Evaluation of Bcl-2, Bcl-x and Cleaved Caspase-3 in Malignant Peripheral Nerve Sheath Tumors and Neurofibromas

CUNHA, KARIN S.; CARUSO, ANABELA C.; FARIA, PAULO A.; SILVA, LICíNIO E. DA; FONSECA, ELIENE C. DA; GELLER, MAURO; MOURA-NETO, RODRIGO S. DE; LOPES, VÂNIA S.

doi:10.1590/0001-3765201320120026

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Health Sciences • An. Acad. Bras. Ciênc. 85 (04) • 2013 • https://doi.org/10.1590/0001-3765201320120026 copy

Evaluation of Bcl-2, Bcl-x and Cleaved Caspase-3 in Malignant Peripheral Nerve Sheath Tumors and Neurofibromas

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

AIMS

To study the expression of Bcl-2, Bcl-x, as well the presence of cleaved caspase-3 in neurofibromas and malignant peripheral nerve sheath tumors. The expression of Bcl-2 and Bcl-x and the presence of cleaved caspase 3 were compared to clinicopathological features of malignant peripheral nerve sheath tumors and their impact on survival rates were also investigated.

MATERIALS AND METHODS

The evaluation of Bcl-2, Bcl-x and cleaved caspase-3 was performed by immunohistochemistry using tissue microarrays in 28 malignant peripheral nerve sheath tumors and 38 neurofibromas. Immunoquantification was performed by computerized digital image analysis.

CONCLUSIONS

Apoptosis is altered in neurofibromas and mainly in malignant peripheral nerve sheath tumors. High levels of cleaved caspase-3 are more common in tumors with more aggressive histological features and it is associated with lower disease free survival of patients with malignant peripheral nerve sheath tumors.

apoptosis regulatory proteins; malignant peripheral nervous sheath tumors; neurofibroma; Neurofibromatosis 1

Patient	Age at diagnosis	Sex	Race	NF1	Site	Free surgical margins	Treatment	Local recurrence	Metastasis	Site of metastasis	Death	Overall survival (months)	Disease-free survival (months)
1	27	F	—	Yes	Lumbar	No	Resection	Yes	No		No	21.60	18.23
2	44	F	W	No	Left elbow	No	Resection + Rxt	No	No		No	13.60	13.60
3	29	F	—	Yes	Right flank	No	Resection + Rxt	No	No		Yes	12.47	12.47
4	23	F	B	Yes	Pelvis	No	Resection	No	No		Yes	4.87	4.87
5	28	F	W	Yes	Right flank	Yes	Resection	No	No		No	76.13	76.13
6	32	F	W	No	Left lower limb	Yes	Resection	No	Yes	Lung	No	12.10	.00^* * these patients presented metastasis at the moment of the tumor diagnosis.
7	34	F	W	No	Right lower limb	Yes	Resection	No	No		No	44.77	44.77
8	40	F	W	No	Breast	No	Resection + Rxt	No	No		No	96.90	96.90
9	20	F	—	Yes	Lumbar	—	Rxt	No	No		Yes	1.83	1.83
10	53	F	B	Yes	Left shoulder	Yes	Resection	No	No		Yes	10.87	10.87
11	21	F	W	Yes	Left lower limb	Yes	Resection	No	No		No	67.50	67.50
12	23	M	W	Yes	Left lower limb	—	Ct	No	Yes	Lung	Yes	2.73	.00^* * these patients presented metastasis at the moment of the tumor diagnosis.
13	42	F	W	No	Pelvis	No	Resection + Rxt	No	Yes	Liver and pancreas	Yes	11.30	9.60
14	68	M	W	No	Right upper limb	—	Resection + Rxt	Yes	No		No	9.50	7.00
15	19	M	W	No	Right upper limb	—	Rxt	No	Yes	Lung	No	16.10	.00^* * these patients presented metastasis at the moment of the tumor diagnosis.
16	23	F	W	Yes	Sacrum and spine	—	Rxt	No	Yes	Lung	Yes	7.73	7.67
17	34	F	B	Yes	Abdomen	No	Resection	Yes	No		No	10.10	5.43
18	60	F	B	Yes	Right lower limb	Yes	Resection	No	Yes	Lung	No	40.80	22.83
19	40	F	B	No	Thorax	Yes	Resection + Rxt	No	No		No	61.10	61.10
20	78	F	W	No	Face sinus	No	Resection + Rxt	Yes	No		Yes	77.90	50.20
21	24	M	W	Yes	Right upper limb	—	Biopsy + Ct	No	Yes	Lung	Yes	12.80	6.60
22	45	M	B	Yes	Abdomen	—	Resection	Yes	Yes	Lung	Yes	14.70	13.07
23	63	M	B	Yes	Supraclavicular	Yes	Resection	No	No		Yes	60.30	60.30
24	85	M	W	No	Head (temporal)	Yes	Resection	No	No		Yes	20.20	20.20
25	72	F	W	No	Left lower limb	Yes	Resection + Rxt	No	Yes	Lung	Yes	42.00	39.93
26	80	F	W	No	Right foot	Yes	Resection	Yes	No		Yes	13.40	8.10
27	30	F	B	No	Thorax	Yes	Resection + Rxt	No	Yes	Bone	No	35.70	4.67
28	41	M	B	Yes	Right lower limb	—	Rxt	No	Yes	Cervical region	Yes	7.20	6.97

