1
Congenital disseminated extrarenal malignant rhabdoid tumor
2 3
Sabah BOUDJEMAA (1), Arnaud Petit (3), Linda Dainese (1), Franck Bourdeaut (4), Jill Lipsett (2) and Aurore Coulomb (1).
4
Authors’ affiliations
5 6
1: Service d’Anatomie et de Cytologie Pathologiques, Hôpital d’Enfants Armand Trousseau, 26 Avenue du Dr Arnold Netter, 75571 Paris Cedex 12, France
7
Université Pierre et Marie Curie, Paris 6, France.
8
[email protected], [email protected]
9 10
2: SA Pathology, Women’s and children’s Hospital, 72 King Hospital Rd, North Adelaide, South Autralia 5006.
11
[email protected]
12 13
3: Service d’Oncohématologie Pédiatrique, Hôpital d’Enfants Armand Trousseau, 26 Avenue du Dr Arnold Netter, 75571 Paris Cedex 12, France.
14
[email protected]
15
4 : Département de Pédiatrie et INSERM U830, Institut Curie, 26 rue d’Ulm, 75248 Paris Cedex.
16
[email protected]
17
Corresponding author
18 19
Dr Sabah BOUDJEMAA, MD, Service d’Anatomie et de Cytologie Pathologiques, Hôpital d’Enfants Armand Trousseau, 26 Avenue du Dr Arnold Netter, 75571 Paris Cedex 12, France
20
Phone number : +33(1)44736182, Fax number : +33(1)44736282, e-mail:
21
[email protected]
22 23 24 25 26 27 28 29 30 31 32 33 34
Key words: malignant rhabdoid tumor, rhabdoid predisposition syndrome, extrarenal malignant rhabdoid tumor.
35
Abstract
36
Soft tissue tumors arising in association with genetic or malformation syndromes
37
have been increasingly reported.
38
aggressive neoplasm of infancy and young childhood, characterized by typical
39
morphology and biallelic inactivation of the INI1 (hSNF5/SMARCB1/BAF47) gene on
40
chromosome 22q.2.
41
clinicopathologic presentation of this tumor. We report a case occurring in a female
42
neonate which presented at birth a voluminous left thigh mass. Surgical biopsy
43
performed at day 9 showed morphology and immunoprofile of MRT. Staging
44
evaluation identified hypercalcemia and distant nodules. The mass showed rapid
45
growth. Despite chemotherapy, the tumor progressed with exteriorization through the
46
biopsy scar. Chemotherapy was discontinued and treatment limited to palliative care
47
and the child died on day 51. The tumor was homozygous for the INI1 deletion with
48
apparent de novo heterozygous germ line deletion in the infant, not identified in the
49
parents.
50 51 52 53 54 55 56 57 58 59
Malignant rhabdoid tumor (MRT) is a highly
Congenital infantile disseminated MRT represents a unique
60
Introduction
61
Congenital infantile disseminated MRT represents a unique clinicopathologic
62
presentation of malignant rhabdoid tumors (MRTs).
63
MRT are lethal pediatric tumors most commonly observed in the brain, kidney and
64
soft tissues of infants and young children. They are characterized by germline
65
mutations, deletions and somatic mutations of the INI1 (hSNF5/SMARCB1/BAF47)
66
gene on chromosome 22q11.2.
67
The rhabdoid predisposition syndrome is caused by a mutation and/or deletion in the
68
gene. The syndrome is inherited in an autosomal dominant manner, with a second
69
sporadic mutation (second hit). Patients with germline mutations are predisposed to
70
MRT of brain, kidney and soft tissues and usually present with multiple tumors.
71
Case report
72
A female infant was born at 38 weeks gestation at which time a voluminous left thigh
73
mass was identified. The pregnancy and vaginal delivery had been unremarkable
74
with three normal obstetric ultrasounds. Examination at birth showed an increase in
75
left thigh size with a soft tissue mass evident (Figure 1). The baby was medically
76
stable and, in the absence of compressive signs, was discharged home on day 4 with
77
an MRI booked for day 11 and orthopedic follow-up. On day 6, the parents presented
78
to the emergency department reporting rapid growth of the mass and the appearance
79
of a separate subcutaneous nodule on the posterior aspect of the same thigh.
80
Physical examination confirmed tumor growth with a thigh diameter of 22 cm,
81
extension to the inguinal area and the presence of multiple satellite nodules. The
82
overlying skin appeared reddish with turgescent veins.
