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Original articles

Anerysmal bone cyst and Nodular fasciitis have been traditionally seen as completely distinct
clinicopathologic entities, especially considering their distinct anatomical location. Although ABC is
primarily a skeletal lesion, NF is a soft tissue neoplasm. However, new evidence suggests that they may be
more closely related than previously thought.

USP6-induced neoplasms: the biologic spectrum of aneurysmal bone cyst
and nodular fasciitis
Pages 1-11
Andr M. Oliveira, Margaret M. Chou
USP6 (also known as TRE17) is a ubiquitin-specific protease that was identified as an oncogene in transfection
experiments with Ewing sarcoma DNA 2 decades ago. Until recently, little was known about USP6 function and
mechanisms of oncogenic activation. The identification of USP6 fusion genes in aneurysmal bone cyst (ABC) and,
more recently, in nodular fasciitis led to a better understanding of the pathogenesis of these lesions. Furthermore, the
detection of USP6 genomic rearrangements or USP6 fusion genes may be used as a diagnostic tool for these
lesions. In this review, we discuss the clinicopathologic features, molecular pathology, and pathogenesis of ABC and
nodular fasciitis. We also discuss the possible line of differentiation of ABC and its relationship to nodular fasciitis and
other lesions.
Original articles
PDGFRA-mutated GISTs display the same chromosomal aberrations as KIT-mutated GISTs, although they have a
lower degree of chromosomal instability in line with their generally favorable outcome.
Chromosomal aberrations in primary PDGFRA-mutated gastrointestinal
stromal tumors
Pages 85-97
Inga-Marie Schaefer, Christian Delfs, Silke Cameron, Bastian Gunawan, Abbas
Agaimy, B. Michael Ghadimi, Florian Haller
Approximately 15% of gastrointestinal stromal tumors (GISTs) harbor mutations in the platelet-derived growth factor
receptor (PDGFRA) gene. Chromosomal aberrations play a crucial role in tumor progression and correlate with
clinical behavior. Imbalances, particularly in PDGFRA-mutated GISTs, have not yet been evaluated in larger series.
We analyzed 53 PDGFRA-mutated GISTs (including 2 with corresponding metastases) for chromosomal imbalances
by conventional comparative genomic hybridization and compared them with a historical collective of 122 KIT-
mutated GISTs. PDGFRA exon 18 mutations (91% of cases) and exon 12 mutations (9% of cases) correlated
significantly with gastric and intestinal sites, respectively. The most common aberrations were identical to those found
in KIT-mutated GISTs, with 14q in 70%, 1p in 28%, and 22q in 17% of cases. Overall, there were significantly
fewer chromosomal aberrations compared with KIT-mutated GISTs, with a mean of 2.8 (0.6 gains, 2.1 losses)
aberrations per tumor. There was a statistically significant association of more than 5 chromosomal imbalances with
intermediate/high-risk categories. Regarding specific chromosomal aberrations, 9p, 13q, and 22q correlated with
Human Pathology
Volume 45, Issue 1, Pages 1-
190 (January 2014)

Bone and soft tissue tumor articles
intermediate/high risk, and 1p and +8q with poorer survival, although progression occurred in only 2 cases.
Altogether, PDGFRA-mutated GISTs display the same chromosomal aberrations as KIT-mutated GISTs, although
they have a lower degree of chromosomal instability in line with their generally favorable outcome.
Original articles
In a defined subset of bone and soft tissue tumors, including benign tumors, Akt was frequently overexpressed and
activated, and AKT1/2 copy number was increased.

Significance of Akt activation and AKT gene increases in soft tissue tumors
Pages 127-136
Yoh Dobashi, Eiichi Sato, Yoshinao Oda, Johji Inazawa, Akishi Ooi
To clarify the aberrations of AKT genes, their protein products and clinicopathologic significance in bone and soft
tissue tumors, expression profiles of total Akt, its isoforms and activated Akt, and increases in copy number of
AKT1/AKT2 genes were examined. Immunohistochemical analysis in 77 cases revealed overexpression of total Akt,
Akt1, Akt2, and phosphorylated Akt in 84.4%, 67.5%, 72.7%, and 71.4%, respectively. Positive results were also
observed in benign lesions but at a lower frequency. Overexpression of Akt1 was more frequent than that of Akt2 in
well-differentiated liposarcoma (6/7 versus 3/7 cases) and schwannoma (4/4 versus 1/4 cases), whereas Akt2
overexpression and Akt activation were more frequent than Akt1 overexpression in malignant nerve sheath (3/4 and
4/4, respectively, versus 2/4 cases) and muscular tumors (8/9 and 8/9 versus 4/9 cases). By fluorescence in situ
hybridization analysis, increase of gene copy number was observed in 13.3% for AKT1 and in 25.0% for AKT2 due to
polysomy of chromosome 14 or 19, respectively, but not gene amplification. One case of schwannoma exhibited
polysomy of both chromosomes 14 and 19. Akt activation was correlated with total Akt cytoplasmic localization (P =
.0031) and subsequent metastasis (P = .0454). Moreover, AKT2 gene increase correlated with tumor size (P = .0352)
and metastasis (P = .0344). In conclusion, in a defined subset of bone and soft tissue tumors, including benign
tumors, Akt was frequently overexpressed and activated, and AKT1/2 copy number was increased. Because
abnormality of Akt/AKT correlated with clinicopathologic profiles, novel therapies targeting isoform-specific Akts may
be useful for these particular types of tumors.

Original articles
Their postulate an invasion-independent mechanism for entry into circulation, in which cancer cells are shed into
vessels, while being completely enveloped by endothelial cells, and are subsequently entrapped at recipient organs.

Histological analysis suggests an invasion-independent metastatic
mechanism in alveolar soft part sarcoma
Pages 137-142
Nokitaka Setsu, Akihiko Yoshida, Fumiaki Takahashi, Hirokazu Chuman, Ryoji
Kushima
In this study, we histologically analyzed 32 surgically resected ASPSs, with particular attention to the mode of
vascular involvement. Among 188 instances of unequivocal vascular involvement, 184 (98%) were in the form of
variously sized cohesive clusters that were completely enveloped by endothelial cells, confirmed by CD31
immunostaining. Discohesive intravascular tumor cells without endothelial wrapping were rare (2%). The clinical
relevance of vascular involvement was supported by survival analysis where the average number of vascular
involvements per slide was an independent risk factor for shorter progression-free survival. Our findings suggest that
ASPSs do not actively break through the vascular walls to initiate the metastatic process. They instead suggest that
ASPSs almost exclusively follow the recently postulated invasion-independent mechanism for entry into circulation,
in which cancer cells are shed into vessels, while being completely enveloped by endothelial cells, and are
subsequently entrapped at recipient organs. Because the latter mechanism is reportedly dependent on tumor
angiogenesis and vascular remodeling, our data provide a morphological rationale for the use of anti-angiogenic
therapy to treat ASPSs.