Journal of Surgical Oncology 51:109-113 (1992)

Skeletal Metastasis From Occult Carcinoma LIH-YUANN SHIH, MD, TIEN-HSIUNG CHEN, MD, AND WAI-HEE LO, MO From the Department of Orthopedics and Traumatology, Veterans Genera/ Hospital-Taipei, Young Ming Medical College, Taipei, Taiwan, Republic of China

We reviewed 177 patients with skeletal metastases, seen between 1984 and 1989, to define the characteristics of metastatic bone disease from an occult primary carcinoma. In 52 (30%) patients, the primary carcinomas could not be identified when the bone metastases were first diagnosed. This group was predominantly male, with intractable pain the most common symptom. The primary tumors were identified on antemortem evaluation in 28 (54%) patients after extensive examination. Among these, the primary tumor was in the lung in 9 patients, followed by liver (8), kidney (3,prostate (3), thyroid gland (2), and rectum (1). The identifiable occult malignancies possessed three common features: all were osteophilic tumors, all had a high incidence in the specific geographic area, and all were not amenable to early detection. The mean survival of these patients was 1 1 months. Current treatment modalities failed to affect the course of these patients, except for those with primary carcinomas of the kidney and prostate. This observation attests to our limitations in both the diagnosis and treatment of this problem. Efforts should be directed primarily toward excluding those common and/or treatable tumors only. 0 1992 Wiley-Liss, Inc.

KEYWORDS: osseous metastasis, osteophilic tumors, a-fetoprotein levels

INTRODUCTION Patients with metastatic cancers to the liver, lung, or bone from an occult primary lesion are more common than often expected. Metastatic carcinoma from an unknown primary site can account for 3-5% of all malignant solid tumors [I-61. In 5-20% of these patients, a skeletal metastasis is the first lesion to be detected [ 1-3,7]. When the primary tumor is occult and a skeletal metastasis is the presenting problem, a challenging situation emerges. The orthopedist not only has to make a meticulous search for the elusive primary tumor but is also faced with the management of the overt lesion(s). The frequency, distribution and treatment of skeletal metastases from various carcinomas have been previously described [S-1 01. However, the true incidence, behavior, and origin of bone metastases from an unknown primary site have not been well documented. There is also little information as to the relative value of specific investigations in these patients. This review focuses on the problems of skeletal metastases from an occult carcinoma from the beginning of the diagnostic investigation and from the orthopedist’s point of view. 0 1992 Wiley-Liss, Inc.

Special attention was given to finding an efficient and humane diagnostic strategy for locating the primary cancer, as well as defining the therapeutic approach toward these patients.

MATERIALS AND METHODS During January 1984 to December 1989, 177 patients with skeletal metastases were treated at Veterans General Hospital, Taipei. In 52 patients, the primary lesions could not be identified when the bone metastases were first diagnosed. The patients were considered to have skeletal metastases from an unknown primary site if they had clinical and radiological evidence of metastatic cancer, but a complete history review and thorough physical examination did not reveal a primary tumor. Histologic proof of malignancy was mandatory for inclusion in the survey. Accepted for publication May 29, 1992 Address reprint requests to Dr. Lih-Yuann Shih, Department of Orthopedics and Traumatology, Veterans General Hospital-Taipei, Taipei, Taiwan 11217, Republic of China.

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Shih et al. TABLE 1. Workup for Skeletal Metastasis From an Occult Carcinoma S r q I : History revicw and physical examination Stc~p2: Initial workup Laboratory: blood, urine, and stool routine; multiphasic scruin chemistry; tumor markers (e.g., AFP, prostatic acid phosphatase); cytology (e.g,, sputum, urine); protein electrophoresis Imaging: chest and bone roetgenogranis; chest C T scan; abdominal CT scan or ultrasound; TC””’- phosphate bone scan Stc,p 3: Biopsy and frozen section Internal fixation for impending o r pathological fracture Neurological decompression or other procedures S r q 4: Permanent tissue diagnosis Radiotherapy, chemotherapy, or other definitive treatment Stq>5 : Further evaluation according to specific symptoms

