The single supratentorial lesion. An evaluation of preoperative diagnostic tests

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1 J Neurosurg 53: , 1980 The single supratentorial lesion An evaluation of preoperative diagnostic tests RAND M. VOORHIES, M.D., NARAYAN SUNDARESAN, M.D., AND H. Tzvl THALER, PH.D. Department of Neurosurgery, New York Hospital-Cornell University Medical School, and the Neurosurgical Service and Biostatistics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York The role of preoperative diagnostic tests was evaluated in 210 adult patients with single supratentorial lesions demonstrated by computerized tomography. At craniotomy, 59.5% of these patients proved to have primary brain tumors, 36.2% had metastatic tumors, and 4.3% had non-neoplastic lesions. In 23 (11%) of these patients, a single brain metastasis was the first manifestation of a systemic cancer. The primary site of cancer was identified in 14 patients (10 in the lung, three in the kidney, and one in the colon), and in nine patients the primary site could not be established. Using simple conditional probability theory, we established that the probability of a metastatic lesion in patients without a history of previously treated cancer is about 7%, if their chest x-ray film and intravenous pyelogram (IVP) are negative. Extensive preoperative testing to try to establish a primary site is unrewarding if the chest x-ray film and IVP are negative, since these are the only sites likely to be identified in these patients. In patients with a history of previously treated cancer, these tests are justified because they have prognostic value in determining treatment. KEY WORDS 9 single brain lesion 9 computerized tomography 9 diagnostic test 9 metastatic tumor W 'HA'r is the role of diagnostic testing in identifying the primary site of cancer in patients who present with a metastatic focus? How extensively should one pursue this search? These questions are the subject of continuing debate in the literature, s,l~ On occasion, a single brain metastasis may be the initial manifestation of a systemic cancer? Most of us are intuitively aware that a search for a primary site can be vexing, and the yield often meager. In the clinical setting, this search is often undertaken when the radiologist is unable to distinguish a primary from a metastatic neoplasm by computerized tomography (CT) evaluation alone. Although angiography may provide supplemental information, the clinician often must decide whether a single brain lesion is a primary or metastatic tumor. In this dilemma, he often feels compelled to obtain numerous diagnostic tests in an effort to identify a possible primary site in an area that may be biopsied with greater ease and safety. Since these tests are often time-consuming and expensive, they can be justified if they yield information of value in the care of these patients. Since there are no data in the literature that address this problem, we undertook a retrospective survey to identify which tests might be most useful in this group of patients. Clinical Material and Methods We analyzed the case records of 210 patients who underwent craniotomy at the Memorial Sloan- Kettering Cancer Center and the New York Hospital, from July, 1977, through June, 1979, for a solitary brain tumor presumed to be supratentorial. The following groups of patients were excluded from this analysis because the probability of distinguishing between a primary and metastatic neoplasm appeared unlikely: I) patients under 30 years of age; 2) patients with suprasellar and cerebellopontine angle lesions; 3) patients with posterior fossa tumors; and 4) patients in whom a previous tissue diagnosis was available, that 364 J. Neurosurg. / Volume 53 / September, 1980

2 Preoperative tests for solitary cerebral lesions is, patients with recurrent tumors. Patients who presented with multiple intracranial lesions were also excluded from the study. In addition, this series only includes patients who underwent craniotomy for the tumor, and does not include patients in whom surgery was not performed because they were thought to have advanced metastatic cancer at the initial diagnosis on clinical or radiological grounds alone. The results of laboratory, radiological, and other diagnostic tests performed on these patients were analyzed from the charts. All patients underwent a routine work-up, which consisted of a complete blood count, urinalysis, chest x-ray film, electrocardiogram, and