METASTASES OF UNKNOWN PRIMARY SITE

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CANCER SCREENING AND DIAGNOSIS

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METASTASES OF UNKNOWN PRIMARY SITE Barry C. Lembersky, MD, and Lisa C. Thomas, MD

The definition of metastatic cancer of unknown primary site has varied among published reports, depending, in part, on the extent of the diagnostic evaluation required to accept the diagnosis. Operationally, this syndrome should be considered in any patient presenting with a biopsy-confirmed malignancy in which the anatomic origin remains unidentified after a careful history and physical examination (including digital rectal examination with test for stool occult blood, breast palpation and pelvic examination in women, and prostate and testicular examination in men), routine laboratory studies with complete blood counts, liver and renal function tests, urinalysis, chest radiography, computed tomography (CT) of the abdomen and pelvis, and mammography in women.3Any abnormal finding on this initial evaluation should be considered a clue toward the identification of a primary site and investigated fully. Depending on the specific clinical situation, appropriate diagnostic tests may include sputum cytology, CT of the chest, gastrointestinal endoscopy, and intravenous pyelography. It is now quite clear, however, that the routine use of these and other invasive and expensive tests, in the absence of positive findings on the initial diagnostic evaluation, is fruitless and should be avoided.22,hi, h9, 70 Metastases of unknown primary site account for approximately 5% to 10% of all cancers.1i,30 Few diagnoses engender as much uncertainty. Because modern cancer management typically relies heavily on recognition of the primary tumor, these patients pose difficult diagnostic and therapeutic dilemmas. Under the misconception that improved treatment and prognosis could be possible if the primary tumor were found, ~

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From the Division of Medical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

MEDICAL CLINICS OF NORTH AMERICA VOLUME 80 * NUMBER 1 *JANUARY 1996

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patients and their families often are frustrated that the clinician is unable to establish the primary site. At autopsy, the primary tumor site has been identified in 30% to 82% of patients.22,44, 4y, 61, 6y The reason the primary site remains occult is unknown. One hypothesis is that the primary tumor is either too small to detect by standard methods or has involuted. Clearly, although the clinicopathologic characteristics of metastases of unknown primary site are extremely heterogeneous, these malignancies share biologic features that may differ substantially from those in which the primary site is identifiable. One group of investigators has proposed that unknown primary cancers may result from the early clonal expansion and dominance of malignant cells with a genotype and phenotype that favors metastatic ability but not local growth.4, y, 26 Abbruzzese and colleagues4 found a number of diverse karyotypic abnormalities in tumor biopsy specimens from 13 patients with metastases of unknown primary. Interestingly, however, 12 of 13 had changes in the short arm of chromosome 1. The specific abnormalities included deletions of all or part of lp, translocations, duplication of lq, and evidence for gene amplification. Earlier work described abnormalities in chromosome l p as being associated with advanced malignan~y.~ Previously the lack of effective treatment and poor outcome for patients diagnosed with metastases of unknown primary site resulted in substantial pessimism and therapeutic nihilism on the part of patients and clinicians. In the past decade, however, systematic study has resulted in a better understanding of these tumors and improved therapy for some patients. A new era in the approach to this disease has been heralded by marked advances in diagnostic pathology and recognition of specific clinically defined subsets of patients for which useful treatment may be palliative or even curative. The optimal management should now emphasize a focused diagnostic evaluation to identify those patients for whom effective therapy exists.’, 32 CLINICAL MANIFESTATIONS

The clinical presentation of patients with cancer of unknown primary site is extremely varied. By definition, the presenting symptoms and signs reflect neoplastic involvement of the metastases, which may be in a single organ or in multiple sites. The frequency of predominant presenting site(s) varies in the literature, depending on the selection of patients and referral patterns. Table 1 shows the major sites of initial involvement in three large series.I,43, Involvement of lymph nodes, lung, bone, and liver is most common, although other sites encountered include brain, pleura, peritoneum, pericardium, adrenal, gastrointestinal tract, prostate, uterus, and testes. Antemortem detection of the occult primary site has been reported in 2.3% to 27% of patients.’, 22, 41,6o In older retrospective series, pulmonary and pancreatic cancers were the most commonly identified primary 44, 6o Because effective treatment does not exist for these malignansites.22,

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Table 1. MAJOR SITES OF TUMOR INVOLVEMENT ON INITIAL PRESENTATION Site

Lymph nodes Lung Bone Liver Pleura Peritoneum Brain Adrenal Skin Other

LeChevalier et a144* N = 302

Kirsten et a143' N = 286

Abbruzzese et al't N= 657

37 19 13 5 2 1 10

14 16 16 19 12 6 8

9 4

1 8

37 28 28 31 12 6 8 6 2

-

-

-

'Initial symptomatic site for which patient was seen. tlnvolved at presentation. Most patients had multiple sites.

cies, antemortem detection did not influence patient survival. In contrast, in a cohort of 927 patients presenting with unknown primary tumors, Abbruzzese and colleagues2 employed a prospectively applied limited diagnostic evaluation that included CT scan of the abdomen and pelvis, careful pathologic review using available modern techniques, and directed use of serum tumor markers. The latent primary malignancy was identified antemortem in 24% of patients, frequently by pathology alone. The overall survival duration of patients in whom the primary malignancy was defined was superior to that of patients in whom the primary remained unknown. Patient subsets in whom the diagnosis was made by pathologic techniques (e.g., lymphoma) and women diagnosed with previously occult breast and ovarian cancer contributed most to the improved survival. When all patients with metastases of unknown primary site are considered, the disease is highly aggressive with an overall median survival of 5 to 12 months in recent series.', 40, 43, 66 It is imperative to recognize, however, the extreme heterogeneity of these patients. In a study by Kirsten and ass0ciates,4~the median survival of patients presenting with unknown metastases who had a treatable cancer was 23 months.

