http://noah.cuny.edu/cancer/nci/cancernet/103331.html Unknown Primary - some information sites for Alan http://www3.cancer.org/cancerinfo/res_home.asp?ct=58 http://www.meb.uni-bonn.de/cancernet/103331.html http://tirgan.com/unknown.htm I am so sorry to hear of the loss of your beloved wife. I hope you can now look into this and find some consolation about this diagnosis. Yes, it is not good news that the primary remains undetected. If a primary site can be found, eg colon, ovarian, etc then treatment can proceed for that primary site. Otherwise, it like shooting bullets into the dark. I have this diagnosis (Dec 97) with only a talc pluerdesis as treatment back then. There now newer tests and drugs that might change the dire outlook for this diagnosis. God Bless, Jeanne Some sites for you below. Let us know how you are doing or if you have questions. We are not medical people though I was trained as an R.N. but we do give each other emotional and research help. http://tirgan.com/unknown.htmTitle: Carcinoma of unknown primary (Physician)
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The site of origin of a histologically documented carcinoma is not identified clinically in approximately 3% of patients; this situation is often referred to as carcinoma of unknown primary (CUP) origin or occult primary malignancy.[1-5]
The definition of a CUP varies from study to study; however, at a minimum, this determination should include a biopsy of the tumor and a thorough history and complete physical examination that includes head and neck, rectal, pelvic, and breast examinations; chest x-rays; a complete blood cell count, urinalysis, and an examination of the stool for occult blood. The value of other radiographic tests will be discussed in the stage information section. When these results do not reveal signs of a potential primary lesion, and the biopsy is not consistent with a primary tumor at the biopsy site, a CUP must be assumed. The majority of CUP are adenocarcinomas or undifferentiated tumors; less commonly, squamous cell carcinoma, melanoma, sarcoma, and neuroendocrine tumors can also present with a primary site of origin that cannot be determined. The most extreme examples occur in the 15% to 25% of patients in whom the diagnosis of the primary site cannot be determined even at postmortem examination.
The prognosis for patients with CUP is poor. As a group, the median survival is approximately 3 to 4 months in most studies with less than 25% and 10% of patients alive at 1 and 5 years, respectively. CUP is represented by a heterogeneous group of diseases all of which have presented with metastasis as the primary manifestation. Although the majority of diseases are relatively refractory to systemic treatments, there are certain clinical presentations of CUP that carry a much better prognosis. In each instance, there are distinct clinical and pathologic details that require consideration for appropriate, potentially curative, management.[6-9]
A retrospective review of 657 consecutive patients with CUP (270 additional patients were excluded as a result of identification of a primary malignancy, a noncarcinoma cell type, or no malignancy) reported several variables of significant prognostic importance identified by multivariate analysis. Lymph node involvement and neuroendocrine histology were associated with longer survival; male sex, increasing number of involved organ sites, adenocarcinoma histology, and hepatic involvement were unfavorable prognostic factors.
Conceptually, CUP represents a tumor that has a greater propensity for "early" clinically apparent dissemination than the more common presentation in which the primary tumor is apparent with or without metastases.
The distribution of primary sites that are likely to result in CUP contrasts with the distribution of major primary adenocarcinomas as reported in the SEER (Survival and End Results Program) data. Most large studies have shown that carcinoma of the lung and pancreas are the most common primary carcinomas that initially present as CUP. Other common malignancies such as colorectal, breast, and prostate cancers infrequently present as CUP.[6-9]
The pattern of spread of CUP at diagnosis can provide clues to the likelihood of the primary disease being above or below the diaphragm. Lung metastases are twice as common in primary sites ultimately found to be above the diaphragm. Liver metastases are more common from primary disease below the diaphragm. The pattern of metastasis from a carcinoma presenting as CUP may be significantly different from that which would be expected from the usual presentation. For instance, bone metastases are approximately 3 times more common in pancreatic cancer presenting as CUP, while osseous metastasis from lung cancer is about 10 times less common when it presents as CUP compared with the usual presentation. The biologic bases for these differences in presentation, incidence, and pattern of metastases are unknown.
Although only a minority of patients will have curable disease or a disease for which there is substantial palliative benefit, the opportunity for treating such patients should not be ignored or lost. This knowledge combined with the appropriate use of special diagnostic pathology and selected radiologic studies will provide the optimal benefit for patients who present with CUP.
