Evaluation of new putative tumor markers for melanoma

Background: The early diagnosis of recurrent melanoma can contribute to better outcome if the disease can be surgically resected or if the metastases are responsive to systemic therapies. Lipid-associated sialic acid (LASA-P) and the S-100 protein (S-100) were evaluated as tumor markers for melanoma with the goal of early detection of recurrence. Methods: Sixty-seven patients were identified who had levels of S-100 and LASA-P drawn during their clinical course. A multivariate regression analysis was performed to determine the significance of the serum markers in relation to other prognostic factors for melanoma. Results: After a median follow-up of 30 months, 58 patients had recurrences, and 49 patients died of disease. LASA-P elevation was not associated with the time to recurrence (p=0.2176) or survival (p=0.2507). S-100 positivity was a significant predictor of recurrence (p<0.0001) and survival (p=0.0059). The median time to recurrence for S-100-positive and S-100-negative patients was 7.6 and 33.8 months, respectively. The median survival time was 59.2 months for S-100-negative patients and 29.6 months for patients positive for S-100. Conclusions: Serum S-100 shows significant correlations to both time to recurrence and survival and could be useful in the clinical detection of malignant melanoma.Presented at the 47th Annual Cancer Symposium of The Society of Surgical Oncology, Houston, Texas, March 17–20, 1994.     

Plasma Neuroendocrine Markers in Patients with Benign Prostatic Hyperplasia and Prostatic Carcinoma

Purpose

Approximately 50 percent of all malignant prostatic tumors contain neuroendocrine cells, which cannot be attributed to small cell prostatic carcinoma or carcinoid-like tumors, and which represent only 1 to 2 percent of all prostatic malignancies. Only limited data are available concerning the plasma levels of neuroendocrine markers in patients with prostatic tumors. Therefore, we determined the incidence of high plasma levels of neuroendocrine markers in patients with benign and malignant prostatic disease.

Materials and Methods

The presence of elevated plasma neuropeptide levels was investigated in 135 patients with prostatic carcinoma and 28 with benign prostatic hyperplasia. Plasma chromogranin A, neurone-specific enolase, substance P, calcitonin, somatostatin, neurotensin and bombesin levels were analyzed by immunoassays, and were compared to clinical and pathological stages of disease. Plasma prostatic acid phosphatase and prostate specific antigen levels were also determined. All patients were followed for at least 2 years after inclusion in the study.

Results

Significantly elevated levels of chromogranin A were detected in 15 percent of patients with prostatic carcinoma before any treatment. During hormone resistant prostate cancer progression plasma chromogranin A and neuron-specific enolase levels were elevated in 55 percent and 30 percent of the patients, respectively. In patients with stage D3 disease survival curves were generated by the Kaplan-Meier method, and log rank analysis revealed a statistically significant difference between groups positive and negative for chromogranin A. Substance P and bombesin were also occasionally elevated in prostatic tumors. Determination of neuroendocrine differentiation by neuron-specific enolase or chromogranin A immunoassays was not helpful in the prediction of progressive localized prostatic carcinoma.

Conclusions

Future studies of plasma neuropeptide levels should confirm whether these parameters can be used as prognostic markers during late progression of prostatic carcinoma or for the selection of patients suitable for evaluation of new antineoplastic drugs known to be active against neuroendocrine tumors.     

Metastatic prostate cancer with normal level of serum prostate-specific antigen

The clinical and pathological features of metastatic prostate cancer with normal level of serum prostate-specific antigen (PSA) were investigated. Four patients with metastatic prostate cancer had serum PSA within the normal range at the diagnosis. All tumors were poorly-differentiated adenocarcinoma. Endocrine therapy was performed as the initial therapy in all patients. Despite subsequently treatment, all cases died of prostate cancer at 2, 8, 9 and 38 months. During disease progression, 3 of 4 patients had elevated serum markers such as carcinoembryonic antigen (CEA), CA19-9, CA15-3, CA125, neuron-specific enolase and pro-gastrin releasing peptide. Immunohistochemical examination of the initial biopsy specimens revealed that 4 and 3 cases were positive for CEA and chromogranin A, respectively. In advanced prostate cancer patients with low PSA level, those markers may aid in the follow up of disease.     

