Pineal Region Tumors: Diagnosis and Treatment Options (Progress in Neurological Surgery Vol 23)

Pineal Region Tumors. Diagnosis and Treatment Options

Progress in Neurological Surgery Vol. 23

Series Editor

L. Dade Lunsford

Pittsburgh, Pa.

Pineal Region Tumors Diagnosis and Treatment Options

Volume Editors

Tatsuya Kobayashi Nagoya L. Dade Lunsford Pittsburgh, Pa. 58 figures, 19 in color, and 28 tables, 2009

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Shanghai · Singapore · Tokyo · Sydney

Tatsuya Kobayashi, MD, PhD

L. Dade Lunsford, MD, FACS

Nagoya Radiosurgery Center Nagoya Kyoritsu Hospital Nagoya, Japan

Lars Leksell and Distinguished Professor of Neurological Surgery The University of Pittsburgh Pittsburgh, Pa., USA

Library of Congress Cataloging-in-Publication Data Pineal region tumors: diagnosis and treatment options / volume editors, Tatsuya Kobayashi, L. Dade Lunsford. p. ; cm. – (Progress in neurological surgery, ISSN 0079-6492 ; v. 23) Includes bibliographical references and indexes. ISBN 978-3-8055-9077-8 (hardcover: alk. paper) 1. Pineal gland–Tumors. 2. Pineal gland–Tumors–Surgery. I. Kobayashi, Tatsuya, 1938- II. Lunsford, L. Dade. [DNLM: 1. Pinealoma–therapy. 2. Brain Neoplasms–therapy. 3. Pineal Gland–physiopathology. W1 PR673 v. 23 2009 / WK 350 P649245 2009] RC280. P5P56 2009 616. 99’447 – dc22 2008055657

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Contents

VII Series Editor’s Note Lunsford, L.D. (Pittsburgh, Pa.) IX Preface Kobayashi, T. (Nagoya) Introduction 1 Statistical Analysis of Pineal Tumors Based on the Data of Brain Tumor Registry of Japan Shibui, S.; Nomura, K. (Tokyo) Tumors of Pineal Cell Origin 12 Pathology of Pineal Parenchymal Tumors Sato, K.; Kubota, T. (Fukui) 26 Occipital Transtentorial Approach and Combined Treatments for Pineal Parenchymal Tumors Tsumanuma, I. (Niigata); Tanaka, R. (Tsubame); Fujii, Y. (Niigata) 44 Role of Stereotactic Radiosurgery in the Management of Pineal Parenchymal Tumors Kano, H.; Niranjan, A.; Kondziolka, D.; Flickinger, J.C.; Lunsford, L.D. (Pittsburgh, Pa.) Tumors of Germ Cell Origin 59 Pathology of Intracranial Germ Cell Tumors Sato, K.; Takeuchi, H.; Kubota, T. (Fukui) 76 Pineal Germ Cell Tumors Matsutani, M. (Saitama) 86 Strategy of Combined Treatment of Germ Cell Tumors Sawamura, Y. (Sapporo/Tokyo) 96 Radiation Therapy for Intracranial Germ Cell Tumors Aoyama, H. (Sapporo) 106 Stereotactic Radiosurgery for Pineal and Related Tumors Mori, Y.; Kobayashi, T. (Nagoya); Hasegawa, T.; Yoshida, K.; Kida, Y. (Komaki)

V

119 Management of Central Nervous System Germinoma: Proposal for a Modern Strategy Shibamoto, Y. (Nagoya) 130 Quality of Life of Extremely Long-Time Germinoma Survivors Mainly Treated with Radiotherapy Sugiyama, K.; Yamasaki, F.; Kurisu, K.; Kenjo, M. (Hiroshima) 140 Author Index 141 Subject Index

VI

Contents

Series Editor’s Note

Despite their relative rarity, tumors of the pineal region have remained of great interest to neurosurgeons, radiation, and medical oncologists. At many international meetings, controversy reigns as the merits and risks of various treatment strategies are debated. In Asia, the incidence of germ cell tumors seems much greater than the incidence seen in North American or European populations. Classification systems are occasionally confusing as tumors of the pineal region may arise from cells within the pineal parenchyma, from germ cell origin, from adjacent structures including the dorsal midbrain, from other midline structures, or from the tentorium. In this volume, the authors report various diagnostic and treatment strategies for tumors of the pineal region, emphasizing multimodality management in many patients. For some patients of the pineal region, the evaluation often needs to include pertinent serum or cerebrospinal fluid markers, which may be elevated in nongerminomatous germ cell tumors (a rather oxymoronic term developed by pathologists to confuse clinicians, I suppose). High-resolution magnetic resonance imaging is critical to assess the tumor and to follow the response to treatment. A variety of treatment modalities as well as various surgical approaches are discussed in this volume. We have asked many Asian colleagues to present their experience in this volume, in part because of the more frequent management of these tumors in the Asian population. I am sure that their findings are applicable to all patients and all centers that diagnose pineal region tumors. L. Dade Lunsford, Pittsburgh, Pa., USA

VII

Preface

The pineal region is an anatomic location where a wide variety of intracranial tumors occur. Germ cell tumors (GCTs) and pineal parenchymal tumors are the most frequently encountered. The frequency of pineal GCTs is higher in Asian countries, including Japan, while pineal parenchymal tumors are less frequently detected in Asia than in the United States and European countries. Emeritus Prof. Naoki Kageyama, Nagoya University School of Medicine, my teacher and one of the pioneers of GCT studies in Japan, described ‘ectopic pinealoma’ as another name for suprasellar germinomas in 1961. Many original studies of intracranial GCTs by Japanese investigators have contributed to the evolution of the treatment for pineal region tumors. The current volume of Progress in Neurological Surgery takes advantage of the knowledge of Japanese experts on pineal tumors, with special emphasis on epidemiology, pathological diagnosis, and surgical, radiotherapeutic, radiosurgical and chemotherapeutic management options. We hope that this volume will enhance the knowledge of our colleagues about the various manifestations and treatment options available in the modern era of neurosurgery. Tatsuya Kobayashi, Nagoya

IX

Introduction Kobayashi T, Lunsford LD (eds): Pineal Region Tumors. Diagnosis and Treatment Options. Prog Neurol Surg. Basel, Karger, 2009, vol 23, pp 1–11

Statistical Analysis of Pineal Tumors Based on the Data of Brain Tumor Registry of Japan Soichiro Shibuia ⭈ Kazuhiro Nomurab a

Neurosurgery Division, National Cancer Center Hospital, Tokyo, bTokyo Labour Welfare Hospital, Tokyo, Japan

Abstract In this study, we present statistical analyses of pineal tumors based on the data from Brain Tumor Registry of Japan. The most frequent tumor in the pineal region was germinoma, and it accounted for 49.2% of all pineal tumors; it was followed by pineocytoma (8.5%), glioma (6.5%), pineoblastoma (5.1%), malignant teratoma (5.2%) and teratoma (5.1%). Germinoma is most frequent among patients between 10 and 19 years of age, and there are some patients aged >30 years; however, there are few patients with choriocarcinoma, embryonal carcinoma, and yolk sac tumor who are aged >30 years. Pineoblastoma is most frequent among patients under 5 years of age, while pineocytoma is evenly distributed in patients between 10 and 60 years of age. The 5-year survival rate of germinoma was 89.4%, while those of embryonal carcinoma, yolk sac tumor and choriocarcinoma were 35.3, 37.3 and 58.1%, respectively. Copyright © 2009 S. Karger AG, Basel

The Committee of Brain Tumor Registry of Japan (BTRJ) was founded in 1975 in order to investigate the incidence and characteristics of brain tumors in Japan; it is organized by 80 professors of neurosurgical departments of universities and medical colleges throughout Japan. The first report was published in 1978, and in September 2003 the 11th edition of the report was issued [1]. The number of collaborating neurosurgical institutions is now 473. This report was based on the data of the 11th edition of BTRJ (1969–1996) and 12th edition of BTRJ (1984– 2000), which we are now preparing to publish. Statistical analyses of the pineal region tumors were performed mainly for the patients registered during 1984 and 2000. Permission to use the data was obtained from the Committee of BTRJ in June 2008.

Registration

Patients with brain tumors who were treated during 1969 and 2000 have been registered in the brain tumor registration office of National Cancer Center Hospital according to the registration forms which had been sent from the collaborating neurosurgical institutions throughout Japan. The numbers of the patients by diagnosis, age, location and treatment were summarized, and survival rates were calculated using Cutler’s method [1]. Every year about 5,000 cases are registered, and more than 117,000 cases have been registered so far. According to the Central Brain Tumor Registry of the United States (CBTRUS), the incidence rate of all primary and brain and central nervous system tumors was 14.8 cases per 100,000 person-years [2]. If the incidence rate in Japan was similar to that of the United States, the registration rate of the primary brain tumors would be estimated at 40% of the brain tumors occurring in Japan in a year.

Frequencies of Primary Brain Tumors

The frequencies of various primary brain tumors registered between 1984 and 2000 are listed in table 1. Meningioma was the most frequent and accounted for 26.5% of the primary brain tumors; it was followed by glioma (25.6%), pituitary adenoma (17.9%) and schwannoma (10.5%); however, the frequency of each tumor was different by age of patients. Among patients under 15 years of age, glioma was the most frequent. It accounted for 54.1% of all primary brain tumors; it was followed by germ cell tumors (14.6%), craniopharyngiomas (8.5%), meningioma (2.0%) and pituitary adenomas (2.0%). Frequency was quite different among patients over 70 years of age. Among elderly patients, meningioma was the most frequent. It accounted for 41.3%, followed by glioma 25.6%, pituitary adenoma 9.6% and schwannoma 7.0%. Malignant lymphoma was as high as 6.7%. Compared with the data of CBTRUS 1998–2002, glioma and meningioma were less frequent, and pituitary adenoma and germ cell tumor were much more frequent in Japan.

Neuroepithelial Tumor

Frequencies of neuroepithelial tumors are listed in table 2. Glioblastoma was the most frequent neuroepithelial tumor. It accounted for 34.5% of all neuroepithelial tumors and was followed by astrocytoma (26.7%) and anaplastic astrocytoma (17.6%). Among patients under 15 years of age, astrocytoma was the most frequent. It accounted for 32.9% of all neuroepithelial tumors and was followed by

2

Shibui · Nomura

Table 1. Frequencies of primary brain tumors (Brain Tumor Registry of Japan 1984–2000) Total

Age ≤14 years

Meningioma

26.5

Glioma

25.6

Schwannoma Pituitary adenoma

15–69 years ≥70 years 26.5

41.3

31.4

54.1

23.4

25.6

43.6

10.5

1.4

11.9

7.0

8.0

17.9

2.0

20.6

9.6

6.3

Germ cell tumor

2.7

14.6

1.9

0.0

0.6

Craniopharyngioma

3.9

8.5

3.3

1.6

0.7

Dermoid, epidermoid

1.5

1.4

1.6

0.4

N/A

Hemangioblastoma

1.7

4.9

1.9

1.0

0.9

Sarcoma

2.1

5.2

1.9

0.2

N/A

Malignant lymphoma 3.0

0.3

2.7

6.7

3.1

Others

5.6

4.3

6.6

5.4

Total

4.6

2.0

CBTRUS 1998–2002

100.0 100.0 100.0 100.0 (n = 67,293) (n = 5,148) (n = 53,674) (n = 8,471)

100.0 (n = 63,698)

Figures indicate percentages.

medulloblastoma (22.2%), anaplastic astrocytoma (9.1%), ependymoma (8.7%) and glioblastoma (6.9%). Among patients over 70 years of age, glioblastoma was the most frequent and it accounted for 59.4% of all neuroepithelial tumors; it was followed by anaplastic astrocytoma (19.6%). It was observed that 80% of neuroepithelial tumors in aged patients were malignant gliomas.