The pathologist has a central role in the evaluation of carcinoma of unknown primary (CUP). There is probably no more important clue to the diagnostic puzzle of CUP than a thorough evaluation of an adequate specimen for histologic, immunohistochemical, and, when appropriate, electron microscopic evaluations. These evaluations provide guidance for the appropriate clinical evaluation that ensues. An obvious corollary to the pathologist's role is the critical interaction between the pathologist, oncologist, and primary physician.
The complexity of the pathologic evaluation tends to be inversely related to the degree of differentiation of the tumor. For well or moderately differentiated tumors, the pathologic diagnosis of an epithelial cancer versus lymphoma, sarcoma, melanoma, or a germ cell tumor, for instance, is often readily apparent. Commonly used stains such as mucicarmine or diastase sensitive Periodic Acid Schiff can be important in confirming the diagnosis of certain tumors of gastrointestinal or renal origin.
Special studies can help in distinguishing more poorly differentiated tumors.[2,3] Often, the generic distinction between a poorly differentiated tumor of epithelial, hematopoietic, or neuroectodermal origin (i.e., melanoma) is of importance.
Immunohistochemical: Several studies can be important in making these broad distinctions, in particular, studies that evaluate staining for keratins, leukocyte common antigen, and S-100, a neuroectodermal antigen expressed in melanomas.
Prostate specific antigen (PSA): This histochemical study can accurately differentiate tumors of prostatic origin from other types of cancer. Most often prostate cancer is found as an obvious prostatic cancer by digital rectal examination. However, approximately 3% of CUPs are ultimately shown to be prostatic cancer. These cancers, as mentioned above, appear to have a different metastatic distribution than the predominant bony distribution that is generally encountered in prostate cancer. Thus, when there is any suspicion that the primary disease may have arisen from the prostate, the specificity of the test and the availability of relatively nontoxic hormonal approaches emphasize the need to evaluate this diagnostic possibility in the CUP setting.
Human chorionic gonadotropins (HCG) and alpha-fetoprotein (AFP): Immunohistochemical stains are available for both of these proteins. Although neither is absolutely specific for germ cell tumors (HCG and AFP) or hepatoma (AFP), they are important because germ cell tumors are effectively treated with combination chemotherapy. Undifferentiated tumors presenting as CUP can be germ cell tumor, the recognition of which would lead to a substantial clinical response or even to cure. The finding of germ cell tumors by genetic analysis has been associated with a high response rate to cisplatin therapy, thus suggesting that molecular or cytogenetic studies may be useful in identifying undifferentiated tumors that are otherwise unclassifiable.
Polymerase chain reaction: In patients with suspected nasopharyngeal carcinoma, DNA amplification of Epstein-Barr virus (EBV) genomes can be used for diagnosis with tissue provided by fine-needle aspiration biopsy. The presence of EBV in metastases from an occult primary tumor suggests the development of overt nasopharyngeal carcinoma. A single study has shown that the i(12p) marker chromosome may be used as a diagnostic tool in patients with suspected midline germ cell tumors.
Electron microscopy: Electron microscopy (EM) evaluation can sometimes aid in the diagnosis of CUP. In particular, the presence of desmosomes and bundles of tonofilaments are characteristic of squamous cell cancers. The presence of core granules that are diagnostic of neuroendocrine origin is seen in poorly differentiated neuroendocrine tumors of unknown primary site.
Acinar spaces and microacinic spaces are seen with adenocarcinomas. Electron dense secretory granules are seen in tumors of neuroectodermal origin. Premelanosomes can be found in most amelanotic melanomas.
The features mentioned above are generally associated with differentiation along a particular line. Often poorly differentiated tumors do not display such characteristics, making the EM evaluation of little value. It is estimated that EM may aid in distinguishing a primary diagnosis that has not been obtained by light microscopy approximately 10% of the time.[11-13]
There are divergent opinions concerning the value and extent of evaluation that should be performed to determine the primary tumor in patients who present with carcinoma of unknown primary (CUP). Clinical and pathological investigations to detect tumors which are potentially responsive to treatment (e.g. lymphoma, germ cell tumor, breast or ovarian tumor) may be undertaken.
