Dennis A. Casciato
The definition of metastases of unknown origin (MUOs). MUOs are metastatic solid tumors (hematopoietic malignancies and lymphomas are excluded) for which the site of origin is not suggested by thorough history, physical examination, chest radiograph, routine blood and urine studies, and thorough histologic evaluation.
The predicament of MUO. The detection of MUO usually represents the discovery of a far-advanced malignancy that is rarely curable and that is usually refractory even to palliative chemotherapy. Tumors that are potentially responsive to systemic treatment are found in only about 20% of all patients with MUO. The diagnostic evaluations inflicted on these patients in pursuit of the primary site are typically excessive and futile. The primary site is found in <15% of cases, and that discovery rarely affects the prognosis or treatment. All efforts to manage patients who meet the criteria defined above should be guided by the understanding that there are two basic categories of MUOs: (1) those that are treatable and (2) those that are not.
I. EPIDEMIOLOGY AND BIOLOGY
A. Incidence. About 6% of patients with cancer present with MUO. MUO is the seventh most frequent malignancy, ranking below only cancers of the lung, prostate, breast, cervix, colon, and stomach. About 75% of tumors in the MUO syndrome originate below the diaphragm.
B. Age. The average age at onset is 58 years. Patients who present with a midline distribution of poorly differentiated carcinoma (10% of all MUO patients) have a median age of 39 years.
C. Manifestations. Symptoms of metastasis, which are present in nearly all patients with MUO syndrome, are multiple in 30% of patients. The most frequent presenting features are the following:
1. Pain (60%)
2. Liver mass or other abdominal manifestations (40%)
3. Lymphadenopathy (20%)
4. Bone pain or pathologic fracture (15%)
5. Respiratory symptoms (15%)
6. Central nervous system abnormalities (5%)
7. Weight loss (5%)
8. Skin nodules (2%)
D. Aberrant natural history of tumors in the MUO syndrome compromises the ability to predict the primary site of disease. Patterns of dissemination by tumors often do not follow typical pathways in the MUO syndrome. Examples are shown in Table 20.1. This observation represents the distinct biology of these malignancies wherein the metastatic behavior predominates unpredictably, while the primary tumor remains occult.
Table 20.1 Patterns of Dissemination by Tumors
MUO, metastases of unknown origin.
E. Mechanisms that could explain the presence of occult primary neoplasms include the following:
1. Excision or electrocautery may have removed unrecognized primary lesions years before the appearance of metastatic lesions.
2. The primary cancer may have shed metastases and then undergone spontaneous regression.
3. The primary tumor may be too small to be detected, even at autopsy.
4. The site of origin may be obscured by the extensiveness of metastases or by the atypical pattern of dissemination.
II. DIAGNOSIS AND HISTOPATHOLOGY
A. Performing a biopsy should be the first order of business. The pathologist should be informed before the biopsy that the primary site is not evident so that special studies can be planned.
1. Patients with metastases to neck lymph nodes only. Suspicious cervical nodes should not undergo excisional biopsy until a complete diagnostic evaluation of the head and neck has been performed (see Chapter 7, Section X). About 35% of these patients have potentially curable cancers of the upper aerodigestive tract. This is not the case for patients with supraclavicular lymph nodes, which may be directly excised for histologic examination.
2. Other patients who have suspected metastatic cancer. Biopsy of the most accessible site should be performed before specialized blood or radiologic studies are done; the histologic findings provide an invaluable guide for a rational diagnostic workup. Biopsy proof of metastatic cancer is necessary at only one site. If several areas of tumor involvement are suggested by the findings from the screening evaluation, the preferred biopsy site is that associated with the least morbidity (e.g., peripheral lymph nodes when palpable, bone marrow when a leukoerythroblastic blood picture is present, cytology of sampled effusions, or suspect skin lesions). The biopsy specimen should be placed in a fixative that allows immunoperoxidase analysis.
B. Role of the pathologist Close communication between the clinician and the pathologist is especially important in cases of MUO. Morphologic clues may make certain anatomic sites more likely and direct the sequence of investigation.
1. Histologic problems
a. Poorly differentiated tumors, including adenocarcinomas, carcinomas, and small cell neoplasms, may be indistinguishable by light microscopy.
b. Squamous metaplasia overlying adenocarcinoma may be misread as squamous cell cancer.
c. Extensive fibrosis, a common sequela of squamous cell carcinoma and breast adenocarcinoma, may mask the underlying tumor.
d. Limitations of pathology. Pathologists are able to identify the primary site based on review of the biopsy alone in about 20% of cases of MUO. If they are given clinical information (especially the site of metastasis), the accuracy improves, but these tumors usually defy categorization for the origin of the tumor.
