Recently, serum tumor marker CYFRA 21-1 has shown a high

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1 670 CORRESPONDENCE Serum CYFRA 21-1 Is One of the Most Reliable Tumor Markers for Breast Carcinoma Recently, serum tumor marker CYFRA 21-1 has shown a high sensitivity and specificity in patients with breast carcinoma as well as an important usefulness in monitoring for recurrence, evaluating the efficacy of the treatment in advanced disease, and acting as an independent prognostic factor. 1 Based on these results we tested the sensitivity of CYFRA 21-1 in patients with metastatic breast carcinoma in our institution, before using it as a marker of recurrence in early stages or in the evaluation of the therapeutic effect in advanced disease. PATIENTS AND METHODS Between October 2000 and June 2001, serum samples from 40 consecutive patients with confirmed metastatic breast carcinoma were obtained. We simultaneously measured the titers of CYFRA 21-1, carcinoembryonic antigen (CEA), and CA The mean patient age was 60.4 years. Most patients had a single metastatic location 25 out of 40, or 62.5% and the organ most frequently involved was bone in 19 patients (47.5%), followed by the lung in 24% of patients. The cutoff value of CYFRA 21-1 was 3.0 ng/ml, and the recommended cutoff values of CEA and CA 15.3 were 5.0 ng/ml and 51 U/mL, respectively. RESULTS A total of 23 patients had CYFRA 21-1 levels higher than the cutoff value. Sensitivity was 57.5%, with titers ranging from 0.10 to ng/ml (median, 3.87; mean, 23.96). The sensitivity of CEA and CA 15.3 reached 50% and 45%, respectively (Fig. 1). Considering only the values of CEA and CA 15.3, 26 patients (65%) were positive for at least one of these two markers, and, when CYFRA 21-1 was added, the rate of patients with at least one positive marker increased to 77.5%. In eight cases of negative CYFRA 21-1, the titers of CEA, CA 15.3, or both were positive. There were no statistically significant differences between the sensitivities of the markers. DISCUSSION Although numerous tumor markers for breast carcinoma have been tested, most have not been utilized in clinical practice, with the exception of CEA and CA However, the guidelines of the American Society for Clinical Oncology for the use of tumor markers in breast carcinoma conclude that current data are insufficient to recommend either CA 15.3 or CEA for screening, diagnosis, staging, surveillance following primary treatment, or monitoring response to treatment. 2 It is well known that breast carcinoma cells express cytokeratin 19 fragments, 3 and that these fragments can be detected by CYFRA Nakata et al. have recently reported a high sensitivity and specificity for CYFRA 21-1 in breast carcinoma as well as a strong value for CYFRA 21-1 as a prognostic factor. 1 In our institution, before 2002 American Cancer Society

2 Correspondence 671 FIGURE 1. Sensitivity of CYFRA 21-1, carcinoembryonic antigen (CEA), and CA 15.3, alone and in combination in patients with metastatic breast carcinoma. using CYFRA 21-1 as a routine marker in breast carcinoma, we have confirmed its sensitivity in metastatic disease, with results comparable to those obtained by Nakata et al. Based on these data, we can conclude that CYFRA 21-1 is a sensitive tumor marker for breast carcinoma when compared with CEA or CA In our institution the sensitivity in metastatic breast carcinoma was 57.5%, which is at least equivalent to that obtained in previously reported studies. Measurement of CYFRA 21-1 together with CEA and CA 15.3 may improve the usefulness of these two markers. These results have led us to study the role of CYFRA 21-1 as a predictor of relapse in early breast carcinoma after treatment, as well as its role in monitoring the efficacy of therapies in advanced disease. 1. Nakata B, Ogawa Y, Ishikawa T, et al. Serum CYFRA 21-1 is one of the most reliable tumor markers for breast carcinoma. Cancer. 2000;89: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Adopted on May 17, 1996 by the American Society of Clinical Oncology. J Clin Oncol. 1996;14: Brotherick I, Robson CN, Browell DA, et al. Cytokeratin expression in breast cancer: phenotypic changes associated with disease progression. Cytometry. 1998;32: Pujol JL, Grenier J, Daures JP, Daver A, Pujol H, Michel FB. Serum fragments of cytokeratin subunit 19 measured by CYFRA 21-1 immunoradiometric assay as a marker of lung cancer. Cancer Res. 1993;53: César A. Rodríguez, M.D. Juan J. Cruz, M.D. Teresa Martín, M.D. Amalia Gómez, Ph.D. Amaya Olaverri Department of Medical Oncology Hospital Universitario Salamanca, Spain Marisa Hernández, Ph.D. Department of Biochemistry Hospital Universitario Salamanca, Spain DOI /cncr We are grateful for the results from Dr. Rodríguez et al. supporting our previous article. 