DIAGNOSTIC EVALUATION

When the initial limited clinical screening does not reveal a potential primary site, a vast array of diagnostic tests is available. The diagnostic strategy must balance the fact that most patients have a poor prognosis, and therefore time-consuming, invasive, and expensive testing should be limited, with the need to identify treatable subsets quickly.

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Pathology A comprehensive pathologic analysis of the tissue specimen is the initial step in the diagnostic evaluation of these patients and in many respects the most important.33 Advances in the techniques available for pathologic characterization have greatly influenced the approach to patients with metastases of unknown primary site. Communication with the surgeon, radiologist, and pathologist is essential to ensure that an adequate volume of fresh tissue is submitted to the laboratory and appropriately allocated for specialized pathologic studies that may be needed. This helps to reduce the need for a second biopsy. Light Microscopy

Based on the appearance of routine hematoxylin and eosin-stained material, the pathologist is usually able to judge whether the tumor is metastatic or primary in the organ sampled. For the former, approximately 60% of patients are found to have well-differentiated or moderately well-differentiated adenocarcinoma, and 5% have squamous cancer (Table 2).20For these patients, the clinical setting and judicious use of immunocytochemistry may help to identify a treatable cancer. For the remaining patients, the tumor specimen is poorly differentiated, making initial classification into a particular cell lineage difficult by light microscopy alone. It is in these groups of poorly differentiated neoplasms that immunocytochemistry, electron microscopy, and cytogenetic analysis are most lmmunocytochemistry

The development and availability of monoclonal antibodies that can be reliably used in routine processed and paraffin-embedded tissue sections have revolutionized the field of pathology and contributed greatly in the evaluation of patients with metastases of unknown priTable 2. HISTOLOGIC DIAGNOSES OF METASTASES OF UNKNOWN PRIMARY SITE USING LIGHT MICROSCOPY AND SPECIALIZED PATHOLOGIC TECHNIQUES Well-differentiated and moderately well-differentiated adenocarcinoma (majority of patients) Poorly differentiated adenocarcinoma and poorly differentiated carcinoma Poorly differentiated neoplasm Lymphoma Germ cell tumor Neuroendocrine tumor Sarcoma MeIanoma Other Squamous cell carcinoma

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mary The demonstration of specific cell products or antigens by immunocytochemical techniques can unequivocally establish the diagnosis of lymphoma, sarcoma, neuroendocrine tumors, germ cell tumors, melanoma, and others. The precise identification of these malignancies is essential and carries important therapeutic implications. Table 3 outlines the immunocytochemical stains useful in the workup of patients with poorly differentiated neoplasms. It is likely that future advances in this field with new, more specific reagents will further enhance the ability to identify responsive subsets of patients. Electron Microscopy

Currently, transmission electron microscopy has a role in the diagnosis of unknown primary malignancies, although the requirement for a pathologist experienced in the technique and special preservation of the tissue sample poses limitations in its use. The observation of particular cellular structures, such as melanosomes (melanoma), dense core granules (neuroendocrine tumors), desmosomes (squamous cancer), and extensive endoplasmic reticulum (lymphoma), is frequently helpful in identifying a specific tumor lineage. Cytogenetic Analysis

Cytogenetic analysis plays an important role in the diagnosis of hematologic malignancies. Only recently, however, has this technique been successfully applied to solid tumors. In the evaluation of patients with poorly differentiated metastases of unknown primary site, cytogenetic analysis may be of considerable diagnostic value.57Nonrandom Table 3. IMMUNOCYTOCHEMISTRY USEFUL IN THE EVALUATION OF POORLY DIFFERENTIATED NEOPLASMS Epithelial markers Cytokeratin Epithelial membrane antigen (HMFG) PSA CEA Lymphoid markers Leukocyte common antigen Ki-1 antigen Sarcoma markers Desmin Vimentin Factor VIII-related antigen Neuroendocrine markers Neuron-specific enolase Chromogranin Synaptophysin

Germ cell markers AFP HCG Hormonal markers Estrogen receptor Progesterone receptor Melanoma markers s-100 HMB-45

HMFG = Human milk fat globulin; PSA = prostate specific antigen; CEA antigen; AFP = a-fetoprotein; HCG = human chorionic gonadotropin.

=

carcinoembryonic

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chromosomal changes may be observed in lymphomas (translocation 8,14), Ewing’s tumor and peripheral neuroectodermal tumor (translocation 11,22),germ cell tumors (variable abnormalities of chromosome 12), and others. Motzer and c o l l e a g ~ e sperformed ~~ conventional karyotyping and specific molecular genetic testing for abnormalities of chromosome 12 in 40 patients presenting with poorly differentiated cancer of unknown primary site. Most of these patients had predominant disease in the midline structures of the mediastinum and retroperitoneum. In 17 patients, a specific diagnosis was suggested by the genetic studies. This included a germ cell tumor in 12 patients and 1 patient each with lymphoma, neuroepithelioma, melanoma, desmoplastic small cell tumor, and clear cell sarcoma. Response to cisplatin-based chemotherapy was correlated with the molecular or karyotypic abnormalities suggestive of a germ cell neoplasm. The drawbacks to cytogenetic analysis include the requirement for fresh tissue and limited availability. Clinical Investigations

Computed Tomography Scans

The role of abdominopelvic CT scanning is well defined. In two retrospectively reported series, McMillan and coworkersS’ and Karsell and associates4’observed that CT scans led to the ultimate identification of the primary site in 46% and 32%. Pancreatic carcinoma was the most commonly diagnosed primary malignancy, although CT scanning also revealed occasional other primary sites, including liver, kidney, adrenal, ovary, and gallbladder. Tissue confirmation of the primary site by CTdirected fine-needle biopsy may also be facilitated by this procedure. It should be pointed out that the abdominopelvic CT appears to serve the purpose of quickly identifying largely untreatable neoplasms, thus limiting the diagnostic workup. In contrast, CT scan is rarely any more useful than plain chest films.51 Radiographic and Radionuclide Studies

Upper and lower gastrointestinal contrast radiographic studies have a low diagnostic yield and should be reserved for patients with signs and symptoms referable to these organs.22, 70 Mammography is also not likely to be helpful because few patients with metastases of unknown primary site have an occult breast cancer. Even in patients presenting with axillary lymph node metastases, the sensitivity of modern mam24 The importance of detecting mography techniques is only 8% to 29Y0.~. an occult breast primary, however, cannot be overstated and provides ample rationale for this procedure. Radionuclide bone scanning should be reserved for the evaluation of symptomatic bone pain to direct palliative irradiation. A bone scan is not likely to provide information about the primary site.