2. Histologic and histochemical clues for origin are shown in Appendix C1.
3. Poorly differentiated, undifferentiated, or anaplastic carcinomas should be further evaluated with immunoperoxidase stains and, in special circumstances, electron microscopy or molecular genetic analysis (if possible).
4. Immunoperoxidase stains are useful for poorly differentiated neoplasms to confirm the diagnosis of carcinoma, to identify patients with other neoplasms (e.g., lymphoma or melanoma). The predominant tumors identified by specific antigens delineated by immunohistochemistry are shown in Appendix C2. A word of caution: These markers are stains attached to antibodies that must be interpreted for positivity, negativity, and relevance; none of these results is perfect.
a. Immunohistochemistry diagnostic algorithms
(1) An immunohistochemistry diagnostic algorithm based on microscopic findings (spindle cell, epithelioid, small cell, or undifferentiated morphologies) is diagrammed in Appendix C3.I.
(2) An immunohistochemistry diagnostic algorithm for carcinoma of unknown origin is diagrammed in Appendix C3.II.
(3) Expected immunophenotypes for specific tumors are shown in Appendix C4.
b. The most useful immunoperoxidase stains in the evaluation of patients with MUO syndrome are cytokeratins (CK) and those for lymphoma (CD45, leukocyte common antigen) and for melanoma (S100 protein, HMB45, Melan-A/Mart-1).
The CK phenotypes (relative patterns of positivity and negativity for CK 7 and CK 20) have been employed in attempts to identify primary tumor sites with variable success (see Appendix C3.I.). A “colon cancer profile” (CK20-positive, CK7-negative, CDX2-positive) is a useful paradigm. More discriminatory immunostains can then be selected based on these phenotypes; examples of such are shown in Appendix C4.IX.
c. Immunoperoxidase stains for neuron-specific enolase, synaptophysin, chromogranin, CD56, and CD57 are helpful in patients who could have primitive neuroendocrine tumors (PNETs).
d. Immunoperoxidase stains for β-human chorionic gonadotropin (β-hCG) and α-fetoprotein (α-FP) are frequently performed for the possibility of a germ cell neoplasm but have not been helpful in these patients unless the clinical presentation suggests this entity.
e. A few immunohistochemical markers have enough tissue-type specificity that allows for their use in trying to establish a primary tumor. These include
(1) PSA (prostatic adenocarcinoma and benign prostatic epithelium)
(2) Thyroglobulin (thyroid follicular epithelium and nonmedullary thyroid carcinomas)
(3) Thyroid transcription factor-1 (TTF-1; thyroid and lung cancers and carcinoid tumors)
(4) Gross cystic disease fluid protein-15 (breast carcinoma and tumors of apocrine sweat glands or salivary glands)
(5) RCC (renal cell carcinoma) and HepPar-1 (hepatocellular carcinoma)
5. Molecular diagnostics continue to rapidly expand. Interphase cytogenetic analysis with fluorescent in situ hybridization (FISH) and gene expression profiling can be performed on paraffin tissue. These techniques may provide anatomic pathologists with the tools to improve their ability to correctly predict the primary site for MUO in the future.
C. Histologic types of metastases
1. Adenocarcinomas and undifferentiated carcinomas account for >75% of cases of MUO. The natural history, prognosis, and poor responsiveness to therapy are similar for both of these histopathologies. The primary site is determined antemortem in only 15% of cases, even with exhaustive diagnostic efforts. When a primary site is determined, the sites of origin and relative frequencies are as follows:
a. Pancreas (25%)
b. Lung (20%)
c. Stomach, colorectum, hepatobiliary tract (8% to 12% each)
d. Kidney (5%)
e. Breast, ovary, prostate (2% to 3% each)
2. “Undifferentiated and poorly differentiated” large cell neoplasms may represent carcinoma, extragonadal germ cell tumors, malignant melanoma, or large cell lymphoma. Lymphomas rarely are mistaken for adenocarcinomas, but the chance of confusion is increased if the tissue obtained is small or of poor quality. For example, gastric lymphoma and anaplastic large cell lymphoma are frequently misdiagnosed as carcinoma. These patients, in particular, require special study with immunoperoxidase techniques. Many patients with MUO who have been reported to achieve good results with chemotherapy ultimately were proved to have lymphomas.
