2006.11.06 – POLYCYTHEMIA PROTOCOL: THE INVESTIGATION OF POLYCYTHEMIA VERA INCIDENCE IN THE TAMAQUA AREA OF PENNSYLVANIA

By ATSDR

November 6, 2006

Project Title: The Investigation of Polycythemia Vera Incidence in the Tamaqua Area of Pennsylvania

PI/Collaborators/Agencies:
ATSDR – Vince Seaman, MS, PhD, Presidential Management Fellow; Toxicologist
Mohammed Uddin, MD, MPH; Medical Officer
Aisha Jumaan, PhD, MPH; Senior Epidemiologist
Lynn Wilder, MSHyg, CIH; Environmental Health Scientist
Lora Werner, MPH; Senior Representative, Region 3
EIS Officer – Emad Yanni, MD
Pennsylvania Department of Health (PADOH)
Gene Weinberg, MPH, DrPH; Division of Community Epidemiology
Mark White, MD, MPH; Division of Environmental Health Epidemiology
Barbara Allerton, MPH, RN; Health Assessment Program
Greg Bogdan, DrPH; Division of Community Epidemiology
Robin Otto, Cancer Registry

Duration: 3 to 6 months

Background:
History of Site: In the spring of 2004, PA Representative David Argall asked the state to follow-up on health outcome data issues and environmental contamination in the Tamaqua area located in eastern Schuylkill County near the former McAdoo Associates Superfund Site. Based on an initial examination of cancer rates in eight zip codes and three counties (Carbon, Luzerne, and Schuylkill) surrounding the site and reports from concerned citizen groups regarding numerous cases of a rare cancer, polycythemia vera (PV), the Pennsylvania Department of Health (PADOH) conducted a comprehensive study using Cancer Registry data to determine the burden and geographic distribution of cancers in an 80 zip code area, spanning Schuylkill, Carbon and Luzerne counties (Tamaqua Area Cancer Incidence Study, 1996-2002). Published in December, 2005, the study found that during the 1996-2002 period, rates for the majority of cancer types in the tri-county area were generally similar to the state’s rates with few exceptions. Many of the cancers that did have elevated rates had known risk factors, except for PV. The incidence of PV was 4 times higher in Luzerne county (statistically significant) and 3 times higher in Schuylkill county compared to the overall PA rates. The rates among males were 6 and 5 times higher in these two respective counties compared to the males in PA. However the limited data available for this cancer (reporting for PV began in 2001) made drawing inferences about its occurrence problematic. Further analysis of the 2003 and 2004 data continue to indicate an overall increase in PV in Luzerne and Schuylkill counties.

Despite the results of the PADOH study, a group of concerned citizens (Army for a Clean Environment or ACE) and a local physician continued requests for further investigation into the incidence of cancers in the area and specifically that of PV in the Tamaqua area. The physician claimed awareness of at least 90 cases of PV in the area for the period 2001-2004 which were reported from only two oncology practices, compared to 82 available in the cancer registry. It is not clear if some of the cases overlap the ones in the registry. Several media reports claim that 5-7 cases of PV cases were clustered on Ben Titus Road (1.5 miles), which is adjacent to Still Creek Reservoir. The physician and ACE also believed that a likely cause of the cancer was exposure to environmental contaminants from the former McAdoo Associates EPA Superfund site. Exposure pathways of concern include private wells and a nearby reservoir (Still Creek Reservoir), which provides drinking water to local residents. Numerous tests of the drinking water in the Tamaqua area over the past 8 years have failed to substantiate these concerns.

In response to the concerns of the community, environmental groups, and elected officials, PADOH requested the assistance of ATSDR through an EPI-AID to verify undocumented cases of PV in the three county area and to describe the characteristics of these cases with respect to possible risk factors (residential, occupational, personal). ATSDR has agreed to this request. This protocol is designed to address the PADOH request for assistance.