Pineal Region Tumor

Apart from 105 histologically unknown cases, 1,188 cases of pineal region tumor were registered during 1984 and 2000. The most frequent tumor was germinoma. It accounted for 49.2% of all pineal region tumors and was followed by pineocytoma (8.5%), glioma (6.5%), pineoblastoma (5.5%), malignant teratoma (5.2%), and teratoma (5.1%; table 3). There was a 13:1 male predominance in germinoma, 14:1 in teratoma and malignant teratoma, 2:1 in pineoblastoma and totally 5:1, while there was no predominance in pineocytoma.

Statistical Analysis of Pineal Tumors from BTRJ

3

Table 2. Frequencies of neuroepithelial tumors (Brain Tumor Registry Japan 1984–2000) All

Age ≤14 years

15–69 years ≥70 years

Glioblastoma

34.5

6.6

36.1

60.9

Astrocytoma

26.7

32.9

27.6

13.2

Anaplastic astrocytoma

17.6

9.5

19.0

19.8

Oligodendroglioma

3.5

1.4

4.3

1.2

Anaplastic oligodendroglioma

0.9

0.1

1.1

0.7

Ependymoma

3.1

8.1

2.4

0.4

Anaplastic ependymoma

0.9

3.4

0.5

0.2

Plexus papilloma

1.0

2.8

0.7

0.4

Medulloblastoma

4.0

21.3

0.8

0.1

Other glioma

7.8

14.0

7.5

3.1

Total

100.0 100.0 100.0 100.0 (n = 17,492) (n = 2,787) (n = 12,536) (n = 2,169)

Figures indicate percentages.

Age distribution of patients with various pineal tumors is shown in figure 1. Germinoma is most frequent among patients between 10 and 19 years of age and there are some patients over 30; however, there are a few patients over 30 with choriocarcinoma, embryonal carcinoma, and yolk sac tumor. Pineoblastoma is most frequent among patients under 5 years of age, while pineocytoma is evenly distributed in patients between 10 and 60 years of age. Benign teratoma is common in patients under 20 years of age, and so is malignant teratoma. Treatment of pineal region tumors depends on the histological diagnosis, and it will be discussed in the other chapters. Generally, the benign tumors, such as teratoma, dermoid and epidermoid tumors, are resected surgically, and the malignant tumors are treated with chemotherapy and radiotherapy after histological diagnosis by biopsy or surgical removal. Germinoma is sensitive to chemotherapeutic agents such as cisplatin and carboplatin. They are usually administered with etoposide and followed by low-dose radiation [3–6]. Most of malignant tumors such as choriocarcinoma, embryonal carcinoma and yolk sac tumors are usually treated with ifosfomide, cisplatin and etoposide and radiation in Japan.

4

Shibui · Nomura

180

Male Female

160 140

Patients

120 100 80 60 40 20 0 0

5

10

15

20

25

30

35

a

40 45 Age (years)

50

55

60

65

70

75

20

80

Male Female

18 16 14

Patients

12 10 8 6 4 2 0 0

5

10

15

20

b

25

30

35

40 45 Age (years)

50

55

60

65

70

Fig. 1. Age distribution and sex ratio of patients with primary brain tumors in the pineal region. a Germinoma (n = 585; male:female ratio = 12.6:1). b Choriocarcinoma (n = 27; male:female ratio = 5.8:1).

Statistical Analysis of Pineal Tumors from BTRJ

5

75

80

20

Male Female

18 16 14

Patients

12 10 8 6 4 2 0 0

5

10

15

20

25

30

35

c

40 45 Age (years)

50

55

60

65

70

75

20

80

Male Female

18 16 14

Patients

12 10 8 6 4 2 0 0

5

d

10

15

20

25

30

35

40 45 Age (years)

50

55

60

65

70

75

80

Fig. 1. c Embryonal carcinoma (n = 34; male:female ratio = 10.3:1). d Yolk sac tumor (n = 34; male:female ratio = 10.3:1).

6

Shibui · Nomura

25 Male Female 20

Patients

15

10

5

0 0

5

10

15

20

25

30

35

e

40 45 Age (years)

50

55

60

65

70

75

20

80

Male Female

18 16 14

Patients

12 10 8 6 4 2 0 0

5

10

15

20

f

25

30

35

40 45 Age (years)

50

55

60

65

70

Fig. 1. e Other germ cell tumor (n = 68; male:female ratio = 7.5:1). f Pineoblastoma (n = 65; male:female ratio = 1.7:1).

Statistical Analysis of Pineal Tumors from BTRJ

7

75

80

20

Male Female

18 16 14

Patients

12 10 8 6 4 2 0 0

5

10

15

20

25

30

35

g

40 45 Age (years)

50

55

60

65

70

75

20

80

Male Female

18 16 14

Patients

12 10 8 6 4 2 0 0

5

h

10

15

20

25

30

35

40 45 Age (years)

50

55

60

65

70

75

80

Fig. 1. g Pineocytoma (n = 101; male:female ratio = 1:1). h Teratoma (n = 61; male:female ratio = 14.3:1).

8

Shibui · Nomura

20

Male Female

18 16 14

Patients

12 10 8 6 4 2 0 0

5

10

15

20

i

25

30

35 40 45 Age (years)

50

55

60

65

70

Fig. 1. i Malignant teratoma (n = 62; male:female ratio = 14.5:1).

Cumulative survival rates of each pineal tumor were calculated by Cutler’s method. Five-year survival rate of germinoma was 89.4%, while those of embryonal carcinoma, yolk sac tumor and choriocarcinoma were 35.3, 37.5 and 58.1%, respectively (table 4).

Discussion

The incidence of the pineal tumors according to the centralized brain tumor registries varies from 0.4 to 1% among adult patients and from 3 to 5% among children [7]. Especially germ cell tumors are very frequent in Asian countries such as Japan and Korea [8]. The frequency in Japan is 5 times as high as in the western countries. In the registries of the United States, germ cell tumors were classified only into germinoma and mixed germ cell tumors, and the details of choriocarcinoma, embryonal carcinoma and yolk sac tumors were not reported. Even in Japan these tumors are rare, but 95 cases apart from 68 cases with mixed germ cell tumors were registered in BTRJ during 1984 and 2000 and survival rates were calculated. Compared with pure germinomas, survival rates of these tumors were very low, and especially those of embryonal carcinoma and yolk sac

Statistical Analysis of Pineal Tumors from BTRJ

9

75

80

Table 3. Frequencies of pineal tumors by histology (BTRJ 1984–2000) Male Germinoma

Female

Total

542

43

585 (49.2%)

Pineoblastoma

51

50

101 (8.5%)

Pineoblastoma

41

24

65 (5.5%)

Teratoma

57

4

61 (5.1%)

Malignant teratoma

58

4

62 (5.2%)

Embryonal carcinoma

31

3

34 (2.9%)

Yolk sac tumor

31

3

34 (2.9%)

Choriocarcinoma

23

4

27 (2.3%)

Other germ cell tumor

60

8

68 (5.7%)

Glioma

42

35

77 (6.5%)

4

1

5 (0.4%)

Epidermoid

13

2

15 (1.3%)

Others

32

22

54 (4.5%)

985

203

1,188 (100.0%)

84

72

Dermoid

Total Unknown

105

Table 4. Cumulative survival rates of pineal tumors (BTRJ 1984–2000) Patients

1 year

2 years

3 years

4 years

5 years

Germinoma

486

96.2

92.4

91.3

90.3

89.4

Pineocytoma

77

95.4

89

87.5

87.5

84.1

Pineoblastoma

30

74.8

57.1

50.7

48.5

46.1

Teratoma

50

96.4

96.4

92.2

92.2

89.6

Malignat teratoma

41

84.2

74.9

72.8

70.6

70.6

Embryonal carcinoma

12

64.7

38.2

35.3

35.3

35.3

Yolk sac tumor

13

55.6

44.8

37.3

37.3

37.3

Choriocarcinoma

15

62.3

62.3

62.3

62.3

58.1

Rates are expressed as percentages.

10

Shibui · Nomura

tumors were less than 40%. Although chemotherapies such as ifosfomide, cisplatin and etoposide and carboplatin + etoposide improved the survival, the latter is still unsatisfactory. Nationwide registry is important. It is a retrospective study and the evidence level is not as high as it would be in a prospective study. But thanks to it we can understand the global aspects of the tumors, especially rare tumors such as pineal tumors. In 2008, BTRJ started to register tumors online. The registration rate is expected to be much higher, and most of the brain tumors in Japan will be registered.

References 1

2

3

4

The Committee of Brain Tumor Registry of Japan: Brain Tumor Registry of Japan (1969– 1996). Neurol Med Chir 2003;43(suppl):i–vii, 1–111. Central Brain Tumor Registry of the United States: Statistical Report: Primary Brain Tumors in the United States, 1998–2003. Chicago, Central Brain Tumor Registry of the United States, 2005. Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O, Funata N, Seto T: Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 1997;86: 446–455. Matsutani M, The Japanese Pediatric Brain Tumor Study Group: Combined chemotherapy and radiation therapy for CNS germ cell tumors – the Japanese experience. J Neurooncol 2001;54: 311–316.

5

6

7

8

Shibamoto Y, Abe Y, Yamashita J, Takahashi M, Hiraoka M, Ono K, Tsutsui K: Treatment result of intracranial germinoma as a function of the irradiated volume. Int J Radiat Oncol Biol Phys 1998; 15:285–290. Sawamura Y, Shirato H, Ikeda J, Tada M, Ishii N, Kato T, Abe H, Fujieda K: Induction chemotherapy followed by reduced-volume radiation therapy for newly diagnosed central nervous system germinoma. J Neurosurg 1998;88:66–72. Villano JL, Propp JM, Porter KR, Stewart AK, Valyi-Nagi T, Li X, Engelhard HH, McCarthy BJ: Malignant pineal germ-cell tumors: an analysis if cases from three tumor registries. Neuro Oncol 2008;10:121–130. Nomura K: Epidemiology of germ cell tumors in Asia of pineal region tumor. J Neurooncol 2001; 54:211–217.

Soichiro Shibui, MD, DMSc Neurosurgery Division, National Cancer Center Hospital 5-1-1 Tsukiji, Chuo-ku Tokyo 104-0045 (Japan) Tel. +81 3 3542 2511, Fax +81 3 3542 3815, E-Mail [email protected]

Statistical Analysis of Pineal Tumors from BTRJ

11

Tumors of Pineal Cell Origin Kobayashi T, Lunsford LD (eds): Pineal Region Tumors. Diagnosis and Treatment Options. Prog Neurol Surg. Basel, Karger, 2009, vol 23, pp 12–25

Pathology of Pineal Parenchymal Tumors Kazufumi Sato ⭈ Toshihiko Kubota Division of Neurosurgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Science, University of Fukui, Fukui, Japan

Abstract Pineal parenchymal tumors (PPTs) are neuroepithelial tumors that arise from pineocytes or their precursors. According to the currently revised WHO classification of tumors of the central nervous system, PPTs are subdivided into well-differentiated pineocytoma, poorly differentiated pineoblastoma, and PPT with intermediate differentiation (PPTID). Pineocytomas are slow-growing neoplasms composed of small mature cells resembling pineocytes. Large pineocytomatous rosettes are the most characteristic appearance. Pineoblastomas are the most primitive form and have a highly malignant biological behavior. PPTIDs show an intermediate histological grade of malignancy between pineocytomas and pineoblastomas. Immunohistochemically, PPTs are positive for several neuronal markers, including synaptophysin, neurofilaments, class III β-tubulin, and chromogranin A. Photosensory differentiation is associated with immunoreactivity for retinal S-antigen and rhodopsin. Ultrastructurally, dense core vesicles and clear vesicles are present in both cytoplasm and cellular processes, the latter showing occasional synapse-like junctions. In some cases, ultrastructural evidence of photoreceptor differentiation, such as synaptic ribbons, microtubular sheaves, and cilia, is observed. Little is known about the genetics responsible for the development of PPTs. Several chromosomal abnormalities have been identified frequently in pineoblastomas and PPTIDs but less commonly in pineocytomas. Pineoblastomas are known to occur in patients with RB1 gene abnormalities, and these tumors also develop in patients with familial bilateral retinoblastomas (trilateral retinoblastoma syndrome). However, specific gene abnormalities involved in the tumorigenesis of PPTs have not been identified. Copyright © 2009 S. Karger AG, Basel

Histology of the Normal Human Pineal Gland

The normal adult pineal gland has a lobulated architecture in that parenchymal cells (pineocytes) are intersected by vascular-rich connective tissue stroma (fig. 1a). These pineal parenchymal cells are a specialized form of neuronal cells, and are immunopositive for synaptophysin (fig. 1b) and neurofilaments, as well as

a

b

c

Fig. 1. Normal adult human pineal gland. a The pineal gland shows a lobulated structure, and pineal parenchymal cells are intersected by vascular-rich connective tissue stroma. HE. b Immunohistochemistry of synaptophysin showing positivity for parenchymal cells. c Immunohistochemistry of GFAP showing positivity for most of interstitial cells and a small number of parenchymal cells.

chromogranin A, retinal S-antigen, serotonin, and melatonin [1, 2]. A pineocyte has a club-shaped cytoplasmic process terminating on the neighboring blood vessel wall. The pineal gland also contains a moderate number of astrocytes, which are concentrated at the stroma and less frequently distributed in the lobules. These cells are strongly positive for glial fibrillary acidic protein (GFAP; fig. 1c) and S-100 protein [1, 3].

