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Modified histologic grading of
neuroblastomas by replacement of mitotic rate with mitosis
karyorrhexis index. A clinicopathologic study of 223 cases from
the Pediatric Oncology Group.Cancer.
1996 Apr 15;77(8):1582-8.
Neuroblastoma.
Lancet. 2007 Jun 23;369(9579):2106-20.
The clinical
hallmark of neuroblastoma is heterogeneity, with the likelihood of
cure varying widely according to age at diagnosis, extent of
disease, and tumour biology. A subset of tumours will undergo
spontaneous regression while others show relentless progression.
Around half of all cases are currently classified as high-risk for
disease relapse, with overall survival rates less than 40% despite
intensive multimodal therapy. This Seminar focuses on recent
advances in our understanding of the biology of this complex
paediatric solid tumour. We outline plans for the development of a
uniform International Neuroblastoma Risk Group (INRG)
classification system, and summarise strategies for risk-based
therapies. We also update readers on new discoveries related to
the underlying molecular pathogenesis of this tumour, with special
emphasis on advances that are translatable to the clinic. Finally,
we discuss new approaches to treatment, including recently
discovered molecular targets that might provide more effective
treatment strategies with the potential for less toxicity.
Proliferation marker KI-S5 discriminates between
favorable and adverse prognosis in advanced stages of
neuroblastoma with and without MYCN amplification.Cancer.
2002 Feb 1;94(3):854-61.
BACKGROUND:
The biologic behavior of neuroblastoma is notoriously variable,
and even carefully elaborated prognostic models fail to predict
the clinical course in a portion of cases. Because the
proliferative activity is determined by the sum of all molecular
imbalances that influence cell cycling, the authors investigated
the potential prognostic relevance of the tumor growth fraction in
neuroblastoma. METHODS: A retrospective analysis was conducted on
a cohort of 161 neuroblastoma patients with a median follow-up
period of 72.8 months. Tumors were classified according to Hughes
typing and grading criteria. The proliferative index (PI) was
assessed immunohistochemically on archival biopsy specimens using
monoclonal antibody Ki-S5 (Ki-67), and the MYCN status was
determined by means of Southern blot analysis. RESULTS: The PI,
MYCN status, International Neuroblastoma Staging System (INSS)
stage, International Neuroblastoma Pathology Classification grade,
Hughes grade, and the patients' age at diagnosis were all found to
be significant predictors of event free survival by univariate
Kaplan-Meier analysis. However, the PI identified prognostically
distinct subsets in higher tumor stages and Grade 2 and 3
neuroblastomas as well as tumors with unfavorable histology, and
enabled risk stratification in tumors with and without MYCN
amplification (P = 0.034 and 0.002, respectively). Multivariate
Cox regression analysis selected INSS stage (relative risk [RR],
4.05; P < 0.0001) and the PI (RR, 2.49; P = 0.007) as the sole
independent prognostic indicators, whereas MYCN entered the
selection only after exclusion of the PI. CONCLUSIONS: It emerges
that the PI as a single factor has greater predictive power than
the MYCN status. Proliferation measurements therefore might
significantly improve the accuracy of current prognostic models
for neuroblastoma.
Histopathology (International Neuroblastoma Pathology
Classification) and MYCN status in patients with peripheral
neuroblastic tumors: a report from the Children's Cancer Group.
Cancer 2001 Nov 15;92(10):2699-708.
BACKGROUND: The International Neuroblastoma Pathology
Classification (International Classification), which was
established in 1999, is significant prognostically and is relevant
biologically for the evaluation and analysis of patients with
neuroblastic tumors (NTs). MYCN amplification is a known molecular
marker for aggressive progression of NTs. These have been used
together as important prognostic factors to define risk groups for
patient stratification and protocol assignment. METHODS: A total
of 628 NTs (535 neuroblastomas [NBs]); 21 ganglioneuroblastoma,
intermixed [GNBi]; 9 ganglioneuromas [GN]; and 63
ganglioneuroblastoma, nodular [GNBn]) from the Children's Cancer
Group studies were evaluated histologically (favorable histology [FH]
tumors vs. unfavorable histology [UH] tumors) according to the
International Classification and were tested molecularly for MYCN
status (amplified vs. nonamplified). Four tumor subsets (FH-nonamplified,
FH-amplified, UH-nonamplified, and UH-amplified) were defined by
histopathology and MYCN status, and their prognostic effects were
analyzed. Detailed analysis between morphologic indicators (grade
of neuroblastic differentiation and mitosis-karyorrhexis index [MKI])
and MYCN status was done by using tumors in the NB category.