3. Squamous cell carcinomas account for 10% to 15% of all MUO cases, and <5% if patients with metastases to cervical lymph nodes alone are excluded. Most squamous cancers that appear as MUO originate in the head and neck or lung. Other squamous cell cancer primary sites include the uterine cervix, penis, anus, rectum, esophagus, and, occasionally, urinary bladder. Acanthocarcinomas (squamoid tumors) may develop in the gastrointestinal (GI) tract, notably in the pancreas and stomach. Squamous skin cancer that arises in a chronic osteomyelitis fistula may not be apparent until regional draining lymph nodes become involved.
4. Melanoma constitutes 4% of all cases of MUO, and about 4% of malignant melanoma cases present as MUO. It is important to distinguish melanoma from other histologies because metastases frequently involve lymph nodes alone, and these patients may be cured with appropriate therapy.
Amelanotic melanoma may be mistaken as undifferentiated carcinoma. Malignant melanoma may be distinguished from tumors having obscure histology by use of immunohistochemical reagents that are specific for melanocytic lineage (HMB45, Melan-A/Mart1, PNL2) or for S100 protein (a cytoplasmic protein that is specific for nervous system tissue and is also present on human melanoma cell lines).
5. Clear cell tumors. Polygonal cells with clear cytoplasm can represent artifactual changes, benign neoplasms, or malignancies. Seminomas, nonseminomatous germ cell carcinomas, lymphomas, and benign tumors can be clear cell tumors with a virtually identical clear cell appearance. Differentiation requires detailed analysis of clinical, histologic, immunohistochemical, and, occasionally, electron microscopic features.
6. Neuroendocrine tumors. Small cell neoplasms, including PNETs or “oat cell” carcinomas, can develop in the entire alimentary canal, upper aerodigestive tract, thymus, breast, prostate, urinary bladder, uterine cervix, endometrium, and skin, as well as in the lung. About 2% of small cell carcinomas originate in extrapulmonary sites. Although this subtype comprises only a small percentage of the patients who present with MUO, it represents one of the treatable varieties.
a. PNETs. Low-grade PNETs are usually recognizable by light microscopy, have features of islet cell or carcinoid tumors, and often have an indolent behavior. Pheochromocytoma, paragangliomas, and medullary thyroid carcinoma are other examples of indolent PNETs.
Anaplastic small cell carcinomas and poorly differentiated PNETs behave aggressively and require immunohistochemical analysis of biopsies for synaptophysin and chromogranin. Merkel cell tumors and neuroblastomas are other types of aggressive PNETs.
b. Undifferentiated small cell neoplasms may also represent a number of cancers that can be simply recalled with the mnemonic MR. MOLSEN (myeloma, rhabdomyoblastoma, melanoma [amelanotic], oat cell carcinoma, lymphoma, seminoma [anaplastic], Ewing sarcoma, neuroblastoma).
III. SITES OF METASTASES AND PROGNOSIS
The prognosis in patients with MUO syndrome is unaffected by whether the primary lesion is ever found.
A. Survival according to sites of metastases
1. Patients with metastases to lymph nodes alone have 5-year survival rates according to sites of involvement, which are as follows:
a. Upper or middle cervical nodes alone (30% to 50%)
b. Axillary nodes alone in women (>65%)
c. Axillary nodes alone in men (25%)
d. Groin nodes alone (50%, perhaps)
e. Midline lymph node distribution with poorly differentiated adenocarcinoma, particularly in young men (30%)
f. Melanoma to single peripheral lymph node region (30% to 45%)
2. Patients with metastases to sites other than peripheral lymph nodes alone. Except for peritoneal carcinomatosis in females, the median survival time for all patients ranges between <1 month and 5 months. More than 75% of patients die within 1 year of diagnosis. Subcutaneous metastases have a more favorable prognosis if the primary site is not the lung; bone marrow and epidural metastases have the worst prognosis (median survival time of <1 month).