Initial Diagnostic Evaluation

RESULTS

A consistent diagnostic strategy (Table I) was employed in an attempt to identify the site of the primary carcinoma prior to biopsy. Included were a complete history and thorough physical examination with particular attention to the thyroid gland, the breast, and the prostate. Laboratory tests included a complete blood count (CBC), erythrocyte sedimentation rate (ESR), multiphasic blood chemistry, urinalysis, and stool guaiac test. The serum level of certain tumor markers, such as carcinoembryonic antigen (CEA) and a-fetoprotein (AFP) were checked routinely. Serum acid phosphatase (prostatic fraction) levels in male patients and Ca- 199 levels in female patients were also determined. If the serum globulin was abnormal, protein electrophoresis was performed. Sputum and urine cytology were checked three times for each patient. In all cases, diagnostic imaging studies prior to biopsy included a chest roentgenogram and roentgenograms of the obviously affected bone and other areas with increased scintigraphic activity on bone scan. A TcY9lnphosphate bone scan was performed in every patient. Abdominal ultrasound or computed tomography (CT) scans, or both, were undertaken and reviewed in all patients prior to biopsy. A CT scan of the chest was performed on the basis of clinical suspicion. The surgical biopsy was performed after the initial screening tests.

The patients consisted of 44 men and 8 women whose ages averaged 63 years (range, 46-80 years). The initial symptoms were pain in 28 patients, pathological fracture in 13 patients, palpable mass in 4 patients, and paraplegia or paraparesis in 7 patients. A complete historical revicw revealed unusual body weight loss and general weakness in 16 patients. More specific symptoms were not found. A thorough physical examination failed to disclose the primary site.

Further Evaluation Additional studies were performed after the initial examinations and biopsy in an attempt to locate the tumor origin, if the patient could tolerate the procedures. These included 24 intravenous pyelograms (IVP), 20 upper gastrointestinal (GI) contrast studies, 24 barium enema examinations, 34 liver-spleen scans, 16 thyroid scans, and 26 gallium scans. Castroscopic examination was performed in 28 patients, colonoscopic examination in 21 patients, and bronchoscopic examination in 28 patients.

Initial Examination Laboratory findings, such as elevated lactic dehydrogenase (LDH), alkaline phosphatase, and hypercalcemia, supported the diagnosis of bone metastasis. Occult blood was present in the stool of 10 patients, none of whom was found to have GI tract cancer. The ESR, a nonspecific indicator for inflammation or malignancy, was elevated in 43 patients. Serum AFP levels were significantly raised in eight patients. All were proved to have a hepatoma. In one patient, a marginal elevation of AFP was found to be due to chronic liver disease. The serum concentration of CEA was increased in 18 patients. In seven cases, the primary tumor site could be discovered. One had rectal cancer, and six had lung cancer. The serum acid phosphatase (prostatic fraction) level was measured in all male patients and was elevated in four. In three of them, prostate cancer was diagnosed by biopsy. One patient was diagnosed as having benign prostate hypertrophy after transurethral prostatectomy. Sputum cytology was performed routinely, with seven patients having malignant cells. Urine cytology was performed in 33 patients, with only one positive for malignant cells. The initial X-ray abnormality was in the spine in 16 patients, in the pelvis and the proximal femur in 22 patients, and in the shoulder region in 8 patients. Other sites, such as the clavicle, proximal tibia, and distal fe-

Skeletal Metastasis From Occult Carcinoma

mur, were involved in the other 6 patients. Bone scans identified single-site involvement in 13 patients, while 39 patients had multiple bone involvement. Abdominal ultrasonic examinations disclosed a single hepatic lesion in four patients, multiple hepatic lesions in six patients, a solitary renal lesion in five patients, and an irregular echo in the prostates of three patients. Eight of the hepatic lesions were proved to be hepatomas. The other two patients had hepatic metastases. Five patients with renal lesions were found to have renal cell carcinomas. The patients with irregular echoes of the prostate were finally proved to have prostate cancer. The rectal cancer was not found by abdominal ultrasonic examination. CT scan of the abdomen was performed in 21 patients, revealing six liver lesions, one rectal lesion, two prostate lesions, and two renal lesions. Two of the liver lesions had multiple foci and were due to hepatic metastases. One prostatic lesion was diagnosed as benign hypertrophy after biopsy. CT scan of the chest was performed in 2 I patients and disclosed a single pulmonary tumor in six patients and multiple pulmonary lesions in another six patients. Bronchoscopic examination failed to disclose two of the pulmonary tumors, while seven of them had bronchoscopic as well as a tissue diagnosis. Three patients with multiple lung lesions were proved to be due to lung metastases.

