Contribution of alkaline phosphatase in the detection of “superscan” finding in bone scintigraphy

Abstract

AimDistant osteoblastic bone metastases are frequent manifestations of prostate cancer. Widespread bone metastases can occasionally give rise to uniform distribution of “Tc99m methylene diphosphonate” resulting in a nearly normal appearance on the bone scintigraphy. This situaition is defined as superscan, afinding that can be seen in some malignancies and some metabolic diseases. We think that alkaline phosphatase values, may be aparameter that can prevent erroneous evaluation in prostate cancer patients with extensive bone metastasis,”superscan”finding that can cause an appearance similar to normal bone scintigraphy. This study aimed to investigate the relationship between alkaline phosphatase levels and the superscan finding during the evaluation of bone scintigraphy images.MethodsProstate cancer patients who underwent bone scintigraphy inour unit between 2014 and 2022 were retrospectively scanned and those reported as “superscan” were selected. The relationship between serum ALP levels and the “Superscan” finding was evaluated and ROC analysis was performed.ResultsWhen the bone scintigraphy images of the patients were evaluated, 12 had normal scintigraphy and 12 had superscan findings. While the mean ALP levels ofthe patients with superscan appearance in the bone scintigraphy were 515.17 ± 476.71, the mean ALP levels of the patients whose bone scintigraphy was reported as normal were calculated as 83.58 ± 25.41 (P=0.005).ConclusionALP levels in patients who were reported as superscan during bone scintigraphy were found to be statistically significantly higher than in patients whose bone scintigraphy was reported asnormal. Therefore, evaluation of ALP levels while reporting bone scintigraphy examinations by nuclear medicine specialists can greatly prevent false negative results in patients.

Keywords

Introduction

Prostate cancer is the most common type of cancer among men in the world, with an estimated 1,600,000 cases and 366,000 deaths annually.¹ Distant bone metastases are a frequent manifestation of many types of solid cancers, especially prostate, lung and breast cancers.² Due to the high prevalence of bone metastases, treatments are being developed that can prolong life in patients with bone metastases.^3-4 One of the important factors in reducing the quality of life in these patients is bone metastases, especially those that cause pathological fractures.^5-6 Due to the aging of the population, in the coming years, bone metastases will become a probable problem that will constitute an expected healthcare burden in patients with malignancy.^7-8 Osteoblastic lesions in the bones are the most common areas of metastasis in prostate cancer patients. Detection of bone metastases in prostate cancer patients is of great importance in terms of determining treatment management. From the past to the present, technetium-99 radionuclide bone scan has been the most widely used imaging procedure for the diagnosis of bone metastases in prostate cancer, despite its limited sensitivity at PSA levels <10 ng/mL.⁹
During normal bone scintigraphy, less than 40% of the Tc-99m hydroxymethylene diphosphonate given intravenously to a patient is retained in the bones, while the majority of the remainder is absorbed by the kidneys.¹⁰ If the bone is very hypermetabolic during this examination, the uptake of the given radiopharmaceutical in the bones is very high compared to the soft tissue and kidneys, and as a result, the amount received from the kidneys is low or lost. Widespread bone metastases can occasionally give rise to a uniform distribution of Tc99m methylene diphosphonate (Tc-99m MDP), resulting in a nearly normal appearance on the bone scan.¹¹ In bone scintigraphy, faint or absent kidney and soft tissue activity and intense symmetrical diffuse markedly increased activity uptake in the bones relative to soft tissues is defined as a superscan, a finding that can be seen in some malignancies and some metabolic diseases.¹² This situation can be observed especially in prostate and breast cancer, as well as in lymphomas.¹³ Metastatic carcinoma of the prostate is one of the most common causes of a malignant superscan and approximately 15% of prostate cancer patients may have a “superscan” image during diagnosis or follow-up.¹⁴ Superscan may also be associated with some metabolic bone diseases. However, the uptake in metabolic bone disease is different from the metastatic state. Radiopharmaceutical uptake in metabolic bone disease is uniform and more in the distal appendicular skeleton. Another feature of metabolic superscan is more intense calvarial uptake than in other parts of the skeleton.^15-16 Diffuse uniform uptake and the absence of focal increased osteoblastic activity in prostate cancer patients with “Superscan” signs may lead to failure to recognize diffuse bone metastases, false-negative results and delayed diagnosis-treatment processes. Failure to recognize the superscan finding in bone scintigraphy examination in prostate cancer patients is a significant error that can have consequences in patient treatment management for diagnosis and treatment. To prevent this, evaluation of the alkaline phosphatase levels should be used to distinguish between a normal patient and the superscan finding. Bone metastases in prostate cancer patients are mostly osteoblastic. We think that alkaline phosphatase values, which are an indicator of bone formation, may be a parameter that can prevent erroneous evaluation in prostate cancer patients with extensive bone metastasis, a “superscan” finding that can cause an appearance similar to normal bone scintigraphy. This study aimed to investigate the relationship between alkaline phosphatase levels and the superscan finding during the evaluation of bone scintigraphy images.