3. Particularly unfavorable prognostic features in patients with MUO include the following:
a. Multiple metastatic sites, particularly the liver
b. Supraclavicular lymph node involvement
c. Well-differentiated or moderately differentiated adenocarcinoma histology
d. Elevated serum alkaline phosphatase or lactic dehydrogenase levels; lower serum albumin levels or lymphocyte counts
e. Older age
f. Lower performance status
B. Neck lymph node metastasis. Neck masses in adults, other than thyroid nodules, are malignant in 80% of cases. After 50 years of age, 90% of neck masses are malignant. About 35% of patients with MUO to upper and middle cervical lymph nodes can potentially be cured. However, MUO to lower cervical or supraclavicular lymph nodes is associated with an ominous prognosis. MUO to neck nodes is discussed in detail in Chapter 7, Section X.
C. Axillary lymph node metastasis. Axillary lymphadenopathy that is excised for diagnosis is found to have benign disease in 75% of cases, lymphoma in 15%, and solid tumors (particularly adenocarcinoma) in 10%.
1. The most likely sites of origin of a solid tumor metastasizing to the axilla are the breast, lung, arm, and regional trunk. In patients with isolated malignant axillary lymphadenopathy, the primary site is detected in only half of the cases.
2. Breast cancer. About 0.5% of all breast cancer patients present with masses palpable in the axilla and not in the breast. Breast cancer accounts for 70% of cases of MUO involving axillary lymph nodes in women when the primary site is eventually diagnosed. Ultimately, 30% to 50% of female patients develop evidence of a primary breast cancer; the primary tumor becomes evident in <20% of these patients if the breast is treated with radiation therapy (RT), most likely emanating from the upper outer quadrant of the ipsilateral breast.
D. Groin lymph node metastasis. The primary tumor is detectable in 99% of patients having malignant groin lymphadenopathy. Metastases are most likely to arise from the skin (especially the lower extremities and lower half of the trunk), vulva, vagina, cervix, penis, scrotum, rectum, anus, or urinary bladder.
E. Midline lymphadenopathy (anterior mediastinal or retroperitoneal with or without peripheral lymphadenopathy) represents a highly treatable presentation of MUO when it is associated with poorly differentiated carcinomas (including undifferentiated carcinomas and poorly differentiated adenocarcinomas). The cell lineage with this form of MUO is uncertain, but some are extragonadal germ cell tumors. Most patients are men, with a median age of 39 years and rapidly growing tumor masses. Many patients have achieved excellent responses to cisplatin-based combination chemotherapy.
F. Other sites of metastases
1. Bone and bone marrow metastases
a. Bone cortex. When a primary site is found, carcinoma of the lung accounts for most patients with MUO who have bone metastases. When presenting as an MUO, pancreatic carcinoma frequently involves the skeleton (in contrast to its usual behavior). The median survival time of patients presenting with MUO and predominantly bone metastases is 3 months.
b. Bone marrow is shown to be involved by aspiration or biopsy techniques in 10% to 15% of MUO cases during life, particularly in patients who prove to have lung, breast, or prostate cancer. Leukoerythroblastic peripheral blood smears are the most accurate barometers of bone marrow involvement in patients with solid tumors. The median survival time of patients presenting with MUO as marrow metastases is <1 month.
2. Intrathoracic metastases
a. Pulmonary metastases may be solitary, and primary lung cancer lesions may be multiple. MUO presenting as a solitary pulmonary nodule is rare; when it does occur, it is most frequently associated with colorectal carcinoma or sarcoma.
b. Effusions. Pleural effusions, when caused by malignant disease, are associated with an unknown primary tumor in 20% of cases. Pericardial effusions rarely occur as the predominant manifestation of MUO.
3. Intra-abdominal metastases most frequently involve the liver and originate in the GI tract, but the primary site is determined during life in only about 30% of cases.
a. Liver metastases. Differentiating between primary hepatocellular carcinoma and metastatic carcinoma of unknown origin in the liver may be difficult. Carcinomas of the prostate or ovary metastasize to the liver more frequently when they present as MUO than when they occur as known primaries. The median survival time of patients presenting with MUO and, predominantly, liver metastases is <4 months.
b. Ascites, when caused by malignant disease, is associated with MUO in 10% of cases. The median survival time of patients presenting with MUO and predominantly malignant ascites is <1 month, except for women with peritoneal carcinomatosis, which is considered to be a variant of ovarian carcinoma with similar associated survival (see Section V.F). Approximately 55% of women who present with malignant ascites have a primary site identified in the ovary. Histologic features that suggest ovarian carcinoma include papillary configuration, psammoma bodies, and poorly differentiated carcinoma.