Case number	Size (cm)	Grade	Presence of heterologous differentiation	Necrosis	Mitotic index (mitotic figures in 10 high-power fields)^* * these patients presented metastasis at the moment of the tumor diagnosis.
1	4.6	high	no	no	7.0 (sd=2.0)
2	17.0	high	rabdomiosarcomatous areas	yes	9.3 (sd=1.5)
3	15.0	high	no	yes	5.3 (sd=1.2)
4	21.0	high	rabdomiosarcomatous areas	yes	17.0 (sd=2.0)
5	7.0	low	chondrosarcomatous areas	no	3.7 (sd=1.5)
6	21.0	high	no	yes	7.0 (sd=3.5)
7	10.0	high	no	no	9.0 (sd=2.0)
8	16.0	low	no	no	0.3 (sd=0.6)
9	—	high	no	no	18.0 (sd= 4.0)
10	28.0	high	no	yes	19.0 (sd=1.0)
11	17.0	high	no	yes	13.0 (sd=2.6)
12	—	high	no	yes	10.7 (sd=1.5)
13	13.0	high	chondrosarcomatous areas	yes	10.3 (sd=5.7)
14	—	high	no	no	10.3 (sd=4.0)
15	—	low	epithelioid	no	3.0 (sd=0.0)
16	—	high	no	yes	7.0 (sd=2.6)
17	13.0	high	epithelioid	yes	7.3 (sd=1.2)
18	12.0	high	chondrosarcomatous area	no	6.0 (sd=2.0)
19	6.0	low	no	no	2.3 (sd=1.5)
20	—	low	no	no	3.0 (sd=1.0)
21	—	high	no	yes	7.0 (sd=2.0)
22	23.0	high	no	yes	13.3 (sd=3.2)
23	5.0	high	chondroma area	no	7.0 (sd=2.0)
24	10.0	low	no	no	3.7 (sd=1.5)
25	13.0	low	no	no	3.7 (sd=1.2)
26	3.0	high	no	no	6.7 (sd=0.6)
27	11.0	high	no	no	13.0 (sd=3.0)
28	—	high	no	yes	8.0 (sd=1.0)