Classification and Grading of Pineal Parenchymal Tumors

In older literature, pineal parenchymal tumors (PPTs) have occasionally been referred to as ‘true pinealomas’ [4]. Herrick and Rubinstein [4] reported 28 cases of PPTs, and confirmed that these tumors have a potential towards divergent glial and neuronal differentiation. In one example, differentiation towards neurosensory photoreceptors was demonstrated. In 1993, Schild et al. [5] proposed the classification of PPTs into pineocytomas, pineoblastomas, PPTs with intermediate differentiation (PPTIDs), and mixed PPTs. In the 1993 WHO classification of tumors of the central nervous system (CNS), mixed pineocytoma/pineoblastoma was referred to as ‘a tumor containing area composed of immature (pineoblastic) and differentiated (pineocytic) neoplastic cells’. In the recently revised WHO classification of tumors of the CNS [6], PPTs are subdivided into well-differentiated pineocytoma, poorly differentiated pineoblastoma, and PPTID. Pineocytomas are slow-growing neoplasms composed of small mature cells resembling pineocytes. The WHO classification designates pineocytomas as grade I lesions. Pineoblastomas are the most primitive, and have a highly malignant biological behavior. These tumors correspond to WHO grade IV. PPTIDs show an intermediate-grade of malignancy, which may correspond to

Pathology of Pineal Parenchymal Tumors

13

WHO grade II or III. Although definite grading criteria have not been established, this malignancy scale showed a correlation (p < 0.001) with overall survival, event free survival, and local control [7]. Histologically, a strong correlation was shown between overall survival and necrosis or expression of neurofilament protein. In terms of event-free survival, a strong correlation was found with mitosis and necrosis [7]. Grade I pineocytomas do not metastasize, and the 5-year event-free survival is 100%. Local recurrence (21%) and rare spinal metastasis (5%) may occur with grade II PPTIDs. Grade III PPTIDs and grade IV pineoblastomas can recur locally and metastasize [7]. The MIB-1 (Ki-67) labeling index (LI) is significantly higher in pineoblastomas than in other types of PPTs. The LI for pineocytomas and pineocytomas with anaplasia was less than 7%, but that for pineoblastomas was more than 8% [8, 9]. The MIB-1 LI correlated well with histological malignancy and neuronal differentiation evaluated immunohistochemically by both neurofilaments and synaptophysin [9, 10]. In PPTIDs, the mean MIB-1 LI was reported to range from 3 to 10% [9, 10].

Incidence, Age, and Sex Distribution

Pineal region tumors are uncommon and account for less than 1% of primary tumors of the CNS. PPTs account for 14–30% of pineal tumors [5, 6]. Based on previous criteria, pineocytomas represent 14–60% of PPTs [5, 6, 11]. Pineocytomas occur throughout life but most frequently affect adults (mean age: 38–45 years) [4–6, 11–14]. They are distributed evenly between the sexes. Pineoblastomas comprise approximately 40% of all PPTs, and they usually occur in the first two decades of life (mean age: 18.5 years) [4, 6, 7, 11, 13, 15]. There is no sex predilection. PPTIDs comprise at least 20% of all PPTs [6]. The reported incidence of 0–60% may reflect the frequent misdiagnosis of this tumor and/or the inclusion of mixed pineocytoma/pineoblastoma and other unusual PPTs [6]. PPTIDs affect all ages, with a peak incidence in early adulthood (mean age: 38 years) [5, 6, 11, 13, 15]. There is a slight female preponderance [6, 7].

Neuroimaging

On computed tomography, pineocytomas typically show round, well-demarcated, isodense or hypodense masses, measuring less than 3 cm in diameter. Most tumors show homogenous contrast enhancement. Some cases show calcification (tumoral and/or pineal gland origin) or occasional cystic changes [16, 17]. Mild hydrocephalus is a common feature. On MRI, pineocytomas tend to be hypointense or

14

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Fig. 2. Pineocytoma. Enhanced MRI showing well-demarcated pineal mass with homogeneous enhancement.

isointense on T1-weighted images and hyperintense on T2-weighted images with usually homogenous contrast enhancement [16, 17] (fig. 2). On computed tomography, pineoblastomas appear as a large, lobulated mass, which usually shows heterogeneous contrast enhancement [16]. Hydrocephalus is present in most cases. The tumors are variably cystic. On MRI, large portions of the tumors are hypointense to isointense on T1-weighted images and hyperintense on T2-weighted images with heterogeneous contrast enhancement [16–19] (fig. 3). The margins between tumors and adjacent structures are occasionally less well defined, suggesting an invasive nature [16, 17]. Extensive cystic change is rare. In PPTIDs, there are no specific neuroradiological manifestations that permit their reliable distinction from other PPTs.

Pathology

Pineocytoma Macroscopy

Pineocytomas are usually well-defined lesions with a pale and grayish appearance, and the cut surface shows homogeneous or granular appearance [4, 20]. Degenerative changes including cyst formation and focal hemorrhage can be present [11]. There is no evidence of local infiltration into adjacent brain parenchyma and leptomeninges.

Pathology of Pineal Parenchymal Tumors

15

Fig. 3. Pineoblastoma. Enhanced MRI showing marked enhancement of a pineal mass with cystic change.

Microscopy

Pineocytomas are well-differentiated neoplasm composed of relatively small, uniform, mature cells resembling mature pineocytes (fig. 4a) [1, 4–7, 13, 20]. The majority of nuclei are round-to-oval with inconspicuous nucleoli. The cells grow in sheets or in a lobulated structure with large anucleate areas called pineocytomatous rosettes (fig. 4b). These rosettes are a characteristic feature of pineocytoma, and they have been interpreted as evidence of neuronal differentiation. Pineocytomas are also characterized by cytoplasmic processes with club-like terminal expansion oriented towards blood vessels. These processes are argyrophlic and can be visualized with specific silver carbonate or Bodian stains (fig. 4c). Mitotic figures or necrotic areas are not conspicuous. The pleomorphic variant of pineocytomas contains ganglioid giant cells with hyperchromatic and bizarre nuclei, but usually mitotic figures are not seen (fig. 5) [5, 8, 13, 20, 21]. This pleomorphism is characteristic of neuronal differentiation [4]. Immunohistochemistry

Pinocytomas show immunopositivity for several neuronal markers, including synaptophysin, neurofilaments (fig. 6a), class III β-tubulin, and chromogranin A [6, 7, 14, 21, 22]. Photosensory differentiation is associated with immunoreactivity for

16

Sato · Kubota

a

b

c

Fig. 4. Pineocytoma. a The tumor is composed of relatively small, uniform, mature cells resembling mature pineocytes. HE. b Pineocytomatous rosettes. HE. c Club-like processes oriented towards blood vessels. Bodian stain.

Fig. 5. Pleomorphic pineocytoma. Photomicrograph showing numerous ganglioid giant cells with hyperchromatic and bizarre nucleus. HE.

retinal S-antigen and rhodopsin [10, 11, 22]. Pineocytomatous rosettes are strongly positive for synaptophysin and neurofilaments, and the latter demonstrates the fibrillar meshwork of cytoplasmic processes [1]. In typical pineocytoma, interstitial cells are usually positive for GFAP (fig. 6b) and S-100 protein [1, 8]. In some pineocytomas, tumors show evidence of an extensive astrocytic component [4, 20]. In pleomorphic pineocytoma, tumor cells are strongly positive for neuronal markers especially for synaptophysin (fig. 7) and neurofilaments [7, 8, 13, 21]. Electron Microscopy

Pineocytoma cells are characterized by moderate size, round to oval nuclei with moderate amounts of heterochromatin. Nucleoli are not prominent. Their

Pathology of Pineal Parenchymal Tumors

17

a

b

Fig. 6. Pineocytoma. a Immunohistochemistry for neurofilament (68 kDa) showing numerous positive cell processes. b Immunohistochemistry of GFAP showing strong positivity in interstitial cells.

cytoplasm is abundant and contains well-developed organelles, including smooth and rough endoplasmic reticulum, Golgi apparatus, mitochondria, microtubules, and lysosomes. Membrane-bound dense core vesicles (fig. 8a) and clear vesicles (fig. 8b) are present in both cytoplasm and cellular processes, the latter showing occasional synapse-like junctions (fig. 8b) [1, 4, 14, 23–25]. Pineocytoma cells share ultrastructural findings with normal pineocytes, such as synaptic ribbons, 9 + 0 cilia, microtubular sheaves, annulate lamellae (fig. 8c), paired twisted filaments, membranous whorls (fig. 8d), and fibrous bodies (fig. 8e) [1, 4, 14, 23–26]. In cases with retinoblastic differentiation, microrosettes bearing microvilli and bulb-ended 9 + 0 cilia are observed (fig. 8f) [4, 11, 14, 25]. Cell junctions are rarely seen.

Pineoblastoma Macroscopy

Pineoblastomas are pinkish-gray, soft, and gelatinous tumors and occasionally show diffuse infiltration of local structures [20]. Hemorrhage and/or necrosis are common, and craniospinal dissemination through the CSF occurs frequently [4, 5, 11, 20, 27]. Extracranial metastatic spread of the tumor may occur to the peritoneal cavity via the ventriculoperitoneal shunt. Extremely rare extracranial metastases to the bone [28] or lung [29] have been described in a few cases with pineoblastomas. Microscopy

Pineoblastomas are composed of hypercellular and closely packed patternless sheets of small cells, mimicking primitive neuroectodermal tumor or

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Sato · Kubota

Fig. 7. Pleomorphic pineocytoma. Immunohistochemistry of synaptophysin showing strong positivity in most of the tumor cells.

medulloblastoma. The tumor cells have high nuclear-to-cytoplasmic ratios and indistinct cellular borders (fig. 9a). Nuclei are round to irregular and rich in chromatin. Necrosis is common, but mitotic activity varies considerably. No lobular arrangement could be discerned. Numerous Homer Wright rosettes (fig. 9b) and occasional Flexner-Wintersteiner rosettes are observed, but pineocytomatous rosettes are absent. In rare cases, fleurettes (a bundle of cytoplasmic processes showing bulbous expansion at their distal portion) indicative of photoreceptor differentiation may be found [4, 30]. Silver carbonate stains show scant cytoplasm and few cellular processes. Melanin production as well as cartilaginous and rhabdomyoblastic differentiation are encountered in rare pineoblastomas referred to as ‘pineal anlage tumors’ [31, 32]. Immunohistochemistry

The immunophenotype of pineoblastoma is similar to that of pineocytoma and includes reactivity for neuronal and photoreceptor markers, such as synaptophysin, neurofilaments, class III β-tubulin, chromogranin A, and retinal S-antigen [7, 10, 11, 13, 22, 33]. However, reactivities are variable and usually lower in intensity than in other PPTs. Flexner-Wintersteiner rosettes and fleurettes are strongly positive for retinal S-antigen. Thus, pineoblastomas share morphological and immunohistochemical features with photoreceptor cells of the developing pineal gland and retina. In rare cases immunopositive for GFAP and αB-crystallin, the presence of entrapped reactive astrocytes should be excluded [6].