83
heterogeneous tissue mass with a cystic component developed in the posterior and
84
lateral muscular compartments, extending to the pelvis. MRI confirmed a 97x46x60
Ultrasonography showed a
85
mm mass, extending from the upper extremity of the leg to the left paravesical region
86
with infiltration of whole thigh. The mass had a low signal intensity on T1 weighted
87
images and a high signal on T2 weighted images, with a mild enhancement after
88
gadolinium IV injection. Proposed diagnoses included congenital fibrosarcoma,
89
rhabdomyosarcoma and generalized congenital myofibromatosis. A surgical biopsy
90
was subsequently performed simultaneously on the mass and one of the satellite
91
nodules.
92
Histological study
93
Both biopsies showed a small round blue cell tumor with a trabecular and alveolar
94
growth pattern, focal necrosis and calcifications). The major component comprised
95
large monomorphic cells with well-defined cell borders and eosinophilic cytoplasm
96
containing some intracytoplasmic inclusions. Nuclei were eccentric, with
97
vesicular chromatin and central prominent nucleoli (Figure 2). This histological
98
appearance
99
immunohistochemical panel was performed including muscular, neural, epithelial,
100
mesenchymal, melanocytic and lymphoid markers, MIB1 and INI1 antibodies. Tumor
101
cells expressed vimentin and cytokeratin with strong spheroid perinuclear positivity
102
and were negative for desmin, myogenin, NSE, S100, EMA and CD45. There was
103
loss of nuclear INI1 expression. A final diagnosis of extrarenal congenital malignant
104
rhabdoid tumor was made. Placental examination was unremarkable.
105
On staging evaluation performed on day 8, whole body MRI showed iliac
106
lymphadenopathies, distant subcutaneous nodules of the chest wall, the left
107
shoulder, the right upper extremities of leg and thigh and a right pulmonary
108
intraparenchymatous nodule. There was hypercalcemia at 3.10 mmol/L. No cerebral
109
involvement
was
was
highly
suggestive
observed.
Palliative
of
rhabdoid
chemotherapy
tumor
with
and
a
Vincristin®
wide
and
110
cyclophosphamide® was started on day 13 and genetic counseling was planned in
111
view of the possibility of germ line mutation. As the tumor continued to progress and
112
exteriorized through the biopsy scar, chemotherapy was discontinued and treatment
113
limited to palliative care. The child died on the day 51.
114
Molecular studies
115
. DNA was extracted from frozen tumoral tissue and blood lymphocytes according to
116
classical procedures. All coding exons and splite sites regions were sequenced using
117
the sanger method and ABI automated fluorescent sequencer. Large size deletions
118
were searched for using the multiplex ligation-dependant probe amplification assay
119
(Salsa MLPA KIT P258-B1 SMARKB1). INI1 deletion was identified with the nine
120
exons of the gene deleted): homozygous deletion in tumoral tissue and heterozygous
121
constitutionally. The germ line deletion appeared de novo as it was not evident in
122
either parent.
123
Discussion
124
Malignant rhabdoid tumor was originally described in the kidney by Beckwith and
125
Palmer in 1978 as a variant of Wilms’ tumor characterized by its distinct morphology,
126
precocious occurrence (first year) and more aggressive behavior (1,2,3). Subsequent
127
genetic and biological data have distinguished it as a separate entity. The CNS
128
atypical teratoid/rhabdoid tumor (ATRT) is the most common extrarenal site (4,3,2)
129
with malignant extrarenal RTs (MERT) well recognised to arise in multiple sites
130
including deep axial locations, extremities, cutaneous and viscera, the liver being the
131
most common. Congenital MRT (fetal or neonatal) is more likely to be MERT than
132
renal or CNS and may present as disseminated disease with no primary site evident.
133
So called composite extrarenal rhabdoid tumors (CERTs) showing areas of rhabdoid
134
morphology within a recognizable tumor of another type (5) have been separated
135
from the MRT group as distinct molecular changes are now recognized.
136
Rhabdoid tumors were so named for their large, polygonal tumor cells likened to
137
rhabdomyoblasts, with eccentric nuclei, macronucleoli, abundant cytoplasm and
138
eosinophilic,
139
paranuclear intracellular bundles and globular aggregates of intermediate filaments
140
on electron microscopy (6). Histological variants, however, include small round or
141
spindled undifferentiated cells or gland-like areas with cells in cords, sheets or
142
dispersed in variable hyaline or myxoid stroma. Diagnosis requires excluding other
143
pediatric small round blue cell tumors, particularly desmoplastic round cell tumor,
144
rhabdomyosarcoma and Ewing’s family tumors, epithelioid or synovial sarcoma,
145
using a combination of EM, immunohistochemistry panel and genetic studies.
