Virchows Arch (2006) 449:529–538 DOI 10.1007/s00428-006-0285-3
ORIGINAL ARTICLE
Histopathologic indicators of recurrence in meningiomas: correlation with clinical and genetic parameters Yoo-Jin Kim & Ralf Ketter & Wolfram Henn & Klaus D. Zang & Wolf-Ingo Steudel & Wolfgang Feiden
Received: 11 July 2006 / Accepted: 26 July 2006 / Published online: 3 October 2006 # Springer-Verlag 2006
Abstract Meningiomas in general are circumscribed slow-growing tumors. However, despite gross total resection, tumor relapse and patients’ outcome are still an issue. Risk stratification based on histomorphology alone remains problematic. This study explored the independent prognostic value of potential risk factors among 206 patients who underwent meningioma resection and followed-up until death or a median of 44 months. The statistical analysis considered clinical data, histomorphologic parameters, cytogenetic findings, Ki-67 immunoreactivity, and activity of tissue non-specific alkaline phosphatase (ALPL). Recurrence-free survival estimates were computed and prognostic factors were identified using Cox proportional hazards model. Independent predictors of recurrence included (1) anaplasia; (2) mitotic index ≥20/10 high-power fields; (3) subtotal tumor resection; (4) loss of short arm of chromosome 1 (1p−); and (5) Ki-67 labeling index (LI) >12%. Among totally resected WHO grade I meningiomas, neither histopathologic nor clinical parameters were predictive, whereas 1p− was the Y.-J. Kim (*) : W. Feiden School of Medicine, Institute of Neuropathology, Saarland University, Bldg. 90.3, 66421 Homburg-Saar, Germany e-mail:
[email protected] R. Ketter : W.-I. Steudel Department of Neurosurgery, School of Medicine, Saarland University, Homburg/Saar, Germany W. Henn : K. D. Zang School of Medicine, Institute of Human Genetics, Saarland University, Homburg/Saar, Germany
only independent prognostic factor. ALPL did not reach significance in the multivariate modeling, however, the fast and low-cost histochemical detection of ALPL expression could be proved as a highly sensitive screening method for 1p−. In particular, biologically aggressive meningiomas of histologically benign or “borderline” phenotype could be therefore identified by ALPL detection followed by 1p in situ hybridization. Keywords Meningioma recurrence . Prognosis . Ki-67 . Alkaline phosphatase . Cytogenetics
Introduction Meningiomas are tumors that arise from the leptomeningeal covering of the brain and the spinal cord, accounting for 15% to 20% of all central nervous system tumors [26]. According to the current World Health Organization (WHO) histological grading system, three grades of meningiomas with increasing risk of recurrence are distinguished [14]. Benign or common-type tumors with a low rate of recurrence (7% to 20%) are assigned to Grade I. Grade II meningiomas include atypical meningiomas as well as the rare chordoid and clear cell (intracranial) variants and exhibit a higher risk of recurrence (29% to 40%). Grade III meningiomas are anaplastic meningiomas with high mitotic activity (≥20/10 high-power fields) and/or obviously malignant cytology as well as the rare variants, papillary and rhabdoid meningiomas. Recurrence rate of anaplastic meningiomas is suggested to be 50% to 78%. While the application of histomorphologic criteria can be considered as a means of risk stratification, the prognostic impact of the proposed criteria—particularly the mitotic thresholds distinguishing
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between the three different grades—are not irrevocable in individual cases [25]. Regarding the recurrence rate of up to 20% in histologically benign meningiomas [8] on the one hand, and the variable recurrence rate among atypical meningiomas on the other, accurate risk estimation in individual cases based on histomorphologic criteria alone remains problematic. Apart from histomorphologic parameters, incompleteness of tumor resection is known to be the major risk factor of recurrence. However, 7–20% of gross totally resected meningiomas tend to recur—even phenotypically benign tumors. Therefore, an adequate prognosis of biological behavior and individual assessment of recurrence risk requires additional prognostic factors or markers. It is well-known, that high expression of immunohistochemically detectable markers of proliferative activity, e.g. Ki-67 antigen, indicates a more aggressive behavior and thus, a higher risk of recurrence. However, the determination of the independent predictive value of Ki-67 as well as the appropriate quantitation method still needs to be cleared. Cytogenetically, meningiomas are characterized by monosomy 22 as a typical primary aberration [33] and progression-associated secondary aberrations, of which monosomy of the short arm of chromosome 1 (1p−) is the most important. Monosomy 1 or loss of the distal part of the short arm of chromosome 1 was found to be correlated with higher histologic grade and with a higher recurrence rate in meningiomas [6, 10, 12, 18, 32]. The tissue non-specific isoform of alkaline phosphatase (ALPL), located on 1p36.1–p34, is strongly active in normal arachnoid cells and in cells of common-type meningiomas, but in contrast, enzyme activity lacks in meningiomas with deletion of 1p. Since karyotyping by means of classic cytogenetics is laborious and not a routine part of tumor diagnostics, the histochemical detection of the loss of ALPL was introduced by Niedermayer et al. [20] as a fast and low-cost technique for the detection of 1p−. The gene, encoding ALPL, is suggested as a putative and not yet identified tumor suppressor gene on chromosome 1p. Beyond its role as enzyme marker for 1p−, loss of ALPL activity could be applied as a predictor of recurrence, as it has been recently demonstrated—at least in univariate manner—by Bouvier et al. [4]. However, neither the independent predictive value of 1p− and loss of ALPL expression nor the correlation of ALPL to 1p− has yet been clarified in a multivariate setting and among a large cohort. The presented study aims to identify independent prognostic factors and to reveal complex interrelationships among clinical data, histomorphologic parameters, proliferative marker, histochemical expression of ALPL, and cytogenetic parameters in a multivariate approach.