1 We agree with their conclusion that a combination assay of CYFRA 21-1 with carcinoembryonic antigen (CEA) and CA 15-3 is very useful for breast carcinoma, since the epitope of CYFRA 21-1 is a polypeptide whereas those of CEA and CA 15-3 are glycoproteins. We are particularly interested in the prognostic value of CYFRA 21-1 for disease recurrence after surgery. We now routinely measure CYFRA 21-1 for our patients with breast carcinoma prior to operation and at serial times after operation. Some patients with abnormal serum CYFRA 21-1 titers have maintained elevated levels of the marker after curative resection. These patients may have high risk of the disease relapse. The coming data from Dr. Rodríguez et al. will contribute to a followup system for patients with breast carcinoma. 1. Nakata B, Ogawa Y, Ishikawa T, et al. Serum CYFRA 21-1 is one of the most reliable tumor markers for breast carcinoma. Cancer. 2000;89: Bunzo Nakata, M.D. Yoshinari Ogawa, M.D. Kosei Hirakawa, M.D. Department of Surgical Oncology (First Department of Surgery) Osaka City University Graduate School of Medicine Osaka, Japan DOI /cncr Clinical and Histologic Features of Level 2 Cutaneous Malignant Melanoma Associated with Metastasis In a recent article, Taran and Heenan maintained that metastasis from Clark level 2 cutaneous malignant melanoma (CMM) is rare, if it occurs at all, a conclusion based on the examination of all pathology reports of patients diagnosed with a primary malignant melanoma at the Cancer Registry of Western Australia between They found that no level 2 CMM in their data set was 1 mm thick. There were 1716 patients with a CMM that measured 1 mm in thickness, 67 of whom developed metastases

3 672 CANCER August 1, 2002 / Volume 95 / Number 3 within a follow-up period of 7 15 years. After excluding 18 patients with multiple CMMs, 5 of the remaining 49 patients with metastases were found to have a level 2 CMM. All five patients displayed focal to extensive regression; therefore the authors concluded that the assessment of level of invasion may have been inaccurate, with these CMMs being invasive to level 3 or 4 before the onset of regression. We would like to present corresponding figures from the Sydney Melanoma Unit (SMU) database, which contains the records of nearly 19,500 melanoma patients treated between January 1950 and July 2001 at Royal Prince Alfred, St. Vincent s, and Sydney Hospitals. All pathology slides were reviewed by specialists from the Department of Anatomical Pathology at the Royal Prince Alfred Hospital who had extensive experience in melanoma pathology. Metastases developed in 164 of 2761 patients with Clark level 2 CMMs who had only a single Stage I or II lesion (American Joint Committee on Cancer/International Union Against Cancer staging system) over a follow-up period of 1 45 years. Approximately 22% of these metastasizing CMMs were 1 mm thick, with 50% of the latter having a polypoid architectural pattern. Early, intermediate, or late regression was found in 73% of metastasizing level 2 CMMs, a figure that was nearly identical to the proportion with regression in 2597 nonmetastasizing level 2 CMMs (74%). In the majority of metastasizing level 2 CMMs displaying regression (57%), the regression was at the early stage. We previously have shown that in very thin CMMs ( 0.5 mm), evidence of regression did not constitute a risk for recurrence. 2 Part of the discrepancy between the current results and those of Taran and Heenan appears to lie in pathologic definitions and interpretation of Clark levels 2 and 3 and the presence or absence of regression. Interobserver variability in reporting the level of invasion is referred to by Taran and Heenan. 1 Some of our metastasizing level 2 CMMs were 1 mm thick and some of these were polypoid. Such CMMs may be associated with expansion but not filling of the papillary dermis by melanoma cells and the cells may not reach the papillary/reticular dermal interface and hence can be designated as level 2. Although we accept that some authors regard such polypoid CMMs as level 3, 3,4 applying the criteria of Clark et al. 5 (as used by Taran and Heenan in their study 1 ), such CMMs are level 2. Furthermore, some of our metastasizing level 2 CMMs measuring 1 mm thick were acral lesions, which may become this thick as a result of their epidermal thickening. The definition of regression used by Taran and Heenan 1 encompasses the definitions of intermediate and late regression as used by the SMU. Because our analysis also included CMMs with early regression (defined as the presence of tumor-infiltrating lymphocytes), the proportion of CMMs displaying regression in our metastasizing level 2 CMMs was not comparable to that in the study by Taran and Heenan. 1 The SMU is a major referral center for melanoma in New South Wales and therefore is not populationbased like the Cancer Registry of Western Australia. However, it appears from our results that metastases from level 2 CMMs are not as uncommon as maintained by Taran and Heenan. 1 Although the majority of these metastasizing CMMs displayed regression, this alone could not explain their metastatic potential. We conclude that it is injudicious to dismiss level 2 CMMs as having practically no metastatic potential. 