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Serum Tumor Markers

A variety of serum tumor markers are currently available and are reviewed in detail elsewhere in this issue. These typically include carcinoembryonic antigen (CEA), prostate specific antigen (PSA), afetoprotein (AFP), human chorionic gonadotropin (HCG), CA-125, and CA 15-3. Because of the diagnostic uncertainty posed by the patient with metastases of unknown primary site, there is a tendency to order them indiscriminately. Although one or more are frequently elevated, as an isolated finding in unselected patients they generally are not helpful in 63 Used judiciously predicting response to chemotherapy or progn~sis.~, in the appropriate clinical setting, serum tumor markers should be considered adjuncts in the diagnostic evaluation (Table 4). TREATMENT

The treatment of patients with metastases of unknown primary site is as varied as the disease entity. In the rare instances that the completed pathologic evaluation reveals a lymphoma, sarcoma, melanoma, or germ cell tumor, appropriate therapy can be instituted. The more common adenocarcinomas or undifferentiated carcinomas pose a difficult therapeutic challenge. Although local therapy with surgery, irradiation, or both may be considered for the few patients presenting with only a single site of malignancy, most commonly, systemic treatment needs to be considered because of multiorgan involvement. Unfortunately, for the majority of patients, treatment is suboptimal. As previously noted, Table 4. CLINICAL ROLE OF TUMOR MARKERS IN PATIENTS WITH METASTASES OF UNKNOWN PRIMARY SITE Appropriate Tumor Markers

Clinical Situation

Need to Rule Out

Young men or women with mediastinal or retroperitoneal masses Women with adenocarcinoma in an axillary node Women with ascites with or without pelvic masses Men with diffuse metastatic disease to bone and/or bone and lungs Men or women with a single mass or multiple masses with the liver

Extragonadal germ cell primaries

AFP, P-HCG

Breast cancer

CA 15-3, CEA

Ovarian cancer

CA-125

Prostate cancer

PSA

Hepatocellular cancer

AFP, CEA

AFP = a-Fetoprotein; HCG = human chorionic gonadotropin; CEA = carcinoembryonic antigen: PSA = prostate specific antigen. Adapfed from Bitran JB, Ultmann JE: Malignancies of undetermined primary origin. Dis Mon 38:213, 1992; with permission.

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however, a minority of patients present with disease characteristics that have been recognized as favorable based on responsiveness to therapy and a better prognosis. Awareness of these favorable subgroups is imperative (Table 5).

Favorable Clinical Subgroups Women with Peritoneal Carcinomatosis

In women with peritoneal carcinomatosis, there have been complete responses to treatment and long-term, disease-free survival reported when patients were administered regimens used in the management of metastatic ovarian carcinoma.58These women frequently have pathologic and diagnostic similarities to patients with ovarian carcinoma and may actually have occult ovarian carcinoma or peritoneal neoplastic syndromes, which have been labeled multifocal extraovarian serous carcinoma or peritoneal papillary serous carcinoma. The latter syndrome has been noted in the literature for more than 30 years. Chen and FlamI4 were the first to report long-term, diseasefree survival in three patients diagnosed with peritoneal papillary serous carcinoma who were treated with primary surgical cytoreduction followed by combination chemotherapy consisting of cisplatin and doxorubicin, with or without cyclophosphamide. All three patients remained alive 5 years or longer after initial diagnosis. Three larger series have also been reported. The first was a retrospective study of 18 patients reported by Strnad and c o l l e a g ~ e s All .~~ patients presented with ascites and were managed with treatment used in advanced ovarian carcinoma. This consisted of primary surgical cytoreduction performed at the time of initial laparotomy. Sixteen of 18 patients were subsequently treated with cisplatin-based chemotherapy regimens following surgery. The median survival for the entire group was 23 months, with complete response to chemotherapy reported in seven patients. Three patients continued to be long-term, disease-free survivors for more than 4 years after treatment at the time the series was reported. The second series, reported by Dalrymple and coworke r ~ ,was * ~ a retrospective study in which 31 of 236 patients were assessed as having peritoneal serous papillary carcinoma. They were managed with primary surgical cytoreduction at the time of initial surgical exploration followed by chemotherapy used in the treatment of primary ovarian cancer. This consisted of combination or sequential therapy with chlorambucil and cisplatin in 25 patients, chlorambucil alone in 5 patients, and a cisplatin plus etoposide combination in l patient. Median survival was 11 months with a response to treatment reported in 10 of 31 patients, of whom 3 had a complete response. Two patients remained long-term, disease-free survivors at the time the series was reported. Ransom and c011eagues~~ retrospectively identified 33 patients with the diagnosis of papillary serous carcinoma of the peritoneum. Thirty-one

CT scan of abdomen Men: serum PSA Women: mammograms, CA-125 Additional studies to evaluate signs, symptoms

CT abdomen, chest Serum HCG, AFP Additional studies to evaluate signs, symptoms

Cervical presentation: Direct laryngoscopy, nasopharyngoscopy, fiberoptic bronchoscopy Inguinal presentation: Pelvic, rectal examination, anoscopy

Adenocarcinoma (well differentiated or moderately differentiated)

Poorly differentiated carcinoma, poorly differentiated adenocarcinoma

Squamous carcinoma

lmmunoperoxidase staining Electron microscopy Chromosomal analysis

Men: PSA stain Women: ER, PR

Special Pathologic Studies

Inguinal adenopathy

=

human chorionlc gonadotropin; AFP

=

a-fetoprotein.