Prognosis for recurrent stage I malignant melanoma

The outcome of patients with stage I malignant melanoma has been well assessed in terms of prognostic factors and their effect on survival; however, little is known of the recurrence patterns of cutaneous melanoma or the survival of these patients subsequent to recurrence. A retrospective, computer-aided chart review identified 4185 patients with melanoma who had stage I disease clinically. During a follow-up period of one to 14 years, 35.9% suffered a recurrence. Melanoma of the trunk (37.8%) and head and neck area (46.1%) had an increased incidence of recurrent metastases compared with melanoma of the extremities (29.8%). Local regional metastases accounted for 62.5%, 77.3%, and 85.6% of the recurrences in the head and neck, trunk, and extremity primary sites, respectively, with 65% of the relapses occurring within the first three years. Actuarial five-year survival rates of patients who had recurrent disease were significantly decreased compared with those of patients who had no evidence of metastases during their clinical course. A multivariate analysis was performed to estimate the survival of patients after recurrence. One may use this mathematical model to predict the outcome of individual patients after recurrence and provide a more rationally based prognosis for them and their families.     

Malignant Melanoma and Adenocarcinoma of a Barrett Oesophagus

An adenocarcinoma with a malignant melanoma in a Barrett oesophagus is extremely rare. We did not find any other cases in the English literature. The diagnosis of a malignant melanoma can be difficult but can be made by tissue examination with a special immunoreaction with several markers to see it expresses S-100, but lacks activity for KER and EMA. S-100 is relatively non-specific as a single immunodeterminant in the diagnostic separation of melanoma and anaplastic carcinoma, but very sensitive. Immunohistochemically, these tumours react to S-100 protein, neuron-specific enolase and HMB-45 antibody (less sensitive than S-100), but not to cytokeratin or CEA. In our case it was obvious that there were two different tumours because the MM was negative for cytokeratin, but the adenocarci-noma was positive for cytokeratin.     

Malignant melanoma and adenocarcinoma of a Barrett oesophagus

An adenocarcinoma with a malignant melanoma in a Barrett oesophagus is extremely rare. We did not find any other cases in the English literature. The diagnosis of a malignant melanoma can be difficult but can be made by tissue examination with a special immunoreaction with several markers to see it expresses S-100, but lacks activity for KER and EMA. S-100 is relatively non-specific as a single immunodeterminant in the diagnostic separation of melanoma and anaplastic carcinoma, but very sensitive. Immunohistochemically, these tumours react to S-100 protein, neuron-specific enolase and HMB-45 antibody (less sensitive than S-100), but not to cytokeratin or CEA. In our case it was obvious that there were two different tumours because the MM was negative for cytokeratin, but the adenocarcinoma was positive for cytokeratin.     

Node-positive transcranial recurrent melanoma: is an aggressive resection warranted?

Locally advanced, node-positive recurrence of malignant melanoma is a harbinger of distant metastases and signifies poor prognosis. However, the clinical course may vary due to the unpredictable biology of malignant melanoma. The presented patient developed a recurrent melanoma of the scalp that eroded through the skull and involved regional lymph nodes with extracapsular extension. He was treated with wide local excision of the recurrence, bilateral posterolateral neck dissection, and immediate microvascular reconstruction followed by adjuvant radiation therapy. The patient remains free of disease at 12 years. This case illustrates that an aggressive resection should be considered for the operable patients with locally advanced recurrent melanoma to render them disease free surgically.     

Desmoplastic melanoma of the nail

Desmoplastic melanoma represents a variant of melanoma that is difficult to diagnose because 71% of patients have amelanotic skin lesions. In the acral region of the limbs, the clinical diagnosis is more difficult, especially in cases in which there are not clear, rapidly growing, pigmented nail streaks. Histopathological identification of desmoplastic melanoma is confusing because of the intense fibrous reaction in the dermis and minimal, atypical melanocytic proliferation at the dermal-epidermal junction. For these reasons, it is still misdiagnosed unfortunately as a variety of entities, including simple scar, fibrohistiocytic neoplasms, neural tumors, and superficial fibromatoses-with potentially devastating consequences. In equivocal cases, the use of immunohistochemistry (in particular S-100 and neuron-specific enolase) may be helpful in establishing the diagnosis. Because of the high local recurrence rate for desmoplastic melanoma of the finger, amputation is recommended in an effort to gain effective tumor control. Lymph node dissection may be reserved for patients with positive axillary nodes.     

Parathyroid hormone-related protein induced coupled increases in bone formation and resorption markers for 7 years in a patient with malignant islet cell tumors.