The chest radiograph has become an almost routine procedure in general medical practice. Although chest radiography is routinely performed, in the setting of CUP, there is no distinguishing feature that clearly separates primary from metastatic disease within the chest. The abdominal computed tomographic (CT) scan is the only radiographic test that may frequently be of value in defining the primary site. The value of abdominal CT scans may be because of the inordinately high representation of pancreatic cancer in the CUP process. However, with the exception of ovarian cancer, CT scans rarely identify treatable primary cancers.[2,3]
The clinical biology of the disease, the types of tumors most often encountered, and the high level of inaccuracy of unguided radiographic studies raise issues of cost effectiveness for intensive diagnostic work-up. Two studies have indicated that there is a large negative cost/benefit ratio for an extensive unguided clinical evaluation, with a single study citing a 9.5% increase in 1-year survival at a cost of 2 to 8 million dollars. The most reasonable approach is to develop a comprehensive knowledge of the manner in which CUP patients present and to remember that this presentation is associated with tremendous heterogeneity regarding outcome.[4-9]
Cervical lymph nodes: A histologic diagnosis of metastatic carcinoma in cervical nodes requires a meticulous examination of the upper aero-respiratory tract. Histologically, these tumors are either squamous cell carcinoma, adenocarcinoma, or anaplastic tumors. Metastatic adenocarcinoma is generally associated with a poor prognosis. Approximately 2% to 5% of patients with primary squamous cell carcinoma of the head and neck region will present with cervical adenopathy as the primary disease manifestation; about 10% of this group will present with bilateral adenopathy. The 3-year survival rate ranges from 35% to 59% when patients with squamous or undifferentiated tumors are treated with radical radiation therapy, surgery, or both.[10-12]
Poorly differentiated carcinomas: Investigators at Vanderbilt and elsewhere have defined a subpopulation of potentially curable patients with 1 or more of the following characteristics: aged younger than 50 years; midline tumor distribution, multiple pulmonary nodules or lymph nodes, elevated serum levels of beta human chorionic gonadotropins (HCG) or alpha-fetoprotein (AFP); cells positive for beta HCG or AFP by immunohistochemical stain; the presence of neuroendocrine granules; clinical evidence for rapid tumor growth; and/or tumors that were very responsive to chemotherapy or radiation therapy. In retrospective review, many of these patients, including some complete responders to chemotherapy, did not have any recognizable histopathologic features of germ cell tumors.[13-15] A single study has shown that the i(12p) marker chromosome may be used as a diagnostic tool in patients with suspected midline germ cell tumors.
Metastatic melanoma to a single nodal site: Approximately 5% of patients with malignant melanoma will present without a documented primary site. In such instances, the pattern of nodal metastasis generally follows the anticipated pattern for females and males with inguinal and axillary adenopathy, respectively. Special stains and electron microscopy may be important in establishing the diagnosis. Patients with this diagnosis should, like those with stage II melanoma, have a radical lymph node dissection. Survival characteristics are identical to those seen in stage II melanoma with a documented primary site.[5,17-19]
Isolated axillary metastasis: Most patients who present with nodal metastasis above the diaphragm ultimately are documented to have the most common supradiaphragmatic primary malignancy, i.e., lung cancer. However, the presence of isolated axillary metastasis in females raises another possibility. A few studies involving a small number of patients have shown that approximately one-half of patients who present with isolated axillary metastasis of an adenocarcinoma will ultimately be shown to have breast cancer. Although some of these patients will have a positive mammogram after the initial evaluation, approximately one-half the patients will not. When these patients are treated with local excision, or as having primary breast cancer, 2- to 10-year survival has been obtained in approximately 10% of patients. The availability of estrogen receptor (ER) and progesterone receptor (PR) assays may aid in this diagnosis, and these studies should be performed in this setting. If the clinical setting is consistent with breast cancer and ER and/or PR levels are elevated, CUP with this distribution should be treated as breast cancer.[1,4,20]
Inguinal node metastasis: Squamous carcinoma detected in the inguinal lymph nodes is almost always metastatic from the genital or anal/rectal area. In females, careful examination of the vulva, vagina, and cervix is indicated, with biopsy of any suspicious areas. The penis of uncircumcised males should be carefully inspected. In both sexes, the anorectal area should be carefully examined, including biopsy of suspicious areas. Isolated metastases present in the central nervous system, the liver, and the genitourinary tract. Information about these presentations may be found in PDQ summaries that specifically detail their management.
In addition to the above situations, there are certain instances in which significant palliation can be achieved in patients with CUP. Breast, prostate, ovarian, and thyroid cancers are all treatable malignancies, even when metastatic, and they represent approximately 15% of all CUP tumors. As with other CUP presentations, the pattern of spread of these malignancies is somewhat atypical. For instance, patients with prostate cancer who present with CUP have an inordinately high incidence of metastases to nonosseous sites such as lung (75%), liver (50%), and brain (25%). Bone metastases are also less common in thyroid cancer presenting as CUP than lung metastases.