Pathology of Pineal Parenchymal Tumors

19

a

b

d

c

e

f

Fig. 8. Pineocytoma. Electron micrographs. a Dense core vesicles (arrows) in the cell processes. b Numerous clear vesicles and a few synapse-like junctions (arrows). c Annulate lamellae. d Membranous whorls. e Fibrous body. f Microvillous projections and cilia.

a

b

Fig. 9. Pineoblastoma. a The tumor is composed of hypercellular and closely packed patternless sheets of small cells with necrosis. HE. b Homer Wright rosettes (arrows). HE.

Electron Microscopy

The fine structure of pineoblastomas is similar to that of any poorly differentiated neuroectodermal tumors. Tumor cells are composed of closely packed small cells with round to oval nuclei, which are often irregularly indented (fig.

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Fig. 10. Pineoblastoma. Electron micrograph showing poorly differentiated tumor cells with no recognizable neuronal structures.

10). Cytoplasm is scant and contains few profiles of rough and smooth endoplasmic reticulum, annulate lamellae, membranous whorls as well as occasional microtubules, intermediate filaments and lysosomes [1, 10, 14, 24, 34]. Scattered dense core vesicles are observed in the cytoplasm, but they are very infrequent compared with those seen in pineocytomas [14, 24]. Poorly formed, short cell processes may contain microtubules as well as scant dense core vesicles [24]. In some cases, tumor cells show ultrastructural evidence of photoreceptor differentiation, such as synaptic ribbons, microtubular sheaves, and club-shaped giant cilia with a 9 + 0 configuration [1, 14, 24, 34]. Junctional complexes are usually inconspicuous.

Pineal Parenchymal Tumor of Intermediate Differentiation Macroscopy

The gross appearance of PPTIDs is similar to that of pineocytomas. The tumors are circumscribed, soft in texture, and usually lacking in gross evidence of necrosis. Microscopy

PPTIDs are either diffuse (neurocytoma-like) or somewhat lobulated tumors characterized by moderately high cellularity, mild to moderate nuclear atypia, and low

Pathology of Pineal Parenchymal Tumors

21

Fig. 11. PPTID. Tumor cells showing moderately high cellularity and mild nuclear atypia. HE.

to moderate mitotic activity (fig. 11) [6]. Preliminary studies suggest that tumors corresponding to grade II or III can be distinguished on the basis of mitotic activity and neurofilament protein immunoreactivity [7, 13]. PPTIDs include transitional form cases in which typical pineocytomatous areas are associated with a diffuse pattern [6]. In the current WHO classification [6], mixed pineocytoma/pineoblastoma is considered an extremely rare neoplasm interpreted as harboring both primitive and mature components and being subsumed under the category of pineoblastomas. Immunohistochemistry

Immunohistochemically, the tumor cells show synaptophysin positivity. Variable labeling is seen with antibodies to neurofilaments, chromogranin A, and retinal S-antigen [1, 9, 10, 13].

Genetics

Little is known regarding molecular genetic alterations underlying the formation of PPTs. Cytogenetic studies have suggested that monosomy in the distal 12q region and partial deletion or loss of chromosome 11 are related to tumor progression [35–37]. A microarray analysis of pineocytoma has shown high-level expression of genes coding for enzymes related to melatonin synthesis (HIOMT) and phototransduction

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(OPN4, RGS16), and such reactivities indicate bi-directional neurosecretory and photosensory differentiation [38]. A relationship between the RB1 gene and pineocytoma has not been established. In pineoblastomas, monosomy for chromosomes 20 and 22, and trisomy for chromosome 14 have been described [7]. In another analysis of pineoblastomas, both monosomy 22 and INI1 gene (22q11) mutation were reported [39]. Pineoblastomas are known to occur in patients with RB1 gene abnormalities, and their prognosis is significantly worse than that of sporadic cases [40]. Pineoblastomas develop in patients with familial bilateral retinoblastomas, an occurrence termed ‘trilateral retinoblastoma syndrome’ [19, 41], and have also been reported in patients with familial adenomatous polyposis [42]. Familial pineoblastoma has been described, and a genetic basis and mutual exposure to an environmental factor responsible for the gene abnormalities were suggested [43]. By comparative genomic hybridization, frequent chromosomal gains and losses have been identified in PPTIDs but not in pineocytomas [44]. The most common chromosomal imbalances in PPTID are +4q, +12q, and –22. In a real-time RT-PCR analysis, the expression level of four genes (PRAME, CD24, POU4F2, and HOXD13) in PPTID is distinctly higher, almost the same level as in pineoblastomas, and in contrast to the low expression level of these genes in pineocytomas [38].

References 1 Jouvet A, Fèvre-Montange M, Besançon R, Derrington E, Saint-Pierre G, Belin MF, Pialat J, Lapras C: Structural and ultrastructural characteristics of human pineal gland, and pineal parenchymal tumors. Acta Neuropathol (Berl) 1994;88:334–348. 2 Huang SK, Klein DC, Korf HW: Immunocytochemical demonstration of rodopsin, S-antigen, and neuron-specific proteins in the human pineal gland. Cell Tissue Res 1992;267:493–498. 3 Zang X, Nilaver G, Stein BM, Fetell MR, Duffy PE: Immunocytochemistry of pineal astrocytes: species differences and functional implications. J Neuropathol Exp Neurol 1985;44:486–495. 4 Herrick MK, Rubinstein LJ: The cytological differentiating potential of pineal parenchymal neoplasms (true pinealomas). A clinicopathological study of 28 tumours. Brain 1979;102:289–320. 5 Schild SE, Scheithauer BW, Schomberg PJ, Hook CC, Kelly PJ, Frick L, Robinow JS, Buskirk SJ: Pineal parenchymal tumors. Clinical, pathologic, and therapeutic aspects. Cancer 1993;72:870–880.

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6 Nakazato Y, Jouvet A, Scheithauer BW: Tumours of the pineal region; in Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds): WHO Classification of Tumours of the Central Nervous System, ed 4. Lyon, IARC, WHO press, 2007, pp 123–127. 7 Jouvet A, Fauchon F, Bouffet E, Saint-Pierre G, Champier J, Fevre-Montange M: Tumors of pineal parenchymal and glial cells; in McLendon RE, Rosenblum MK, Bigner DD (eds): Russell & Rubinstein’s Pathology of Tumors of the Nervous System, ed 7. London, Hodder Arnold, 2006, pp 413–425. 8 Kuchelmeister K, von Borcke IM, Klein H, Bergmann M, Gullotta F: Pleomorphic pineocytoma with extensive neuronal differentiation: report of two cases. Acta Neuropathol (Berl) 1994;88: 448–453. 9 Tsumanuma I, Tanaka R, Washiyama K: Clinicopathological study of pineal parenchymal tumors: correlation between histopathological features, proliferative potential, and prognosis. Brain Tumor Pathol 1999;16:61–68.

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10 Numoto RT: Pineal parenchymal tumors: cell differentiation and prognosis. J Cancer Res Clin Oncol 1994;120:683–690. 11 Mena H, Rushing EJ, Ribas JL, Delahunt B, McCarthy WF: Tumors of pineal parenchymal cells: a correlation of histological features, including nucleolar organizer regions, with survival in 35 cases. Hum Pathol 1995;26:20–30. 12 Cho BK, Wang KC, Nam DH, Kim DG, Jung HW, Kim HJ, Han DH, Choi KS: Pineal tumors: experience with 48 cases over 10 years. Childs Nerv Syst 1998;14:58. 13 Jouvet A, Saint-Pierre G, Fauchon F, Privat K, Bouffet E, Ruchoux MM, Chauveinc L, Fèvre-Montange M: Pineal parenchymal tumors: a correlation of histological features with prognosis in 66 cases. Brain Pathol 2000;10:49–60. 14 Min KW, Scheithauer BW, Bauserman SC: Pineal parenchymal tumors: an ultrastructural study with prognostic implications. Ultrastruct Pathol 1994;18:69–85. 15 Hoffman HJ, Yoshida M, Becker LE, Hendrick EB, Humphreys RP: Pineal region tumors in childhood. Experience at the Hospital for Sick Children. 1983. Pediatr Neurosurg 1994;21:91–104. 16 Chiechi MV, Smirniotopoulos JG, Mena H: Pineal parenchymal tumors: CT and MR features. J Comput Assist Tomogr 1995;19:509–517. 17 Nakamura M, Saeki N, Iwadate Y, Sunami K, Osato K, Yamaura A: Neuroradiological characteristics of pineocytoma and pineoblastoma. Neuroradiology 2000;42:509–514. 18 Korogi Y, Takahashi M, Ushio Y: MRI of pineal region tumors. J Neurooncol 2001;54:251–261. 19 Provenzale JM, Weber AL, Klintworth GK, McLendon RE: Radiologic-pathologic correlation. Bilateral retinoblastoma with coexistant pinealoblastoma (trilateral retinoblastoma). AJNR 1995; 16:157–165. 20 Borit A, Blackwood W, Mair WG: The separation of pineocytoma from pineoblastoma. Cancer 1980;45:1408–1418. 21 Sato K, Kubota T, Kawano H: Immunohistochemical and ultrastructural study of pineocytoma with pure neuronal differentiation. J Clin Electron Microscopy (Jpn) 1992;25:191–198. 22 Perentes E, Rubinstein LJ, Herman MM, Donoso LA: S-antigen immunoreactivity in human pineal glands and pineal parenchymal tumors. A monoclonal antibody study. Acta Neuropathol (Berl) 1986;71:224–227.

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23 Hassoun J, Gambarelli D, Peragut JC, Toga M: Specific ultrastructural markers of human pinealomas. A study of four cases. Acta Neuropathol (Berl) 1983;62:31–40. 24 Markesbery WR, Haugh RM, Young AB: Ultrastructure of pineal parenchymal neoplasms. Acta Neuropathol (Berl) 1981;55:143–149. 25 Nielsen SL, Wilson CB: Ultrastructure of a ‘pineocytoma’. J Neuropathol Exp Neurol 1975;34: 148–158. 26 Hassoun J, Devictor B, Gambarelli D, Peragut JC, Toga M: Paired twisted filaments: a new ultrastructural marker of human pinealomas? Acta Neuropathol (Berl) 1984;65:163–165. 27 DeGirolami U, Schmidek H: Clinicopathological study of 53 tumors of the pineal region. J Neurosurg 1973;39:455–462. 28 Constantine C, Miller DC, Gardner S, Balmaceda C, Finlay J: Osseous metastasis of pineoblastoma: a case report and review of the literature. J Neurooncol 2005;74:53–57. 29 Banerjee AK, Kak VK: Pineoblastoma with spontaneous intra and extracranial metastasis. J Pathol 1974;114:9–12. 30 Stefanko SZ, Manschot WA: Pinealoblastoma with retinoblastomatous differentiation. Brain 1979;102:321–332. 31 Berns S, Pearl G: Review of pineal anlage tumor with divergent histology. Arch Pathol Lab Med 2006;130:1233–1235. 32 Schmidbauer M, Budka H, Pilz P: Neuroepithelial and ectomesenchymal differentiation in a primitive pineal tumor (‘pineal anlage tumor’). Clin Neuropathol 1989;8:7–10. 33 Yamane Y, Mena H, Nakazato Y: Immunohistochemical characterization of pineal parenchymal tumors using novel monoclonal antibodies to the pineal body. Neuropathology 2002;22: 66–76. 34 Kline KT, Damjanov I, Katz SM, Schmidek H: Pineoblastoma: an electron microscopic study. Cancer 1979;44:1692–1699. 35 Bello MJ, Rey JA, de Campos JM, Kusak ME: Chromosomal abnormalities in a pineocytoma. Cancer Genet Cytogenet 1993;71:185–186. 36 Rainho CA, Rogatto SR, de Moraes LC, BarbieriNeto J: Cytogenetic study of a pineocytoma. Cancer Genet Cytogenet 1992;64:127–132. 37 Sreekantaiah C, Jockin H, Brecher ML, Sandberg AA: Interstitial deletion of chromosome 11q in a pineoblastoma. Cancer Genet Cytogenet 1989;39: 125–131.