a semiautomated screening profile (SMA 12). We defined an extensive diagnostic evaluation as any or all of the tests shown in Table 1. The number of these tests performed on any individual patient varied, but 116 patients (55%) underwent an extensive diagnostic evaluation consisting of at least four of these diagnostic tests. Since radiological tests may give false-positive or false-negative results, these tests were analyzed specifically to see if they contributed to the possible identification of a primary site of cancer. In patients in whom a metastatic neoplasm appeared likely, based on their clinical history of a known cancer in the past, we assumed that these tests were being performed for prognostic information prior to craniotomy rather than for any diagnostic value. We next computed the probability of a patient having a metastatic tumor in this patient population, using data derived from the diagnostic evaluation. Since the chest film and intravenous pyelogram were the only two tests that provided additional data, the conditional probability of having either a primary, metastatic, or nonneoplastic lesion was calculated according to whether 1) the patient had a past history of diagnosed cancer; 2) in addition to (I), whether the chest film was positive or negative; and 3) in addition to (1) and (2), whether the intravenous pyelogram was positive or negative. A positive test was one in which the radiologist raised the possibility of a neoplastic lesion that might represent a primary focus of cancer. Results Table 2 indicates the distribution of primary and metastatic tumors in patients who underwent craniotomy at this institution, and Table 3 indicates the primary sites of cancer in those adult patients who had a history of treated cancer. Of the 210 patients, 76 (36.2%) were found to have metastatic tumors. In nine patients (4.3%), a non-neooplastic lesion was identified at craniotomy. These included vascular malformations in four, demyelinating disease in two, gliosis in one, congophilic angiopathy in one, and radiation necrosis in one. When the history of previously treated cancer was taken into consideration, two subgroups could be Work-Up routine extended work-up surgical TABLE 1 Studies in the diagnostic work-ups Study complete blood count urine analysis semiautomated blood screening (SMA 12) chest x-ray film electrocardiogram stool for occult blood (guaiac test) intravenous pyelogram barium enema upper gastrointestinal series mammogram radionuclide studies bone scan liver scan gallium scan thyroid scan ultrasound abdomen computerized tomography abdomen cytology, sputum, urine, etc. blood for tumor markers carcinoembryonic antigen alphafetoprotein bone marrow biopsy rib biopsy TABLE 2 Classification of single intracranial lesions No. of Classification Cases Percent primary tumors metastatic tumors nontumor masses total TABLE 3 Classification of metastatic supratentorial tumors in adult patients with a past history of cancer Primary No. of Site Cases lung 15 adenocarcinoma 9 epidermoid 2 undifferentiated 4 melanoma 13 renal 9 clear cell 8 undifferentiated 1 colon 5 breast 3 testicular 3 miscellaneous 5 rhabdomyosarcoma, adrenal, mesothelioma, carcinoid tumor, Ewing's sarcoma total 53 J. Neurosurg. / Volume 53 / September,

3 R. M. Voorhies, N. Sundaresan and H. T. Thaler FIG. 1. Venn diagram illustrating probabilities of primary, metastatic, and non-neoplastic lesions, based on clinical and laboratory data. IVP = intravenous pyelogram. identified (Table 4). Group 1 included 57 patients with a history of treated cancer. Of these, three patients (5%) were discovered to have a second primary intracranial neoplasm (two meningiomas, one glioblastoma), 53 (93%) had metastatic tumors, and only one patient had a non-neoplastic lesion. Thus, the probability of having a metastatic tumor if there was a previous history of treated cancer was 93%. In the 153 patients (Group 2) who had no previous diagnosis of cancer, 122 (79.7%) were found to have primary tumors, 23 (15%) had metastatic tumors, and eight (5.3%) had non-neoplastic lesions (Fig. 1). From these data, it is apparent that, given a history of no previous cancer, the probability of finding a primary tumor at craniotomy is approximately 80%, and only 15% of patients will be found to have metastatic lesions. Of the 23 patients who were diagnosed as having metastatic tumor at the time of craniotomy, but who had no history of cancer, 10 patients were found to have an abnormal chest