Neurofibromas
Antibody	Group	% positive cases (n)	Mean of PI	Standard Deviation	Mean of PI	IP min - max	IQ Range
Anti-Bcl-2	Neurofibromas
	Plexiform neurofibromas	18.8% (n=3)	0.0299	0.0266	0.0285	0.0000 - 0.0571	—
	Non-plexiform neurofibromas	42.9% (n=9)	0.0789	0.1081	0.0355	0.0000 - 0.3583	0.0570
Anti-Bcl-x	Neurofibromas	43.2% (n=16)	0.0043	0.0055	0.0019	0.0000 - 0.0171	0.0091
	Plexiform neurofibromas	37.5% (n=6)	0.0046	0.0050	0.0044	0.0000 - 0.0094	0.0092
	Non-plexiform neurofibromas	47.6% (n=10)	0.0041	0.0061	0.0019	0.0000 - 0.0171	0.0064
Anti-CC3	Neurofibromas	100% (n=28)	0.0044	0.0486	0.0275	0.0000 - 0.0240	0.0545
	Plexiform neurofibromas	100% (n=28)	0.0347	0.0038	0.0025	0.0000 - 0.0130	0.0036
	Non-plexiform neurofibromas	100% (n=28)	0.0050	0.0055	0.0027	0.0004 - 0.0240	0.0070
Malignant Peripheral Nerve Sheath Tumors (MPNSTs)
Antibody	Group	% of positive cases (n)	Mean of PI	Standard Deviation	Mean of PI	IP min - max	IQ Range
Anti-Bcl-2	MPNST	78,6% (n=22)	0.4684	0.0543	0.2500	0.0000 - 0.2176	0.0724
Anti-Bcl-x	MPNST	75.% (n=21)	0.0347	0.0526	0.0054	0.0000 - 0.2036	0.0533
Anti-CC3	MPNST	100.0% (n=28)	0.1672	0.1352	0.0990	0.0324 - 0.5346	0.1900

Variables	Total SV (months)	Total SV (p log-rank)	Disease-free SV (months)	Disease-free SV (p log-rank)
NF1
Yes	31.6	0.044	31.4	0.959
No	59.9		41.6
Histological Grade
High	31.7	0.045	23.94	0.095
Low	68.6		65.28
Necrosis
Yes	19.1	0.003	23.95	0.138
No	62.4		50.23
Epithelioid Variant
Yes	^* * these patients presented metastasis at the moment of the tumor diagnosis.	^* * these patients presented metastasis at the moment of the tumor diagnosis.	6.21	0.036
No	44.49		43.98
Bcl-2 protein expression
Positive	43.2	0.922	26.1	0.679
Negative	46.1		47.4
Low PI	50.0	0.811	42.5	0.867
High PI	34.3		36.0
Bcl-x protein expression
Positive	46.7	0.916	29.5	0.579
Negative	47.2		49.2
Low PI	46.9	0.803	54.7	0.312
High PI	41.0		27.3
CC3 protein expression
Nuclear	54.2		42.5
Nuclear and cytoplasmic	37.6	0.301	36.0	0.867
Low PI	55.3		56.8
High PI	14.6	0.024	6,9	< 0.00

Co-variables		p-value	Exp(B)	95,0% CI for Exp(B)
Co-variables		p-value	Exp(B)	Lower	Upper
Overall Survival
Step 1	Neurofibromatosis type 1	0.448	0.591	0.152	2.301
	Histological Grade	0.831	1.248	0.164	9.529
	Necrosis	0.343	0.468	0.097	2.250
	High PI of CC3	0.469	1.657	0.423	6.497
	Mitotic Index	0.525	1.054	0.895	1.242
Step 2	Presence of NF1	0.417	0.573	0.149	2.196
	Necrosis	0.318	0.451	0.095	2.152
	High PI of CC3	0.472	1.655	0.419	6.543
	Mitotic Index	0.438	1.062	0.913	1.235
Step 3	Presence of NF1	0.465	0.609	0.161	2.301
	Necrosis	0.255	0.413	0.090	1.897
	Mitotic Index	0.289	1.083	0.935	1.254
Step 4	Necrosis	0.143	0.343	0.082	1.434
Step 4		0.226	1.093	0.947	1.261
Step 5	Necrosis	0.007	0.199	0.062	0.639
Disease Free Survival
Step 1	Epithelioid variant	0.705	0.801	0.254	2.528
Step 1	High PI of CC3	0.001	7.727	2.194	27.208
Step 2	High PI of CC3	0.002	7.707	2.183	27.210

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[1] Karin Soares Gonçalves Cunha E-mail: karingcunha@gmail.com