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38 Fèvre-Montange M, Champier J, Szathmari A, Wierinckx A, Mottolese C, Guyotat J, FigarellaBranger D, Jouvet A, Lachuer J: Microarray analysis reveals differential gene expression patterns in tumors of the pineal region. J Neuropathol Exp Neurol 2006;65:675–684. 39 Biegel JA, Fogelgren B, Zhou JY, James CD, Janss AJ, Allen JC, Zagzag D, Raffel C, Rorke LB: Mutations of the INI1 rhabdoid tumor suppressor gene in medulloblastomas and primitive neuroectodermal tumors of the central nervous system. Clin Cancer Res 2000;6:2759–2763. 40 Plowman PN, Pizer B, Kingston JE: Pineal parenchymal tumours. II. On the aggressive behaviour of pineoblastoma in patients with an inherited mutation of the RB1 gene. Clin Oncol (R Coll Radiol) 2004;16:244–247. 41 Bader JL, Miller RW, Meadows AT, Zimmerman LE, Champion LA, Voûte PA: Trilateral retinoblastoma. Lancet 1980;2:582–583.

42 Gadish T, Tulchinsky H, Deutsch AA, Rabau M: Pinealoblastoma in a patient with familial adenomatous polyposis: variant of Turcot syndrome type 2? Report of a case and review of the literature. Dis Colon Rectum 2005;48: 2343–2346. 43 Lesnick JE, Chayt KJ, Bruce DA, Rorke LB, Trojanowski J, Savino PJ, Schatz NJ: Familial pineoblastoma. Report of two cases. J Neurosurg 1985; 62:930–932. 44 Rickert CH, Simon R, Bergmann M, DockhornDworniczak B, Paulus W: Comparative genomic hybridization in pineal parenchymal tumors. Genes Chromosomes Cancer 2001;30:99–104.

Kazufumi Sato, MD Division of Neurosurgery, Department of Sensory and Locomotor Medicine Faculty of Medical Science, University of Fukui 23 Shimoaizuki, Matsuoka, Eiheiji-cho Yoshida-gun, Fukui 910-1193 (Japan) Tel. +81 776 61 8474, Fax +81 776 61 8121, E-Mail [email protected]

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Tumors of Pineal Cell Origin Kobayashi T, Lunsford LD (eds): Pineal Region Tumors. Diagnosis and Treatment Options. Prog Neurol Surg. Basel, Karger, 2009, vol 23, pp 26–43

Occipital Transtentorial Approach and Combined Treatments for Pineal Parenchymal Tumors Itaru Tsumanumaa ⭈ Ryuichi Tanakab ⭈ Yukihiko Fujiia Departments of Neurosurgery, aBrain Research Institute, Niigata University, Niigata, and bTsubame Rosai Hospital, Tsubame, Japan

Abstract The deep-seated location of pineal parenchymal tumors (PPTs) and their associations with critical structures make their surgical resection technically challenging; further, the rarity of PPTs and repeated changes in their histopathological diagnostic criteria makes the study of their biological behavior and clinical outcomes difficult. Here, we describe the surgical techniques and results of an occipital transtentorial approach for PPTs together with the results in the clinicopathological study of PPTs. Since 1982, we have treated 93 patients with pineal region tumors, including 17 PPTs, with the occipital transtentorial approach using the lateral semiprone position. The infrasplenial approach is helpful in separating the internal cerebral veins from the tumor, particularly when the tumor is tightly adherent to the veins. Permanent homonymous hemianopsia occurred in 1 of the 17 patients with PPTs. Permanent ocular movement disorders were not encountered. Extensive removal of the tumor significantly prolongs survival at least in patients with pineocytomas and PPT of intermediate differentiation (PPTIMD). Despite extensive resection and adjuvant radiochemotherapy, the prognosis of the patients with pineoblastomas is extremely poor. Although the proliferative potentials of pineocytomas and PPTIMD were significantly lower than those of pineoblastomas, there was no such difference between pineocytomas and PPTIMD.

Copyright © 2009 S. Karger AG, Basel

Pineal parenchymal tumors (PPTs) are very rare neoplasms arising from the pineal gland located on the diencephalic roof at the posterior extremity of the third ventricle. The term ‘pinealoma’, coined by Krabbe [1], was originally used for tumors arising from pineal parenchymal cells. It had become erroneously used to designate neoplasms that are now widely recognized to be germinomas. On the basis of histopathological findings, del Rio-Hortega [2] classified the tumors arising from

pineal parenchymal cells into ‘pineoblastomas’ and ‘pineocytomas’. In 1993, the World Health Organization (WHO) international classification added a category named ‘mixed/transitional pineal tumors’ and organized these three entities as subtypes of ‘PPTs’ [3]. The name ‘mixed/transitional pineal tumors’ was changed to ‘pineal parenchymal tumor of intermediate differentiation (PPTIMD)’ in the 2000 WHO classification of nervous system tumors. Recently, the ‘papillary tumor of the pineal region’ subtype was added to PPTs in the 2007 WHO classification [4]. The deep-seated location of PPTs and their association with critical structures make their surgical resection technically challenging. Pineal region tumors have most commonly been treated using the infratentorial supracerebellar approach [5] or the occipital transtentorial approach (OTA) [6]. One of the advantages of the infratentorial supracerebellar approach is that the deep venous system does not interfere with access to the pineal region. However, this approach requires patients to be placed in the sitting position, which is associated with a risk of air embolism. In contrast, the OTA can be performed with patients positioned either prone or semiprone, thereby avoiding the risk of air embolism. The disadvantage of this approach is that the deep venous system obstructs access to the tumor. Moreover, the rarity of PPTs and repeated changes in the histopathological diagnostic criteria makes the study of their biological behavior and clinical outcomes difficult. The heterogeneity of their management also renders the interpretation of published data more difficult. This chapter describes the role, surgical techniques, and results obtained with the OTA. The clinicopathological features of the PPTs treated have also been mentioned.

Indication and Role of Occipital Transtentorial Approach in the Management of Pineal Parenchymal Tumors

Tumors of varied histological and biological types arising in the pineal region can be removed using the OTA. Since 1982, we have treated 93 patients with pineal region tumors (table 1) with this approach using a lateral semiprone position and an infrasplenial approach [7]. Surgery plays the most important role in the management of patients with PPTs. The establishment of an accurate histological diagnosis has implications for the choice of postoperative adjuvant therapy, necessity for metastatic workup, planning of optimal long-term follow-up, and prediction of long-term prognosis. In patients with pineocytomas, completeness of excision seems to be the most important factor for avoiding disease progression. Tumors are well controlled after complete resection in spite of receiving no radiation therapy in pineocytomas [8] as also in pineocytomas or PPTIMD with cytologic pleomorphism [9]. On the other hand, there is no evidence that surgery improves the prognosis in pineoblastomas.

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27

Table 1. Histological types and extent of resection with OTA in 93 pineal region tumors Histological type

Patients

Extent of tumor removal total

subtotal

partial

9

Germ cell tumors1 Germinomas Teratomas Embryonal carcinomas Yolk sac tumors Choriocarcinomas

44 17 13 6 6 2

4 11 6 5 1

4 2

PPTs Pineocytomas PPT of intermediate differentiation Pineoblastomas

17 7 6 4

5 4 2

2 1 2

Glial tumors Astrocytomas Anaplastic astrocytomas Glioblastomas Ependymomas

16 6 4 1 5

2 1

1 1 1 1

3 2

Miscellaneous Cavernous angioma Cancer metastasis Lipoma Meningioma Epidermoids

11 4 2 2 1 2

1

1 2

Pineal cyst

5

4

1 1

1

4

1 2 4

1

1

Mixed germ cell tumors are classified into each subgroup according to their dominant histopathological features.

Endoscopic biopsy with third ventriculostomy is becoming an important alternative for the initial surgical management of pineal region tumors including PPTs. These procedures can be performed in a single step that further includes tumor biopsy for histological diagnosis, cerebrospinal fluid sampling for tumor markers and cytological diagnosis, and resolution of hydrocephalus [10]. Seeding of the tumor by the endoscopic procedures is a matter of concern. However, for their series of 12 patients with intracranial germinomas, Shono et al. [11] reported that the risk of tumor dissemination due to neuroendoscopic procedures appears to be minimal when the appropriate chemotherapy and radiotherapy are provided

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a

b

Fig. 1. a T1-weighted contrast-enhanced magnetic resonance images of a 3-year-old boy with pineoblastoma. The heterogeneously enhanced tumor obstructs the aqueduct, displaces the splenium of the corpus callosum and cerebellar vermis, and extends into the third ventricle. b T1-weighted contrast-enhanced magnetic resonance images of a 40-year-old male patient with pineocytoma. The well-demarcated and homogeneously enhanced tumor causes obstructive hydrocephalus.

postoperatively. The risk of tumor seeding by endoscopic procedures for patients with PPTs remains largely unknown.

Preoperative Management

Diagnosis It is often difficult to differentially diagnose PPTs from pineal region germ cell tumors with no teratomatous component or glial tumors including ependymomas (fig. 1). Therefore, the initial treatment for PPTs is generally the same as that for pineal region tumors including tumors which can be distinguished from PPTs. PPTs have a propensity for leptomeningeal dissemination similar to germ cell tumors. Preoperative evaluation of leptomeningeal dissemination is essential for selecting appropriate postoperative adjuvant therapies and for predicting the prognosis of the patients. Whole neuraxis magnetic resonance imaging and cytological examination of the cerebrospinal fluid should be undertaken depending on whether the patient’s condition permits it. Tumor markers including human chorionic gonadotropin β-subunit, α- fetoprotein, and placental alkaline phosphatase in the serum or cerebrospinal fluid are assayed for the purpose of excluding germ cell tumors in the pineal region.

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a

b

Fig. 2. Lateral semiprone position for the OTA with the approach side downward. Lateral (a) and anterior (b) views.

Neuroophthalmological evaluation is useful for detecting Parinaud’s syndrome (paralysis of upgaze or convergence, light-near pupillary dissociation, and retraction nystagmus) – which is caused by midbrain tectum compression by the tumor – and deterioration of visual acuity and choked disc caused by obstructive hydrocephalus.

Preoperative Care At the time of admission, most patients with a pineal region tumor have obstructive hydrocephalus associated with symptoms or signs of increased intracranial pressure. Administration of corticosteroids generally improves these symptoms, and patients can then tolerate the preoperative examinations described above. If the increased intracranial pressure is progressive, ventricular drainage is instituted before or during the craniotomy. Even in such cases, shunt operations should be avoided not only because hydrocephalus generally improves after tumor resection but also because it can result in peritoneal dissemination of the tumor cells via the shunting system.

Surgical Technique for Occipital Transtentorial Approach

Positioning (Lateral Semiprone Position) We preferentially use a lateral semiprone position with the approach side downward (fig. 2) [7]. The patient is placed in the head-up position by tilting the

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a

b

Fig. 3. a Lateral semiprone position for the OTA. The sagittal plane of the head is bent toward the surgeon standing at the back of the patient. b Skin incision and craniotomy for the OTA.

operating table, leaving the confluence of the venous sinuses approximately 10 cm above the right atrium to avoid air embolism. The head is rotated toward the floor at approximately a 60° angle. The neck is slightly extended and the sagittal plane of the head is bent toward the surgeon standing at the back of the patient (fig. 3). The occipital lobe on the approach side spontaneously falls away from the midline under the influence of gravity, which minimizes the retraction of the brain. The surgeon can look down not only at the pineal region but also at the dorsorostral or ipsilateral portions of the tumor with great comfort (fig. 3). The cerebellar vermis or aqueduct can also be viewed by standing at the parietal side of the patient.