Further Examination If the initial examination was inconclusive, additional studies were performed after biopsy in an attempt to locate the primary as long as the patients could tolerate the procedures. Twenty upper GI contrast studies were performed. Eighteen were negative, and two were diagnosed as gastric lesions. The results were false positive, since further investigation failed to confirm a primary gastric tumor. Twenty-four barium enemas were performed, but only one patient was found to have primary rectal tumor. IVP was performed in 24 patients. Three patients were diagnosed as having renal tumors, and six had prostate abnormalities. One of the renal tumors was deemed false positive, as subsequent examination did not confirm a primary tumor at this site. One patient with renal cell carcinoma had a false-negative IVP. Three of the prostatic lesions were malignancies, and three were benign prostate hypertrophy. Seventeen thyroid scans were performed. A false-negative thyroid scan was obtained in a patient who was finally established as having papillary carcinoma of the thyroid. Gallium scans were performed in 24 patients but were not useful in detecting the primary site and not as accurate as T ~ ~ ~ " - b oscan n e in assessing the extent of skeletal metastasis. Liver and spleen scans were performed in 34 patients. Seven scans outlined hepatic lesions, two of which were considered metastatic. Two

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false-negative liver and spleen scans failed to detect diffuse hepatic lesions. Twenty-eight gastroscopic examinations and 2 1 colonoscopic examinations revealed no primary lesions in the GI tract. One patient was finally found to have rectal cancer, but the colonoscopic examination was reported as negative. Bronchoscopic examinations were performed in 28 patients suspected of having lung lesions. Seven had positive findings and also provided a tissue diagnosis, while two of the pulmonary tumors were missed.

Pathology Five clear cell carcinomas (most likely from the kidney), two papillary carcinomas of the thyroid gland, and seven hepatomas were readily identifiable by their distinctive morphologic patterns on histologic evaluation. Hepatomas were further confirmed by the presence of monoclonal antibodies (MAb). In the other 38 patients, histological diagnoses were metastatic adenocarcinoma in 27 patients, poorly differentiated carcinoma in seven patients, and metastatic epidermoid carcinoma in four patients. Diagnosis, Treatment, and Survival Antemortem localization of the primary tumor was possible in 28 patients only. Nine were lung cancers and received chemotherapy or radiotherapy according to spread of disease. Eight were hepatomas and received supportive treatment. Five had renal cell carcinomas, and three later received nephrectomies. Two were papillary carcinomas of the thyroid and received total thyroidectomies. Three were prostate carcinomas and received prostatectomies and hormone therapy. One was rectal cancer and received conservative treatment. In the other 24 patients, the primary site could not be located, even after extensive investigation. Thirty-four patients received palliative radiotherapy to the symptomatic osseous metastatic sites. Four patients received en bloc excision of the bone lesion. Sixteen patients had open reduction and internal fixation with cement augmentation for pathological fractures. Six patients had spinal anterior or posterior decompression for neurological deficits, or both, due to spinal metastases. Ten patients received no therapy at all. The mean survival of the patients was 11 months. Four patients survived 61 months, 45 months, 48 months, and 15 months, respectively, from the initial diagnosis to the time of this report. These diagnoses included prostate cancer in one case, thyroid cancer in another and renal cell carcinoma in the other two. The survival period according to the histologic diagnosis is shown in Table 11. Patients with identifiable primary tumors of the kidney and prostate had better prognoses than did others. Among those patients whose primary tumor could not be found,

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Shih et al.

TABLE 11. Frequency and Survival by Histologic Diagnosis of Patients With Skeletal Metastasis From Occult Origin

No. of cases (%)

Histological t w e

Average survival months (range)

With detected origin Renal cell carcinoma Prostate cancer Papillary thyroid cancer Hepatoma Lung cancer Rectum cancer

5 3 2 8 9 I

(10%)

With unknown origin Adenocarcinoma Poorly differentiated Epidermoid carcinoma

16 6 2

(31%) (11%) (4%)

I 1 (3-24) 4 (3-8) 3 (2-4)

52

(100%)

I I (2-61)

Total

-

(6%) (4%) ( I 5%) ( I 7%) (2%)

29 ( 2 4 8 ) 29 (2-61) 26 (-5) 6 (2-1 1) 6 (4-10) 4

patients with adenocarcinoma had a better prognosis than did those with poorly differentiated or epidermoid carcinomas.