146
Vimentin is the most commonly expressed antigen, with EMA and cytokeratin
147
positivity also frequently observed. Less often MRTs can show staining for actin,
148
CD99, CD57, synaptophysin and S-100.
149
identification of loss of nuclear INI1 staining(1) observed in more than 80% of MRT,
150
reflecting consistently identified biallelic deletions or point mutations in the tumor
151
suppressor INI1/SMARCB1 gene (aliases INI1,hSNF5, BAF47) on chromosome
152
22q11.2 (1,9). SMARCB1 (integrase interactor 1 – INI1) is a subunit of the SWI/SNF
153
ATP-dependent
154
expression, and involved in cell cycle control, DNA repair and differentiation. INI1 is
155
thus
156
immunohistochemistry. Some 15-60% of patients harbor sporadic or inherited germ-
157
line mutations of SMARCB1 (1,10). The finding of some familial cases not linked to
158
SMARCB1, and some MRTs that do not show SMARCB1 alterations, imply
hyaline, juxtanuclear
expressed
inclusions.
chromatin-remodeling
in
all
normal
The
with
Diagnosis is further facilitated by
complex
cell
inclusions correlate
nuclei
involved
and
in
regulating
identified
easily
gene
by
159
alternative loci may be involved with SMARCA4 (another member of the SWI/SNF
160
complex) gene mutations or loss implicated in rare cases (13). Recent studies
161
indicate that diverse cell types may develop into MRT as a consequence of
162
congenital or acquired abnormalities involving the INI1/SMARCB1 gene (7).
163
Similarities between MRT and stem cells were underscored by Venneti et al (8) who
164
demonstrated that MRT expressed stem cell-associated transcription factors, which
165
may be regulated by the expression of EZH2 and the Id family of proteins.
166
INI1 represents a useful diagnostic tool, particularly in undifferentiated pediatric
167
tumors, however it is noted that other tumors may also show loss of INI1 expression
168
and INI1 mutations including renal medullary carcinomas, epithelioid sarcomas,
169
epithelioid malignant schwannomas, most choriod plexus carcinomas and a subset of
170
medulloblastomas,
171
myoepithelial carcinomas, extraskeletal myxoid chondrosarcomas and central
172
primitive neuroectodermal tumors (PNETS) (Sevenet).Hollmann) (1).
173
The rhabdoid predisposition syndrome (RPS) is associated with inherited (autosomal
174
dominant) mutations and/or deletions in the INI1/SMARCB1 gene on chromosome
175
22q11.2, rendering individuals vulnerable to a second sporadic mutation (second hit)
176
thence complete loss of expression of the nuclear protein demonstrated by lack of
177
INI1 staining by immunohistochemistry (11) and predisposition to development of
178
MRT, including multiple primaries.
179
expression and incomplete penetrance. Three multigeneration families have been
180
reported in the literature. It has been hypothesized that patients harboring a germline
181
INI1 mutation are at increased risk of MRT during a developmental window in early
182
childhood. If this does not occur then they are at increased risk of other INI1-related
183
tumors, not necessarily malignant, later in life including schwannomatosis and
epithelioid
malignant
peripheral
nerve
sheath
tumors,
INI1 germline mutations can show variable
184
meningiomas. Further, while long term survival is characteristically rare, two of four
185
RPS cousins with MRTs have been reported surviving more than 15 years, indicating
186
more information is needed to characterize genotype-phenotype relationships. Most
187
individuals with germ-line SMARCB1 alterations have acquired de novo deletions or
188
mutations as reported here. In some cases where multiple siblings but not parents
189
have demonstrated the same germline mutation, gonadal mosaicism has been
190
implicated. (12)
191
younger (5 months) than children with apparent sporadic disease (18 months) (10).
192
Malignant rhabdoid tumor may also occur in the setting of a variety of syndromes
193
including Beckwith-Wiedemann, Goldenhar, Phelan-McDermid syndromes and
194
familial schwannomatosis.
195
MRT can present as local or disseminated metastatic disease. In utero development
196
may occur, with possible tumor rupture causing severe fetal anemia (2,14). Patients
197
may have one or multiple cutaneous nodules, resembling the so-called blueberry
198
muffin baby as observed in neonatal neuroblastoma or rhabdomyosarcoma.
199
Metastases can involve skin, placenta (2 reported cases), brain, liver, lymph nodes,
200
lungs and bones (3,14,15).