Parathyroid hormone-related protein (PTHrP) and PTH share the common PTH/PTHrP receptor. Although an elevated level of circulating PTHrP in patients with malignancies causes hypercalcemia as does PTH, chronic and systemic effects of PTHrP on bone metabolism in humans are not well understood because tumor-burden patients showing hypercalcemia usually have a poor prognosis. We investigated bone and calcium metabolism in a patient with malignant islet cell tumors showing hypercalcemia due to the elevated plasma PTHrP level for 7 years. Hypercalcemia and hypercalciuria continued throughout the clinical course in spite of frequent infusions of bisphosphonates. Bone resorption markers and a bone formation marker were consistently elevated as seen in primary hyperparathyroidism, a disease caused by an autonomous hypersecretion of PTH. Based on biochemical measurements including bone markers and serum 1,25-dihydroxyvitamin D, the clinical features of this case essentially are the same as those of primary hyperparathyroidism except for the elevated level of plasma PTHrP with suppressed intact PTH level. Therefore, it is suggested that chronic and systemic effects of PTHrP on bone as well as calcium metabolism are indistinguishable from those of PTH in human.     

Cerebral inflammatory response during and after cardiac surgery

BACKGROUND AND OBJECTIVE: Neurological dysfunction is a common problem after cardiac surgery with cardiopulmonary bypass (CPB). Cerebral ischaemia associated with the use of CPB may result in a release of neuronal-ischaemic markers and a subsequent cerebral inflammatory response which may additionally release inflammatory cytokines. In order to locate the origin and to quantify the release of neuronal-ischaemic markers and cytokines we investigated arterial-cerebral venous concentration gradients during and after CPB in a clinical setting. METHODS: In twenty-five patients scheduled for coronary artery bypass grafting surgery we measured the plasma concentration of neuron-specific enolase, S-100beta protein as well as interleukins (IL) IL-6, IL-8 and IL-10 from arterial and cerebral venous blood samples prior to surgery (baseline), during hypothermic CPB at 32 degrees C, after termination of bypass, as well as 2, 4 and 6 h after admission to the intensive care unit. RESULTS: Arterial-cerebral venous concentration gradients of neuron-specific enolase, S-100beta, IL-6, IL-8 and IL-10 were neither detectable during nor after CPB. Compared to the baseline period, S-100beta and neuron-specific enolase significantly increased during hypothermic CPB. After termination of CPB, neuronal-ischaemic markers as well as cytokines were increased and remained elevated during the investigated time course without reaching baseline values. CONCLUSIONS: Although we found an overall increase in plasma concentrations of neuronal-ischaemic markers, IL-6, IL-8 and IL-10 during and after CPB, arterial-cerebral venous gradients were not detectable for any of these parameters. Our results suggest that the increase of investigated parameters associated with the use of CPB are not primarily caused by a cerebral inflammatory response but rather reflect a release from other sources in the systemic circulation.     

Pulmonary meningioma. Immunohistochemical and ultrastructural features

Two cases of solitary primary pulmonary tumors showing the immunohistochemical and ultrastructural features of meningothelial meningiomas are presented. The benign clinical and radiologic course, the negative computed tomography scan of the brain (case 1), and negative neuropathologic investigation (case 2) support the diagnosis of a primary pulmonary meningioma rather than a metastazing malignant intracranial meningioma. Negative neuroendocrine markers (neuron-specific enolase, chromogranin, bombesin) and the lack of neurosecretory granules by electron microscopy confirm the diagnosis of this rare pulmonary tumor.     

Serial determinations of melanoma tumor-associated antigen and antibody in patients with stage I melanoma

The correlation of circulating immune complexes (CICs) and the clinical course of malignant melanoma has not been consistent when using nonspecific assays for CIC. To improve predictability, serial serum samples from patients with pathologic stage I melanoma were analyzed for the presence of antimelanoma tumor-associated antigen (TAA) antibody by direct radioimmunoassay and for the presence of melanoma TAA in CIC by the antigen competition method. Immunochemically characterized TAA was isolated from the spent culture medium of a melanoma cell line. Seventy-five percent of patients with melanoma TAA-specific immune complex (IC) had recurrences, while 71% of patients without melanoma TAA-specific IC remained free of disease for prolonged periods (up to 14 years of follow-up). Anti-TAA antibody titers did not correlate with disease recurrence. Our results demonstrate a correlation with melanoma TAA-specific IC and disease recurrence. The absence of melanoma TAA-specific IC is associated with a low risk of recurrence. Fluctuations in melanoma TAA-specific IC levels indicate a dynamic tumor host immunobiology and the need for serial follow-up.     

Metastatic carcinoid tumor to the orbit and brain.