RESULTS: There were 339 FH-nonamplified tumors (5-year event free
survival [EFS], 92.1%); 8 FH-amplified tumors (EFS, 37.5%); 172
UH-nonamplified tumors (EFS, 40.9%); and 109 UH-amplified tumors (EFS,
15.0%). The prognostic effects on patients with tumors in the four
subsets were independent from the factors of patient age and
disease stage (P < 0.0001). MYCN amplification was seen almost
exclusively in tumors of the NB category, and no patients with
tumors in either the GNBi category or in the GN category and only
two patients with tumors in the GNBn category had amplified MYCN.
Among the patients with tumors in the NB category, patients with
FH-nonamplified tumors (309 patients) had an excellent prognosis,
and patients with UH-amplified tumors (107 patients) had the
poorest clinical outcome in any age group. The prognosis for
children with UH-nonamplified tumors (111 patients) was poor when
they were diagnosed at age > 1.5 years. It was also noted that
patients with UH-amplified tumors (median age, 2.14 years) were
diagnosed at a significantly younger age compared with the
patients with UH-nonamplified tumors (median age, 3.55 years).
Histologically, MYCN-amplified tumors lacked neuroblastic
differentiation regardless of the age of patients. MYCN
amplification also was linked generally to increased mitotic and
karyorrhectic activities. However, MKI classes in patients with
MYCN-amplified tumors varied significantly, depending on the age
at diagnosis, and younger patients had higher MKI classes.
CONCLUSIONS: The combination of histopathologic evaluation and
MYCN status distinguishes four clinical and biologic tumor subsets
in patients with NTs. MYCN amplification seems to be the powerful
driving force for preventing cellular differentiation regardless
of patient age and for increasing mitotic and karyorrhectic
activities in an age dependent manner.
International neuroblastoma pathology classification for
prognostic evaluation of patients with peripheral neuroblastic
tumors: a report from the Children's Cancer Group.Cancer.
2001 Nov 1;92(9):2451-61.
BACKGROUND: The International Neuroblastoma Pathology
Classification was established in 1999 for the prognostic
evaluation of patients with neuroblastic tumors (NTs). METHODS:
Pathology slides from 746 NTs (the Children's Cancer Group [CCG]-3881
and CCG-3891 studies) were evaluated according to the
International Classification. First, prognostic effects of the
morphologic indicators (grade of neuroblastic differentiation:
undifferentiated [U], poorly differentiated [PD] and
differentiating [D]; and mitosis-karyorrhexis index [MKI]: low [L-MKI],
intermediate [I-MKI], and high [H-MKI]) for tumors in the
neuroblastoma (NB) category were tested. Then, prognostic
significance of the International Classification for all NTs in
four categories (neuroblastoma [NB]; ganglioneuroblastoma,
intermixed [GNBi]; ganglioneuroma [GN]; and ganglioneuroblastoma,
nodular [GNBn]) was analyzed. Finally, age distribution of the
patients in the four categories as well as three subtypes (based
on the grade of differentiation) in the NB category was compared.
