eventually identified during follow-up in approximately 20% of patients, with the tonsil being the most common site, followed by the pyriform sinus and base of the tongue.
Adenocarcinoma is much less common and is generally from either metastatic nonpapillary thyroid carcinoma or advanced malignant disease from a distant site (GI, lung, or breast carcinoma presenting as a metastatic supraclavicular node). Of all malignancies of the head and neck, only 5% to 10% are classified as unknown primary after imaging and panendoscopy. The prognosis for patients with cervical CUP overall is better than that for other CUP clinical subgroups, but even within this group, significant heterogeneity exists. Yalin et al (70), in a retrospective study of 107 patients with cervical CUP (62% PDC, 24% squamous carcinoma, and 14% adenocarcinoma), reported a 5-year OS rate of 35.5%. In another retrospective study by Issing et al (71), 5- and 10-year OS rates were 42.7% and 30.6%, respectively. The prognosis is significantly worse in the presence of any of the following: adenocarcinoma, level III/IV lymphadenopathy, multiple lymph nodes, and bulky disease.
Patients with supraclavicular adenopathy have a far worse prognosis than those with adenopathy in other lymph node–bearing areas. Carcinoma affecting supraclavicular lymph nodes on the right most commonly arises from occult primary tumors of the lungs and breast. When disease affects the lymph nodes on the left side, spread from intra-abdominal malignancies by way of the thoracic duct (Virchow node) is an additional possibility.
The management of patients with cervical CUP has become increasingly controversial, primarily because of the question of postoperative radiation therapy. The notion of adjuvant irradiation of all potential mucosal sites has been questioned because of the absence of any demonstrated survival benefit in randomized studies. To date, postoperative radiation therapy in cervical CUP significantly improves locoregional control, but this does not translate into improved OS. This being said, combined-modality therapy (surgery and radiation therapy) is better than either modality alone (72). Most patients with only cervical or supraclavicular involvement should have regional therapy consisting of surgery, postoperative radiation therapy, and close follow-up. Patients who undergo an excisional biopsy for diagnosis usually do not need additional surgery if no gross disease is left behind, only a single lymph node measuring less than 6 cm is involved, and no extracapsular extension is noted on pathologic review. If any of these features is present, a neck dissection is indicated. In addition, for patients with squamous cell carcinoma, unilateral tonsillectomy ipsilateral to the presenting neck mass is commonly advocated as part of the surgical treatment because occult tonsillar carcinomas are usually found in 18% to 39% of patients who undergo tonsillectomy (71,72). Identification of the primary site would thereby reduce morbidity by limiting the field of radiation and would improve surveillance.
In patients with N1 or N2a disease (squamous cell), it is unclear whether postoperative radiation improves local control because studies have been contradictory. In this case, close surveillance would also be an acceptable option after surgery. All other patients should receive postoperative radiation to the bilateral neck covering all potential occult primary sites (ie, nasopharynx, oropharynx, and hypopharynx). The 3-year survival rate after radical neck dissection or radical neck irradiation ranges from 35% to 60%. Within this group, patients with N1 disease have a better prognosis; patients with N3 disease, regardless of the local treatment modality used (surgery, radiotherapy, or both), fail to achieve complete remission in 65% of cases.
Although the role of chemotherapy in patients with cervical CUP remains poorly defined, extrapolation of phase II/III data in head and neck cancer indicates a role in patients with advanced nodal disease (N3). A recent large meta-analysis of more than 10,000 patients in 63 trials with head and neck squamous cell carcinoma demonstrated a small but significant absolute survival benefit of 4% at 5 years for chemotherapy (73). Intensive concurrent chemoradiotherapy in unresectable squamous cell head and neck cancers with cisplatin/5-fluorouracil–based and cetuximab-based regimens has resulted in improved complete response rates, locoregional control, and preservation of organ function, albeit at the cost of significant toxicities.
Women With Carcinomas of Unknown Primary and Isolated Axillary Adenopathy
Women who present with adenocarcinoma in the axillary lymph nodes compose another subset with a more favorable prognosis. These patients are often managed as women with stage II breast cancer. Isolated axillary adenopathy is an uncommon presentation of breast cancer, accounting for only 1 to 3 of every 1,000 diagnosed breast cancers. Mammography and ultrasound should be performed, and biopsies should be performed on any identified lesions. If mammography findings are normal, additional imaging of the breast with MRI is indicated because of its greater ability to detect small primary breast tumors (70%-95% sensitivity). Magnetic resonance imaging has a very low false-negative rate. Of approximately 40 women reported in the literature with isolated axillary adenocarcinoma and negative breast MRI findings, only 4 were found to have breast cancer at surgery or during follow-up (74).
The present recommended management of women with CUP of the axilla includes axillary dissection, axillary radiotherapy for those at high risk of local recurrence (eg, extracapsular invasion or more than four positive lymph nodes), and appropriate systemic therapy for breast cancer, depending on age and menopausal status. If breast MRI findings are negative, neither mastectomy nor breast irradiation is recommended (75,76,77). If the breast MRI is positive or suspicious, radiation to the breast is usually recommended. The prognosis is not as favorable in men who present with axillary adenopathy only (75).