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Materials and methods Patients and clinical data The retrospective cohort study is based on the data of 265 patients with initial diagnosis of meningioma operated on 1997–2002 at the Department of Neurosurgery, Saarland University. This subset consists of all meningioma patients within the given period where vital tumor tissue was available for histochemical detection of alkaline phosphatase. Mean age (±SD; range) was 59 (±13 years; 4–88 years). The cohort consisted of 186 females and 79 males (sex distribution 7:3). 13 patients (median age at diagnosis 61 years; SD ±9.6; range 51–78) died because of disease within a mean period of 11 months after surgery. Patients were followed-up for a mean period of 44 months (range 6–96 months). After 6 months, 59 patients were lost to follow-up and were not considered in the statistical analyses. Clinical data recorded included dates of birth and death, gender, tumor location, date of surgery for primary and recurrent tumor resections, date of recurrence/ regrowth as defined radiologically (CT or MRI), extent of resection, and grossly apparent invasion of adjacent structures. The extent of resection was documented along the guidelines suggested by Simpson [28]. Complete surgical extirpation of the tumor (gross total resection: GTR) was defined as Simpson grade I or II, corresponding to macroscopically determined complete tumor resection with bipolar coagulation of the dural insertion. Histomorphology All available slides from primary meningiomas as well as additional hematoxylin and eosin or specially stained slides in all cases were reviewed by two independent pathologists (Y.K. and W.F.) who were unaware of the patients outcomes. When there were discrepancies for parameters between the two investigators, the case was examined simultaneously by both observers and the results were recorded after an agreement was reached. According to the predominant feature or growth pattern, each tumor was assigned to a histologic prototypical guise (meningotheliomatous, fibrous, transitional, microcystic, secretory, lymphoplasmocyte-rich, xanthomatous or otherwise metaplasia, atypical, clear cell, chordoid, papillary, rhabdoid, and anaplastic) and graded according to the current WHO criteria [14]. Further histologic parameters, including hypercellularity, nuclear polymorphism, macronucleoli, small cell formation with high nuclear to cytoplasmic ratio, patternless architecture, inflammatory infiltrate, macrophages/foamy cells, calcification, necrosis, brain invasion, invasion of structures other than the brain, and mitotic index were evaluated in each case. Brain invasion was defined as irregular projections of tumor or tumor cells into
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adjacent central nervous system parenchyma without an intervening layer of leptomeninges. Except for mitoses, all parameters were recorded as either absent or present. The mitotic index (MI) was defined as the highest count in 10 consecutive high-power fields (HPF; 1 HPF=0.16 mm2). According to the mitotic thresholds as suggested by Perry et al. [22] and adopted by the WHO, a MI 65 years Sex (female vs male) Convexity vs other locations GTR vs STR Local infiltration Histopathologic parameters Hypercellularity Small cell formation Macronucleoli Necrosis Brain invasion vs non-invasion WHO grade II vs I III vs I and II Mitotic index ≥4/10 HPF ≥20/10 HPF Ki-67 LI >8% >12% ALPL At least partial loss Complete loss Karyotype 1p− vs others
Relative recurrence risk (%)
p
19 11 vs 19 12 vs 9 (WHO °I:8 vs 3) 12 vs 47 28 STR and GTR
0.0011 n.s. 0.02 (0.0152)