Potential long-term survival

5-year survival rate of 25% to 50%

Neck dissection and/or radiation therapy Inguinal dissection and/or radiation therapy

High response rate 10% to 20% cured with therapy

Hormonal therapy for prostate cancer

Men, blastic bone metastases or high serum PSA or ( + ) tumor PSA staining Neuroendocrine tumors Tumor location in mediastinum, retroperitoneum, lymph nodes Cervical adenopathy (high or midcervical)

Poor for entire group (median survival = 4 months) Better for special subgroups

Prognosis

Cisplatin-based therapy Cisplatin/etoposide ? bleomycin

Treat as primary breast cancer Surgical cytoreduction plus chemotherapy effective in ovarian cancer

Therapy

Women, axillary node involvement Women, peritoneal carcinomatosis

Subsets with Responsive Tumors

EVALUATION AND THERAPY OF SUBSETS

CT = Computed tomography: PSA = prostate specific antigen; ER = estrogen receptor; PR = progesterone receptor; HCG From Greco FA, Hainsworth JD Tumors of unknown origin. Ca Cancer J Clin 42:96,1992; with permission.

Clinical Evaluation

Histopathology

Table 5. CARCINOMA OF UNKNOWN PRIMARY SITE-RECOMMENDED

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patients underwent primary surgical cytoreduction followed by chemotherapy. Nineteen patients received cyclophosphamide and cisplatin; 6 received a combination of intravenous cyclophosphamide, doxorubicin, and cisplatin along with oral hexamethylmelamine; 4 patients received carboplatin and cyclophosphamide; and 4 patients received nonspecified cisplatin-based regimens. The median survival for the entire group was 17 months with long-term, disease-free survival of more than 6 years observed in three patients. Axillary Nodal Metastases

In women, and rarely men, who present with axillary node metastases histologically confirmed to be a well-differentiated or moderately well-differentiated adenocarcinoma, breast cancer should be suspected. Even in the absence of a palpable mass or mammographic abnormality, mastectomy reveals the occult breast primary in 55% to 75% of cases.*, 55, 62 Initial evaluation should include axillary node dissection with measurement of estrogen and progesterone receptors either by routine quantitative methods or immunocytochemistry. A positive receptor status is seen in more than 50% of patients7 l o providing strong evidence for the diagnosis of breast cancer. Patients with isolated axillary metastases should be treated as if they have stage I1 breast cancer. As such, therapy must address issues of both local-regional and systemic control. Based on previously held surgical management paradigms for primary breast cancer, modified radical mastectomy has traditionally been recommended for patients with isolated axillary metastases.6z, 66 Because breast-preserving surgery combined with irradiation is known to yield equivalent survival results to modified radical mastectomy in women with operable primary breast cancers, however, it is only logical to consider whether breast preservation is possible in women with an occult breast cancer. Two retrospective studies suggest that breast preservation is an appropriate strategy for this group of women. Ellerbroek and coworkersz4reported on 42 women presenting with isolated axillary metastases. Thirteen patients underwent mastectomy, whereas the remaining 29 patients did not have any surgery on the breast. Among these 29 patients, 16 had elective breast irradiation, leaving 13 patients with no local treatment directed to the breast. Fourteen patients received adjuvant chemotherapy. The actuarial 10-year freedom from appearance of a primary in the untreated and irradiated breast was 43% and 69%. The actuarial 10-year survival for the entire group was 65%. No survival difference was detected between those patients with breast preservation and those with mastectomy. The use of adjuvant chemotherapy was associated with a 93% 5-year survival compared with 64% in patients who did not receive chemotherapy, although this difference did not reach statistical significance. Baron and coworkerss reported similar findings in the series of 35 patients from Memorial Sloan-Kettering Cancer Center. Seven of these patients had breast-preserving surgery and irradiation and had a similar 5-year sur-

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viva1 compared to the 28 patients who underwent mastectomy. Although the role of adjuvant systemic hormonal treatment, chemotherapy, or both has not been prospectively evaluated in women with isolated axillary lymph node metastases, the disease-free and overall survival advantages observed in stage I1 breast cancer suggests that such treatment is indicated for these women.1s,23, 25, 37 The prognosis for these patients appears to be similar to stage I1 breast cancer and much better than the overall population of patients with metastases of unknown primary site. Men with Skeletal Metastases or Increased Serum Prostate Specific Antigen

Skeletal metastasis identified in men, especially if they are osteoblastic in nature, should raise the suspicion of metastatic prostate carcinoma. An elevated serum PSA level or a biopsy sample that stains positive for PSA or prostatic acid phosphatase by immunocytochemistry techniques2*,72 should allow definitive recommendations concerning palliative treatment options to be made in this subset of patients, even in the absence of radiologic or biopsy-proven prostatic carcinoma. Hormonal manipulation is indicated in patients with metastatic prostate carcinoma. Historically, orchiectomy has been the mainstay of therapy. Several large randomized cooperative group studies have evaluated the role of total androgen blockade using a combination of the L-RH agonist, leuprolide, with flutamide, a nonsteroidal antiandrogen. Improved duration of response and median survival was observed most frequently in patients with minimal tumor volume, a good performance l7 status, and few to no symptoms at the time treatment was initiated.13,16, Poorly Differentiated Adenocarcinoma and Poorly Differentiated Carcinoma

