(i) Soft tissue tumors are diagnostically challenging due to clinical, radiological, and histological overlap. Molecular classification divides tumors into those with specific genetic alterations like translocations or mutations, and those with complex karyotypes. (ii) Recent updates include classification of additional tumor types like EWSR1-SMAD3 positive fibroblastic tumor and NTRK-rearranged spindle cell neoplasm. Dedifferentiated liposarcoma may have a worse prognosis with high-grade or rhabdomyoblastic differentiation. (iii) Emerging entities include CIC-rearranged round cell sarcoma and sarcoma with BCOR rearrangements, expanding the molecular

1. Molecular Genetics and Recent
Updates of Soft tissue tumours
DR.ARGHA BARUAH
MODERATOR:DR.SHIRAJ AHMED

2. Soft tissue tumours
• Complex ,diagnostically challenging
• Clinical,radiological,histopathological
immunohistochemical and even molecular
overlap

5. Molecular classification
Divided into two main categories-
(i) sarcomas with specific genetic alterations-
• a) reciprocal translocations resulting in oncogenic fusion
transcripts e.g. EWSR1-FLI1 in Ewing sarcoma, FUS-DDIT3 in
myxoid liposarcoma, and SS18-SSX in synovial sarcoma,
• b) specific oncogenic mutations e.g. KIT and PDGFRA
mutations in gastrointestinal stromal tumors and
(ii) sarcomas displaying multiple complex karyotypic
abnormalities with no specific pattern, including
• malignant fibrous histiocytoma (MFH / undifferentiated
sarcoma), leiomyosarcoma,and pleomorphic liposarcoma

13. ADIPOCYTIC TUMOURS

14. Atypical spindle cell/Pleomorphic
lipomatous tumour
• Median age of 54 years.
• Approximately 2/3rd occur in the limbs and limb girdles, with a
predilection for the hands and feet, and an approximately equal
distribution between superficial and deep sites.
• IHC, show variable expression of CD34, S100 protein, and desmin,
whereas MDM2 and CDK4 are generally negative (rarely, weak or
focal staining for the latter markers may be seen).
• No MDM2 amplification,loss of RB1.
• Excellent prognosis, low rate of recurrence

16. Myxoid Pleomorphic Liposarcoma
• Exceptionally rare and aggressive neoplasm
occurring in children and young adults with a
predilection for the mediastinum
• Lack both FUS/EWSR1- DDIT3 fusions (of
conventional myxoid liposarcoma) and MDM2
amplification (of well-differentiated and DDLPS)
• Clinically aggressive, with a high rate of local
recurrence and distant metastasis and poor
outcomes.

18. FIBROBLASTIC TUMOURS

19. Superficial CD34 + FIBROBLASTIC
TUMOUR:
• Low-grade neoplasm of the skin and subcutis and is rare
• Occur in middle-aged adults, with a slight male
predominance, and a predilection for the lower
extremities, followed by upper extremities, buttock, and
shoulder
• By IHC, there is strong CD34 expression , and keratins are
positive in 70% of cases.
• The prognosis in reported cases has been excellent

22. Angiofibroma of soft tissue
• Benign fibroblastic neoplasm that typically arises in the
lower extremities, often involving or adjacent to large
joints, uncommonly in the back, abdominal wall, pelvic
cavity, and breast
• IHC-variable expression of EMA and CD34
• Recurrent translocation t(5;8)(p15;q13), resulting in the
fusion of aryl hydrocarbon receptor repressor (AHRR) at
5p15 with nuclear receptor coactivator 2 (NCOA2) at 8q13
in most cases
• Rare recurrences locally and no metastatic potential

24. EWSR1-SMAD3-positive Fibroblastic
Tumor
• Benign fibroblastic neoplasm, with a wide age range, female
predilection, and distribution largely in the hands and feet, in
superficial (dermal or subcutaneous) locations
• IHC reveals diffuse ERG expression, whereas SMA and CD34 are
typically negative.
• This tumor type is defined by fusion of exon 7 of EWSR1 with exon
5 of SMAD3; SMAD3 is an important signal transducer in the TGF-
β/SMAD pathway, involved in extracellular matrix synthesis by
fibroblasts.
• This benign neoplasm may recur locally following incomplete
excision

26. EPITHELIOID INFLAMMATORY
MYOFIBROBLASTIC SARCOMA
• Located in deep visceral locations such as GIT
• ALK rearrangements are common
• IHC-Perinuclear halo membranous reaction
• Harbor RANB2-ALK rearrangement

28. Inflammatory leiomyosarcoma
• Rare low-grade sarcoma and previously included as a
variant of leiomyosarcoma
• Young adults and occurs in the soft tissues of the
extremities and trunk
• NF1 gene mutation
• Prognosis appears to be favorable, in contrast to the
high rate of metastasis and often poor prognosis of
conventional leiomyosarcoma.