This management paradigm is changing as molecular profiling complements pathology as a diagnostic tool in this subset of patients. All women with axillary adenopathy do not have occult breast cancer. Profiling for ToO can help with treatment decisions especially if the IHC does not correlate with breast cancer and ER, PR, and Her-2 status is negative.
Carcinomas of Unknown Primary Presenting as Isolated Inguinal Adenopathy
A few patients with CUP present with inguinal adenopathy. Undifferentiated (anaplastic) carcinoma is identified in at least half of these cases. Some of these anaplastic “carcinomas” appear to be melanomas with no obvious primary skin lesion. The remaining patients have squamous cell carcinomas arising from the skin, genitourinary tract, anus, or pelvis. A detailed investigation for primary lesions in these areas is important because curative therapy is available for carcinomas of the anus, vulva, vagina, and cervix even with spread to regional lymph nodes. In patients with carcinomas and PDCs confined to the groin nodes, where no primary site was identified, a superficial groin dissection should be performed with or without radiation therapy. Bimodality therapy with surgery and radiation may increase the risk of significant lymph edema and requires careful planning. Chemotherapy, before definitive therapy and in the context of a clinical trial, may be offered to patients with bulky locoregional adenopathy and is not an uncommon practice in the clinic.
Carcinomas of Unknown Primary and Isolated Pleural Effusions
Most patients with isolated pleural effusions have adenocarcinomas, which may sometimes be difficult to differentiate from mesotheliomas. Newer IHC markers (eg, calretinin, CK 5/6, and WT1 [Wilms Tumor-1]) that are more sensitive in differentiating epithelioid malignant mesothelioma from pulmonary adenocarcinoma can assist in the diagnosis (78). Additional IHC markers, including TTF-1, CK 7/20, and breast markers, should routinely be done as first- and second-tier diagnostics to aid in treatment. If the effusion reaccumulates quickly, pleurodesis may be attempted to slow the rate of fluid reaccumulation, or as done more often currently, a pleural catheter with daily aspirations is preferred (this can be removed after chemotherapy response is noted and the flow decreases). Chemotherapy is initiated in most patients based on their IHC profile and taxane plus carboplatin versus gemcitabine plus cisplatin are commonly used doublets.
Carcinomas of Unknown Primary Presenting as Malignant Ascites
Patients with malignant ascites usually belong to one of two subsets, each with a very different natural history of disease. The first group consists of patients with mucin-producing adenocarcinoma, who may present with ascitic fluid that contains signet-ring cells. These patients often have multiple peritoneal implants, with the primary site most likely being the GI tract (ie, stomach, small bowel, appendix, colon, or pancreaticobiliary). Given the current armamentarium of drugs available for treatment of metastatic colon cancer and the improved survival, it is important to consider those combinations for patients with IHC suggestive of colon profile (CK20+, CK 7−, and CDX-2+). The second subset is composed of women patients with primary serous papillary peritoneal carcinomatosis. This disease is often also associated with pelvic adenopathy or masses. These patients may have elevated CA 125 levels but do not have detectable ovarian cancer. Some investigators consider these patients to have true unknown primary ovarian tumors or primary serous carcinomas of the peritoneum (79,80). Disease management should be the same as for women with ovarian carcinoma. A prolonged median survival of 13 months, with 25% of patients having a progression-free survival lasting more than 2 years, was reported for paclitaxel/carboplatin-based chemotherapy in patients with peritoneal carcinomatosis. In this study, a high overall response rate (ORR) and number of complete responses were reported for this subgroup of patients with CUP (68.4% and 20%, respectively).
Carcinomas of Unknown Primary Presenting as Isolated Bony Metastases
When bone metastases are detected, men should be evaluated for prostate cancer and women for breast cancer given that they may be candidates for hormonal therapy, which is relatively easier compared to cytotoxic therapies. Other cancer profiles include lung, cholangiocarcinoma, renal, and rarely melanoma. Patients with a single bony metastasis may be candidates for surgery or radiation and then monitored. Patients with disease at multiple sites and good performance status and whose tumors progress after radiation therapy should be offered a trial of chemotherapy. Many experimental agents are currently available in ongoing clinical trials. Therapy with bone-seeking radioisotopes (eg, strontium 89) may be useful in the treatment of disseminated painful bone metastases in a few patients. Bisphosphonates are routinely used as in other malignancies, such as multiple myeloma, breast cancer, and prostate cancer. Often, PET-CT is the imaging modality of choice to follow response to therapy for disseminated osseous metastatic disease.