Patients diagnosed with poorly differentiated carcinoma or adenocarcinoma of an unknown primary site represent a distinct subset of patients, some of whom exhibit responsiveness to treatment and in whom long-term cure may be achieved. Three series with a substantial number of patients have been re~~ treated 220 paported.', 34, 73 Hainsworth and a s s o c i a t e ~prospectively tients with cisplatin-based combination chemotherapy. Patients were initially treated with two cycles of chemotherapy at 3-week intervals and then reevaluated for response. If any evidence of response was noted, the patients received an additional two cycles. The overall response rate was 62% with 58 patients (26%) achieving a complete response and 80 patients (36%) a partial response. One patient had a partial response with chemotherapy and was rendered disease free after resection of residual tumor followed by irradiation. The median survival for the entire group was 12 months with an actuarial survival of 16% at 12 years. Thirty-six patients (16%) were disease free at a median of 5

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years following therapy, including 3 patients who relapsed after an initial complete response and were rendered disease free after salvage chemotherapy. In those patients who achieved a complete response, the actuarial survival at 12 years was 62%. Favorable prognostic factors identified by Cox regression analysis included (1) predominate tumor location in the retroperitoneum or peripheral lymph nodes, (2) tumor limited to one or two metastatic sites, (3) negative smoking history, and (4) younger age. Within this group were 34 men all younger than 45 years of age who had predominant disease involving the mediastinum and retroperitoneum. Six had increased levels of HCG, AFP, or both. These clinical features suggest an extragonadal germ cell tumor syndrome. The result of treatment in this subset was much better, compared with the overall group. Eighty-five percent of patients responded to therapy with 50% achieving a complete response. Ten patients (29%) enjoyed long-term disease-free survival at the time the series was reported. prospectively treated 79 patients van der Gaast and with cisplatin, etoposide, and bleomycin (BEP) administered at 3-week intervals or cisplatin given weekly combined along with oral etoposide. Of the 77 evaluable patients, the median survival was 8 months. The overall and complete response rates were 42% and 12%, and estimated 5-year survival was 15%. In this series, favorable prognostic factors included (1) World Health Organization performance score of 0 and (2) normal serum alkaline phosphatase. Abbruzzese and coworkers' retrospectively reviewed the results obtained in 109 unselected patients with poorly differentiated or undifferentiated carcinoma seen at the M. D. Anderson Cancer Center. Sixtyfour patients received systemic chemotherapy and 45 did not. Although there were a small number of long-term survivors in each group, there was no significant difference in the overall survival curves noted. Poorly Differentiated Neuroendocrine Tumors A subset of patients with poorly differentiated neuroendocrine tumors of unknown primary site has been described.27, 35 This clinicopathologic entity represents a diverse group of tumors and is noteworthy for its responsiveness to chemotherapy. The biologic origins of this disease remains undefined and classification controversial. In the literature, it has been variously named poorly differentiated neuroendocrine tumor, anaplastic neuroendocrine carcinoma,s3and extrapulmonary undifferentiated small cell cancer.74Patients usually have rapidly growing tumors in multiple sites. Involvement of mediastinal, retroperitoneal, or cervical lymph nodes predominates, although some patients present with extensive hepatic or bone metastases. Electron microscopy of the biopsy specimen usually demonstrates neurosecretory granules, and immunocytochemical stains for neuron-specific enolase, chromogranin, and cytokeratin are frequently positive. Consistent with the undifferentiated nature of the neoplasms, patients do not have symptoms suggesting a

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hormone-mediated syndrome seen in more well-differentiated carcinoid or islet cell cancers. Hainsworth and c011eagues~~ retrospectively identified 29 patients with poorly differentiated neuroendocrine tumors of unknown primary site. Twenty-three evaluable patients with tumor involving more than one site received combination chemotherapy, with a cisplatin-based regimen or a regimen used in the treatment of small cell lung carcinoma. The overall response rate was 78%, including six patients with a complete response. Among the six complete responders, three patients (50%) remained disease free for more than 2 years after the completion of therapy, whereas the median duration of the partial responses ranged from 3 to 15 months. Similar results have been reported in the small series by van der Gaast and and Moertel and with an overall response rate of 82% and 67% and a few patients experiencing extended long-term survival. It is therefore imperative for clinicians to be aware of this diverse family of treatable neoplasms when evaluating patients with metastases of unknown primary site. Squamous Cancer Involving Cervical Lymph Nodes

In patients presenting with metastatic squamous carcinoma involving high and middle cervical lymph nodes, a primary head and neck cancer can be identified in 20% to 50% of patients with careful evaluation of the upper aerodigestive tract. Even if the primary site remains occult, however, a management strategy similar to that employed in the treatment of primary head and neck cancer results in long-term disease-free survival in a substantial number of patients. Many retrospective, single institution series have been reported using radical neck dissection, high-dose radiation,I2 or both. Similar 5year survivals are observed with all of these treatments. As expected, the tumor burden is a prognostic factor and should be used to guide therapy. Patients with only a single involved lymph node may be treated successfully with either surgery or irradiation. A subsequent primary head and neck cancer, however, is more likely to develop with radical neck dissection. If there is a large tumor burden in the neck, involvement of multiple lymph nodes, or extracapsular extension of tumor, a com39, 48, so, 54, 5y, 67 Similar to bined treatment approach is re~ommended.~~, patients with a recognized head and neck primary cancer, the role of neoadjuvant chemotherapy for patients remains undefined and the 38 subject of current investigations.21, Patients with low cervical or supraclavicular adenocarcinoma cancer fair less well. The source is more likely to be an occult lung or gastrointestinal primary. Involved field irradiation is recommended if no other sites of disease are dete~ted.4~ Inguinal Lymph Nodes

Zaren and C ~ p e l a n dretrospectively ~~ reviewed 2232 cases of inguinal node metastases. In 99% of patients, the primary site was easily