201
heterogeneous in terms of age at presentation and survival. They usually occur
202
before the age of 5 years, while in neonates and fetuses, unlike children and older
203
infants, tumors more frequently affect soft tissues rather than kidneys or CNS (14).
204
Like renal MRTs, MERTs are characterized by a rapidly progressive course with less
205
than 50% of patients surviving 5 years and those with germ-line mutations have a far
206
worse prognosis (0% 2 years survival vs 48%) than other pediatric malignancies
207
(14,15). In a series of 9 infants with congenital disseminated malignant rhabdoid
208
tumor, reported by White and al in 1999, the age at presentation ranged from 33
The median age of children with MRT in the setting of RPS is
Unlike ATRT, non-CNS MERTs are more
209
weeks gestation to 3 months. Survival ranged from a few minutes to 3 months (mean
210
6 weeks). In comparing our case, the tumor was discovered postnatally and the
211
patient died on the 51th day of life, despite chemotherapy. No placental involvement
212
was observed in this case. In this family, two other healthy children have been born
213
subsequently with no germ-line SMARCB1 genetic abnormalities detected.
214
hildren were born subsequently with no germ line deletion detected.
215 216
CONCLUSION
217
Pitfalls in the diagnosis of MRT are attributed to the rarity and the morphological
218
pleomorphism and heterogeneity of this tumor.
219
valuable
220
immunohistochemical workup of pediatric tumors. Moreover, genetic investigation is
221
an important consideration for families following diagnosis of MRT because of the
222
possibility of germline mutation (35%) with further implications for prognosis and
223
development of multiple tumors. As germline mutation is most frequently de novo, the
224
family history will often be negative. Unfortunately despite progress in MRT
225
classification and diagnosis, the prognosis remains dismal, making early recognition
226
even more important.
227
where innovative therapies need to be developed.
diagnostic
tool
and
should
be
Anti-INI 1 antibody represents a systematically
included
in
The tumor represents an aggressive pediatric malignancy
228 229 230
the
References
231
1. Bourdeaut F, Freneaux P, Thuille B et Al. Hsnf5/INI1-deficient tumours and
232
rhabdoid tumours are convergent but not fully overlapping entities. J Pathol
233
2007;211:323-330.
234
2. Kwon JY, Park KI, Lee KS, Yang WI, Kim YH. Prenatal detection of
235
congenital malignant extrarenal rhabdoid tumor primarily involving the right
236
upper extremity that ruptured in utero. Prenat Diagn 2009; 29:819-821.
237
3. Yurdakul Z. Congenital disseminated malignant rhabdoid tumor of the soft
238
tissue. Pediatr Blood Cancer 2007; 49(3): 364-365.
239
4. Burger PC, Yu IT, Tihan T et al. Atypical teratoid/rhabdoid tumor of the central
240
nervous system: a highly malignant tumor of infancy and childhood frequently
241
mistaken for medulloblastoma: a Pediatric Oncology Group study. Am J Surg
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Pathol 1998; 22(9):1083-92.
243
5. Wick MR, Ritter JH, Dehner LP. Malignant rhabdoid tumors: a clinico-
244
pathologic review and conceptual discussion. Semin Diagn Pathol
245
1995;12(3):223-48).
246
6. Haas JE, Palmer NF, Weinberg AG et al. Ultrastructure of malignant rhabdoid
247
tumor of the kidney. A distinctive renal tumor of children. Hum Pathol.
248
1981;12(7):646-57).
249
7. Salamanca J, Rodriguez-Peralto JL, Azorin D, Ballestin C, De Agustin P.
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Paratesticular congenital malignant rhabdoid tumor diagnosed by fine-needle
251
aspiration cytology. A case report. Diagn Cytopathol 2004;30(1):46-50.
252
8. Venneti S, Le P, Martinez D et al. Malignant rhabdoid tumors express stem
253
cell factors , which relate to the expression of EZH2 and Id proteins. Am Surg
254
Pathol 2011;35:1463-1472.
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9. Judkins AR, Mauger J, Rorke LB, Biegel JA. Immunohistochemical analysis of Hsnf5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol 2004;28:644-650.
257
10. Eaton KW, Tooke LS, Wainwright LM, Judkins AR, Biegel JA. Spectrum of
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SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr
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Blood Cancer 2011; 56(1): 7-15.
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11. Teplick A, Kowalski M, Biegel JA; Screening in cancer predisposition
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syndromes: guidelines for the general pediatrician. Eur J Pediatr
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2011;172:285-294.