Objectives:
1) Ensure all diagnosed cases of malignant polycythemia vera (PV) in the study area (Carbon, Luzerne and Schuylkill counties in Pennsylvania) are reported to the State Cancer Registry.
2 ) Characterize all cases of malignant p.vera documented in the State Cancer Registry who reside in the study area.
3) Confirm the diagnosis of all cases of malignant p.vera documented in the State Cancer Registry who reside in the study area by testing for the presence of the JAK2 V617F mutation in the bone marrow stem cells.

Investigation Methods:
1) Ensure all diagnosed cases of malignant polycythemia vera (PV) in the study area (Carbon, Luzerne and Schuylkill counties in Pennsylvania) are reported to the State Cancer Registry..

ATSDR and PADOH have mailed a fact sheet to approximately twelve local physicians in the area and made presentations at two local hospital physician staff meetings (Miner’s Memorial and Good Samaritan) to solicit the cooperation of the local medical community in reporting all cases of PV to the cancer registry. ATSDR and PADOH personnel will further encourage reporting of new and existing cases by:
– utilizing public media to urge residents of the study area who have been diagnosed with PV, or believe that they may have PV, to contact their physician and verify that their case has been reported to the Cancer Registry.
– contacting physicians of record for PV cases currently in the Cancer Registry and requesting their cooperation in reporting all cases
– investigate all anecdotal PV case reports identified by local community interest groups (i.e. Army for a Clean Environment). ATSDR/PADOH personnel will attempt to contact the medical providers for these cases to ensure that all diagnosed PV cases are reported to the Cancer Registry.

2) Collect demographic, occupational, and personal information from all PV cases contained in the Cancer Registry database who reside in the study area. In addition, we will collect information on the major symptoms associated with PV such as thrombosis, heart attacks, stroke, infarction, chest pain, skin color, itching, etc. These data will aid in the confirmation of PV diagnosis in questionable cases.

ATSDR/PADOH personnel will:
a) Attempt to contact every person identified in the Cancer Registry database who has malignant PV and resides in the three-county area (currently 82 cases from 2001-2004).
b) Provide information on the study to individuals with PV
c) Obtain a signed consent from each participant [appendix #II]
d) Administer the questionnaire [appendix #III] to each participant.

3) Confirm all cases of malignant PV in the cancer registry database that reside in the study area by testing for the presence of the JAK2 V617F mutation.

All persons identified in the Cancer Registry database diagnosed with PV who reside in the study area will be contacted by ATSDR/PADOH personnel and requested to provide a blood sample for analysis. The blood sample may be drawn at a hospital where the person receives treatment or a physician’s office. If the participant is homebound or unable to utilize the above options, a phlebotomist will visit the home (at the participant’s request) to collect the sample. The PCR laboratory analysis will be provided at no charge by the University of Illinois Cancer Center (UICC), and will be facilitated by Dr. Ronald Hoffman, Director of the Center. All costs associated with sample collection, shipping and analysis will be covered by Dr. Hoffman/UICC. The participant will be asked to designate the name of the physician, if any, that will receive the test results.

Data Analysis :
Descriptive statistics will be calculated. A total of the PV cases diagnosed in the three counties for the period 2001-2006 will be calculated identifying numbers and percent with confirmatory lab diagnosis and type of lab tests done. Numbers and percent of symptoms reported by the cases will be estimated. Frequencies will be calculated for all PV cases by age, gender, length of residence, and employment. If the number of cases is sufficient, we will compare the characteristics of the cases in the area (zip codes) with higher than expected PV cases to those with lower than expected PV cases.