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identified in the lower extremity or the perineal or anorectal regions. In the remaining 22 patients without a recognizable primary, three groups were identified based on histopathologic findings: unclassified carcinoma in 14 patients, squamous carcinoma in 6 patients, and adenocarcinoma in 2 patients. Surgical treatment consisted of superficial inguinal lymph node dissection in 7 patients and excisional biopsy only for diagnosis in 15 patients. Of the 15 patients who underwent excisional biopsy, only 4 patients received systemic chemotherapy or involved field irradiation. The overall survival of these 22 patients was 55%. None of the patients who had superficial groin dissection died from cancer at the time the series was reported, whereas 9 of the 15 patients who had excisional biopsy with or without irradiation or chemotherapy died within 24 months. The authors concluded that patients with inguinal node metastases from an unknown primary site had a reasonably favorable prognosis and that local treatment with complete superficial lymph node was the treatment of choice. Guarischi and associates3*retrospectively examined 56 cases of carcinoma presenting as inguinal node metastasis from an unknown primary site. Histologic diagnoses included anaplastic carcinoma, squamous carcinoma, adenocarcinoma, and melanoma. Initially, all patients had a diagnostic excisional biopsy. In nine patients, no other therapy was administered. Of the remaining 47, 8 patients had inguinal node dissection, 35 patients had irradiation, and 4 received chemotherapy. The overall 5-year survival for the entire group was 27%. The 20-month median survival among the eight patients treated with inguinal node dissection was similar to the 27-month median survival seen in those patients treated with excisional biopsy and curative intent irradiation. Occasional long-term survival was achieved by both of these local treatment strategies. These authors concluded that irradiation was a valid treatment alternative to lymph node dissection in patients with isolated inguinal lymph node metastases of unknown primary site. Empiric Treatment of Well-Differentiated and Moderately Well-Differentiated Adenocarcinoma

Unfortunately, approximately 60% of patients do not fit into the above-described favorable subgroups. Effective therapy does not currently exist for these patients. The results of selected reports of systemic combination chemotherapy are shown in Table 6. In each of these trials, small numbers of patients were treated, and some of the patients had poorly differentiated carcinoma of unknown primary site. Thus, it is difficult to draw conclusions about the true effectiveness of chemotherapy in patients with well-differentiated and moderately well-differentiated adenocarcinoma. Most regimens include cisplatin or doxorubicin. Response rates vary between 20% and 50% but are generally of short duration, and median survivals have been only 2 to 11 months. No regimen appears to be superior.

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METASTASES OF UNKNOWN PRIMARY SITE

Table 6. SELECTED PHASE II CHEMOTHERAPY TRIALS IN PATIENTS WITH METASTATIC ADENOCARCINOMA OF UNKNOWN PRIMARY SITE

Regimen Cisplatin-based chemotherapy PEF PFL PVB Doxorubicin-based chemotherapy CAV AM FAM Other combinations CMeF PaMeFL

No. Response Rate of Patients (“/.I

Median Survival

(mos)

Reference

11 5

64 46 52

36 25 50

22 32 30

20 25 43

50

36 30

8 4 11

6 75 29

22 21

5 5

3 2

75 42

-

P = cisplatin; E = etoposide; L = leucovorin; V = vinblastine; B = bleornycin; C = cyclophospharnide; A = Adriamycin (doxorubicin); M = rnitornycin; F = fluorouracil; Me = rnethotrexate; Pa = PALA.

Nevertheless, in patients with a good performance status, a careful discussion about the low likelihood of benefit and potential toxicity associated with systemic chemotherapy is warranted. These patients may be ideal candidates for investigational clinical trials of new drugs or combinations. If a clinical trial is not available but active therapy is desired, chemotherapy should be given for two cycles with careful monitoring of toxicities and tumor response. Treatment should be stopped in the presence of significant toxicity or the lack of a clear-cut response. In patients with a poor performance status, the likelihood of benefit is even lower. Supportive care alone with attention to palliation of symptoms is recommended. SUMMARY

Despite the fact that effective therapy does not currently exist for the majority of patients presenting with metastases of unknown primary site, the last decade has witnessed significant advances in the approach to this heterogeneous disease. The use of modern pathologic techniques that frequently provide better diagnostic precision and the recognition of specific subgroups with a favorable prognosis and responsiveness to treatment has improved the outcome for some patients. Currently the diagnostic strategy should emphasize the rapid identification of patients likely to benefit from available therapy, whereas clinical research should focus on the development of more effective treatments for those patients with unresponsive tumors. In the future, continued improvements in the molecular characterization of these tumors will likely enhance under-