263
12. Sévenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O.
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Constitutional mutations of the hSNFf5/INI1 gene predispose to a variety of
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cancers. Am J Hum Genet 1999;65:1342-1348.
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13. Schneppenheim R, Frühwald MC, Gesk S, Hasselblatt M, Jeibmann A, Kordes
267
U, Kreuz M, Leuschner I, Subero JIM, Osber T, Oyen F, Vater I, Siebert R.
268
Germline Nonsense mutation and somatic inactivation of SMARCB4/BRG1 in
269
a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet
270
2010;86:279-284.
271 272 273
14. Issacs H Jr. fetal and neonatal rhabdoid tumor. Journal of Pediatric Surgery 2010; 45:619-626. 15. White F, Dehner L, Belchis D, Conard K, Davis M, Stocker JT, Zuppan C,
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Biegel J, Perlman E. Congenital Disseminated Malignant Rhabdoid Tumor: A
275
distinct clinicopathologic entity demonstrating abnormalities of chromosome
276
22q11. Am J Surg Pathol 1999;23(3):249-256.
277 278 279 280
281 282
Legends
283
Figure 1: Voluminous mass of the left thigh with satellite nodule, covered by reddish
284
thin skin with turgescent veins.
285
Figure 2: surgical biopsy: monomorphic tumor cells with well-defined cell borders,
286
eosinophilic cytoplasm and eccentric nuclei with vesicular chromatin and central
287
prominent nucleoli. H&EX400.
288
.
289
.
290
Congenital disseminated extrarenal malignant rhabdoid tumor
2 3
Sabah BOUDJEMAA (1), Arnaud Petit (3), Linda Dainese (1), Franck Bourdeaut (4), Jill Lipsett (2) and Aurore Coulomb (1).
4
Authors’ affiliations
5 6
1: Service d’Anatomie et de Cytologie Pathologiques, Hôpital d’Enfants Armand Trousseau, 26 Avenue du Dr Arnold Netter, 75571 Paris Cedex 12, France
7
Université Pierre et Marie Curie, Paris 6, France.
8
[email protected], [email protected]
9 10
2: SA Pathology, Women’s and children’s Hospital, 72 King Hospital Rd, North Adelaide, South Autralia 5006.
11
[email protected]
12 13
3: Service d’Oncohématologie Pédiatrique, Hôpital d’Enfants Armand Trousseau, 26 Avenue du Dr Arnold Netter, 75571 Paris Cedex 12, France.
14
[email protected]
15
4 : Département de Pédiatrie et INSERM U830, Institut Curie, 26 rue d’Ulm, 75248 Paris Cedex.
16
[email protected]
17
Corresponding author
18 19
Dr Sabah BOUDJEMAA, MD, Service d’Anatomie et de Cytologie Pathologiques, Hôpital d’Enfants Armand Trousseau, 26 Avenue du Dr Arnold Netter, 75571 Paris Cedex 12, France
20
Phone number : +33(1)44736182, Fax number : +33(1)44736282, e-mail:
21
[email protected]
22 23 24 25 26 27 28 29 30 31 32 33 34
Key words: malignant rhabdoid tumor, rhabdoid predisposition syndrome, extrarenal malignant rhabdoid tumor.
35
Abstract
36
Soft tissue tumors arising in association with genetic or malformation syndromes
37
have been increasingly reported.
38
aggressive neoplasm of infancy and young childhood, characterized by typical
39
morphology and biallelic inactivation of the INI1 (hSNF5/SMARCB1/BAF47) gene on
40
chromosome 22q.2.
41
clinicopathologic presentation of this tumor. We report a case occurring in a female
42
neonate which presented at birth a voluminous left thigh mass. Surgical biopsy
43
performed at day 9 showed morphology and immunoprofile of MRT. Staging
44
evaluation identified hypercalcemia and distant nodules. The mass showed rapid
45
growth. Despite chemotherapy, the tumor progressed with exteriorization through the
46
biopsy scar. Chemotherapy was discontinued and treatment limited to palliative care
47
and the child died on day 51. The tumor was homozygous for the INI1 deletion with
48
apparent de novo heterozygous germ line deletion in the infant, not identified in the
49
parents.
50 51 52 53 54 55 56 57 58 59
Malignant rhabdoid tumor (MRT) is a highly
Congenital infantile disseminated MRT represents a unique
60
Introduction
61
Congenital infantile disseminated MRT represents a unique clinicopathologic
62
presentation of malignant rhabdoid tumors (MRTs).