1. Taran JM, Heenan PJ. Clinical and histologic features of level 2 cutaneous malignant melanoma associated with metastasis. Cancer. 2001;91: McCarthy WH, Shaw HM, McCarthy SW, Rivers JK, Thompson JF. Cutaneous melanomas that defy conventional prognostic indicators. Semin Oncol. 1996;23: McGovern VJ, Mihm MC, Bailly C, et al. The classification of malignant melanoma and its histologic reporting. Cancer. 1973;32: Elder DE, Murphy GE. Atlas of tumor pathology. AFIP. Washington, DC: Armed Forces Institute of Pathology, Clark WH, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 1969;29: Helen M. Shaw, Ph.D. William H. McCarthy, M.D., M.Ed. Richard A. Scolyer, M.D. Sydney Melanoma Unit Royal Prince Alfred Hospital Camperdown, Australia DOI /cncr Comparisons between histologic studies of cutaneous malignant melanoma (CMM) are likely to be meaningless unless the same histologic criteria are used by pathologists who interpret those criteria in similar fashion. 1 Because the histologic reporting of the slides from the enormous number of cases in the Sydney Melanoma Unit database was performed by a large number of pathologists over a long period of time, it appears likely that there would have been considerable variation in their assessments of both level and regression. To the best of our knowledge, no

4 Correspondence 673 recent histologic review of these cases has been performed. Dr. Shaw and her colleagues state that the 164 patients in their database who had level 2 CMM that metastasized had only a single primary tumor. No details are given concerning the extent of their search for a second primary CMM in these patients. Only an extremely painstaking search in our study revealed the important fact that 18 of the 67 patients with a CMM measuring 1 mm in thickness had another primary CMM. 2 Without reviewing all the pathology reports concerning these patients and their hospital records, we would not have identified this group of patients with multiple primary CMM, thereby resulting in a substantial overestimate of the proportion of metastatic cases. Furthermore, we agree with the authorities quoted by Shaw et al. that polypoid CMM should be classified as level 3, 3,4 thus excluding them from the group of level 2 tumors. Regression has been reported as showing every possible effect (i.e., adverse, no effect, or a favorable effect) on prognosis because of the lack of consensus with regard to defining and quantifying this histologic feature. 5 We did not attempt to assess the overall effect of regression on prognosis, but our careful microscopic review of the histologic features by one pathologist demonstrated evidence of regression in the five study cases with level 2 primary melanoma associated with metastasis, without another primary CMM. Accordingly, we suggested that metastasis from a level 2 melanoma without regression is very rare, if it occurs at all. However, we also proposed that it remains to be proved that level 2, radial growth phase CMM does not have metastatic potential, and suggested that the presumably low number of neoplastic cells entering the circulation from level 2 CMM may constitute a crucial quantitative factor in the failure of these lesions to establish clinical metastases Heenan PJ, Matz LR, Blackwell JB, et al. Inter-observer variation between pathologists in the classification of cutaneous malignant melanoma in Western Australia. Histopathology. 1984;8: Taran JM, Heenan PJ. Clinical and histologic features of level 2 cutaneous malignant melanoma associated with metastasis. Cancer. 2001;91: McGovern VJ, Mihm MC, Bailly C, et al. The classification of malignant melanoma and its histologic reporting. Cancer. 1973;32: Elder DE, Murphy GE. Atlas of tumor pathology. AFIP. Washington, DC: Armed Forces Institute of Pathology, Barnhill RL, Fine JA, Roush GC, Berwick M. Predicting fiveyear outcome for patients with cutaneous melanoma in a population-based study. Cancer. 1996;78: Peter J. Heenan, M.B., B.S. John M. Taran, M.B., B.S. Department of Pathology University of Western Australia Queen Elizabeth II Medical Centre Nedlands Western Australia DOI /cncr Hypothyroidism: A Frequent Event after Radiotherapy for Patients with Head and Neck Carcinoma The incidence of hypothyroidism after radiotherapy (RT) for head and neck carcinoma may well be even higher than that reported by Mercado et al. 1 Their use of thyroid-stimulating hormone (TSH) levels as the sole criteria for documenting hypothyroidism most likely underestimated the frequency of thyroid deficiency in their patients because of a reduction in TSH levels caused by radiation injury to pituitary and hypothalamic tissues. To our knowledge, Tam and Kunaratnam 2 were the first to report hypopituitarism after RT for nasopharyngeal carcinoma (NPC) in Although both hypothalamic and pituitary tissues are relatively radioresistant, their proximity to the nasopharynx requires that they be included in many primary radiation fields used to treat NPC. They also receive significant scatter radiation from nearby primary target tissues. Multiple studies have demonstrated impairment of hypothalamic-pituitary function after nasopharyngeal RT, changes that become progressively more evident over at least 5 post-rt years. 