Pitfalls in the diagnosis of soft tissue tumors in childhood - Recent advances topic

1. PITFALLS IN THE DIAGNOSIS OF
SOFT TISSUE TUMOURS OF
CHILDHOOD
Dr.E Kiran Kumar
Associate Professor of Pathology
MIMS, Vizianagaram

2. • Tumours in children and adolescents differ
from that in adults in many ways
Most malignant tumours in adults are
Carcinomas, and classifed acc to site to origin.
But Childhood tumors are histologically diverse.
The same tumor can occur at many sites.
There are 12 main diagnostic groups, with
variation in the age distribution.

3. • The outcome for most types of childhood
tumors has dramatically improved over the
last 20 yrs, unlike the small improvement in
common adult cancers.
• The most important long-term serious side
effects of therapy in childhood tumors are –
growth failure, reduced fertility, major organ
damage and significant increase in risk of
secondary cancer in adulthood.

4. • Hence, more attention is needed to minimise the
toxic effects of therapy and also to prevent the
misdiagnosis in pediatric oncology.
• The potential pitfalls encountered in soft tissue
tumor pathology is worth knowing, to avoid
misdiagnosis.
• Due to significant overlap in the histology and
immunoprofile of many tumors, cytogenetic or
molecular genetic confirmation of the
characteristic translocations is very valuable.

5. • FISH & RT-PCR assays can be reliably performed
on paraffin-embedded tissue. Tumor cells can
also be retrieved from fixed tissue by Laser
capture microdissection, for RT-PCR analysis, for
the signature translocations.
• Soft tissue sarcomas constitute 5-8% of childhood
tumors. Diagnostic challenges are due the
infrequent occurrence and histological diversity.

7. Potential pitfalls
1) Misclassification of specific sarcomas :
Diagnosis of the precise type of sarcoma has major
therapeutic significance. Pediatric STSs are classifed as
– RMS, NRSTS and USTS (Undifftd STS).
Rhabdomyosarcoma (RMS) – It is the most common
sarcoma (50-60%) of the STS in childhood. Primitive
mesenchymal tumor.2/3rd of cases diagnosed before
10 yrs age.
Typing into embryonal and alveolar RMS is of extreme
importance, since alveolar RMS has adverse outcome.

8. The intl classfn of RMS used currently places RMS
into 3 prognostic groups –
The superior prognostic group ,includes the
botryoid and spindle-cell variants of embryonal
RMS.
Embryonal RMS-NOS – Intermediate group
Alveolar RMS – Poor prognosis.
Typing is not recommended on poor quality or
small sample – in such cases, the term ‘RMS-NOS’
should be used.

9. • Mixed RMS,composed of both embryonal and alveolar
RMS, is classified as alveolar RMS.
• Embryonal RMS is a spindle-cell tumor( to be difftd from SS,
MPNST, FS), while alveolar RMS is round cell tumor ( to be
difftd from EFT, DRCT, MRT, NHL/ALL, Neuroblastoma,
blastemal component of WT), by using difft sets of
antibodies in IHC, whenever there is overlap in histology.
• More than 95% of RMSs show expression of myogenic TFs,
myogenin/myf4 & myoD1/myf3( To diffte from non RMS
lesions)

10. The extent and intensity of staining of Myogenin
and myoD1 is used as an aid in distinguishing
between the two main types of RMS.
Most alveolar RMS display extensive(>50%) nuclear
staining for Myogenin, whereas embryonal RMS
show a focal pattern of staining.
Myogenin expression is reliable in separating RMS
from MPNST. Also to exclude Nodular fasciitis,
inflammatory myofibroblastic tumor, smooth
muscle and neural tumors.

11. Myogenin expression should be interpreted with
caution, since focal immunoreactivity is also seen
in blastemal component of WT, SS & Infantile FS.
Myogenin positivity also seen in some benign nuclei
in nodes and in entrapped, non-neoplastic or
regenerating skeletal muscle fibres ( along with
myoD1 positivity) – A potential pitfall, while
assessing immunoreactivity at the infiltrative
edges of round or spindle cell tumor.