4. Central nervous system metastases
a. Brain metastases are most frequently associated with bronchogenic carcinoma and second most frequently with MUO syndrome. The primary site eventually becomes evident during life in 40% of cases, and 90% of these are lung carcinomas. Excision of single metastatic brain lesions does not improve survival beyond that experienced by other patients with MUO syndrome, but occasional patients experience prolonged survival without evidence of further recurrence. The median survival time of patients presenting with MUO and single brain metastasis that is resected is 3 to 6 months.
b. Spinal cord compression is occasionally a manifestation of MUO syndrome. In these cases, laminectomy has been traditionally recommended as the first step to establish the histopathologic diagnosis. However, the median survival time of patients presenting with MUO and epidural metastasis is <2 months, and such an aggressive approach is often not justified.
5. Cutaneous metastases are associated with carcinomas of the breast and lung in most cases. When skin metastases represent the initial manifestation of cancer, renal adenocarcinoma or bronchogenic carcinoma is the most likely possibility. The region of the skin near the primary tumor is most often involved. Umbilical nodules (Sister Joseph nodules) represent intra- abdom inal carcinomatosis. The median survival time of patients presenting with MUO and predominantly skin metastases is 7 months if the primary site does not prove to be the lung.
IV. SEARCHING FOR THE PRIMARY TUMOR SITE
When the primary site of cancer is evident, the biopsy is performed 1 week earlier, and the number of diagnostic tests ordered is significantly fewer than when patients present with MUO. Unfortunately, the usual behavior of physicians is to pursue the occult primary site through a prolonged investigative pathway with a broad scope of expensive, time-consuming, and potentially dangerous tests.
Even if all patients undergo exhaustive evaluation with barium enema, upper GI series, skeletal survey, mammography (women), whole body CT scans, endoscopy, and a variety of radionuclide scans, <15% of patientswith MUO syndrome (excluding those who have disease only in cervical nodes) have the primary site established before death. Part of the 15% includes patients in whom the primary tumor becomes clinically evident on follow-up.
Searching for the primary tumor site should be guided by the following questions:
A. What is the effect on outcome of finding the primary site? None! To reiterate: The prognosis in patients with MUO syndrome is unaffected by whether the primary lesion is ever found. This observation applies not only to metastases involving visceral or skeletal sites but also to metastases involving lymph nodes alone at any site (including the neck) with any histology (carcinoma or melanoma).
B. What are the clinical clues?
1. Histology. The finding of squamous carcinoma obviates the need to investigate organs in which adenocarcinomas develop. If the pathologist is not certain of the diagnosis because of the morphology or quality of the specimen, special studies or another biopsy may be in order.
2. Presentation. The history, physical examination, and screening studies should be reviewed with awareness of the natural histories of the potentially causal malignancies. The atypical behavior patterns of certain malignancies when presenting as MUO should also be remembered (see Section I.D).
C. Which advanced malignancies are treatable? They are
1. Metastases to unilateral lymph nodes alone
a. Melanoma to peripheral lymph nodes in a single region
b. Squamous cell or undifferentiated carcinoma in the upper two-thirds of the cervical chain
c. Adenocarcinoma in the axillary chain in women
d. Carcinoma in unilateral groin nodes
2. Metastases that are sensitive to systemic therapy
a. Small cell carcinomas or PNETs
b. Peritoneal carcinomatosis in women
c. Poorly differentiated carcinoma metastatic to retroperitoneum and/or mediastinum, with or without involvement of peripheral lymph nodes, particularly in younger men
d. Adenocarcinomas that are treatable in advanced stages (breast, ovary, prostate, colon, and thyroid). Together, these constitute <15% of cases of MUO, but they should be considered in patients with appropriate constellations of findings.
e. Lymphomas should be considered in any patient with a poorly differentiated or undifferentiated neoplasm or with tumors that respond exquisitely to chemotherapy.
D. What are the limitations of diagnostic studies? Despite subjection to an alarming battery of tests, >85% of patients with MUO do not have the primary site determined while they are alive. Furthermore, many of the diagnostic tests are just as frequently misleading as they are helpful.
1. Pathology. Review of the initial biopsy does not contribute to the origin of the malignant neoplasm in 80% of cases of MUO. Histopathologic classification of tumors can vary by >50% among different reviewers of the same specimen.