Roles/Responsibilities:
PADOH will provide administrative support and personnel
ATSDR will provide technical support and personnel
UICC/Dr.Ronald Hoffman will provide PCR laboratory analysis

Appendices:
Appendix I: Polycythemia Vera Description, Incidence and Epidemiology, Cancer Registry Definition
Appendix II: Consent Form
Appendix III: Questionnaire

Appendix I – Polycythemia Vera Description, Incidence and Epidemiology, and Cancer Registry Definition,

Polycythemia vera (PV) description: PV is a stem cell disorder characterized as a panhyperplastic, malignant, and neoplastic marrow disorder. The most prominent feature of this disease is an elevated absolute red blood cell mass because of uncontrolled red blood cell production. This is accompanied by increased white blood cell (myeloid) and platelet (megakaryocytic) production, which is due to an abnormal clone of the hematopoietic stem cells (CD34) with increased sensitivity to the different growth factors for maturation. Recent studies indicate that a point mutation (JAK2 V617F) in one copy of the Janus kinase 2 gene (JAK2) on chromosome 9 is present in a majority of patients with malignant PV. The etiology of PV is currently unknown and the clinical course of the disease is not well understood.

Clinical Presentation: PV usually occurs within the age range of 20-80 years, with 60 being the mean age of onset. The disease is slightly more common in males than in females. The hyperviscosity, sludging of blood flow, and thromboses, can lead to poor oxygen delivery and symptoms that include headache, dizziness, vertigo, tinnitus, visual disturbances, angina pectoris, or intermittent claudication.. Splenomegaly and hepatomegaly are seen in 75% and 30% of patients, respectively. Weight loss may result from early satiety because of (1) gastric filling being impaired by the enlarged spleen or, rarely, (2) symptoms of splenic infarction. Pruritus occurs in 40% of the patients, and results from increased histamine levels released from increased basophils and mast cells and can be exacerbated by a warm bath or shower.
Diagnostic Criteria: The PCV Study Group (PVSG) was the first to set rigorous criteria for the diagnosis of PV in the 1970s. Diagnostic criteria set by the PVSG, which are still accepted as confirmatory for PV,are as follows:
Category A (Major Criteria)
1. Total RBC vol: males = 36 mL/kg; females = 32 mL/kg
2. Arterial oxygen saturation = 92%
3. Splenomegaly

Category B (Minor Criteria)
1. Thrombocytosis (platelet count >400,000/?L )
2. Leukocytosis (WBC > 12,000/?L )
3. leukocyte alkaline phosphatase (LAP) > 100 U/L (no infection)
4. Serum vitamin B-12 > 900 pg/mL or binding capacity > 2200 pg/mL

Diagnosis is established with A1 plus A2 plus A3 or A1 plus A2 plus any 2 criteria from category B

Unfortunately, the clinical criteria above are not universally used in PV diagnosis. In addition, they do not always distinguish PV from other myeloproliferative disorders (MPDs), thus their use may overestimate the number of true PV cases. The recent establishment of PCR-based methods for detecting the JAK2 V617F mutation may result in the first molecular diagnostic marker for PV, similar to BCR/ABL for CML. Recent studies indicate that 95% of PV patients have the JAK2 V617F mutation (ref), which occurs in less than 0.1% of the general population in a latent or unexpressed form. Thus, while the presence of the JAK2 V617F mutation alone is not diagnostic for PV, it could be considered confirmatory when coupled with the clinical diagnostic criteria. The absence of the mutation would indicate that the patient either does not have PV or that their PV is the result of a different pathological process.

Cancer Registry Definition: Cancer registries (including PA) document “reportable” cases of PV based on the diagnosis by a physician in a medical record that the patient has PV. The diagnostic criteria used by the physician is not recorded. For reporting purposes, PV is recorded as ICD-O-3 9950/3, which also includes polycythemia rubra vera, proliferative polycythemia, and chronic erythemia.

Incidence and Epidemiology: PV is a rare disease with a reported annual incidence ranging from < 1-3 per 100,000 populations (1-6). In the US, two studies in Rochester, Minnesota reported an estimated steady annual incidence of 2.3/100,000 for the period1935-1989 (7,8). The national incidence increases with age (median age of diagnosis is 60 years), and is more common among men compared to women (9). Some studies suggest that PV aggregates in families, and results are conflicting on whether Jewish ancestry is a risk factor (10-16).
Despite the community’s concern that environmental contamination may have contributed to the high PV in the Tamaqua area, current knowledge does not support such a hypothesis (17). Some studies have suggested a higher risk of mortality due to PV among people exposed to benzene (18), petroleum refineries(19), and low doses of radiation, however the numbers were too small (2 confirmed and 2 suspected cases) to make any statistically significant associations(20). An additional small study suggested a higher death due to PV among white and non white embalmers and funeral home directors(21).