Craniotomy and Tentorial Incision An occipitoparietal scalp flap and a craniotomy beyond the midline are created to expose the superior sagittal sinus and the superior sagittal sinus-straight sinus corner. The dura is opened in two flaps: one based on the superior sagittal sinus and the other on the transverse sinus. Ventricular drainage via the posterior horn of the ipsilateral lateral ventricle minimizes the retraction of the occipital lobe. Bridging veins that can disturb the retraction of the occipital lobe rarely present within this craniotomy. The tentorium is divided slightly obliquely to the straight sinus. The medial cut edge of the tentorium is pulled up and retracted to expose the posterior fossa widely.

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Tumor Exposure The arachnoid spanning the quadrigeminal cistern is generally thick and cloudy in patients with pineal region tumors. It is sharply dissected to expose the deep venous system. The vein of Galen and its tributaries tightly guard the dorsorostral aspect of the tumor (fig. 4). The vein of Galen and both internal cerebral veins are located above the tumor. The internal cerebral veins are generally elevated by the tumor and hidden under the splenium of the corpus callosum. Both basal veins are displaced rostrally and laterally. The precentral cerebellar vein is displaced rostrally and dorsally. The ipsilateral basal vein and precentral cerebellar vein can hamper the access to the tumor in the OTA. The tumor must be resected through the space between these deep veins. It has been reported that the precentral cerebellar vein can be sacrificed to gain additional exposure without increasing the morbidity significantly [5].

Infrasplenial Approach to Expose the Internal Cerebral Veins The infrasplenial approach is useful for exposing the internal cerebral veins and the tumor through the velum interpositum cistern in an earlier stage of tumor resection. This optional approach is indicated when it is difficult to separate the tumor from the ventral aspect of the vein of Galen or the internal cerebral veins, or when internal decompression of the tumor is tough on account of its hardness, largeness, or hypervascularity. The arachnoid between the splenium and the vein of Galen is dissected, and the splenium is retracted 5–10 mm ventrally using a thin spatula to expose the internal cerebral veins displaced laterally by the tumor (fig. 4). Then the internal cerebral veins are separated from the tumor. The feeding arteries from both the medial posterior choroidal arteries can be coagulated in these procedures. Wide arachnoid dissection of the posterior interhemispheric fissure above the corpus callosum facilitates the infrasplenial approach.

Tumor Removal Pineal region tumors are removed through the narrow space between the important deep veins. Great attention should be paid in order to preserve these veins. Repeated internal decompression, piecemeal resection, and shrinking the tumor with coagulation of the tumor surface are mandatory to avoid deep venous system injury. The tumor is removed with a variety of techniques, such as suction, section with surgical scalpels and scissors, or ultrasonic aspiration.

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a

b

Fig. 4. A schematic drawing of the OTA (a) combined with the infrasplenial approach (b). The vein of Galen and its tributaries tightly guard the dorsorostral aspect of the tumor. The tumor must be resected through the space between these veins (1). The infrasplenial approach can expose the internal cerebral veins and the tumor through the velum interpositum cistern (2). F = Falx; GV = vein of Galen; PCV = precentral cerebellar vein; BV = basal vein; ICV = internal cerebral vein; SS = straight sinus; Sp = splenium of corpus callosum; Te = tentorium; Tu = tumor.

PPTs, except for invasive pineoblastomas, are generally well demarcated and can be separated from the surrounding structures including the thalamus, velum interpositum, cerebellar vermis, deep venous system, or the medial surface of the occipital lobe. The only attachment of the tumor to the brain is around the midbrain tectum and the posterior commissure. To avoid brainstem injury by the retraction of the tumor, the attachment should be detached at an earlier stage of the resection after adequate internal decompression of the tumor. Even while using the infrasplenial approach, it is occasionally difficult to confirm the completeness of resection of the tumor at the posterior roof of the third ventricle. Endoscopy is very useful in visualizing the velum interpositum, the inferior aspect of which is difficult to perceive under the microscopic view in the OTA (fig. 5).

Closure The tentorium divided in the approach procedures does not have to be sutured. The dura covering brain surface is closed, and the bone flap is replaced and fixed using titanium plates. The ventricular drainage system should remain in place for a few days even if the tumor is completely resected, because it takes 3–4 days for

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Fig. 5. Endoscopic image showing residual tumor at the inferior aspect of the left internal cerebral vein. ICV = Internal cerebral vein; Tu = tumor; V = velum interpositum.

the obstruction of the aqueduct to be released after tumor resection. The aqueduct obstruction is generally relieved even after partial tumor resection and a shunt operation is unnecessary.

Complications There were no surgical deaths among our 17 patients with PPTs. However, permanent homonymous hemianopsia occurred in one patient who had huge and hard tumors, which likely reflected lengthy retraction of the occipital lobe. Permanent ocular movement disorders were not encountered. Bruce and Ogden [12] reported that the surgical major morbidity rate associated with pineal region tumors was 3–6.8% and the permanent minor morbidity rate was 3–28%.

Adjuvant Therapy

Little clinical data is available in the literature regarding the role of radiation therapy in the management of PPTs. Schild et al. [13] recommended craniospinal irradiation in patients with tumors with seeding potential (PPTs other than

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pineocytomas) and localized fields for pineocytomas. In the patients receiving radiation therapy with 50 Gy or more, 0 of 12 had local failure compared with 6 of 7 (86%) patients receiving lesser doses even in patients with PPTIMD or pineoblastomas. Furthermore, in the patients with PPTs other than pineocytomas, 1 of 7 (14%) developed leptomeningeal failure when treated with craniospinal irradiation, compared with 4 of 8 (50%) treated with lesser volumes. Radiation therapy should be considered for patients with pineocytomas that are resected incompletely. It is still controversial whether irradiation is required when the tumor is excised completely. Recently, in a clinicopathological study of 14 patients with pineocytomas or PPTIMD with cytologic pleomorphism, Fèvre-Montange et al. [9] reported that no tumor progression was encountered in any of the 10 patients who underwent complete resection of the tumor, even in the 7 patients who received no radiation therapy. Prophylactic spinal irradiation for patients with PPTs is still a matter of debate. Spinal irradiation is generally taken into account when magnetic resonance imaging shows evidence of leptomeningeal dissemination. Ghim et al. [14] treated 3 children with pineoblastomas with neoadjuvant chemotherapy consisting of etoposide, cisplatin, and vincristine followed by craniospinal irradiation. Although 2 patients remained in complete remission (CR) or near CR, one died of the progressing tumor. Combined chemotherapy and radiotherapy may be effective in older children with pineoblastoma. Hinkes et al. [15] studied a series of 11 children with pineoblastoma treated within prospective multicenter trials. All of 5 children younger than 3 years of age who received chemotherapy (carboplatin, vincristine, etoposide, procarbazine, vincristine, or methotrexate) after surgery died of tumor progression with a median progression-free survival of 0.6 years. In contrast, 5 of 6 children older than 3 years who received chemotherapy (ifosfamide, etoposide, high-dose methotrexate, cisplatin, or cytarabin) and craniospinal irradiation immediately after the surgery remained in CR with a median progression survival of 7.9 years. A recent trial has shown that the outcome of patients with relapses remained poor even with a multimodal high-dose chemotherapy regimen [16].

Prognosis

Schild et al. [13] reported good prognosis of pineocytomas with 1-year, 3-year, and 5-year survival rates of 100, 100, and 67%, respectively; the median survival rate was 88%. However, other PPTs including pineoblastomas, PPTIMD, and mixed PPTs had the propensity for leptomeningeal failure with 1-, 3-, and 5-year survival rates of 88, 78, and 58%, respectively. Min et al. [17] classified PPTs into pineoblastomas, PPT of intermediate or mixed differentiation, and pineocytomas based on

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a combination of their light microscopic and ultrastructural features. Although pineoblastomas behaved as highly malignant tumors, a correlation between the morphology and prognosis was less evident between intermediate tumors and pineocytomas. Pineoblastomas generally occur with a predilection for children, whereas pineocytomas most frequently affect adults [18]. Chang et al. [19] reported that among 11 adult patients with pineoblastomas, 4 patients died of the disease with a median survival of 10 months and 5 patients remained alive without disease progression after a median follow-up of 26 months. Lutterbach et al. [20] documented that the 3-, 5-, and 10-year survival rates of adult patients with pineoblastomas were 88, 78, and 58%, respectively. D’Andrea et al. [21], on the other hand, reported that 4 of 6 children with pineocytomas had tumor recurrence at a median of 2 years after diagnosis; further, these tumors were considered to be aggressive with a high propensity for leptomeningeal dissemination in the pediatric population. As mentioned above, pineoblastomas are highly malignant tumors with a propensity for leptomeningeal dissemination, and pineocytomas have a good prognosis if they are properly treated with surgery and additional radiation therapy. However, the incidence and prognosis of each histological subtype including PPTIMD vary considerably in the literature. The characterization of PPTs has been far from adequate and no firm diagnostic criteria – light microscopic or ultrastructural – have been established. The heterogeneity of management also renders the interpretation of published data more difficult.

Clinicopathological Study

We have previously reported a clinicopathological study of 13 patients with PPTs for whom the tumor specimens and precise clinical data were available [22]. The data described below include these 13 patients and 1 additional patient (patient 9). In the previous report [22], we classified the tumors showing intermediate differentiation as ‘pineocytoma with anaplasia’ based on the histological findings including Bodian’s staining. This category is very similar to ‘PPTIMD’ described later in the WHO 2000 Classification [18].

Patient Characteristics The patients evaluated consisted of 9 male and 5 female patients with an age range of 0–73 years (mean, 30.4 years; median, 28 years), and the follow-up periods from the time of diagnosis ranged from 7 to 294 years (mean, 103.9 months; median, 111 months). Clinical data are briefly summarized in table 2.

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Histopathological Diagnosis In cases 1–4, the tumors were moderately cellular with round to oval-shaped nuclei. The tumor cells had abundant cytoplasmic processes and were arranged in a sheet-like or ill-defined lobular pattern, which consisted of pineocytomatous rosettes. Occasional tumor cells with markedly large nuclei were seen. Mitotic figures were rare or absent. These tumors were diagnosed as pineocytomas (fig. 6). In cases 5–8, the tumors were highly cellular with intermediate-sized nuclei showing moderate atypia. The tumor cells had scant cytoplasmic processes. Mitotic figures were occasional or absent. In cases 5–7, a few Homer-Wright rosette-like structures were seen. Bodian’s staining revealed argyrophilic processes with terminal expansions in the center of the rosette (data not shown). These tumors were classified into PPTIMD. In case 9, the tumor tissue was characterized for the major part by features suggestive of pineocytoma, but it also included a localized area showing nuclear atypia and necrosis; this case was also diagnosed as PPTIMD (fig. 6). In cases 10–14, the tumors were composed of densely packed cells with scanty, ill-defined, and wispy cytoplasm. The tumors had polygonal or carrot-shaped, small and hyperchromatic nuclei with marked atypia. The cells were diffusely arranged and interrupted only by Homer-Wright rosettes or Flexner-Wintersteiner rosettes. Hemorrhage, necrosis, and prominent mitotic figures were common. No argyrophilic processes were demonstrated by Bodian’s stain (data not shown). These findings are common in primitive neuroectodermal tumors. These tumors were diagnosed as pineoblastomas (fig. 6).

Extent of Tumor Removal and Outcomes Pineocytomas were resected totally in 2 out of 4 patients and subtotally in 2 other patients. Adjuvant external-beam radiation therapies, including prophylactic whole neuraxis irradiation, were carried out for all the patients. In the 5 PPTIMD patients, the tumors were resected totally in 3 patients and subtotally in 1 patient. Radiation therapies, including prophylactic whole neuraxis irradiation, were performed for all of these 4 patients. Another case (case 8) received local radiation therapy with no biopsy. Although the tumor regressed after radiation, it recurred at the left cerebellopontine angle. With the use of open biopsy the recurrent tumor was diagnosed as PPTIMD, and local brain radiation therapy resulted in CR. Eventually, the patient died of leptomeningeal dissemination of the PPTIMD, which was confirmed on autopsy. Apart from this one case and another pineocytoma patient who died of other causes, the patients with pineocytomas or PPTIMD are still alive with no progression of the tumor. Completeness of excision

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a

d

b

e

c

Fig. 6. Histopathological findings in the PPTs. a Pineocytoma (case 2). Moderately cellular tumor cells with abundant cytoplasmic processes are arranged in a sheet-like pattern. b PPT of intermediate differentiation (case 8). The tumors are highly cellular and the nuclei have medium-toabundant chromatin and show moderate atypia. Tumor cells have scant cytoplasmic processes. c PPT of intermediate differentiation (case 5) showing Homer-Wright rosette-like structures. d Pineoblastoma (case 14). Densely packed tumor cells with small and hyperchromatic nuclei with marked atypia are diffusely arranged and interrupted only by Homer-Wright rosettes. e Pineoblastoma (case 11) showing Flexner-Wintersteiner rosettes. HE staining.