63
MRT are lethal pediatric tumors most commonly observed in the brain, kidney and
64
soft tissues of infants and young children. They are characterized by germline
65
mutations, deletions and somatic mutations of the INI1 (hSNF5/SMARCB1/BAF47)
66
gene on chromosome 22q11.2.
67
The rhabdoid predisposition syndrome is caused by a mutation and/or deletion in the
68
gene. The syndrome is inherited in an autosomal dominant manner, with a second
69
sporadic mutation (second hit). Patients with germline mutations are predisposed to
70
MRT of brain, kidney and soft tissues and usually present with multiple tumors.
71
Case report
72
A female infant was born at 38 weeks gestation at which time a voluminous left thigh
73
mass was identified. The pregnancy and vaginal delivery had been unremarkable
74
with three normal obstetric ultrasounds. Examination at birth showed an increase in
75
left thigh size with a soft tissue mass evident (Figure 1). The baby was medically
76
stable and, in the absence of compressive signs, was discharged home on day 4 with
77
an MRI booked for day 11 and orthopedic follow-up. On day 6, the parents presented
78
to the emergency department reporting rapid growth of the mass and the appearance
79
of a separate subcutaneous nodule on the posterior aspect of the same thigh.
80
Physical examination confirmed tumor growth with a thigh diameter of 22 cm,
81
extension to the inguinal area and the presence of multiple satellite nodules. The
82
overlying skin appeared reddish with turgescent veins.
83
heterogeneous tissue mass with a cystic component developed in the posterior and
84
lateral muscular compartments, extending to the pelvis. MRI confirmed a 97x46x60
Ultrasonography showed a
85
mm mass, extending from the upper extremity of the leg to the left paravesical region
86
with infiltration of whole thigh. The mass had a low signal intensity on T1 weighted
87
images and a high signal on T2 weighted images, with a mild enhancement after
88
gadolinium IV injection. Proposed diagnoses included congenital fibrosarcoma,
89
rhabdomyosarcoma and generalized congenital myofibromatosis. A surgical biopsy
90
was subsequently performed simultaneously on the mass and one of the satellite
91
nodules.
92
Histological study
93
Both biopsies showed a small round blue cell tumor with a trabecular and alveolar
94
growth pattern, focal necrosis and calcifications). The major component comprised
95
large monomorphic cells with well-defined cell borders and eosinophilic cytoplasm
96
containing some intracytoplasmic inclusions. Nuclei were eccentric, with
97
vesicular chromatin and central prominent nucleoli (Figure 2). This histological
98
appearance
99
immunohistochemical panel was performed including muscular, neural, epithelial,
100
mesenchymal, melanocytic and lymphoid markers, MIB1 and INI1 antibodies. Tumor
101
cells expressed vimentin and cytokeratin with strong spheroid perinuclear positivity
102
and were negative for desmin, myogenin, NSE, S100, EMA and CD45. There was
103
loss of nuclear INI1 expression. A final diagnosis of extrarenal congenital malignant
104
rhabdoid tumor was made. Placental examination was unremarkable.
105
On staging evaluation performed on day 8, whole body MRI showed iliac
106
lymphadenopathies, distant subcutaneous nodules of the chest wall, the left
107
shoulder, the right upper extremities of leg and thigh and a right pulmonary
108
intraparenchymatous nodule. There was hypercalcemia at 3.10 mmol/L. No cerebral
109
involvement
was
was
highly
suggestive
observed.
Palliative
of
rhabdoid
chemotherapy
tumor
with
and
a
Vincristin®
wide
and
110
cyclophosphamide® was started on day 13 and genetic counseling was planned in
111
view of the possibility of germ line mutation. As the tumor continued to progress and
112
exteriorized through the biopsy scar, chemotherapy was discontinued and treatment
113
limited to palliative care. The child died on the day 51.
114
Molecular studies
115
. DNA was extracted from frozen tumoral tissue and blood lymphocytes according to
116
classical procedures. All coding exons and splite sites regions were sequenced using
117
the sanger method and ABI automated fluorescent sequencer. Large size deletions
118
were searched for using the multiplex ligation-dependant probe amplification assay
119
(Salsa MLPA KIT P258-B1 SMARKB1). INI1 deletion was identified with the nine
120
exons of the gene deleted): homozygous deletion in tumoral tissue and heterozygous
121
constitutionally. The germ line deletion appeared de novo as it was not evident in
122
either parent.
