Pathologic grading for predicting metastasis in phaeochromocytoma

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    Pathologic grading for predicting metastasis in phaeochromocytoma and 1

    paraganglioma 2


    Noriko Kimura1, Ryoichi Takayanagi

    2, Nae Takizawa

    3, Eiji Itagaki

    4, Takayuki Katabami

    5, Narihiko 4

    Kakoi6, Hiromi Rakugi

    7, Yukihiro Ikeda

    8, Akiyo Tanabe

    9, Takeshi Nigawara

    10, Sadayoshi Ito

    11, 5

    Itaru Kimura12

    and Mitsuhide Naruse13


    The Phaeochromocytoma Study Group in Japan 7


    1Department of Clinical Research, Pathology Division, National Hospital Organization, Hakodate 9

    Hospital, Hakodate, Japan 10

    2Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, 11

    Kyushu University, Fukuoka, Japan 12

    3Department of Urology & Andrology, Kansai Medical University, Osaka, Japan 13

    4Third Department of Internal Medicine (Diabetes, Endocrine and Metabolism), Kyorin University 14

    School of Medicine, Tokyo, Japan 15

    5Department of Medicine, Metabolism and Endocrinology, St. Marianna University, School of 16

    Medicine, Kawasaki, Japan 17

    6 Department of Urology, Miyagi Cancer Center, Natori, Japan 18

    Page 1 of 45 Accepted Preprint first posted on 12 February 2014 as Manuscript ERC-13-0494

    Copyright 2014 by the Society for Endocrinology.

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    7Department of Geriatric Medicine & Nephrology, Osaka University Graduate School of Medicine, 19

    Osaka, Japan 20

    8Department of Medicine, Division of Nephrology, Hypertension and Endocrinology, Nihon 21

    University Itabashi Hospital, Tokyo, Japan 22

    9Department of Endocrinology and Metabolism, Tokyo Womens Medical University, Tokyo, 23

    Japan 24

    10Department of Endocrinology and Metabolism, Hirosaki University, School of Medicine, Japan 25

    11Department of Medicine, Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku 26

    University School of Medicine, Sendai, Japan 27

    12Council Member Examination Committee of Social Insurance, Ministry of Health, Labour and 28

    Welfare, Japan, Tokyo, Japan 29

    13Department of Endocrinology, Metabolism, and Hypertension, National Hospital Organization 30

    Kyoto Medical Center, Kyoto, Japan 31


    Corresponding author: postal cord 041-8512, 18-16 Kawahara Hakodate Hokkaido Japan 33

    Department of Clinical Research, Pathology Division, National Hospital Organization, Hakodate 34

    Hospital, Hakodate, Japan, Telephone: 81-138-51-6281, Fax: 81-138-30-1020, 35

    E-mail: 36

    Page 2 of 45

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    Short title: Pathologic grading in paragangliomas 37

    Key words: phaeochromocytoma, paraganglioma, histopathologic diagnosis, succinate 38

    dehydrogenase gene subunit B, immunohistochemistry, metastasis, survival 39


    Page 3 of 45

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    Abstract 41

    Phaeochromocytomas and paragangliomas are rare catecholamine-producing tumours. 42

    Although 10 to 30% of these tumours metastasise, histopathologic criteria to discriminate 43

    malignant from benign tumours have not been established; therefore, reliable histopathologic 44

    markers predicting metastasis are urgently required. One hundred sixty-three tumours, including 45

    40 metastatic tumours, collected by the Phaeochromocytoma Study Group in Japan (PHEO-J) 46

    were analysed using a system we have called GAPP (grading system for adrenal 47

    phaeochromocytoma and paraganglioma ). The tumours were scored based on GAPP criteria as 48

    follows: histologic pattern, cellularity, comedo-type necrosis, capsular/vascular invasion, Ki67 49

    labelling index, and catecholamine type. All tumours were scored from 0 to 10 points, and were 50

    graded as one of three types: well differentiated (0-2 points), moderately differentiated (3-6), and 51

    poorly differentiated (7-10). GAPP scores of the non-metastatic and metastatic groups were 2.08 52

    0.17 and 5.33 0.43, (mean SE, P

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    in 13 (8%) moderarely or poorly differentiated tumours, and 10 of the 13 (77%) had metastases. 59