References :

1. Berglund S, Zettervall O. Incidence of polycythemia vera in a defined population. Eur J Haematol. 1992;48:20-26.

2. Ridell B, Carneskog J, Wedel H, et al. Incidence of chronic myeloproliferative disorders in the city of Goteborg, Sweden 1983-1992. Eur J Haematol. 2000;65:267-271.

3. Modan B. An epidemiological study of polycythemia vera. Blood. 1965;26:657-667.

4. Prochazka AV, Markowe HL. The epidemiology of polycythaemia rubra vera in England and Wales 1968-1982. Br J Cancer. 1986;53:59-64.

5. Heudes D, Carli PM, Bailly F, Milan C, Mugneret F, Petrella T. Myeloproliferative disorders in the department of Cote d’Or between 1980 and 1986. Nouv Rev Fr Hematol. 1989;31:375- 378.

6. Carli PM. Epidemiology of polycythemia vera in Cte d’Or (Burgundy). Nouv Rev Fr Hematol. 1994;36:147-149.

7. Silverstein MN, Lanier AP. Polycythemia vera, 1935-1969: an epidemiologic survey in Rochester, Minnesota. Mayo Clin Proc. 1971;46:751-753.

8. Ania BJ, Suman VJ, Sobell JL, Codd MB, Silverstein MN, Melton LJ III. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989. Am J Hematol. 1994;47:89-93.

9. McNally RJ, Rowland D, Roman E, Cartwright RA. Age and sex distributions of hematological malignancies in the U.K. Hematol Oncol. 1997;15:173-189.

10. Reznikoff P, Foot NC, Bethea JM, Dubois FF. Racial and geographic origin by patients suffering from polycythemia vera and pathologic findings in blood vessels and bone marrow. Trans Assoc Am Physicians. 1934;49:273.

11. Damon A, Holub DA. Host factors in polycythemia vera. Ann Intern Med. 1958;49:43.

12. Modan B, Kallner H, Zemer D, Yoran C. A note on the increased risk of polycythemia vera in Jews. Blood. 1971;37:172-176.

13. Chaiter Y, Brenner B, Aghai E, Tatarsky I. High incidence of myeloproliferative disorders in Ashkenazi Jews in northern Israel. Leuk Lymphoma. 1992;7:251-255.

14. Najean Y, Rain JD, Billotey C. Epidemiological data in polycythaemia vera: a study of 842 cases. Hematol Cell Ther. 1998; 40:159-165.

15. Brubaker LH, Wasserman LR, Goldberg JD, et al. Increased prevalence of polycythemia vera in parents of patients on poly- cythemia vera study group protocols. Am J Hematol. 1984;16: 367-373.

16. Hemminki K, Jiang Y. Familial polycythemia vera: results from the Swedish Family-Cancer Database [letter]. Leukemia. 2001;15: 1313-1315.

17. Modan B. The epidemiology of polycythemia vera. In: Wasserman LR, Berk PD, Berlin NI, eds. Polycythemia Vera and the Myeloproliferative Disorders. Philadelphia, Pa: WB Saunders Co; 1995:140-146.

18. Hunter FT. Chronic exposure to benzene (benzol), II: the clinical effects. J Indust Hygiene. 1939;21:331.

19. Kaplan SD. Update of a mortality study of workers in petroleum refineries. J Occup Med. 1986;28:514-516.

20. Caldwell GG, Kelley DB, Heath CW Jr, Zack M. Polycythemia vera among participants of a nuclear weapons test. JAMA. 1984; 252:662-664.

21. Hayes RB, Blair A, Stewart PA, Herrick RF, Mahar H. Mortality of U.S. embalmers and funeral directors. Am J Ind Med. 1990; 18:641-652.

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