123
Discussion
124
Malignant rhabdoid tumor was originally described in the kidney by Beckwith and
125
Palmer in 1978 as a variant of Wilms’ tumor characterized by its distinct morphology,
126
precocious occurrence (first year) and more aggressive behavior (1,2,3). Subsequent
127
genetic and biological data have distinguished it as a separate entity. The CNS
128
atypical teratoid/rhabdoid tumor (ATRT) is the most common extrarenal site (4,3,2)
129
with malignant extrarenal RTs (MERT) well recognised to arise in multiple sites
130
including deep axial locations, extremities, cutaneous and viscera, the liver being the
131
most common. Congenital MRT (fetal or neonatal) is more likely to be MERT than
132
renal or CNS and may present as disseminated disease with no primary site evident.
133
So called composite extrarenal rhabdoid tumors (CERTs) showing areas of rhabdoid
134
morphology within a recognizable tumor of another type (5) have been separated
135
from the MRT group as distinct molecular changes are now recognized.
136
Rhabdoid tumors were so named for their large, polygonal tumor cells likened to
137
rhabdomyoblasts, with eccentric nuclei, macronucleoli, abundant cytoplasm and
138
eosinophilic,
139
paranuclear intracellular bundles and globular aggregates of intermediate filaments
140
on electron microscopy (6). Histological variants, however, include small round or
141
spindled undifferentiated cells or gland-like areas with cells in cords, sheets or
142
dispersed in variable hyaline or myxoid stroma. Diagnosis requires excluding other
143
pediatric small round blue cell tumors, particularly desmoplastic round cell tumor,
144
rhabdomyosarcoma and Ewing’s family tumors, epithelioid or synovial sarcoma,
145
using a combination of EM, immunohistochemistry panel and genetic studies.
146
Vimentin is the most commonly expressed antigen, with EMA and cytokeratin
147
positivity also frequently observed. Less often MRTs can show staining for actin,
148
CD99, CD57, synaptophysin and S-100.
149
identification of loss of nuclear INI1 staining(1) observed in more than 80% of MRT,
150
reflecting consistently identified biallelic deletions or point mutations in the tumor
151
suppressor INI1/SMARCB1 gene (aliases INI1,hSNF5, BAF47) on chromosome
152
22q11.2 (1,9). SMARCB1 (integrase interactor 1 – INI1) is a subunit of the SWI/SNF
153
ATP-dependent
154
expression, and involved in cell cycle control, DNA repair and differentiation. INI1 is
155
thus
156
immunohistochemistry. Some 15-60% of patients harbor sporadic or inherited germ-
157
line mutations of SMARCB1 (1,10). The finding of some familial cases not linked to
158
SMARCB1, and some MRTs that do not show SMARCB1 alterations, imply
hyaline, juxtanuclear
expressed
inclusions.
chromatin-remodeling
in
all
normal
The
with
Diagnosis is further facilitated by
complex
cell
inclusions correlate
nuclei
involved
and
in
regulating
identified
easily
gene
by
159
alternative loci may be involved with SMARCA4 (another member of the SWI/SNF
160
complex) gene mutations or loss implicated in rare cases (13). Recent studies
161
indicate that diverse cell types may develop into MRT as a consequence of
162
congenital or acquired abnormalities involving the INI1/SMARCB1 gene (7).
163
Similarities between MRT and stem cells were underscored by Venneti et al (8) who
164
demonstrated that MRT expressed stem cell-associated transcription factors, which
165
may be regulated by the expression of EZH2 and the Id family of proteins.
166
INI1 represents a useful diagnostic tool, particularly in undifferentiated pediatric
167
tumors, however it is noted that other tumors may also show loss of INI1 expression
168
and INI1 mutations including renal medullary carcinomas, epithelioid sarcomas,
169
epithelioid malignant schwannomas, most choriod plexus carcinomas and a subset of
170
medulloblastomas,
171
myoepithelial carcinomas, extraskeletal myxoid chondrosarcomas and central
172
primitive neuroectodermal tumors (PNETS) (Sevenet).Hollmann) (1).
173
The rhabdoid predisposition syndrome (RPS) is associated with inherited (autosomal
174
dominant) mutations and/or deletions in the INI1/SMARCB1 gene on chromosome
175
22q11.2, rendering individuals vulnerable to a second sporadic mutation (second hit)
176
thence complete loss of expression of the nuclear protein demonstrated by lack of
177
INI1 staining by immunohistochemistry (11) and predisposition to development of
178
MRT, including multiple primaries.