Materials and Methods

Patient PopulationProstate cancer patients who underwent bone scintigraphy in our nuclear medicine unit between 2014 and 2022 were retrospectively scanned, and those reported as “superscan” were selected. In this retrospective study, 24 patients diagnosed with prostate adenocarcinoma were included. While 12 of these patients had normal bone scintigraphy findings, 12 patients had a “Superscan” appearance on bone scintigraphy. Medical records, scintigraphy findings and other data of the patients were evaluated retrospectively. The study was carried out with the permission of the Clinical Research Ethics Committee (Date: 2023-03-08, Decision No: 49).Bone Scintigraphy ProtocolFor bone scintigraphy examination, a whole-body scan was performed with a double-headed gamma camera approximately 3 hours after intravenous injection of “Tc-99m Methylene diphosphonate” radiopharmaceutical. Oral hydration was provided to the patients before the examination. Spot images were taken of the required areas and SPECT imaging was performed when necessary. Bone scintigraphy was performed using on average 20 mCi Tc-99m MDP. Bone scintigraphy imaging was performed using the MEDISO AnyScan S gamma camera system (Mediso Medical Imaging Systems Ltd., Budapest, Hungary).
According to bone scintigraphy images, patients were divided into two groups: normal, and superscan. Alkaline phosphatase values were compared between these two patient groups. Bone scintigraphy images were analyzed by an experienced nuclear medicine specialist who was blinded to the clinical details of the patients. Intense and diffusely or heterogeneously increased tracer uptake throughout the skeleton system with markedly diminished or no renal activity and excellent bone details with poor soft tissue uptake were reported as superscan. ALP levels very close to bone scintigraphy in all patients were obtained via the hospital automation system. Serum ALP level reference range was 30-120 U/L.Ethical ApprovalThis study was approved by the Noninterventional Clinical Research Ethics Committee of Sancaktepe Sehit Prof. Dr. Ilhan Varank Training and Research Hospital (Date: 08.03.2023, Decision No: 49)Statistical AnalysisAnalysis was performed using the SPSS Statistical Software program (SPSS version 23.0, SPSS Inc., Chicago). A p-value of <0.05 was considered statistically significant during the tests. When comparing categorical and numerical data, the Independent Student’s t-test was used for normally distributed data, and the Mann-Whitney U test was used for the analysis of non-normally distributed data. All continuous variables in the study were described by descriptive statistics such as mean, median, and standard deviation (SD). Categorical variables were described by frequencies and percentages. ROC curves were used to calculate the serum ALP cutoff levels with maximum sensitivity and specifcity to predict superscan appearance (AUC<0.5, no predictive value; 0.5≤AUC<0.7, less predictive value; 0.7≤AUC<0.9, moderate predictive value; and 0.9≤AUC<1, high predictive value).

