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

André 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 α (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.