2. Chest radiographs. No chest radiographic pattern, including the number of lesions, can distinguish a metastasis from a primary lung cancer.
3. Upper GI series and barium enema. Fewer than 5% of patients with MUO who undergo these studies have abnormal results in the absence of abdominal symptoms or occult blood in the stools. Abnormal results usually consist of findings that provide no useful information (e.g., organ displacement by tumor). These studies each suggests a primary malignant lesion in 5% to 10% of cases of MUO; the numbers of true-positive and false-positive results and the minimum number of false-negative results are about equal, however.
4. Mammography is usually performed in women with MUO but has not been helpful in identifying the primary site, even in women with axillary lymph node metastases alone. MRI of the breasts may increase the yield of detecting primary lesions in the latter group of patients.
5. CT scans. Some reported series have detected the primary site in about 30% of patients with MUO. However, most series reported that CT scans have not improved the frequency of detecting occult primary sites except in patients with squamous cell MUO to cervical lymph nodes. These scans often detect other sites of metastases. However, it is unusual for the information resulting from CT scans to result in improved outcome.
6. Radionuclide scans. Staging disease in asymptomatic sites is a dubious practice for patients with disease that is already considered lethal.
a. Thyroid scans are associated with equal frequencies of true-positive, falsepositive, and false-negative results. Thus, these scans are nearly useless in MUO.
b. Positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (FDG) still needs to be adequately investigated to determine its true usefulness for patients with MUO. FDG PET has not been helpful in evaluating MUO patients with the exceptions of patients with squamous cell carcinoma metastasis to cervical lymph nodes alone and possibly of women with metastatic adenocarcinoma in axillary lymph nodes alone.
c. Bone scans may be abnormal in the absence of symptoms related to the skeleton and may be useful for determining the extent of disease if that information is believed to be helpful.
7. Ultrasonograms have a high rate of false positivity in the evaluation of MUO, giving particularly erroneous results in retroperitoneal areas.
8. Arteriography and screening endoscopy, including bronchoscopy, upper GI endoscopy, sigmoidoscopy, and colonoscopy, are overly invasive and of no value in patients with the MUO syndrome and no other clinical indication to invoke these procedures.
9. Serum tumor markers, including CEA, CA 125, CA 15-3, CA 19-9, and b-hCG, are generally of little use in determining the primary site because of their lack of specificity. All five of these markers are commonly elevated in patients with MUO. Even PSA determinations are associated with false-positive and falsenegative results.
10. Estrogen receptor determination has not been helpful in identifying the primary site or in prescribing therapy for patients with MUO.
11. Postmortem examination, the ultimate diagnostic test, fails to detect the primary site in 25% to 40% of MUO cases.
V. MANAGEMENT
My recommendations for the management of patients with MUO syndrome are diagrammed in Figure 20.1.
Figure 20.1. An approach to the treatment of patients with metastases of unknown ori gin. AC, adenocarcinoma; PDC, poorly differentiated carcinoma; SC, squamous cell carcinoma; UC, undifferentiated carcinoma; MM, malignant melanoma; CNS, central nervous system.
A. Malignant melanoma involving peripheral lymph nodes only. Inquire about skin lesions that may have been removed previously. Search the skin carefully for a possible primary lesion; biopsy any suspect lesion. Exclude visceral metastases.
1. Recommended treatment for malignant melanoma involving lymph nodes alone is radical lymphadenectomy of the affected nodal region. The procedure is repeated if the tumor recurs and the patient has no other evidence of disease. Systemic treatment for melanoma is discussed in Chapter 16, in the Section “Malignant Melanoma.”
2. Results of treatment. Both the 5- and 10-year survival rates using radical lymphadenectomy are 30% to 45%. The prognosis with lymphatic metastasis is affected neither by knowing the primary site nor by having a history of a preexisting lesion. The prognosis is best if the metastasis involves only one node, and not the cervical chain, and if surgical intervention is prompt and aggressive.
B. Metastatic disease in neck lymph nodes only, particularly in the upper and middle cervical nodes, is potentially curable with RT or node dissection under appropriate circumstances. The evaluation and management of MUO to neck lymph nodes are discussed in detail in Chapter 7, Section X.
C. Metastatic disease in unilateral axillary lymph nodes only. The major treatable malignancies presenting as MUO in axillary lymph nodes are occult breast carcinoma, amelanotic melanoma mistaken as undifferentiated carcinoma, and malignant lymphoma mistaken as carcinomas.