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standing of the metastatic process, allow for more specific definitions of cell lineage, and provide insights for better therapy. References 1. Abbruzzese JL, Abbruzzese MC, Hess KR, et al: Unknown primary carcinoma: Natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 12:1272, 1994 2. Abbruzzese JL, Abbruzzese MC, Lenzi R, et al: Latent primary malignancies: Diagnostic evaluation, common primaries, and survival patterns of patients presenting with unknown primary tumors [abstr 13861. In Proceedings of the American Society of Clinical Oncology, Los Angeles, 1995, p 435 3. Abbruzzese JL, Raber M N Unknown primary. In Abeloff MD, Armitage JO, Lichter AS, et a1 (eds): Clinical Oncology. New York, Churchill Livingstone, 1995, p 1833 4. Abbruzzese JL, Lenzi R, Raber MN, et al: The biology of unknown primary tumors. Semin Oncol 20:238, 1993 5. Abbruzzese J, Raber MN, Frost P: The role of CA-125 in patients with unknown primary tumors [abstr 291. In Proceedings of the American Society of Clinical Oncology, Houston, 1991, p 39 6. Anderson H, Thatcher N, Rankin E, et al: VAC chemotherapy for metastatic carcinoma from unknown primary site. Eur J Cancer Clin Oncol 19:49, 1983 7. Atkin NB: Chromosome 1 aberrations in cancer. Cancer Genet Cytogenet 21:279, 1986 8. Baron PL, Moore MP, Kinne DW, et al: Occult breast cancer presenting with axillary metastases: Updated management. Arch Surg 125:210, 1990 9. Bell C, Pathak S, Frost P: Unknown primary tumors: Establishment of cell lines, identification of unique chromosomal abnormalities and implications for a second type of tumor progression. Cancer Res 49:4311, 1989 10. Bhatia SK, Saclarides TJ, Witt TR, et al: Hormone receptor studies in axillary metastases from occult breast cancers. Cancer 59:1170, 1987 11. Bitran JD, Ultmann JE: Malignancies of undetermined primary origin. Dls Mon 38:213, 1992 12. Carlson LS, Fletcher GH, Oswald MJ: Guidelines for radiotherapeutic techniques for cervical metastases from an unknown primary. Int J Radiat Oncol Biol Phys 12:2101, 1986 13. Carter HB, Issacs J T Experimental and theoretical basis for hormonal treatment of cancer. Semin Urol 6962, 1988 14. Chen KT, Flam MS: Peritoneal papillary serous carcinoma with long-term survival. Cancer 58:1371, 1986 15. Coker DD, Casterline PF, Chambers RG, et al: Metastases to lymph nodes from the head and neck from an unknown primary site. Am J Surg 134:517, 1977 16. Crawford ED, Blumenstein BA, Goodman PJ, et al: Leuoprolide with and without flutamide in advanced prostate cancer. Cancer 66:1039, 1990 17. Crawford ED, Eisenberger MA, McLeod DG, et al: A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 321:419, 1989 18. Cummings FJ, Gray R, Davis TE, et al: Adjuvant tamoxifen treatment of elderly women with stage I1 breast cancer. Ann Intern Med 103324, 1985 19. Dalrymple JC, Bannatyne P, Russell P, et al: Extraovarian peritoneal serous papillary carcinoma: A clinicopathologic study of 31 cases. Cancer 64:110, 1989 20. Daugaard G: Unknown primary tumours. Cancer Treat Rev 20:119, 1994 21. de Braud F, Heilbrun LK, Ahmed K, et al: Metastatic squamous cell carcinoma of an unknown primary localized to the neck Advantages of aggressive treatment. Cancer 64:510, 1989 22. Didolkar MS, Fanous N, Elias EG, et al: Metastatic carcinomas from occult primary tumors: A study of 254 patients. Ann Surg 186:625, 1977 23. Early Breast Cancer Trialists’ Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:1, 1992

METASTASES OF UNKNOWN PRIMARY SITE

169

24. Ellerbroek N, Holmes F, Singletary E, et al: Treatment of patiens with isolated axillary nodal metastases from an occult primary carcinoma consistent with breast origin. Cancer 66:1461, 1990 25. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483, 1990 26. Frost P, Raber MN, Abbruzzese JL: Unknown primary tumors as a unique clinical and biological entity: A hypothesis. Cancer Bull 41:139, 1989 27. Garrow GC, Greco FA, Hainsworth JD: Poorly differentiated neuroendocrine carcinoma of unknown primary tumor site. Semin Oncol 20:287, 1993 28. Gentile PS, Carloss HW, Huang TY, et al: Disseminated prostatic carcinoma simulating primary lung cancer: Indications for immunodiagnostic studies. Cancer 62:711, 1988 29. Goldberg RM, Smith FP, Ueno W, et a1 5-fluorouracil, Adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary. J Clin Oncol 4:395, 1986 30. Greco FA, Hainsworth JD: Tumors of unknown origin. CA Cancer J Clin 42:96, 1992 31. Guarischi A, Keane TJ, Elhakim T: Metastatic inguinal nodes from an unknown primary neoplasm: A review of 56 cases. Cancer 59:572, 1987 32. Hainsworth JD, Greco FA: Introduction: Unknown primary tumor. Semin Oncol 20:205, 1993 33. Hainsworth JD, Greco FA: Treatment of patients with cancer of an unknown primary site. N Engl J Med 329:257, 1993 34. Hainsworth JD, Johnson DH, Greco FA: Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: Results of a 12 year experience. J Clin Oncol 10:912, 1992 35. Hainsworth JD, Johnson DH, Greco FA: Poorly differentiated neuroendocrine carcinoma of unknown primary site: A newly recognized clinicopathologic entity. Ann Intern Med 109:364, 1988 36. Hainsworth JD, Wright E, Johnson DH, et al: Poorly differentiated carcinoma of unknown primary site: Clinical usefulness of immunoperoxidase staining. J Clin Oncol 9:1931, 1991 37. Hortobagyi GN, Buzdar AU: Current status of adjuvant systemic therapy for primary breast cancer: Progress and controversy. Ca Cancer J Clin 45:199, 1995 38. Jeremic B, Zivic DJ, Matovic M Cisplatin and 5-fluorouracil as induction chemotherapy followed by radiation therapy in metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck A phase I1 study. J Chemother 5:262, 1993 39. Jose B, Bosch A, Caldwell WL, et al: Metastasis to neck from unknown primary tumor. Acta Radio1 Oncol 18:161, 1979 40. Kambhu SA, Kelsen D, Fiore j, et al: Metastatic adenocarcinoma of unknown primary site. Am J Clin Oncol 13:55, 1990 41. Karsell PR, Sheedy PF, OConnell MJ: Computed tomography in search of cancer of unknown origin. JAMA 248:340, 1982 42. Kelsen D, Martin DS, Colofiore J, et al: A phase I1 trial of biochemical modulation using N-phosphonacetyl-L-aspartate, high-dose methotrexate, high-dose 5-fluorouracil, and leucovorin in patients with adenocarcinoma of unknown primary site. Cancer 70:1988, 1992 43. Kirsten F, Chi HE, Leary jA, et al: Metastatic adeno or undifferentiated carcinoma from an unknown primary site: Natural history and guidelines for identification of treatable subsets. Quart J Med 62:143, 1987 44. LeChevalier T, Cvitkovic E, Caille P, et al: Early metastatic cancer of unknown primary origin at presentation: A clinical study of 302 consecutive autopsied patients. Arch Intern Med 148:2035, 1988 45. Lee NK, Byers RM, Abbruzzese JL, et a1 Metastatic adenocarcinoma to the neck from an unknown primary source. Am J Surg 162:306, 1991 46. Lenzi R, Abbruzzese J, Amato R, et al: Cisplatin, 5-FU and folinic acid for the treatment