x-ray film. In three patients, the initial evaluation of the chest x-ray film was reported to be normal. Following craniotomy, retrospective evaluation showed a possible primary site in the lung. In five of these patients, the diagnosis of a primary tumor of the lung was established by diagnostic bronchoscopy and thoracotomy. In one patient, a primary lung carcinoma was discovered at autopsy. The four remaining patients were presumed to have primary lung carcinomas and were treated with radiation therapy without histological confirmation. Three patients were found on intravenous pyelography to have abnormalities consistent with a primary renal neoplasm. In one of these patients, this diagnosis was only established after histology of the brain tumor revealed a clear-cell adenocarcinoma consistent with a kidney tumor. All three patients underwent radical nephrectomy for removal of their kidney tumors approximately 2 to 3 weeks following craniotomy. One patient was found to have an abdominal mass on physical examination and a guaiacpositive stool. Sigmoidoscopy confirmed cancer of the colon, and he underwent bowel resection following surgical resection of his metastatic brain tumor. In nine patients, no primary source was detected during initial hospitalization, despite an extensive search for a primary tumor. One of these patients was subsequently discovered on a chest film 6 months after craniotomy to have a primary site in the lung, and underwent resection of a primary lung tumor. An additional patient whose initial chest film was normal was found at autopsy to have a primary site in the lung. Of the 143 patients (Group 2A, Fig. 1) who had no history of cancer and in whom the chest film was normal, 85.3% were found to have primary tumors, 9.1% were found to have metastatic tumors, and 5.6% had non-neoplastic lesions. If an intravenous pyelogram was also normal (Group 2B, Fig. 1), then the probability of metastatic tumor was reduced to 7.1%. In all these patients, no additional test contributed any information regarding a possible primary site of cancer. Table 5 indicates the different histological patterns encountered in the 23 patients in whom cerebral metastasis was the initial clinical presentation. The majority of these tumors proved to be adenocarcinomas, and the presence of additional histological characteristics (such as mucin production or papillary differentiation) was not helpful in determining the primary site. Discussion The rationale for ordering multiple preoperative tests in a patient with no history of cancer and who presents with a single intracranial lesion is based upon two premises. One is the clinician's belief that there is a "reasonable" probability that the lesion is indeed a metastasis. The second premise is that the search for a primary site will be successful, based on the knowledge that certain kinds of cancer frequently metastasize to the brain (for instance, cancer of the lung, breast, kidney, gastrointestinal tract, and melanoma). The first assumption is a subjective estimate of probability, and frequently tends to be biased by the radiologist's uncertainty. Studies have shown that subjective estimates of probability that do 366.1". Neurosurg. / Volume 53 / September, 1980

4 Preoperative tests for solitary cerebral lesions not take into account prior probability of outcomes are often erroneous? ~ We have employed a simple mathematical approach using conditional probability to show that the true probability of metastatic tumor (given negative cancer history, normal chest x-ray film, normal intravenous pyelogram) is about 7%. Based on our sample size, the 95% confidence interval for our estimate is between 3.5% and 10.5%. To calculate this percentage, the actual prevalence of patients with cancer who initially present with an intracranial mass in any given patient population has to be determined. In most neurosurgical craniotomy series for brain tumor, metastases account for about 10%. 