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Tsumanuma · Tanaka · Fujii

100 Pineocytoma and PPTIMD

Percent surviving

80

60 Pineoblastoma 40

20

0 0

100 200 Survival (months)

300

Fig. 7. Kaplan-Meier estimate of overall survival for all patients with PPTs. The survival of the patients with pineocytomas or PPTIMD is significantly longer than that of the patients with pineoblastomas (p = 0.00022, log-rank test).

appears to be the most important factor for avoiding disease progression; this has also been mentioned in previous reports [9, 13]. Pineoblastomas were removed totally in 1 patient, subtotally in 1 patient and partially in 2 patients. Another patient underwent local brain radiation with no surgical intervention. In spite of adjuvant radiation therapy and/or chemotherapy, all the 5 patients with pineoblastoma died of leptomeningeal dissemination of the tumor within 14 months after the time of diagnosis. As previously reported [13], surgery does not improve the prognosis in pineoblastomas. Hinkes et al. [15] reported a better prognosis in children older than 3 years who received chemotherapy and craniospinal irradiation after the surgery. Unfortunately, we have no experience of older children with pineoblastoma except for an 8-year-old boy who was treated only with radiation therapy and died due to leptomeningeal dissemination of the tumor. This may be the reason for the prognosis of our patients with pineoblastoma being extremely poor (fig. 7).

Proliferative Potential and Neuronal or Neurosecretory Characteristics The MIB-1 staining indices in the 4 pineocytomas, 5 PPTIMD, and 4 pineoblastomas examined are shown in table 2. The indices for the pineocytomas and PPTIMD specimens were less than 7% but those for all the pineoblastomas examined were more than 8%. The mean MIB-1 staining index of pineoblastomas was

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Table 2. Case representations Patient Age no. years

Sex

Extent of resection

Adjuvant therapy

Outcome

Suvival months

MIB-1 index %

Pineocytoma 1 25

M

subtotal

progression free

2511

6.5

2

40

M

total

progression free

1841

1.0

3

44

F

subtotal

72

6.3

4

57

F

total

whole neuraxis and local brain Rx whole neuraxis and local brain Rx whole neuraxis and local brain Rx local brain Rx

progression free

2941

1.6

local brain Rx local brain Rx whole neuraxis and local brain Rx local brain Rx

progression free progression free progression free

1241 1351 361

3.4 1.6 2.0

CR; recurrence at left 168 cerebellopontine angle 62 months later, whole neuraxis and local brain Rx after biopsy resulting in CR; leptomeningeal dissemination whole neuraxis and progression free 1361 local brain Rx

6.2

PPT of intermediate differentiation 5 61 M total 6 73 F total 7 23 F subtotal 8

31

F

ND

9

57

M

total

Pineoblastoma 10 8 M

ND

11

0

M

partial

12

1

M

subtotal

13

2

M

partial

14

3

M

total

local brain Rx

died of other disease

leptomeningeal dissemination local brain Rx, Cx leptomeningeal (BLM, MTX) dissemination Cx (CBDCA, VP16) PD in spite of whole neuraxis Rx and Cx (VBL, CTX, DACT, BLM, CDDP); leptomeningeal dissemination whole neuraxis and PR; leptomeningeal local brain Rx, Cx dissemination, whole brain (ACNU) and local Rx, Cx (ACNU, MTX) whole neuraxis and CR; leptomeningeal local brain Rx, Cx dissemination, Cx (CBDCA, (CBDCA, VP16) VP16, L-PAM) and local Rx

0.5

10

ND

9

8.2

14

15.8

10

9.1

14

29.5

ND = Not done; Rx = irradiation; Cx = chemotherapy; BLM = bleomycin; MTX = methotrexate; CBDCA = carboplatin; VP16 = etoposide; ACNU = nimustine; VBL = vinblastine; CTX = cyclophosphamide; DACT = actinomycin D; CDDP = cisplatin; L-PAM = melphalan; CR = complete response; PR = partial response; PD = progressive disease. 1 Alive. 2 Died of other disease.

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Table 3. Correlations between histopathological features and mean MIB-1 indices Histopathological features

MIB-1 index, %

Diagnosis Pineocytoma PPTIMD Pineoblastoma

3.9 ± 3.0a 2.7 ± 2.2b 15.7 ± 9.8a, b

Neurofilament protein + –

3.7 ± 3.4c 22.7 ± 9.7c

Chromogranin A + –

6.1 ± 7.0 10.8 ± 13.0

Common superscripts indicate statistically significant difference (p < 0.05). Values are expressed as mean ± SD.

statistically significantly higher than those of pineocytomas and PPTIMD (p < 0.05, Mann-Whitney test). However, there was no significant difference between pineocytomas and PPTIMD (table 3). It is generally believed that PPTs exhibit a continuous spectrum of differentiation, the extent of which is paralleled by differences in biological behavior and clinical outcomes. The proliferative potential of PPTs has been reported by a few authors. Mena et al. [23] investigated 35 patients with PPTs using silver-stained nucleolar organizer region (AgNOR) counts and showed that pineoblastomas were more actively proliferative than pineocytomas, with mixed pineocytoma/pineoblastomas showing intermediate activity. However, no correlation was observed between the mean AgNOR score and the prognosis within tumor groups. Our data suggest that pineoblastomas are more actively proliferative than pineocytomas or PPTIMD and that the proliferative potential of PPTIMD is equivalent to that of pineocytomas. Is the spectrum of biological behavior in PPTs continuous? On the basis of our observations, with regard to the malignant potential, we emphasize that a clear distinction should be made between pineoblastomas in children and other types of PPTs in adults. In our immunohistochemical characterization studies, synaptophysin, a 38-kDa glycoprotein found in the synaptic vesicle membranes of neuroendocrine cells, was immunopositive in all of the 2 pineocytoma, 4 PPTIMD, and 3 pineoblastoma specimens examined. On the other hand, both pineocytomas, all of the 3 PPTIMD, and 1 of 3 pineoblastomas examined were immunopositive for the 160-kDa neurofilament protein. The mean MIB-1 index in neurofilament

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protein-immunopositive specimens was significantly lower than that in immunonegative specimens (p < 0.05, Mann-Whitney test; table 3). Further, 1 of 2 pineocytomas, 2 of 3 PPTIMD, and 1 of 3 pineoblastomas examined were immunopositive for chromogranin A, a member of the secretogranin/chromogranin class of proteins expressed in the secretory granules of endocrine cells and neurons. The level of expression of cytoskeletal elements in PPT is likely to be inversely associated with the proliferative potential of the tumor cells. We reported that the in situ expression of hydroxyindole-O-methyl transferase, the enzyme catalyzing the final step of the melatonin biosynthesis, is observed not only in pineocytomas but also in pineoblastomas [24]. This observation, as well as the synaptophysin immunopositivity in pineoblastomas, suggests that the neurosecretory characteristics of the pinealocytes are retained not only in pineocytomas but also in pineoblastomas, which are the most undifferentiated and proliferative tumors among PPTs.

Conclusion

The OTA using lateral semiprone position can remove PPTs extensively and safely. Combining the infrasplenial approach with the OTA is useful in visualizing the internal cerebral veins directly, particularly when the tumor is tightly adherent to the ventral aspect of the vein of Galen and the internal cerebral veins. Endoscopy can increase the visibility of the posterior part of the third ventricular roof. Extensive removal of the tumor significantly prolongs survival at least in the patients with pineocytomas and PPTIMD, the proliferative potentials of which are likely to be the same. In spite of extensive resection and adjuvant radiochemotherapy, the prognosis of the patients with pineoblastomas is extremely poor. Further elucidation of the biological features of pineoblastomas is required to resolve this issue.

References 1 Krabbe KH: The pineal gland, especially in relation to the problem on its supposed significance in sexual development. Endocrinology 1923;7:379–414. 2 del Rio-Hortega: Pineal gland; in Penfield W (ed): Cytology and Cellular Pathology of the Nervous System. New York, Hoeber, 1932, vol 2, pp 636–703. 3 Kleihues P, Burger PC, Scheithauer BW: Histological Typing of Tumours of the Central Nervous System. World Health Organization International Histological Classification of Tumours, ed 2. Berlin, Springer, 1993.

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4 Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114: 97–109. 5 Stein BM: The infratentorial supracerebellar approach to pineal lesions. J Neurosurg 1971;35: 197–202. 6 Lazar ML, Clark K: Direct surgical management of masses in the region of the vein of Galen. Surg Neurol 1974;2:17–21.

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7 Tanaka R, Washiyama K: Occipital transtentorial approach to pineal region tumors. Oper Tech Neurosurg 2003;6:215–221. 8 Vaquero J, Ramiro J, Martínez R, Coca S, Bravo G: Clinicopathological experience with pineocytomas: report of five surgically treated cases. Neurosurgery 1990;27:612–619. 9 Fèvre-Montange M, Szathmari A, Champier J, Mokhtari K, Chrétien F, Coulon A, FigarellaBranger D, Polivka M, Varlet P, Uro-Coste E, Fauchon F, Jouvet A: Pineocytoma and pineal parenchymal tumors of intermediate differentiation presenting cytologic pleomorphism: a multicenter study. Brain Pathol 2008;18:354–359. 10 Chernov MF, Kamikawa S, Yamane F, Ishihara S, Kubo O, Hori T: Neurofiberscopic biopsy of tumors of the pineal region and posterior third ventricle: indications, technique, complications, and results. Neurosurgery 2006;59:267–277. 11 Shono T, Natori Y, Morioka T, Torisu R, Mizoguchi M, Nagata S, Suzuki SO, Iwaki T, Inamura T, Fukui M, Oka K, Sasaki T: Results of a long-term followup after neuroendoscopic biopsy procedure and third ventriculostomy in patients with intracranial germinomas. J Neurosurg 2007;107:193–198. 12 Bruce JN, Ogden AT: Surgical strategies for treating patients with pineal region tumors. J Neurooncol 2004;69:221–236. 13 Schild SE, Scheithauer BW, Schomberg PJ, Hook CC, Kelly PJ, Frick L, Robinow JS, Buskirk SJ: Pineal parenchymal tumors. Clinical, pathologic, and therapeutic aspects. Cancer 1993;72:870–880. 14 Ghim TT, Davis P, Seo JJ, Crocker I, O’Brien M, Krawiecki N: Response to neoadjuvant chemotherapy in children with pineoblastoma. Cancer 1993;72:1795–1800. 15 Hinkes BG, von Hoff K, Deinlein F, WarmuthMetz M, Soerensen N, Timmermann B, Mittler U, Urban C, Bode U, Pietsch T, Schlegel PG, Kortmann RD, Kuehl J, Rutkowski S: Childhood pineoblastoma: experiences from the prospective multicenter trials HIT-SKK87, HIT-SKK92 and HIT91. J Neurooncol 2007;81:217–223.