1. Recommended treatment
a. Lymphoma. See Chapter 21.
b. Malignant melanoma. See Section V.A.
c. Women with adenocarcinoma or poorly differentiated carcinoma. Treat for stage II breast cancer. Mastectomy had been traditionally performed but is not justifiable in these patients.
d. Other patients. Axillary node dissection is performed, attempting to achieve local control and long-term survival.
e. RT to the axilla is frequently given, but there is no evidence to indicate that survival is improved over that achieved with resection of the involved nodes alone.
2. Results of treatment. Patients who have MUO and prove to have breast cancer can be expected to have the same survival as patients with stage II disease. The 5-and 10-year survival rates are identical with and without mastectomy and with and without the primary tumor ever becoming manifest. All other patients who are treated with excision of clinically involved nodes or axillary dissection have a 20% to 25% long-term survival rate (2 to 10 years).
D. Metastatic disease in unilateral groin lymph nodes only
1. Recommended treatment
a. Lymphoma. See Chapter 21.
b. Melanoma. See Section V.A.
c. Carcinoma. Perform a superficial groin node dissection (affords local control with less morbidity than radical dissection). Simple excision of the involved node may be sufficient treatment, however.
d. RT does not appear to be necessary.
e. Chemotherapy has been useful for carcinomas of the anus and cervix. Although combined chemoradiotherapy has not been extensively used in this relatively small patient population, the empiric addition of platinumbased chemotherapy may be useful.
2. Results of treatment. Half of patients treated with excisional biopsy or superficial groin dissection alone appear to survive >2 years. A significant proportion of these patients had unclassifiable carcinomas that may have been amelanotic melanoma.
E. Poorly differentiated carcinomas with midline lymphadenopathy. (especially in young men with elevated serum levels of β-hCG and α-FP) are managed as extragonadal germ-cell tumors.
1. Recommended treatment. Administer four cycles of cisplatin-based combination chemotherapy using regimens recommended for testicular cancer.
2. Results of treatment. The response rate with disease confined to the mediastinum, retroperitoneum, or peripheral lymph nodes is 60% to 75%, with complete remissions observed in 50% of patients. In some series, the median survival time for patients achieving a complete remission is >4 years; the 5-year survival rate is 35% for patients with disease confined to the retroperitoneum and peripheral lymph nodes and 15% for those with disease affecting predominantly the mediastinum. For patients with this histology and metastases to other sites, the response rate to cisplatin-based chemotherapy is 20%, and the 5-year survival rate is about 5%.
F. Peritoneal carcinomatosis in women
1. Recommended treatment. If no extraovarian primary site is evident, perform exploratory laparotomy. If peritoneal carcinomatosis is confirmed without an extraovarian primary site, treat the patient as if she had ovarian carcinoma by performing total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and cytoreductive debulking of metastases. Thereafter, treat with a platinum-based combination chemotherapy regimen for six to eight cycles. Second-look laparotomy is not a consideration in these patients.
2. Results of treatment. The median survival rates are 1.5 to 2 years for all patients, 2.5 years for patients with limited residual disease after surgery, and 1 year for patients with extensive residual disease after surgery. About 10% to 25% of patients survive 3 years. Most long-term remissions have been observed in patients who had successful cytoreduction before receiving chemotherapy.
G. Small cell carcinoma (PNET) MUO
1. Recommended treatment
a. Low-grade PNETs are relatively resistant to chemotherapy. Aggressive regimens should be avoided. For patients with small cell carcinoma MUO to cervical lymph nodes alone, some authorities recommend treatment with RT or neck dissection alone.
b. Poorly differentiated PNETs are often highly sensitive to chemotherapy. Use cisplatin and etoposide combination chemotherapy. If a complete remission is obtained, consider administering RT to the known previous sites of disease.
2. Results of treatment. The response rate of poorly differentiated PNETs to chemotherapy is 35% to 70%, and the 2-year survival rate is about 40%. Long-term survival can be seen in patients who achieve a complete response after treatment for limited disease. Prolonged survival also occurs in patients presenting with cervical node metastases from occult primary small cell tumors of the minor salivary glands or paranasal sinuses after treatment with RT or neck dissection alone.