Results

The mean age of the patients was 71.2 ± 8.9 years (range=57-91). When the bone scintigraphy images of the patients were evaluated, 12 had normal scintigraphy and 12 had superscan findings. While the mean ALP levels of the patients with superscan appearance in the bone scintigraphy were 515.17 ± 476.71, the mean ALP levels of the patients whose bone scintigraphy was reported as normal were calculated as 83.58 ± 25.41 (P=0.005) (Table 1). ALP levels were high in 9 (75%) patients with a “Superscan” finding, while ALP levels were within normal limits in 3 patients (25%). ALP levels were high in 1 (8.3%) of patients with normal bone scintigraphy, while ALP levels were within normal limits in 11 patients (91.7%) (Table 2). The mean PSA level in patients with superscan appearance in the bone scintigraphy was 65.36. The mean PSA level inpatients whose bone scintigraphy was reported as normal was 1.12. The ROC curve was used to evaluate the serum ALP level for predicting superscan appearance. The serum ALP level cutoff values (superscan / normal scintigraphic appearance) were 105.50 U/L, with AUC predictive sensitivity and specificity of 0.781, 0.750, and 0.750, respectively. In the ROC analysis performed to determine the superscan appearance of ALP levels, the area under the curve (AUC) was determined to be 0.781 (CI:0.561-1) (P=0.019) (Figure 1).

Discussion

Bone metastases are one of the most important causes of increased morbidity in oncological patients, and detection of bone metastases is very important in determining the treatment plan. Early detection of bone metastases is important in terms of preventing possible complications and thus increasing the quality of life. Bone destruction in bone metastases may occur via osteoclasts, tumor cells, macrophages or monocytes. Bone scintigraphy plays a major role in the detection of bone metastases.
ALP is synthesized by many tissues. Alkaline phosphatase of liver and bone origin accounts for most of the serum alkaline phosphatase level. Bone-derived ALP isoenzyme reflects osteoblastic activity in bone tissue. As a result of increased osteoblastic activity in bone metastases, an increase in serum total ALP and ALP isoenzyme of bone origin is expected.
In the study by Garnero et al., they investigated the role of ALP in the detection of bone metastases in 48 patients with prostate cancer and found that total ALP values were significantly higher in patients with bone metastases.¹⁷ Ramaswamy et al. found that total ALP values were significantly higher in patients with bone metastases in a study involving 62 patients with breast cancer and 30 patients with prostate cancer.¹⁸
Bone scintigraphy with Tc99m-MDP is frequently used in the evaluation of bone metastases due to its high sensitivity, easy and rapid evaluation of the entire skeletal system, and low cost compared to other imaging studies.¹⁹ Bone scintigraphy also can detect bone metastases before anatomical changes occur. Min et al. reported that the specificity (44.1%) in patients who underwent bone scintigraphy alone was lower than the specificity (97.3%) in patients whose ALP level was also evaluated with bone scintigraphy.²⁰
Although there are publications evaluating the relationship between bone metastases and ALP, there are very few studies evaluating the relationship between superscan finding in bone scintigraphy and ALP. In one of these studies, Manohar et al. scanned bone scintigraphy examinations taken for 5 years in their unit and investigated the ALP values of the patients reported as superscan. In this study, it was found that of 80 patients of superscan, 71 patients (88.7%) had elevated serum ALP levels (normal serum ALP level 45–125 U/L) with a mean serum ALP level of 615.80 U/L.²¹ However, no comparison was made with normal bone scintigraphy in this study. At the same time, no statistical data was included and only descriptive analysis was performed.
In our study, the ALP levels in the patients who were reported as superscan during bone scintigraphy were found to be statistically significantly higher than in the patients whose bone scintigraphy was reported as normal. In addition, a cutoff value was tried to be calculated by performing ROC analysis, although the number of patients was limited.
The first limitation of our study was that the number of patients was partially insufficient. For this reason, we think that it would be more valuable to conduct our study with a larger patient population. Another limitation of our study was that it was conducted retrospectively. We think that the prospective nature of our study will provide additional data.