DISCUSSION The ages of our patients are consistent with previously noted patterns [5,1 I]. Men have been reported to have a higher incidence of skeletal metastases from occult origin than do women 11 I ] . Men outnumbered women by a 5 : 1 margin in this series. However, it is not certain that this reflects the true incidence as our hospital services veterans giving us a predominantly male patient population. Osseous metastases usually occur in the axial bones or proximal portion of appendicular bones in patients above 40 years of age. Progressive intractable pain is the most common and earliest presenting symptom. Some patients have even been mistreated as degenerative disease for a period until pathological fractures or signs of spinal cord compression occur. It is important to consider the possibility of bone metastases as a cause of pain in aged patients to lessen the incidence of delayed diagnosis. Three factors are important when searching for the origin of an occult malignancy: (1) the osteophilic property of various tumors, (2) the prevalence of tumors in a specific geographical area, and ( 3 ) the accessibility to the early detection of each tumor. Some carcinomas, the so-called osteophilic tumors, are more likely than others to spread to the skeleton. Breast carcinoma is the most common tumor to spread to bone, followed by prostate and lung cancer [8-1 I ] . GI tract cancers are the least likely to metastasize to bone. We found that of the tumors whose primary site was identified, all were osteophilic tumors, except for the one arising in the rectum. Prevalence is also an important factor. The common cancers in male patients in Taiwan are hepatomas, followed by lung, gastric, colon, and esophageal cancers. In women,

this order is lung cancer, followed by hepatoma, then by gastric, colonic, and cervical cancer. Lung cancer has been reported to be the most common site of an occult cancer [ 1,1 I]. We found hepatomas to be nearly as common in our series, which probably reflects the prevalence of hepatoma in Taiwan. We found no cases of breast carcinoma in our series. Breast carcinoma is an infrequent occult cause of bone metastasis, possibly because of its accessibility to examination and the occurrence of symptoms before the development of metastases. On the contrary, a deep-seated organ, such as liver, lung, or kidney, which cannot be examined easily and which may contain a large tumor without causing symptoms, may be the site of an occult primary tumor. Tumors with these three features, namely, deep-seated location, osteophilic propensity, and high prevalence in the specific geographic area, should have the highest possibility of being the occult origin. The diagnosis and location of the primary site can be either relatively easy or an extremely complicated diagnostic exercise. The argument for pursuing the primary site aggressively in these patients is based on the idea that finding the primary might lead to specific treatment and/or give a better guide to prognosis. The dilemma facing the clinician is how aggressively to try to identify this primary site. How to define a diagnostic plan that would permit identification and treatment of those patients who are most likely to benefit while sparing others the discomfort and inconvenience of a futile investigation has not infrequently been a concern of orthopedic surgeons. A CBC, multiphasic chemistry evaluation, stool guaiac test, urinalysis, and whole-body bone scan are unlikely to provide information leading to the primary, but they are necessary for the general evaluation of the patient. Frequently, these evaluations may disclose some abnormalities requiring correction. The bone scan has value in both diagnosis and staging. It is a highly sensitive imaging procedure for the early detection of skeletal metastasis. Also, bone scans may identify sites that are more accessible or less hazardous for biopsy than the initial metastatic site. The gallium scan was proved neither useful in detecting the primary site nor as accurate as the T c ~ ~bone ” ’ scan in assessing the extent of skeletal metastasis. Intra-abdominal and pelvic lesions can be evaluated in various ways. These include liver and spleen scan, upper GI tract contrast study, barium enema study, colonoscopy, gastroscopy, and IVP. These examinations need preparation, cause some discomfort to the patient, and are limited to one organ system. They are low yielding, since GI tract cancers are least likely to metastasize to bone. They are also sometimes misleading [ 12-1 41. Therefore, in the absence of relevant symptoms, radiologic contrast studies are rarely helpful in finding the

Skeletal Metastasis From Occult Carcinoma

primary site. Ultrasonic examination or CT scan examination are minimally invasive and have shown a high sensitivity in detecting abdominal lesions. More importantly, they are remarkably powerful anatomic tools with broad applicability to a host of different primary tumors with varying histology [ 15,161; we therefore recommend routine use of one of these examinations (CT scan or ultrasonic examination) in searching for an occult primary site. Lung cancer is still the most common occult cause of a skeletal metastasis from an unknown origin. We found that the chest CT scan is by far the best examination for localizing lung tumors. A CT scan of the chest should be included when investigating patients with skeletal metastases of unknown origin. Significant strides have been made toward a wider acceptance of magnetic resonance imaging (MRI); however, the impact of MRI on the abdomen and chest to date has been impeded by several technical difficulties that have left this modality second in line to CT scan or ultrasound. Its ultimate role continues to be defined. Additional studies that might aid in identifying the primary site are tumor markers, especially AFP and prostate acid phosphatase. AFP has been studied and characterized extensively. In the nonpregnant women, elevated serum AFP levels are found in most cases of primary hepatoma and in nonseminomatous germ cell tumors. Because of organ specificity, AFP has proved useful in screening for these tumors in clinical situations [ 17,181. Serum prostate acid phosphatase is prostate specific rather than prostate tumor specific and cannot be used as screening for the diagnosis of prostatic cancer. The elevation of this marker, however, alerts the clinician to search for a prostatic origin of the metastasis. Our study stresses the inefficiency of our current diagnostic techniques in searching for the occult primary tumors. Only 54% of cases had an antemortern diagnosis of the primary carcinoma. The explanations for this lack of detection include spontaneous regression of the primary tumor through host immunological defense mechanisms, microscopic tumor foci producing widespread metastatic disease, or a primary too small to be detected by present means of investigation. The mean survival of 1 1 months in our series indicates that the disease was advanced at the time the patients were first seen. Establishing a primary cancer in patients who have skeletal metastasis does little to alter the prognosis, since most possibilities (e.g., lung and liver cancers) are minimally responsive to palliative chemotherapy; however, the identification of a specific type or site of origin might result in some specific therapy. Some