    Our data indicate that a combination of GAPP classification and SDHB immunohistochemistry 60

    might be useful for the prediction of metastasis in these tumours. 61

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    Introduction 62

    Phaeochromocytomas (PHEO) of the adrenal gland and sympathetic paragangliomas (PGL) are 63

    catecholamine-producing tumours. Although 1030% of these tumours metastasise, 64

    histopathologic criteria that discriminate malignant from benign tumours have not been 65

    established and only the presence of metastasis is considered evidence of malignancy in the 66

    current WHO definition (Thompson LDR et al. 2004). Although most cases of PHEO/PGL are 67

    surgically curable, malignant PHEO/PGL are intractable diseases that require an early diagnosis 68

    and effective treatment. We organised a task force group for PHEO/PGL in Japan (PHEO-J) that 69

    was composed of endocrinologists, urologists, endocrine surgeons, radiologists, molecular 70

    biologists, and pathologists and was supported by the Ministry of Health, Labour, and Welfare. 71

    The aim of the study was to survey PHEO/PGL in Japan. Based on the results of PHEO-J in 72

    2012, the estimated total number of patients with PHEO/PGL was 2,920, including 320 patients 73

    with metastasis. The proportion of patients with malignant, multiple, extra-adrenal, and familial 74

    PHEO/PGL was 11%, 12.7%, 17.3%, and 10%, respectively (Naruse 2011). Among patients with 75

    malignant PHEO/PGL, 36.8% were initially diagnosed as benign and 59.6% showed absence of 76

    metastasis at initial operation (Naruse 2011). The results indicated the difficulties associated with 77

    differential diagnosis of malignant from benign disease in the absence of distant metastases, and 78

    strongly emphasized the need to establish reliable histopathologic criteria for predicting 79

    Page 6 of 45

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    metastasis. 80

    Many studies have attempted to discriminate benign and malignant PHEO/PGL. Of these, some 81

    molecular biomarkers such as the Ki67 labelling index (Nagura et al, 1999, Elder et al. 2003), 82

    loss of cell adhesion molecules such as CD44, and human telomerase reverse transcriptase 83

    expression (van der Harst et al. 2000, Elder et al. 2003, August et al.2004) have been proposed 84

    as useful markers for the detection of high-grade malignancy. However, these markers failed to 85

    detect low- and moderate-grade malignant PHEO/PGL. Although the presence of only one 86

    indicator does not allow a definite diagnosis of malignancy in PHEO/PGL, certain pathologic 87

    features, such as size and site (O'Riordain et al. 1996), local extension, angioinvasion, mitotic 88

    index/proliferative activity using Ki67 labeling index (Ki67 LI), irregular zellballen pattern, and 89

    presence of confluent (comedo-type) tumour necrosis (Zelinka et al. 2011) have been used in 90

    previous studies (Linnoila RI et al. 1990, Kimura N & Sasano N, 1990, Unger P et al. 1991). Such 91

    features have been combined in a scoring system named the Phaeochromocytoma of the 92

    Adrenal gland Scaled Score (PASS) for use in diagnosis (Thompson 2003). PASS was the first 93

    scoring system for diagnosis on adrenal PHEO. However, PASS reproducibility and clinical 94

    significance have not been established (Wu et al. 2009), probably because the PASS 95

    classification contains too many histologic parameters that cover classical features of general 96

    malignancy rather than focusing on specific PHEO/PGL features. In general, for endocrine 97

    Page 7 of 45

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    tumours the biological behaviour of the tumours usually reflects the differentiation of 98

    hormone-producing functions. Cell maturation and cell proliferation in endocrine tumours usually 99

    oppose each other; poorly differentiated tumours grow rapidly and cause poor prognosis 100

    whereas well-differentiated tumours grow slowly and metastasise later. The distinction between 101

    poorly differentiated tumours and well-differentiated tumours is important for the determination of 102

    a patients prognosis (Solcia et al. 2000). Kimura et al. (2005) presented a grading system for 103

    PHEO/PGL based on the concept that norepinephrine-producing tumours are less differentiated 104

    than epinephrine-producing tumours. However, this study was a report from a single institute, 105

    and a multicenter study is required. Here, we examined the materials gathered from a nationwide 106

    survey by PHEO-J using the previously described grading system, which we have named GAPP 107

    (Grading of Adrenal Phaeochromocytoma and Paraganglioma ), to determine whether GAPP 108

    has clinical applications. 109

    Recently, there has been rapid progress in the molecular analysis of PHEO/PGL and 110

    approximately 16 genes responsible for PHEO/PGL have been discovered: NF1, VHL, RET, 111


    FH (Gimenez-Roqueplo 2013, King et al. 2013, Castro-Vega et al.2014). Of these, mutations in 113

    the succinate dehydrogenase genes (SDHA, SDHB, SDHC, and SDHD) are responsible for a 114

    large percentage of hereditary PHEO/PGL syndrome (HPPS) cases, and it has been reported 115

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    that an extra-adrenal site, recurrence, and malignancy are strongly associated with the SDH