Conclusion

Prostate cancer continues to be an important cause of morbidity and mortality in male patients, despite a number of new developments in diagnosis and treatment methods in recent years. Bone scintigraphy is an imaging method used to detect bone metastases in patients with prostate cancer. Bone scintigraphy studies have found that the rate of “Superscan” finding in prostate cancer patients can be as high as 23% in some studies.²² Reporting the “superscan” finding as normal instead of pathological during bone scintigraphy may cause false negative results. In our study, ALP levels in the patients who were reported as superscan during bone scintigraphy were found to be statistically significantly higher than in the patients whose bone scintigraphy was reported as normal. Therefore, evaluation of ALP levels while reporting bone scintigraphy examinations by nuclear medicine specialists can prevent false negative results in patients to a great extent.

Declarations

References

1. Collaboration, Fitzmaurice C, Allen C. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):524-548. Published correction appears in JAMA Oncol. 2017;3(3):418. doi:10.1001/jamaoncol.2016.5688
   Article · PubMed · Google Scholar
2. Hong S, Youk T, Lee SJ, Kim KM, Vajdic CM. Bone metastasis and skeletal-related events in patients with solid cancer: a Korean nationwide health insurance database study. PLoS One. 2020;15(7). doi:10.1371/journal.pone.0234927
   Article · PubMed · Google Scholar
3. Chia SK, Speers CH, D’yachkova Y, et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer. 2007;110(5):973-979. doi:10.1002/cncr.22867
   Article · PubMed · Google Scholar
4. Ryan CJ, Elkin EP, Cowan J, Carroll PR. Initial treatment patterns and outcome of contemporary prostate cancer patients with bone metastases at initial presentation: data from CaPSURE. Cancer. 2007;110(1):81-86. doi:10.1002/cncr.22736
   Article · PubMed · Google Scholar
5. Walker MS, Miller PJ, Namjoshi M, Houts AC, Stepanski EJ, Schwartzberg LS. Relationship between incidence of fracture and health-related quality of life in metastatic breast cancer patients with bone metastases. J Med Econ. 2013;16(1):179-189. doi:10.3111/13696998.2012.737883
   Article · PubMed · Google Scholar
6. Brodowicz T, O’Byrne K, Manegold C. Bone matters in lung cancer. Ann Oncol. 2012;23(9):2215-2222. doi:10.1093/annonc/mds009
   Article · PubMed · Google Scholar
7. Schulman KL, Kohles J. Economic burden of metastatic bone disease in the US. Cancer. 2007;109(11):2334-2342. doi:10.1002/cncr.22678
   Article · PubMed · Google Scholar
8. Svendsen ML, Gammelager H, Sværke C, et al. Hospital visits among women with skeletal-related events secondary to breast cancer and bone metastases: a nationwide population-based cohort study in Denmark. Clin Epidemiol. 2013;5:97-103. doi:10.2147/clep.s42325
   Article · PubMed · Google Scholar
9. Koo PJ, David Crawford E. ¹⁸F-NaF PET/CT and ¹¹C-choline PET/CT for the initial detection of metastatic disease in prostate cancer: overview and potential utilization. Oncology (Williston Park). 2014;28(12):1057-1065.
   PubMed · Google Scholar