RESULTS: There were 630 NB tumors, 30 GNBi tumors, 10 GN tumors,
and 76 GNBn tumors. In the NB category, prognostic effects of the
indicators (three grades of differentiation and three mitosis-karyorrhexis
index [MKI] classes: low [L], intermediate [I], and high [H]) were
affected significantly by the age of the patients. The age-linked
evaluation of the indicators according to the International
Classification successfully distinguished two prognostic
subgroups: the favorable histology (FH) subgroup (PD/D and L/I-MKI
tumors in patients age < 1.5 years, D and L-MKI tumors in patients
ages 1.5-5.0 years; 90.4% 5-year event free survival [EFS]) and
the unfavorable histology (UH) subgroup (U and/or H-MKI tumors in
patients of any age, PD and/or I-MKI tumors in patients ages
1.5-5.0 years, any grade of differentiation, and any MKI class in
patients age > or = 5 years; 26.9% EFS) (P < 0.0001). The
International Classification also distinguished the FH group (FH
subgroup with NB, GNBi, and GN tumors) and the UH group (UH
subgroup with NB and GNBn tumors) for all NTs (90.8% EFS and 31.2%
EFS, respectively; P < 0.0001) and provided independent prognostic
information on both patient age and disease stage (P < 0.0001).
Among patients with FH tumors, the median ages of patients with
the PD and D subtype tumors in the NB category were 0.43 years
(range, 0-1.50 years) and 1.50 years (range, 0.02-4.65 years),
respectively, and the median ages of patients with GNBi and GN
tumors were 3.51 years (range, 0.96-14.85 years) and 4.80 years
(range, 1.94-17.05 years), respectively. In contrast, patients
with UH tumors generally were older when they were diagnosed, and
with median ages of 2.99 years (range, 1.30-8.84 years) for
patients with U subtype tumors, 2.59 years (range, 0.0-12.57
years) for patients with PD subtype tumors, 2.16 years (range,
0.35-9.90) for patients with D subtype tumors, and 3.26 years
(range, 0.57-15.90 years) for patients with GNBn tumors.
CONCLUSIONS: This study confirmed the prognostic significance of
the International Classification, substantiated age-linked
prognostic effects of the morphologic indicators for patients with
the tumors in the NB category, and supported the concept of an
age-appropriate framework of maturation for patients with the
tumors in the FH group.
Neuroblastoma.
Eur J Cancer. 1997 Aug;33(9):1430-7.
The
neuroblastic tumours, derived from primordial neural crest cells
which ultimately populate the sympathetic ganglia, adrenal medulla
and other sites, (Brodeur GM and Castleberry RP. Neuroblastoma. In
Pizzo PA, Poplack DG, eds, Principles and Practice of Pediatric
Oncology. Philadelphia, J. B. Lippincott Co., 1997, 761-797) are
an enigmatic group of neoplasms which have the highest rate of
spontaneous regression of all human malignant neoplasms yet one of
the poorest outcomes when occurring as disseminated disease in
children. Significant advances in understanding and predicting the
natural history of neuroblastoma have resulted from translational
studies coupling tumour biology and clinical features to form
prognostic strata and allowing more accurate routeing of patients
to risk-related management. While this strategy has clarified the
management for lower risk tumours, little improvement in survival
for higher risk disease has been realised. Ironically, this latter
patient subset, for which the most innovative therapeutic
strategies are needed, is also the one from which the least tumour
biology is gleaned owing to inadequate tissue sampling. This
update will summarise the evolving biology of neuroblastoma and
its relationship to current risk-related therapy and future
management strategies. Throughout this report, prognostic grouping
by age will be infants (< 1 year) versus children (> or = 1 year)
since the change of risk according to age seems most distinct at
this cut-off point.
Neuroblastoma: an
enigmatic disease.Br
Med Bull. 1996 Oct;52(4):787-801.
Neuroblastoma
is the most common extra-cranial solid tumor of childhood. It
originates in cells of the neural crest, and so can be found
anywhere along the paravertebral sympathetic chain or in the
adrenal gland. In the last 15 years, new developments in the
genetics and biology of neuroblastoma, have led to a better
understanding of the natural history and prognostic features of
this cancer. The presence of identifying biochemical markers
detectable in the urine of patients with neuroblastoma, as well as
the remarkably inferior survival of children diagnosed at more
than 12 months of age, have led some groups to screen infants for
neuroblastoma, in the hope of decreasing both overall mortality,
as well as the incidence of advanced stage disease. This article
reviews some clinical aspects of neuroblastoma, but emphasizes the
genetic and biologic features in relation to prognosis and
treatment. Finally, we discuss the different screening experiences
for this disease, in particular from the Quebec Neuroblastoma
Screening Project.