3 In this study, which focuses on a selected group of patients, this figure was 36%, much higher than that generally reported. However, in those patients with no history of cancer, a cerebral metastasis was the presenting symptom in 15%. Although this prevalence may vary from institution to institution, we believe that our data will have widespread application since the number of patients who present in this fashion will be low. It is interesting to note that this figure was identical for Memorial Hospital and New York Hospital, which have markedly different patient populations. Using Bayesian analysis, numerous studies have shown that diagnostic screening tests will have high predictive value only if the pre-test prevalence is high. 2,~,12 With this method, we have estimated that if the radiologist interprets a lesion as metastatic tumor without using clinical data, the probability of the lesion actually being a metastasis is only 41%. This calculation was performed based on a recent study by Amundsen, et al.? showing that the sensitivity of the CT scan in identifying metastases was 93%, and specificity was 90%. Although this result is surprising, the reason that the CT scan may seem so accurate in actual practice is because radiologists frequently take into account clinical data while interpreting intracranial lesions (see Appendix). Despite the low probability that the intracranial lesion is metastatic, one might be justified in undertaking extensive diagnostic tests if the primary site could be identified. Both our data and the study by Ebels and van der Muelen* suggest, however, that the only sites that can be identified preoperatively are the lung and kidney. Furthermore, studies of patients who present with systemic carcinoma from an occult primary neoplasm suggest that there is an extremely low yield in identifying the primary site of cancer. ~~ Nystrom, et al.? 4 therefore, suggested that the performance of an intravenous pyelogram, barium enema, and upper gastrointestinal series be limited to those patients who manifested specific organ dysfunction, since the incidence of false-positives for these tests equalled true-positives. They also pointed out that those cancers that present initially as a metastatic lesion exhibit a different pattern of metastasis, implying perhaps a fundamental biological difference in the TABLE 4 Classification of lesion based on history of previously treated cancer* Classification Group 1 Group 2 primary tumors metastatic tumors nontumor masses 1 8 total *Group 1 included patients with a history of treated cancer, Group 2 includes patients with no previous history of cancer, TABLE 5 Histology of brain tumor in 23 patients in whom cerebral metastasis was initial diagnosis Brain Tumor Primary Site Histology Lung Kidney Rectum Unknown anaplastic 3" 1 clear cell 2 mucinous 2~ papillary 1 :~ combination adenocarcinoma, 3 nonspecific epidermoid 1 total w 2 3 *Primary site in the lung was presumed on chest film in two patients, and was verified in one. ~Lung cancer was presumed from the chest film. :~Confirmed at autopsy. w of these four were subsequently verified as being primary lung cancer. behavior of these tumors. Carcinoma of the lung is the only common tumor that frequently metastasizes to the brain, and also frequently presents as a cancer of unknown primary site. Any abnormality detected on screening tests should be investigated preoperatively. In view of the high prevalence of lung carcinoma in this group, particular attention should be directed to the chest film. Chest tomography and CT scanning of the thorax may be helpful if any abnormalities are noted. If the screening tests and intravenous pyelogram are normal, craniotomy may then be justified both for tissue diagnosis and as a therapeutic measure. This is predicated on the assumption that the tumor is surgically accessible, and can be removed with minimal morbidity and mortality. We further assume that the surgeon would be willing to consider craniotomy even if he knew the lesion was a metastatic tumor. TM Should a metastatic tumor be found, the postoperative search for a primary site can be guided by pathological evaluation of the tissue. In this regard, electron microscopy and enzyme histochemistry of the neoplastic cells may provide helpful clues? ~ Periodic follow-up examination should be focused on the lungs, where a primary lesion may subsequently be identified. J. Neurosurg. / Volume 53 / September, I