Carcinoid tumors constitute an uncommon source of metastatic lesions to the brain. We report the case of a 63-year-old man who initially sought treatment for proptosis 15 years before coming to our attention with a metastatic intracerebral left parietal carcinoid. The pathological features of the exenterated orbital mass were interpreted as undifferentiated carcinoma, and a lesion of the left lower lobe of the lung that had been removed 6 years earlier had been reported as metastatic malignant melanoma. The long duration between the initial diagnosis and the onset of neurological symptoms brought into question the original diagnosis, which, in retrospect, was most consistent with metastatic carcinoid. Staining for cytokeratin, neuron-specific enolase, and synaptophysin in the absence of staining for S-100 and HMB-45 supported the revised pathological diagnosis. Metastatic intracerebral carcinoid from an unrecognized bronchogenic source is a rare event, particularly after an orbital metastasis, but should be suspected when the clinical course is inconsistent with the more common causes of metastatic disease.     

Predictive value of S-100beta and neuron-specific enolase serum levels for adverse neurologic outcome after cardiac surgery

OBJECTIVES: The aim of this study was to evaluate the time course of S-100beta and neuron-specific enolase serum levels after cardiac surgery and their clinical relevance in predicting postoperative adverse neurologic outcomes; the 2 proteins are only released in peripheral blood in association with nervous system lesions. METHODS: We neurologically assessed 190 consecutive patients undergoing elective cardiac operations for coronary artery bypass (n = 147), valve replacement (n = 29), or both (n = 14), before as well as after the operation. Postoperative outcome was classified as type I (uncomplicated), type II (confusion, agitation, disorientation, or epileptic seizures), or type III (stroke, stupor, or coma). Levels of S-100beta and neuron-specific enolase were evaluated in venous blood samples drawn preoperatively and then daily in the first 5 postoperative days. RESULTS: Levels of S-100beta and neuron-specific enolase differed significantly among the 3 groups (type III > type II > type I) throughout the postoperative period and had a diagnostic specificity and specificity of 89% and 79%, respectively, in identifying patients with type III outcome. S-100beta (but not neuron-specific enolase) levels were identified as significant independent predictors for type II and III outcomes (odds ratio 16.2, P <.0004). The same was true for duration of cardiopulmonary bypass (odds ratio 1.02, P <.006). CONCLUSIONS: Serum levels of S-100beta are reliable markers for adverse neurologic outcomes after cardiac surgery.     

Prevalence and prognostic significance of acinar cell differentiation in pancreatic endocrine tumors

We have noted that many histologically and immunohistochemically confirmed pancreatic endocrine tumors show immunophenotypic evidence of acinar cell differentiation, but the clinical relevance of this finding is unknown. We performed this study to evaluate the prevalence and prognostic significance of exocrine differentiation by immunohistochemistry in pancreatic endocrine tumors that do not show morphologic features of acinar cell differentiation. Routinely processed tissue sections from 87 pancreatic endocrine tumors were immunohistochemically stained with monoclonal antibodies against acinar (lipase, chymotrypsin, trypsin) and endocrine cell markers (chromogranin A, neuron-specific enolase, synaptophysin, Leu-7) and for the proliferation-associated peptide Ki67. The degree of staining with each marker was graded on a three-tier scale for acinar markers (grade 0, <5%; grade 1, 5-10%; grade 2, 11-25%; and grade 3, >25%) and on a four-tier scale for endocrine markers (grade 0, <5%; grade 1, 5-25%; grade 2, 26-50%; grade 3, 51-75%; and grade 4, >75%), and the results were correlated with clinical outcome (mean follow-up 53 months). Greater than 75% of the tumor cells stained for chromogranin A, neuron-specific enolase, synaptophysin, and Leu-7 in 100%, 96%, 93%, and 27% of cases, respectively. Overall, 66% of tumors stained positively for at least one acinar cell marker, 31% stained for at least two acinar cell markers, and 13% stained for all three acinar cell markers. Forty-seven percent stained for lipase (23 grade 1, 11 grade 2, seven grade 3), 37% for trypsin (22 grade 1, three grade 2, seven grade 3), and 25% stained for chymotrypsin (13 grade 1, five grade 2, four grade 3). No correlation was noted between the presence or extent of expression of any single or combination of acinar cell markers and clinical outcome. However, higher tumor stage correlated with a poor clinical outcome (p = 0.002), and location in the tail of the pancreas was associated with a longer interval to tumor recurrence (p = 0.03). The presence of synaptophysin (p = 0.03) and Leu-7 expression (p = 0.03) correlated significantly with less aggressive clinical behavior. An association was observed between increased Ki67 labeling and poorer clinical outcome, but this was not statistically significant (p >0.05). In conclusion, immunophenotypic evidence of acinar cell differentiation is common in pancreatic endocrine tumors, but this feature does not have any relevance to clinical prognosis. However, in addition to tumor stage, location in the pancreatic tail and the immunohistochemical expression of synaptophysin and/or Leu-7 may be useful prognostic indicators in patients with these lesions.     