16 Broniscer A, Nicolaides TP, Dunkel IJ, Gardner SL, Johnson J, Allen JC, Sposto R, Finlay JL: High-dose chemotherapy with autologous stem-cell rescue in the treatment of patients with recurrent non-cerebellar primitive neuroectodermal tumors. Pediatr Blood Cancer 2004;42:261–267. 17 Min KW, Scheithauer BW, Bauserman SC: Pineal parenchymal tumors: an ultrastructural study with prognostic implications. Ultrastruct Pathol 1994;18:69–85. 18 Mena H, Nakazato Y, Jouvet A, Scheithauer BW: Pineal parenchymal tumours; in Kleihues P, Cavenee WK (eds): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Nervous System. Lyon, IARC Press, 2000, pp 115–122. 19 Chang SM, Lillis-Hearne PK, Larson DA, Wara WM, Bollen AW, Prados MD: Pineoblastoma in adults. Neurosurgery 1995;37:383–391. 20 Lutterbach J, Fauchon F, Schild SE, Chang SM, Pagenstecher A, Volk B, Ostertag C, Momm F, Jouvet A: Malignant pineal parenchymal tumors in adult patients: patterns of care and prognostic factors. Neurosurgery 2002;51:44–56. 21 D’Andrea AD, Packer RJ, Rorke LB, Bilaniuk LT, Sutton LN, Bruce DA, Schut L: Pineocytomas of childhood. A reappraisal of natural history and response to therapy. Cancer 1987;59:1353–1357. 22 Tsumanuma I, Tanaka R, Washiyama K: Clinicopathological study of pineal parenchymal tumors: correlation between histopathological features, proliferative potential, and prognosis. Brain Tumor Pathol 1999;16:61–68. 23 Mena H, Rushing EJ, Ribas JL, Delahunt B, McCarthy WF: Tumors of pineal parenchymal cells: a correlation of histological features, including nucleolar organizer regions, with survival in 35 cases. Hum Pathol 1995;26:20–30. 24 Tsumanuma I, Tanaka R, Ichikawa T, Washiyama K, Kumanishi T: Demonstration of hydroxyindoleO-methyltransferase (HIOMT) mRNA expression in pineal parenchymal tumors: histochemical in situ hybridization. J Pineal Res 2000;28:203–209.

Itaru Tsumanuma, MD, PhD Department of Neurosurgery Yamagata Prefectural Central Hospital 1800 Aoyagi Yamagata 990-2292 (Japan) Tel. +81 23 685 2626, Fax +81 23 685 2608, E-Mail [email protected]

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Tumors of Pineal Cell Origin Kobayashi T, Lunsford LD (eds): Pineal Region Tumors. Diagnosis and Treatment Options. Prog Neurol Surg. Basel, Karger, 2009, vol 23, pp 44–58

Role of Stereotactic Radiosurgery in the Management of Pineal Parenchymal Tumors Hideyuki Kano ⭈ Ajay Niranjan ⭈ Douglas Kondziolka ⭈ John C. Flickinger ⭈ L. Dade Lunsford Departments of Neurological Surgery and Radiation Oncology, The University of Pittsburgh, and Center for Image-Guided Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pa., USA

Abstract We evaluated 20 pineal parenchymal tumor patients who underwent radiosurgery at our institution over a 20-year period. Thirteen patients had pineocytoma, 5 patients had pineoblastoma and 2 patients had mixed pineal parenchymal tumors. The median radiosurgery prescription dose to the tumor margin was 15.0 (12–20) Gy. At an average of 54.1 (range, 7.7–149.2) months, 6 patients had died and 14 patients were living. The overall survival after radiosurgery was 95.0, 68.6, and 51.4% at 1, 5 and 10 years, respectively. Patients with pineocytomas had 1-, 3- and 5-year overall survivals of 100, 92.3 and 92.3%, respectively. In 19 patients who were evaluated with imaging, 5 (26%) demonstrated complete regression, 9 (47%) had partial regression, 2 (11%) had stable tumors and 2 (11%) showed local in-field progression. The progression-free survival after stereotactic radiosurgery for all type of pineal parenchymal tumors was 100, 89.2 and 89.2% at 1, 3, 5 years after radiosurgery, respectively. Stereotactic radiosurgery is an effective and safe alternative to the surgical resection of pineocytomas as well as part of multimodal therapy for more aggressive pineal parenchymal tumors. Copyright © 2009 S. Karger AG, Basel

Pineal region tumors (PRTs) are rare neoplasms. PRTs account for 0.4–1% of intracranial tumors in Western countries, but their incidence is higher (2.2–8% of intracranial tumors) in northeastern Asian countries [1–3]. Germ cell tumors are the most frequent, of which germinomas and teratomas account for 25–53.5% of all tumors in the pineal region [4–6]. Pineal parenchymal tumors (PPTs) are the second most common pineal tumors in adults and account for 15–30% of PRTs [7]. The designation of PPT includes pineocytomas, PPTs of intermediate differentiation or mixed pineocytomas/pineoblastomas, and pineoblastomas. Pineocytoma is a slowly growing tumor with a relatively favorable prognosis in

most cases. In contrast, pineal parenchymal tumors of intermediate differentiation have less predictable growth rates and clinical behavior. Pineoblastoma is the malignant variant which has many common features with medulloblastoma and other primitive neuroectodermal tumors. Metastatic spread of pineoblastoma via cerebrospinal fluid pathways is a frequent complication and is often associated with a fatal outcome. Despite improved microsurgical techniques, resection of PPT remains a challenge because of their deep location and associated critical structures [8]. The role of adjuvant radiotherapy has not been clearly defined. The role of radiosurgery in the treatment of PPT is not well documented as only a few studies have been published. The purpose of this report is to review our experience with radiosurgery for PPT. We retrospectively evaluated survival, imaging response, and treatmentrelated morbidity in patients who underwent radiosurgery for PPTs.

Methods and Materials Patient Population

Twenty histologically confirmed PPT patients had stereotactic radiosurgery (SRS) at the University of Pittsburgh between April 1989 and January 2006. The series included 12 males and 8 females with a median age of 34 years (range, 3.5–68.4 years). Six patients had undergone prior surgical resection of their PPTs and 15 patients had either stereotactic or open biopsies (table 1). Prior adjuvant management included fractionated radiation therapy (RT; n = 3), chemotherapy (n = 3), and both RT and chemotherapy (n = 2). All pathological data were reviewed by neuropathologists. Thirteen patients had pineocytomas which corresponded to WHO grade 2 tumors. Five patients had pineoblastomas which corresponded to WHO grade 4 tumors. Two patients had mixed PPTs. All tumors were located in the pineal region.

Radiosurgery Technique Our radiosurgical technique has been described in detail in previous reports [9]. In brief, patients underwent application of an imaging-compatible stereotactic head frame. The procedure was performed under local anesthesia for patients over 13 year of age and under general anesthesia for children younger that 13. After frame application, high resolution magnetic resonance imaging (MRI) was performed. Patients underwent either a sagittal scout MRI or a 3-D localizer sequence which included axial, coronal and sagittal images. The tumor was then imaged using contrast-enhanced volume acquisition images. T2-weighted MR images using Fast Spin Echo technique also were acquired to assess the infiltrative tumor volume. The target volume included enhanced and nonenhanced tumor regions. In all patients, the radiosurgery dose was prescribed to the whole tumor volume. The median tumor volume was 3.1 (0.9–14.2) cm3. A median of five isocenters (1–10) were used for dose planning. The median prescription dose delivered to the tumor margin was 15.0 (12–20) Gy. The maximum dose varied from 24 to 40 Gy (median, 30.0 Gy). SRS was performed

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Table 1. Summary of 20 PPT patients treated by SRS Characteristics

Patients

Sex Male Female

12 8

Prior surgical removal Prior biopsy Prior FRT Prior chemotherapy Prior FRT + chemotherapy

6 15 3 3 2

Histopathology Pineocytoma Pineoblastoma Mixed pineal parenchymal tumor

13 5 2

Target volume, cm3 Margin dose, Gy Maximum dose, Gy Age, years

Median

Mean

Range

3.1 15.0 30.0 34.4

4.4 15.2 30.4 33.6

0.9 ∼14.2 12∼20 24∼40 3.5∼68.4

FRT = Fractionated radiation therapy

with either a Model U, B, C, or 4-C Leksell Gamma Knife (Elekta Inc., Atlanta Ga., USA). All patients received an intravenous dose of 20–40 mg methylprednisolone after radiosurgery and all were discharged from the hospital within 24 h. Patients were evaluated clinically and radiologically using MR imaging at intervals of 3–6 months. Nineteen patients had follow-up that varied from 7.7 to 149.2 months. One patient had no radiological images after SRS. Fourteen patients (70.0%) had follow-up of 24 months or more. The mean follow-up time was 54.1 (range, 7.7–149.2) months. The follow-up MR images were compared with the intraoperative images and tumor dimensions were measured in axial, sagittal, and coronal planes. A complete response was defined as the complete disappearance of enhancing or nonenhancing tumor; partial response was defined as a shrinkage >50% of the tumor area; stable disease was defined as a reduction of tumor area from 0 to 50%, and progressive disease was defined as more than 25% increase in size of enhancing or nonenhancing tumor. Tumor growth adjacent to the irradiated tumor and outside the isodose volume was defined as marginal recurrence; tumors that progressed outside the SRS-treated volume were considered distant recurrences. For statistical analysis, we constructed Kaplan-Meier plots for survival and progression-free survival using the dates of diagnosis, first surgery, first SRS, follow-up MRIs, and death or last follow-up. Progression-free survival and overall survival time were calculated from the day of the first SRS using the Kaplan-Meier method. Univariate analysis was performed on the

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Kano · Niranjan · Kondziolka · Flickinger · Lunsford

Table 2. Tumor type and response after radiosurgery, based on imaging results Lesions Tumor type

CR

PR

SD

PD

No images

Pineocytoma Pineoblastoma/mixed PPT

3 2

8 1

2 1

0 2

0 1

CR = Complete response; PR = partial response; SD = stable disease; PD = progressive disease.

Kaplan-Meier curves using a log rank statistic with p < 0.05 set as significant. Standard statistical processing software (SPSS, version 15.0) was used. This retrospective study was approved by the University of Pittsburgh institutional review board. All chart reviews and data analyses were conducted before October 31, 2007.

Results

Fourteen patients (70.0%) were alive and 6 (30.0%) had died at an average follow-up of 42.5 (range 7.7–149.2) months from radiosurgery, and 45.2 (range 7.8–149.8) months from their initial diagnosis. One pineocytoma and one pineoblastoma patient died secondary to dissemination throughout the neuraxis at 14.7 and 18.6 months after SRS, respectively. One patient died from systemic metastasis from pineoblastoma at 7.7 months after SRS. One pineoblastoma patient had tumor progression and died at 12.8 months after SRS. One pineocytoma and one pineoblastoma patient died from an unknown cause at 149.2 and 48.2 months after SRS, respectively. The mean follow-up time after SRS in the entire series was 54.1 (range, 7.7– 149.2) months. Follow-up imaging studies demonstrated tumor control in 17 (89.5%) of 19 lesions at a median and mean of 43.7 and 54.7 months after SRS, respectively. In 19 patients who were evaluated with follow-up imaging, 5 (3 pineocytomas and 2 pineoblastomas) had complete tumor resolution, 9 (8 pineocytomas and 1 pineoblastoma) had tumor regression, and 3 (2 pineocytomas and 1 pineoblastoma) had stable tumors. Local in-field tumor progression was seen in 2 patients with pineoblastomas at 12.8 and 31.2 months (table 2). One patient underwent repeat radiosurgery for local tumor progression. At the time of this analysis, 14 patients were alive at a median and mean of 43.7 and 59.0 months after radiosurgery, respectively (range 19.2–148.7 months). For surviving patients, the median and mean survival was 47.1 and 66.5 months after the initial diagnosis (range 25.8–150.2). The overall survival after radiosurgery

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was 95.0, 68.6, and 51.4% at 1, 5 and 10 years, respectively. Of the 20 patients, 4 (20%) had intracranial (n = 2) or systemic metastasis (n = 2) after SRS. The progression-free survival after SRS was 100, 89.2 and 89.2% at 1, 3, 5 years after radiosurgery, respectively.

Statistical Analysis We performed a univariate analysis using the log rank test to assess factors that might influence the length of overall and progression-free survival. The following variables were assessed: sex (male or female), age (older or younger than 21 years), histopathology (pineocytoma or pineoblastoma/mixed PPT), radiosurgical target volume (≥ or