H. All other patients with MUO syndrome. All patients should receive a complete history and physical examination (including the breasts, rectum, and pelvis), chest radiograph, and routine laboratory tests. Because of the low frequency of detecting the primary site in patients with MUO and the frequently misleading results of radiologic studies, radiologic or radionuclide studies are justified only in the presence of either specific abnormalities in the screening evaluation or possibilities suggested by review of histopathology.
When the initial database does not suggest a primary organ site, further evaluation is usually fruitless and is not indicated. It is important to recognize that these patients have incurable cancer that is usually refractory to treatment. With the exception of treatable malignancies, documenting a site is more important to the patient (or physician) psychologically than therapeutically.
1. For possible breast or prostate cancer. Treat according to the principles established for those malignancies, especially considering hormonal manipulations.
2. For patients with a “colon cancer profile” (predominant metastatic sites in the liver and/or peritoneum; adenocarcinoma with histology typical of gastrointestinal origin; immunohistochemistry pattern CK20-positive/CK7-negative and CDX2-positive) may respond to chemotherapy with modern regimens developed for metastatic colorectal carcinoma. A regimen such as FolFOX-4 may be tried. These regimens have resulted in substantial improvement in survival for patients with metastatic colorectal cancer compared with earlier regimens.
3. For all other patients with adenocarcinoma MUO to viscera. Nearly 80% of these patients have MUO metastases from cancers of the pancreas, GI tract, lung, and other or never-to-be-known sites that are usually refractory to chemotherapy. When patients with malignancies that are poorly differentiated or metastases that are restricted to lymph nodes are excluded, <20% of patients experience partial tumor regression after treatment with cytotoxic agents (used singly or in combination). Responses are associated with only a minimal (if any) improvement in survival. Median survival is reported to be improved by 4 to 6 months in patients who respond to therapy compared with those who do not, but this form of reporting data is largely discredited. One must be very cautious when reading about chemotherapy results in this heterogeneous group of patients because differences may be due to patient selection factors.
The most optimistic reports of response to therapy were with the combinations of carboplatin plus paclitaxel, carboplatin plus gemcitabine, or irinotecan plus gemcitabine. Response rates to these combinations are reported to be 25% to 35%, with median survivals being 6 to 9 months; combinations using three drugs result in more toxicity without improvements in response. These combinations appear to yield superior survival (20% at 2 years) in phase II clinical trials when compared with previous regimens that used doxorubicin-based or cisplatin-based combinations. Anti-angiogenic drugs have been tried but not yet established to have a role in MUO. The “best” regimen has not been defined.
4. Recommended treatment. For most patients with disseminated MUO, particularly those with low performance status, we do not recommend chemotherapy. My recommendations are based on performance status and are as follows for patients who request therapy:
a. Patients with good performance status
(1) Adenocarcinoma presenting as a single metastatic lesion. Most patients who present with a single metastatic lesion manifest other metastatic sites within a relatively short period of time. However, definitive local treatment (surgical excision or RT) sometimes produces long disease-free intervals.
(2) Multiple metastatic sites. An empiric trial of combination chemotherapy as discussed above may be offered.
b. Patients with poor performance status. Best supportive care without chemotherapy. If the patient demands treatment, nontoxic drugs or dosages can be offered.
Suggested Reading
Fizazi K, ed. Carcinoma of an Unknown Primary Site. New York: Taylor & Francis; 2006.
Greco FA, Navlidis N. Treatment of patients with unknown primary carcinoma and unfavorable prognostic factors. Semin Oncol 2009;36:65.
Hainsworth JD, Fizazi K. Treatment for patients with unknown primary and favorable prognostic factors. Semin Oncol 2009;36:44.
Kemeny MM. Mastectomy: is it necessary for occult breast cancer? N Y State J Med 1992;92:516.
Le Chevalier T, et al. Early metastatic cancer of unknown primary presentation: a clinical study of 302 consecutive autopsied patients. Arch Intern Med 1988;148:2035.
Nystrom JS, et al. Identifying the primary site in metastatic cancer of unknown origin. JAMA 1979;241:381.
Pentheroudakis G, Lazardis G, Pavlidis N. Axillary nodal metastases from carcinoma of unknown primary (CUPAx): a systematic review of published evidence. Breast Cancer Res Treat 2010;119:1.
Pittman KB, et al. Gemcitabine and carboplatin in carcinoma of unknown primary site: a phase 2 Adelaide Cancer Trials and Education Collaborative study. Br J Cancer 2006;95:1309.
Varadhachary GR, et al. Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol 2008;26:4442.