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slow-growing tumors of the thyroid are compatible with longevity. A more aggressive approach toward mammary and prostate cancers has evolved with the concept of hormone dependence of certain tissues and their primary neoplasms. Four patients (8%) in our series are disease free, with a mean follow-up of 42 months (range, 15-61 months).

CONCLUSION On the basis of our observations, indiscriminate screening with tests directed toward detection of the primary tumors is not appropriate. For skeletal metastases from an unknown site of origin, the effort should be directed primarily toward excluding some common and/or treatable primary tumors only. REFERENCES I . Didolkar MS, Fanous N, Elias EG, Moore RH: Metastatic carcinomas from occult primary tumors. Ann Surg 186:625430, 1977. 2. Holmes FF, Fouts TL: Metastatic cancer of unknown primary site. Cancer 26:8 16820, 1970. 3. Moertel CG: Adenocarcinoma of unknown origin. Ann Intern Med91:641-647, 1979. 4. Pasterz R, Savaraj N, Burgess M: Prognostic factors in metastatic carcinoma of unknown primary. J Clin Oncol4: 1652-1657, 1986. 5 . Simon MA, Karluk MB: Skeletal metastases of unknown origin: Diagnostic strategy for orthopedic surgeons. Clin Orthop I66:96103, 1982. 6. Templeton AC: Tumors of unknown origin. Recent Results Cancer Res 41:302-305, 1973. 7. Stewart JF, Tattersall MHN, Woods RL, Fox RM: Unknown primary adenocarcinoma: Incidence of overinvestigation and natural history. Br Med J 9:1530-1533, 1979. 8. Johnston AD: Pathology of metastatic tumors in bone. Clin Orthop 7318-32, 1970. 9. Sherry HS, Levy R N , Shiffert RS: Metastatic disease of bone in orthopedic surgery. Clin Orthop I69:44-52, 1982. 10. Sim FH: “Diagnosis and Management of Metastatic Bone Disease.” New York: Raven Press, 1988, pp. 1-6. 1 1 . Nottebaert M, Exner GU, von Hochstetter AR, Schreiber A: Metastatic bone disease from occult carcinoma: A profile. Int Orthop 13:l 19-123, 1989. 12. Nystrom JS, Weiner JM. Wolf RM, et al: Identifying the primary site in metastatic cancer of unknown origin: Inadequacy of roentgenographic procedures. JAMA 241:381-383, 1979. 13. Osteen RT, Kopf G , Wilson RE: In pursuit of the unknown primary. Am J Surg 135:494-498, 1978. 14. Snee MP, Vyrdmuthu N: Metastatic carcinoma from unknown primary site: The experience of a large oncology centre. Br J Radio1 58: 1091-1095, 1985. 15. Carson PL, Wenzel WW, Avery P, Hendee WR: Ultrasound imaging as an aid to cancer therapy. . _ Int J Radiat Oncol Biol Phys 11335-343, 1976. 16. Robbins AH. Pueatch RD, Gerzof SG. et al: Further observation on the medical ekcacy of computed tomography of the chest and abdomen. Radiology 137:719-725, 1980. 17. Alpert ME, Uriel J , de Nechaud B: Alpha, fetoglobulin in the diagnosis of human hepatoma. N Engl J Med 278:984986, 1968. 18. Javadpour N: “Tumor Markers-Biology and Clinical Applications.” Cancer Research Monographs, Vol4. New York: Praeger, 1987; pp. 21-22.

Skeletal metastasis from occult carcinoma.

We reviewed 177 patients with skeletal metastases, seen between 1984 and 1989, to define the characteristics of metastatic bone disease from an occult...
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