Carcinomas of Unknown Primary Presenting as Hepatic Metastases
Patients with hepatic metastases constitute 30% to 40% of people with CUPs; they compose a clinical subgroup with a relatively poor prognosis, with reported median OS between 49 days and 7 months. The most important diagnostic considerations in this class are to distinguish primary liver and biliary tumors (hepatocellular carcinoma and cholangiocarcinoma) from cancers that have metastasized to the liver and to identify patients with neoplasms of a more indolent nature (eg, neuroendocrine tumors). A careful pathologic review with IHC of liver biopsy specimens is therefore essential. The two most common histologies in primary CUP of the liver are adenocarcinoma (55%) and poorly differentiated/undifferentiated carcinoma (30%). The recommended initial therapy for unresectable disease is systemic chemotherapy, and surgery may be considered an option for those with resectable disease.
Neuroendocrine Tumors of Unknown Primary Site
Neuroendocrine tumors compose about 4% of all CUPs and commonly present with diffuse liver or bone metastases. Histologically, neuroendocrine tumors can be well differentiated or low grade, with features that are typical of carcinoid or islet cell tumors exhibiting a more indolent behavior. Management of these tumors should be similar to established guidelines for metastatic low-grade neuroendocrine tumors from a known primary site. In patients with limited disease, surgical resection or chemoembolization may be appropriate. If not amenable to local therapy, then targeted therapy is considered with (anti–vascular endothelial growth factor [anti-VEGF] agents, including sunitinib, or mammalian target of rapamycin [mTOR] inhibitors, including everolimus.
A second group involves high-grade neuroendocrine tumors that may present as PDC by light microscopy but have strong neuroendocrine features revealed by IHC (ie, neuron-specific enolase, chromogranin A, and synaptophysin positive). These high-grade neuroendocrine tumors are treated like small cell lung carcinoma with etoposide plus platinum or irinotecan plus platinum combinations, with high reported response rates.
Carcinomas of Unknown Primary and Extragonadal Germ Cell Syndrome
As a group, patients who have undifferentiated carcinoma or PDC are younger than 50 years and present with rapidly growing midline tumors involving the lymph nodes, mediastinum, or retroperitoneum; their tumors have been found to be very responsive to chemotherapy, particularly to platinum-containing regimens. It is believed that these patients have poorly differentiated extragonadal germ cell tumors. They have response rates to chemotherapy of 35% to 50%, and those who achieve a complete response often enjoy a durable remission. In a prospective study by Hainsworth and colleagues of 220 patients with PDC or poorly differentiated adenocarcinoma (PDAC) treated between 1978 and 1989 with cisplatin-based chemotherapy regimens, approximately half of the patients had a predominant tumor location in the mediastinum, retroperitoneum, or peripheral lymph nodes. The ORR was 63%, with 26% complete responses and an actuarial 10-year disease-free survival rate of 16%.
However, this was not found to be true by Lenzi and colleagues (4), who retrospectively reviewed the clinical outcomes of 337 patients with PDC/PDAC. No prolonged survival was observed in this cohort of patients, and no significant survival advantage resulted from cisplatin-based chemotherapy. Moreover, elevated serum levels of alpha-fetoprotein or beta-human chorionic gonadotropin, contrary to other reports in the literature, were not found to be predictive of an improved median OS. This discrepancy may have resulted from several confounding factors.
First, older studies of extragonadal germ cell syndrome included patients with PDCs who in actuality did not have CUP but had other highly treatable malignancies (4). In a study by Hainsworth et al (81), of the 36 long-term survivors, 20% were subsequently found to have either lymphoma (5), testicular cancer (1), or leiomyosarcoma (1). Conversely, in the study by Lenzi, patients in whom the primary site was identified were excluded from the analysis. Most of these patients were found to have highly treatable malignancies, such as lymphoma (6%), breast cancer (8%), ovarian cancer (3%), germ cell tumors (2%), and prostate cancer (1%). Exclusion of these patients would significantly reduce response and median survival rates.
Second, even among patients with PDC/PDAC of unknown primary, significant heterogeneity exists. In the study by Lenzi, CART analysis of 337 patients revealed different groups with widely discrepant survival times. The group with the longest median OS (40 months) included patients with PDC, lymph node involvement, and only one or two metastatic sites. By contrast, patients with non–lymph node metastases had a very poor prognosis, with a median OS of only 7 months (4).
Carcinomas of Unknown Primary and Single Sites Discovered Incidentally on Resection
Carcinomas of unknown primary are notorious for unusual, isolated presentations. Such lesions may appear on the skin, in single isolated lymph nodes removed during surgery for benign unrelated conditions, and at other, even more unusual sites. Patients should be examined for primary tumors and other sites of metastasis, as described previously. If no primary tumor and no additional sites of metastasis are found, complete removal of the lesion must be ensured; this often requires additional excision with wider margins (if skin or subcutaneous). The patient may then be monitored without therapy and in selected cases are candidates for radiation. Many such patients may enjoy prolonged survival. Patients with isolated skin lesions may have an undifferentiated primary integumentary tumor with a potential for cure after adequate local surgical treatment.