Effect of hemodialysis on the concentration of the seven tumor markers carcinoembryonic antigen, alpha-fetoprotein, squamous cell carcinoma-related antigen, neuron-specific enolase, CA 125, CA 19-9 and CA 15-3 in uremic patients.

The incidence of the 7 tumor markers carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), squamous cell carcinoma-related antigen (SCC), neuron-specific enolase (NSE), CA 125, CA 19-9 and CA 15-3 was studied before and after hemodialysis (HD) in 144 uremic patients who had no malignancies. Before HD, of all tumor markers, the mean concentration of SCC only exceeded the normal value. The positive rate was highest in SCC (95.1%), and that of CEA and NSE was 25.7 and 10.6%, respectively. However, AFP was within the normal range in all cases. Among CA antigens, the positive rate of CA 125 was 7.6%, of CA 19-9 was 6.3% and of CA 15-3 was 3.5%. After HD, the incidence as well as the mean concentration of all tumor markers increased. A parallel increment of total protein was observed after HD. The membrane filter used in HD appears to be insufficient to remove tumor marker proteins during HD. It is necessary to consider the clinical interpretation of elevated tumor markers in patients with uremia.     

Serum neuron-specific enolase levels after subarachnoid hemorrhage

We examined serum levels of neuron-specific enolase by enzyme immunoassay in 29 patients with subarachnoid hemorrhage due to ruptured cerebral aneurysm. Serum neuron-specific enolase levels were significantly higher in patients with a poor neurological status than in patients with a good neurological status on admission, and the greater the amount of subarachnoid blood, the higher the serum neuron-specific enolase level. Patients with a good outcome had low serum neuron-specific enolase levels throughout their courses. Serum neuron-specific enolase levels increased with development of delayed ischemic neurological deficits and, especially in poor outcome patients, high levels persisted until 3 weeks after the subarachnoid hemorrhage.     

Long term follow-up in cutaneous malignant melanoma: the relationship of maximal tumour thickness to disease free survival, disease recurrence and death

284 patients with invasive cutaneous malignant melanoma and known maximal tumour thickness (MTT) were followed up for 10 to 16 years (or to earlier death) following conventional wide margin excision of the primary tumour. Of these 26 (9%) presented with clinical Stage II disease (enlarged regional lymph nodes). The 10 year disease free survival was 45% for clinical Stage I disease, with 5/26 patients with Stage II disease alive 10 years after tumour excision combined with lymph node dissection. Ninety per cent of first tumour recurrences (lymph node or local skin recurrence) occurred within 5 years of primary surgical treatment for clinical Stage I disease, whilst only 63% of deaths from melanoma occurred within this 5 year period. Although maximal tumour thickness is a valuable prognostic guide, cutaneous malignant melanoma remains an unpredictable disease.     

Recurrent malignant melanoma: the identification of prognostic factors to predict survival.

The prognostic factors for stage 1, 2 melanoma have been elucidated. Tumor thickness, ulceration of the primary melanoma, and perhaps, primary site may be used to predict the percentage of patients with regional nodal disease or systemic metastases and the prognosis of patients who have only cutaneous disease at diagnosis. Very little is known about prognosis once there is a recurrence. A retrospective, computer-aided chart review identified 4,185 patients registered at the Duke University Melanoma Database who had stage 1, 2 disease at diagnosis. During a mean follow-up period of 7 years, 35.9% experienced a recurrence. Local regional recurrences explained 62.5% to 85.5% of the recurrences. Even after elective node dissections, local regional recurrences explained most relapses (58.1%). Sixty-five percent of the recurrences occurred within the first 3 years of of follow-up. There was a pronounced difference in 5-year survival in those patients who suffered a recurrence sometime during their clinical course compared with those who never relapsed (p = 0.00001, for trunk primary melanoma). Patients with local or regional recurrence have a better prognosis than patients who relapse systemically, with 5-year survivals from the time of recurrence of 55% for a patient with a local recurrence, 51% for a patient with a regional nodal recurrence, and 20% for a patient with a systemic recurrence. A multivariate regression analysis identified thickness, ulceration of the primary melanoma, and age and location of the primary melanoma on the extremity as variables that predicted prognosis. The only factors concerning the recurrent state that added prognostic information was the disease-free interval and the presence of systemic metastases as the initial recurrence.