30. EBV RELATED SMOOTH MUSCLE
TUMOUR
• Occur in a setting of immunosupression-
AIDS,Transplant patients,Immunodeficiency
• Associated with EBV infection
• Post transplant most commonly involves liver,HIV
associated –CNS
• IHC-Diffuse positive for SMA,h-caldesmon,EBER
,focal desmin

32. NTRK-rearranged Spindle Cell
Neoplasm
• Monotonous spindle cell morphology, infiltrative growth, and
coexpression of CD34 and S100 protein by IHC
• This category includes the recently described lipofibromatosis like neural
tumor and tumors that resemble peripheral nerve sheath tumors
• IHC-reactive with a panTRK monoclonal antibody
• Tumors retain H3K27me3 (in contrast to many MPNSTs)
• Often have NTRK1 fusion,some with RAF1 or BRAF fusion
• Therapeutically targetable with NTRK oncogenic receptor tyrosine kinase

35. NEW ADDITIONS TO PREVIOUS ENTITIES

36. MPNST:

39. Solitary fibrous tumour

42. Malignant Melanotic Nerve Sheath
Tumor
• This tumor type had been known as melanotic
schwannoma.
• These rare lesions are comprised of Schwann cells with
melanocytic differentiation and are frequently
associated with Carney complex, an autosomal
dominant tumor predisposition syndrome.
• Majority harbor biallelic inactivating mutations in
PRKAR1A on 17q24, which encodes a tumor
suppressor.

44. • By IHC, S100 protein, SOX10, and melanocytic markers including
HMB45, melan A, and tyrosinase are positive; these
immunophenotypic findings are indistinguishable from melanoma.
• PRKAR1A expression is often lost, in sporadic tumors and those
from patients with Carney complex
• Although in the past this tumor type was thought to be generally
benign with occasional cases pursuing an aggressive clinical course,
recent evidence has shown a high rate of malignant behavior,
including a large series of 40 cases with local recurrences in 35%
and metastases in 44% of patients

45. Dedifferentiated Liposarcoma
• DDLPS shares amplification of MDM2 and CDK4 with ALT/WDLPS, with
additional abnormalities more frequently found in DDLPS than in
ALT/WDLPS, including amplification of JUN, TERT, CPM, and MAP3K5, and
deletion of ATRX, ATM, CHEK1, ABTB16, PPP2R1B, and EI24
• Fifth edition includes updated information showing an adverse prognostic
impact associated with high-grade tumors based on the FNCLCC grading
system. Recent studies have indicated that myogenic, particularly
rhabdomyoblastic differentiation is associated with a worse outcome in
DDLPS

46. Epithelioid hemangioma:
• Benign vascular neoplasm
• Occurs most commonly in young to middle-aged adults,
with a predilection for the head and neck region.
• Other sites include the distal extremities, as well as rarely
the oral mucosa, bone, or penis.
• By IHC, the lesional cells are positive for vascular markers
(CD31 and ERG), as well as FOSB.

48. EHE With YAP1-TFE3
• EHE is a malignant vascular neoplasm composed
of epithelioid endothelial cells, distinct from
epithelioid angiosarcoma.
• Although >90% of cases harbor the translocation
t(1;3)(p36;q23-25), resulting in a WWTR1-
CAMTA1 gene fusion, a small subset of tumors
instead have a novel YAP1-TFE3 fusion; this
subset of tumors is reported to occur in younger
patients and shows distinctive histology

50. Pseudomyogenic
Hemangioendothelioma
• It is an endothelial neoplasm of intermediate biologic
potential that often presents as multiple discontiguous
nodules in different tissue planes, typically involving the
limbs, especially the lower extremities
• Most patients present with skin lesions, roughly half have
lesions within skeletal muscles, and a minority have bone
lesions. This tumor type has a marked male predominance,
a peak incidence in young adults, and is rare in adults older
than 50 years.
• Balanced translocation t(7;19)(q22;q13), resulting in a
SERPINE1- FOSB fusion.

56. Updates in Round cell Sarcoma:

57. Ewing’s sarcoma

61. Round cell sarcoma with EWSR1-non ETS fusion

64. CIC rearranged round cell Sarcoma:

67. Sarcoma with BCOR rearrangements:

70. Conclusion:
• Despite the rapidly emerging novel molecular
alterations that have been identified across a broad
array of tumor types, histologic features remain crucial
for accurate subclassification.
• Molecular testing should be used as validation of
morphological diagnosis,corroborated with IHC and
clinical information
• Advances in molecular pathology promises an exciting
future of refined personalized care of patients with
soft-tissue tumors.