170

LEMBERSKY & THOMAS

of carcinoma of unknown primary [abstr 10551. In Proceedings of the American Society of Clinical Oncology, Houston, 1991, p 301 47. Mackay B, Ordonez NG: Pathological evaluation of neoplasms with unknown primary tumor site. Semin Oncol 20:206, 1993 48. Marcial-Vega VA, Cardenes H, Perez CA, et al: Cervical metastases from unknown primaries: Radiotherapeutic management and appearance of subsequent primaries. Int J Radio1 Oncol Biol Phys 19:919, 1990 49. Mayordomo JI, Guerra JM, Guijarro C, et al: Neoplasms of unknown primary site: A clinicopathological study of autopsied patients. Tumori 79:321, 1993 50. McCunnif A, Rabin M Metastatic carcinoma of the neck from an unknown primary. Int J Radiat Oncol Biol Phys 12:1849, 1986 51. McMillan JH, Levine E, Stephens R H Computed tomography in the evaluation of metastatic adenocarcinoma from an unknown primary site: A restrospective study. Radiology 143:143, 1982 52. Milliken ST, Tattersall MH, Woods RL, et al: Metastatic adenocarcinoma of unknown primary site: A randomized study of two combination chemotherapy regimens. Eur J Cancer Clin Oncol23:1645, 1987 53. Moertel CG, Kvols LK, O’Connell MJ, et al: Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin: Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 68:227, 1991 54. Mohit-Tabatabai MA, Dasmaphapatra KS, Rush BF Management of squamous cell carcinoma of unknown origin in cervical lymph nodes. Am J Surg 52152, 1986 55. Moore MP, Yahalom J: Occult primary tumor with axillary metastases. In Harris JR, Hellman S, Henderson IC, et a1 (eds): Breast Diseases, ed 2. Philadelphia, JB Lippincott, 1991, p 817 56. Motzer RJ, Rodriguez E, Reuter VE, et al: Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site. J Clin Oncol 13:274, 1995 57. Motzer RJ, Rodriguez E, Reuter V, et al: Genetic analysis aids in the diagnosis of patients with midline carcinomas of uncertain histologies. J Natl Cancer Inst 83:341, 1991 58. Muggia FM, Baranda J: Management of peritoneal carcinomatosis of unknown primary tumor site. Semin Oncol 20:268, 1993 59. Nordstrom DG, Tewfik HH, Latourette H B Cervical lymph node metastases from an unknown primary. Int J Radiat Oncol Biol Phys 5:73, 1979 60. Nystrom JS, Weiner JM, Heffelfinger-Juttner J, et al: Metastatic and histologic presentations in unknown primary cancer. Semin Oncol4:53, 1977 61. Nystrom JS, Weiner JM, Wolf RM, et al: Identifying the primary site in metastatic cancer of unknown origin: Inadequacy of roentgenographic procedures. JAMA 241:381, 1979 62. Patel J, Nemoto T, Rosner D, et al: Axillary lymph node metastases from an occult breast cancer. Cancer 472923, 1981 63. Pavlidis N, Kalef-Ezra J, Briassoulis E, et a1 Evaluation of six tumor markers in patients with carcinoma of unknown primary. Med Pediatr Oncol 22:162, 1994 64. Raber MN, Faintuch J, Abbruzzese JL, et a1 Continuous infusion 5-fluorouracil, etoposide and cisplatin in patients with metastatic carcinoma of unknown primary origin. Ann Oncol 2:519, 1991 65. Ransom DT, Patel SR, Keeney GL, et al: Papillary serous carcinoma of the peritoneum: A review of 33 cases treated with cisplatin-based chemotherapy. Cancer 66:1091, 1990 66. Rosen PP: Axillary lymph node metastases in patients with occult noninvasive breast carcinoma. Cancer 46:1298, 1980 67. Spiro RH, DeRose G, Strong EW: Cervical node metastasis of occult origin. An1 J Surg 146:441, 1983 68. Sporn JR, Greenberg BR. Empiric chemotherapy in patients with carcinoma of unknown primary site. Am J Med 88:49, 1990 69. Steckel RJ, Kagan AR Diagnostic persistence in working up metastatic cancer with an unknown primary site. Radiology 134:367, 1980

METASTASES OF UNKNOWN PRIMARY SITE

171

70. Stewart JF, Tattersall MH, Woods RL, et al: Unknown primary adenocarcinoma: Incidence of over investigation and natural history. BMJ 1:530, 1979 71. Strnad CM, G o s h WW, Baxter J, et al: Peritoneal carcinomatosis of unknown primary site in women. Ann Intern Med 111:213, 1989 72. Tell DT, Khoury JM, Taylor G, et al: Atypical metastasis from prostate cancer: Clinical utility of the immunoperoxidase technique for prostate specific antigen. JAMA 253:3574, 1985 73. van der Gaast A, Verweij J, Planting A, et a1 Simple prognostic model to predict survival in patients with undifferentiated carcinoma of unknown primary site. J Clin Oncol 13:1720, 1995 74. van der Gaast A, Verwey J, Prins E, et al: Chemotherapy as treatment of choice in extrapulmonary undifferentiated small cell carcinomas. Cancer 65:422, 1990 75. Woods RL, Fox RM, Tattersall MH, et al: Metastatic adenocarcinomas of unknown primary site: A randomized study of two combination-chemotherapy regimens. N Engl J Med 303:87, 1980 76. Zaren HA, Copeland EM: Inguinal node metastases. Cancer 41:919, 1978

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