10. Basu S, Nair N, Awasare S, Tiwari BP, Asopa R, Nair C. 99mTc(V)-DMSA scintigraphy in skeletal metastases and superscans arising from various malignancies: diagnosis, treatment monitoring, and therapeutic implications. Br J Radiol. 2004;77(916):347-361. doi:10.1259/bjr/72600472
    Article · PubMed · Google Scholar
11. Buckley O, O’Keeffe S, Geoghegan T, et al. 99mTc bone scintigraphy superscans: a review. Nucl Med Commun. 2007;28(7):521-527. doi:10.1097/mnm.0b013e3281744440
    Article · PubMed · Google Scholar
12. Chatterjee P, Mukherjee A, Mitra D, Nautiyal A, Roy A. Superscan on methylene diphosphonate skeletal scintigraphy in prostatic adenocarcinoma: a common finding but rare etiology. Indian J Nucl Med. 2017;32(4):369-371. doi:10.4103/ijnm.ijnm_95_17
    Article · PubMed · Google Scholar
13. Hasbek Z, İsmail ŞALK, Yücel B, Babacan NA. Kemik metastazlarının tespitinde hangi görüntüleme yöntemini seçelim? Kemik sintigrafisi, BT, 18F-FDG PET/BT veya MR? [Which imaging method should we choose to detect bone metastases? Bone scintigraphy, CT, 18F-FDG PET/CT, or MR?]. Bozok Tıp Derg. 2013;3(3):44-50.
    PubMed · Google Scholar
14. Manohar PR, Rather TA, Khan SH, Malik D. Skeletal metastases presenting as superscan on technetium 99m methylene diphosphonate whole-body bone scintigraphy in different types of cancers: a 5-year retro-prospective study. World J Nucl Med. 2017;16(1):39-44. doi:10.4103/1450-1147.181153
    Article · PubMed · Google Scholar
15. Marì C, Catafau A, Carriò I. Bone scintigraphy and metabolic disorders. Q J Nucl Med. 1999;43(3):259-267.
    PubMed · Google Scholar
16. Cook GJ, Gnanasegaran G, Chua S. Miscellaneous indications in bone scintigraphy: metabolic bone diseases and malignant bone tumors. Semin Nucl Med. 2010;40(1):52-61. doi:10.1053/j.semnuclmed.2009.08.002
    Article · PubMed · Google Scholar
17. Garnero P, Buchs N, Zekri J, Rizzoli R, Coleman RE, Delmas PD. Markers of bone turnover for the management of patients with bone metastases from prostate cancer. Br J Cancer. 2000;82(4):858-864. doi:10.1054/bjoc.1999.1012
    Article · PubMed · Google Scholar
18. Ramaswamy G, Rao VR, Krishnamoorthy L, Ramesh G, Gomathy R, Renukadevi D. Serum levels of bone alkaline phosphatase in breast and prostate cancers with bone metastasis. Indian J Clin Biochem. 2000;15(2):110-113. doi:10.1007/bf02883737
    Article · PubMed · Google Scholar
19. Mettler FA Jr, Guiberteau MJ, eds. Essentials of Nuclear Medicine Imaging. Elsevier Health Sciences; 2012:276-280.
    PubMed · Google Scholar
20. Min JW, Um SW, Yim JJ, et al. The role of whole-body FDG PET/CT, 99mTc-MDP bone scintigraphy, and serum alkaline phosphatase in detecting bone metastasis in patients with newly diagnosed lung cancer. J Korean Med Sci. 2009;24(2):275-280. doi:10.3346/jkms.2009.24.2.275
    Article · PubMed · Google Scholar
21. Manohar PR, Rather TA, Khan SH, Malik D. Skeletal metastases presenting as superscan on technetium 99m methylene diphosphonate whole-body bone scintigraphy in different types of cancers: a 5-year retro-prospective study. World J Nucl Med. 2017;16(1):39-44. doi:10.4103/1450-1147.181153
    Article · PubMed · Google Scholar
22. Kovacsne A, Kozon I, Bentestuen M, Zacho HD. Frequency of superscan on bone scintigraphy: a systematic review. Clin Physiol Funct Imaging. 2023;43(5):297-304. doi:10.1111/cpf.12821
    Article · PubMed · Google Scholar

Tables