The overwhelming majority of patients presenting with carcinoma of unknown primary (CUP) have disseminated disease that is relatively chemoresistant. However, there are a few situations in which potentially curative treatment can be delivered.
Cervical lymph nodes
All patients should undergo a careful head, neck, and lung evaluation including coronal computed tomography (CT) and/or magnetic resonance imaging (MRI) of the head and neck and blinded biopsies of the nasopharynx and tongue base. In those patients with squamous cell or undifferentiated carcinoma, tonsillectomies have been recommended and should be considered if the tonsils have not been previously removed. If no primary site can be determined, the following approaches should be considered:
More detailed information is available in the PDQ summary for metastatic squamous neck cancer with occult primary cancer.
Poorly differentiated carcinomas
Patients who have poorly differentiated carcinomas with or without serologic or histologic evidence of beta human chorionic gonadotropins or alpha-fetoprotein should be treated with intensive chemotherapy as used in the treatment of disseminated germ cell tumors.
A series of more than 220 patients with excellent performance status were treated with aggressive combination chemotherapy. This chemotherapy generally consisted of vinblastine, bleomycin, and cisplatin; however, some patients received a doxorubicin-containing modification of this regimen and some received etoposide instead of vinblastine. The response rate was 63%, with a complete response rate of 26% and a long-term disease-free survival of 16%. Carboplatin-containing regimens were found to have equal activity. A paclitaxel-based combination yielded a 47% response rate in 35 patients with various histologic types of carcinoma of unknown origin.
Poorly differentiated neuroendocrine carcinomas
In a series of 29 patients, 19 were treated with intensive cisplatin-based combination chemotherapy and 6 additional patients received doxorubicin combinations. Six patients achieved complete response and 4 of these patients were alive 19 to 100 months after diagnosis.
Another subset of patients with favorable response to chemotherapy and improved prognosis is women with peritoneal carcinomatosis of an adenocarcinomatous serous histologic type. Response and survival rates in these patients approach those seen in ovarian cancer patients and therapy appropriate for ovarian cancer should be used.[7,8]
Isolated axillary nodal metastasis
Although lung cancer is the most likely diagnosis, a certain proportion of these patients, especially females, have breast cancer. Mammography should be performed in all patients with isolated axillary nodal metastasis. After an adequate evaluation of the breast and lung to rule out these primary sites, the following treatment options should be considered: lymph node dissection with or without mastectomy or radiation therapy to the breast with curative intent  or the above treatment plus adjuvant chemotherapy with an accepted therapeutic adjuvant approach for breast cancer, especially if breast cancer is proven or if other lymph nodes show adenocarcinoma.
Inguinal node metastases
Metastatic carcinoma in inguinal nodes from an unknown primary source occurs in approximately 1% to 3.5% of patients. A diagnostic excisional node biopsy should be performed when no primary source of carcinoma can be found. The most common pathologic diagnosis in this instance is Hodgkin's disease or non-Hodgkin's lymphoma, with CUP being less frequent. Treatment options:
In a small proportion of patients local excision alone is sufficient therapy. Initial therapy with radiation may be used successfully in certain patients, depending on extent of disease and individual patient characteristics. Isolated metastases also present in the central nervous system, liver, and genitourinary tract. More information can be found in the PDQ summaries for these malignancies.[11,12]
Melanoma (melanotic or amelanotic) occurring in a single nodal site
Approximately 5% of patients present with no detectable primary site. For such patients who present with a single site of nodal metastasis, the following treatment will yield a survival consistent with that obtained in conventional stage II melanoma:
For those patients who present with widespread metastatic disease and for whom special studies reveal a probable primary tumor for which standard systemic therapy is available, such therapy should be administered, i.e., hormonal therapy for prostate and breast cancer, I-131 for thyroid cancer, cytotoxic single-agent or combination chemotherapy for hormone refractory breast and ovarian cancers. Standard approaches for such diseases are available in the specific PDQ summaries for each diagnosis.
The majority of patients will not have a definable primary source. For such patients, a variety of combination chemotherapy approaches has been tried with little success. No treatment can be considered standard at present. Therefore, such patients should be considered for available clinical trials.
The prognosis for any treated cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage. Deciding on further treatment depends on many factors, including the specific cancer, prior treatment, and site of recurrence, as well as individual patient considerations. Treatments that are under clinical evaluation are appropriate and should be considered when possible.
Date Last Modified: 05/1999