3 6 These studies include blunting of the TSH response to injections of thyrotrophin-releasing hormone (TRH), indicating impaired pituitary TSH release. This impairment also would be expected to blunt the TSH response to diminished serum thyroxine levels, rendering TSH inadequately sensitive as a measure of hypothyroidism in these patients. Hypothyroidism has been documented after RT for NPC in patients with normal TSH levels, 5,6 thereby confirming the need for measurements of T3 resin uptake and the T4 and free thyroxine index as well as TSH when these patients are being evaluated for diminished thyroid function. Chen et al. 3 reported serial analyses of hypotha-

5 674 CANCER August 1, 2002 / Volume 95 / Number 3 lamic-pituitary function in patients receiving RT for NPC before this therapy, 1 month after RT, and months after RT. Of their 24 patients, 18 developed subclinical evidence of impaired pituitary-thyroid function. Their patients also demonstrated a pattern of progressive impairment of the increase in luteinizing hormone (LH) levels after the injection of luteinizing hormone-releasing hormone (LHRH) and of the increases in both cortisol and growth hormone (GH) after insulin-induced hypoglycemia. Multiple other studies 4-6 have demonstrated similar changes after RT, including a progressive increase in the response of TSH to TRH, but with the peak of TSH levels becoming increasingly delayed, 4 6 observations that are compatible with a combination of both RT-induced pituitary injury and RT-induced thyroid damage. Lam et al. 5 studied 31 patients before and after RT for NPC. One year after RT the response of GH to insulin and the response of LH to LHRH had decreased substantially and peak TSH levels after TRH injection were delayed from 20 minutes to 60 minutes in 28 of their patients (90%). Two years after RT, 4 patients had developed deficiencies of 1 pituitary hormones. When these same patients were examined 5 years after RT, 6 the average GH response to insulin was found to be only 20% of that before RT, the average LH response to LHRH had decreased progressively to 50% of pretreatment, and baseline testosterone levels had dropped by approximately 33%. TSH response to TRH also decreased progressively (P after 2 postradiation years). None of the four patients with clinical and biochemical hypothyroidism were found to have an elevated TSH value. We also have observed several patients with hypopituitarism after nasopharyngeal RT. It is clear that physicians should be alert to the possibility of this disorder, which may not become evident until many years after RT, and that they should recognize that hypothyroidism in these patients is likely to have a pituitary-hypothalamic component. 1. Mercado G, Adelstein D, Saxton J, et al. Hypothyroidism a frequent event after radiotherapy and after radiotherapy with chemotherapy for patients with head and neck carcinoma. Cancer. 2001;92: Tan B, Kunaratnam M. Hypopituitary dwarfism following radiotherapy for nasopharyngeal carcinoma. Clin Radiol. 1966;17: Chen M, Lin F, Huang M, et al. Prospective hormone study of hypothalamic-pituitary function in patients with nasopharyngeal carcinoma after high dose irradiation. Jpn J Clin Oncol. 1989;19: Huang T, Huang S, Hsu M. A prospective study of hypothalamus pituitary function after cranial irradiation with or without radiosensitizing chemotherapy. J Endocrinol Invest. 1994;17: Lam K, Tse V, Wang C, et al. Early effects of cranial irradiation on hypothalamic-pituitary function. J Clin Endocrinol Metab. 1987;64: Lam K, Tse V, Wang C, et al. Effects of cranial irradiation on hypothalamic-pituitary function: a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q J Med. 1991; 78: Harry W Daniell, M.D. Redding, California DOI /cncr Dr. Daniell points out that direct injury to the pituitary and hypothalamus after treatment for nasopharyngeal carcinoma is another cause of hypothyroidism after head and neck radiation therapy. This is an important addition to our discussion, and would not be identified by an elevation in thyroid-stimulating hormone (TSH). An increase in TSH was used as our definition of hypothyroidism because our patient population did not include individuals with nasopharyngeal carcinoma. As such, the radiation dose received by the pituitary or hypothalamus was minimal. Nonetheless, it is important to note that patients with nasopharyngeal carcinoma will require more than a TSH determination when followed for late, radiation-induced hypothyroidism. David J. Adelstein, M.D. Department of Hematology and Medical Oncology Taussig Cancer Center The Cleveland Clinic Foundation Cleveland, Ohio DOI /cncr.10704