5 R. M. Voorhies, N. Sundaresan and H. T. Thaler In patients with a known history of cancer, the probability of encountering a metastatic tumor is 93%. In this situation, diagnostic tests are performed more for prognostic information and in deciding the most appropriate therapy for the patient. Even in this group, there is a small chance that a second primary tumor or non-neoplastic lesion will be found. In our series, two patients with breast cancer were found to have meningiomas. One patient with lung cancer was found to have a small angiomatous malformation, and a fourth patient with prostate cancer was found to have a glioblastoma. Our purpose is not to lay down rigid criteria for the performance of diagnostic tests, since such inflexible attitudes may hinder the management of any one individual case? Rather, our data may justify limiting extensive testing prior to craniotomy since these tests are time-consuming and expensive, and the yield is extremely meager. An additional important factor may be the anxiety and discomfort generated in the patient by prolonged diagnostic evaluation. At the present time, it has been estimated that medical technology alone is responsible for 25% to 50% of current health care costs?,is It has been suggested that constant evaluation of our diagnostic strategies is important both for optimum patient care and in deciding on a more rational use of our health resources. 7 We hope that this study represents a step in this direction. APPENDIX The terms "sensitivity" and "specificity" are often used to indicate the efficiency of diagnostic tests. The sensitivity of a test relates to the capacity of a test in making a correct diagnosis in confirmed positive cases of the disease. The specificity of a test indicates the capacity for correct diagnosis in confirmed negative cases. sensitivity (S) = specificity (F) = true positive patients with disease' true negative patients without disease" Predictive value of a positive test true positive all positives (true & false) where P = prevalence. S (s P) + (1- F) (1 - P) ' In our study, P = 0.07 (7%), which is the proportion of patients with no history of cancer and with a negative chest x-ray film and intravenous pyelogram. The data for sensitivity and specificity were calculated from Table 8 of Amundsen, et al: 1 14 of 15 metastases were correctly identified, for a sensitivity of 93%, and 28 of 31 nonmetastatic tumors were correctly identified as nonmetastatic, for a specificity of 90%. Feinstein 5 has presented an excellent discussion of these concepts. References 1. Amundsen P, Dugstad G, Syvertsen AH: The reliability of computer tomography for the diagnosis and differential diagnosis of meningiomas, gliomas, and brain metastases. Acta Neurochir 41: , Bell RS: Efficacy... what's that? Semin Nucl Med 8: , Butler AB, Netsky MG: Classification and biology of brain tumors, in Youmans JR (ed): Neurological Surgery, Vol 3. Philadelphia: WB Saunders, 1973, pp Ebels E J, van der Muelen,IDM: Cerebral metastasis without known primary tumour: a retrospective study. Clin Neurol Neurosurgery 80: , Feinstein AR: Clinical Biostatistics. St Louis: CV Mosby, 1977, chapter Feldstein MS, Taylor AK: The Rapid Rise of Hospital Costs. Washington, DC: Office of the President's Council on Wage and Price Stability, Fineberg HV, Hiatt HH: Evaluation of medical practices. The case for technology assessment. N Engl J Med 301: , Gilbert HA, Kagan AR: Metastases: incidence, detection, and evaluation without histologic confirmation, in Weiss L (ed): Fundamental Aspects of Metastasis. New York: American Elsevier, 1976, pp Good l,i: The Estimation of Probabilities. An Essay on Modern Bayesian Methods. Cambridge, Mass: MIT Press, 1965 I0. Hickey RC: Current Problems in Cancer: Metastases of Undetermined Source. Chicago: Yearbook Medical, 1979, 37 pp 11. MacComb WS: Diagnosis and treatment of metastatic cervical cancerous nodes from an unknown primary site. Am J Surg 124: , McNeil B J, Keeler E, Adelstein S,I: Primer on certain elements of medical decision making. N Engl J Med 293: , Nystrom.IS, Weiner JM, Heffelfinger-,iuttner,i, et al: Metastatic and histologic presentations in unknown primary cancer. Semin Oneol 4:53-58, Nystrom.IS, Weiner,IM, Wolf RM, et al: Identifying the primary site in metastatic cancer of unknown origin. Inadequacy of roentgenographic procedures. JAMA 241: , Smith PE, Krementz ET, Chapman W: Metastatic cancer without detectable primary site. Am J Surg 113: , Stewart.IF, Tattersall MHN, Woods RL, et al: Unknown primary adenocarcinoma: incidence of over-investigation and natural history. Br Med J i: , Tversky A, Kahneman D: Judgement under uncertainty: Heuristics and biases. Science 185: , Waldman S: Effect of changing technology on hospital costs. Soc Secur Bull 35:28-30, Wilson CB: Brain metastases: the basis for surgical selection, lnt J Radiat Oneol Biol Pbys 2: , 1977 Address reprint requests to: Narayan Sundaresan, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York J. Neurosurg. / Volume 53 / September, 1980