Prognostic
value of histopathology in advanced neuroblastoma: a report from
the Childrens Cancer Study Group.Hum
Pathol. 1988 Oct;19(10):1187-98
We report
the histopathologic findings in 420 patients with stage III and IV
neuroblastoma enrolled in Childrens Cancer Study Group trials
conducted from 1980 to 1983. A prospective study of individual
cytohistologic features showed that outcome was related in a
statistically significant manner to mitotic rate, multi-nuclearity,
foam cells, ganglion cells, necrosis, and calcification, but only
the latter was consistent for both stages. A similar test of four
selected published classifications indicated the greatest
prognostic value for the system developed by Shimada et al to
distinguish favorable from unfavorable tumors. This classification
proved significant in both stages and on examination of both
primary and metastatic sites. Concordance in histologic assignment
of prognosis by two observers was 83%. We conclude that the
Shimada classification is valid and reproducible, and that it may
be useful in planning therapy in advanced neuroblastoma. Selected
cytohistologic parameters and the other classifications were less
strongly predictive of outcome, but are worthy of continued study.
Prognostic
factors in neuroblastoma in children.Vopr
Onkol. 1984;30(5):21-31.
The
results of clinico-morphological studies of 152 cases of
neuroblastoma are presented. Neuroblastoma should be regarded as a
tumor in which the following patterns may be distinguished:
sympatogonioma (2.6%), sympatoblastoma -1 (38.8%), sympatoblastoma
-2 (15.2%), ganglioneuroblastomia (41.4%), and combined
ganglioneuroblastoma (2%). Mean two-year survival rate was 40.2%.
Such factors as patient's by the time of tumor detection, radical
surgery and excision of primary neoplasm in patients with
metastases were found to improve the prognosis. The two-year
survival rates in sympatoblastoma -1, sympatoblastoma -2 and
ganglioneuroblastoma were 19.6, 50, and 72%, respectively.
Morphology of neuroblastoma.
Light and electron microscopic studies as a contribution on
diagnosis and differential diagnosis.Zentralbl
Allg Pathol. 1983;127(3-4):207-18.
The
neuroblastoma is one of the most frequent malignant solid tumors
in childhood and is thus of great practical importance. The origin
of neuroblastoma cells from neural crest derivatives is generally
accepted now, and this histogenesis explains some biochemical and
morphological characteristics of the tumor. The cytological and
histological features of neuroblastomas can be rather varying and,
therefore, the diagnosis and differential diagnosis may be
difficult. Our study presents the findings of 48 neuroblastomas
after light microscopic examination and the ultrastructural
characteristics of 8 neuroblastomas and 1 ganglioneuroma. At light
microscopic level, completely undifferentiated neuroblastomas and
tumors with variable degrees of differentiation were identified.
The differentiation of the tumor tissue to ganglion cell-like
elements was indicated by an increasing amount of cellular
cytoplasm with development of a cytoplasmic process as well as an
alteration of the picture of the nucleus (nuclear enlargement and
a clearly visible nucleolus). Differentiation to Schwann cell-like
elements was occasionally observed, too. Electron microscopically,
in all tumors neurosecretory granules could be recognized, and in
the better differentiated areas neurite-like cytoplasmic
projections were detectable. Thus, the electron microscopy can be
a valuable aid in establishing an unequivocal diagnosis. The
histology of neuroblastomas is said to be of prognostic
significance. Therefore, grading schemes of malignancy were
developed. At present, the grading procedure after Hughes and
coworkers is mostly used. The criteria of this grading system are
presented and interpreted. Finally, those tumors are briefly
characterized which play the main role in the differential
diagnosis, i.e. juvenile rhabdomyosarcomas, Ewing's sarcoma
(including the extraskeletal type), lymphoblastic lymphoma and
histiocytic reticulosarcoma. The most important clinicopathologic
differences in comparison to neuroblastomas are referred to. Using
a large scale of morphologic methods as well as considering
clinical and paraclinical parameters, the exact diagnosis of
neuroblastoma should be possible in nearly every case.
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