179
expression and incomplete penetrance. Three multigeneration families have been
180
reported in the literature. It has been hypothesized that patients harboring a germline
181
INI1 mutation are at increased risk of MRT during a developmental window in early
182
childhood. If this does not occur then they are at increased risk of other INI1-related
183
tumors, not necessarily malignant, later in life including schwannomatosis and
epithelioid
malignant
peripheral
nerve
sheath
tumors,
INI1 germline mutations can show variable
184
meningiomas. Further, while long term survival is characteristically rare, two of four
185
RPS cousins with MRTs have been reported surviving more than 15 years, indicating
186
more information is needed to characterize genotype-phenotype relationships. Most
187
individuals with germ-line SMARCB1 alterations have acquired de novo deletions or
188
mutations as reported here. In some cases where multiple siblings but not parents
189
have demonstrated the same germline mutation, gonadal mosaicism has been
190
implicated. (12)
191
younger (5 months) than children with apparent sporadic disease (18 months) (10).
192
Malignant rhabdoid tumor may also occur in the setting of a variety of syndromes
193
including Beckwith-Wiedemann, Goldenhar, Phelan-McDermid syndromes and
194
familial schwannomatosis.
195
MRT can present as local or disseminated metastatic disease. In utero development
196
may occur, with possible tumor rupture causing severe fetal anemia (2,14). Patients
197
may have one or multiple cutaneous nodules, resembling the so-called blueberry
198
muffin baby as observed in neonatal neuroblastoma or rhabdomyosarcoma.
199
Metastases can involve skin, placenta (2 reported cases), brain, liver, lymph nodes,
200
lungs and bones (3,14,15).
201
heterogeneous in terms of age at presentation and survival. They usually occur
202
before the age of 5 years, while in neonates and fetuses, unlike children and older
203
infants, tumors more frequently affect soft tissues rather than kidneys or CNS (14).
204
Like renal MRTs, MERTs are characterized by a rapidly progressive course with less
205
than 50% of patients surviving 5 years and those with germ-line mutations have a far
206
worse prognosis (0% 2 years survival vs 48%) than other pediatric malignancies
207
(14,15). In a series of 9 infants with congenital disseminated malignant rhabdoid
208
tumor, reported by White and al in 1999, the age at presentation ranged from 33
The median age of children with MRT in the setting of RPS is
Unlike ATRT, non-CNS MERTs are more
209
weeks gestation to 3 months. Survival ranged from a few minutes to 3 months (mean
210
6 weeks). In comparing our case, the tumor was discovered postnatally and the
211
patient died on the 51th day of life, despite chemotherapy. No placental involvement
212
was observed in this case. In this family, two other healthy children have been born
213
subsequently with no germ-line SMARCB1 genetic abnormalities detected.
214
hildren were born subsequently with no germ line deletion detected.
215 216
CONCLUSION
217
Pitfalls in the diagnosis of MRT are attributed to the rarity and the morphological
218
pleomorphism and heterogeneity of this tumor.
219
valuable
220
immunohistochemical workup of pediatric tumors. Moreover, genetic investigation is
221
an important consideration for families following diagnosis of MRT because of the
222
possibility of germline mutation (35%) with further implications for prognosis and
223
development of multiple tumors. As germline mutation is most frequently de novo, the
224
family history will often be negative. Unfortunately despite progress in MRT
225
classification and diagnosis, the prognosis remains dismal, making early recognition
226
even more important.
227
where innovative therapies need to be developed.
diagnostic
tool
and
should
be
Anti-INI 1 antibody represents a systematically
included
in
The tumor represents an aggressive pediatric malignancy
228 229 230
the
References
231
1. Bourdeaut F, Freneaux P, Thuille B et Al. Hsnf5/INI1-deficient tumours and
232
rhabdoid tumours are convergent but not fully overlapping entities. J Pathol
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2007;211:323-330.
234
2. Kwon JY, Park KI, Lee KS, Yang WI, Kim YH. Prenatal detection of
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U, Kreuz M, Leuschner I, Subero JIM, Osber T, Oyen F, Vater I, Siebert R.
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Biegel J, Perlman E. Congenital Disseminated Malignant Rhabdoid Tumor: A
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276
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277 278 279 280
281 282
Legends
283
Figure 1: Voluminous mass of the left thigh with satellite nodule, covered by reddish
284
thin skin with turgescent veins.
285
Figure 2: surgical biopsy: monomorphic tumor cells with well-defined cell borders,
286
eosinophilic cytoplasm and eccentric nuclei with vesicular chromatin and central
287
prominent nucleoli. H&EX400.
288
.
289
.
290