12. Several other immunocytochemical markers are
identified in RMS – Can lead to diagnostic
errors, if interpreted, out of context of the
clinical and histological findings. E.g – desmin,
CD99, anaplastic lymphoma kinase, CD56,
SMA, CK, S100 &NF protein.

14. EMBRYONAL RMS
They show cytological characteristics that range
from primitive stellate or fusiform mesenchymal
cells to well-differentiated forms with extensive
rhabdomyoblastic diffn.
Hypocellular areas around blood vessels, alternate
with mucoid matrix-rich hypocellular areas.
Adequate sampling is crucial, since wide variety of
myxoid tumors can mimic hypocellular embryonal
RMS.

15. ERMS

17. SPINDLE CELL VARIANT OF ERMS
• Arises in the paratesticular & head/neck
regions. It has cells resembling smooth muscle
cells, arranged in intersecting fascicles. May
display BFH / NF-like pattern.
• May be mistaken for Leiomyosarcoma, and
differentiated from it by Positive Myogenin &
Negative h-caldesmon immunoprofile.

18. ERMS – spindle cell variant

19. ERMS-spindle cell variant

20. BOTYROID VARIANT OF ERMS
• Arises in the hollow cavities of GU, biliary,
auditory and upper aerodigestive tract.
• Definite diagnosis requires the presence of
subepithelial cellular, ‘cambium layer’ of
neoplastic rhabdomyoblasts.
• Its endoscopic finding of grape-like or
polypoid appearance, can be mimicked by
fetal rhabdomyoma & inflammatory
myofibroblastic tumor(IMT).

21. Botyroid ERMS

22. • Fetal rhabdomyoma, also overlaps with E-RMS
in – age at diagnosis, location & histology.
Head/neck are the common site for both. It
can be distinguished from E-RMS by an
absence of cellular pleomorphism.
• Submucosal tumors are differentiated from
botyroid variant of ERMS by the absence of
cambium layer.

23. Fetal rhabdomyoma

24. Fetal rhabdomyoma – plump pink cells

26. Inflamm myofibroblastic tumor(IMT)
• Overdiagnosed as ERMS, due to similarity in gross
appearance & infiltrative growth pattern.
• Also the myofibroblastic/fibroblastic cells may
show high mitotic count, moderate atypia &
vascular bulging.
May show desmin and ERMS may show ALK
positivity, causing further confusion.
Distinguished from ERMS by a mixture of three
growth patterns, absence of atypical mitotic
figures and Myogenin expression

27. IMT

28. ALVEOLAR RMS
• Defined by the cytological appearance of round
cells with frequent mitosis, hyperchromatic
nuclei, coarse chromatin pattern & distinct
smooth nuclear membrane.
• Classic variant – anastomosing fibrous septa,
which delineate cell aggregates.
• Solid variant – Paucity of fibrous septa.
Reticulin stain is helpful, as it encircles the cell
aggregates.
Even a single focus of alveolar morphology is
sufficient to type it as ARMS.

29. ARMS

30. • ANAPLASTIC VARIANT OF RMS : Has a poor prognosis.
Shows large hyperchromatic nuclei and multipolar
mitotic figures. More common in ERMS.
• Sclerosing matrix-rich subtype of RMS – Usually in
head/neck region.
Difficulties in diagnosis are – abundant stroma obscures
the smaller component of small, blue, tumor cells,
causing microalveolar architectures, resembling
angiosarcoma or carcinoma.
• MyoD1 strong diffuse positivity of alveolar
component and and strong Myogenin positivity of
embryonal component is helpful in diagnosis.

31. Anaplastic RMS

32. Sclerosing RMS

33. RMS-strong diffuse desmin positivity

35. Pediatric NonRMS STS
Ewings sarcoma family of tumors(ESFT) : 2nd
common sarcoma in childhood. Usually in chest
wall, paraspinal tissues and abdominal wall.
A range of appearances are seen, depending on the
degree of neural differentiation.
ES represents undifftd end of the spectrum & PNET
shows varying degrees of neural diffn.
A large number of histological variants of ES are
present, like adamantinoma-like, sclerosing-type
and spindle-cell type - Thereby creating a
potential diagnostic trap.

36. EWINGS SARCOMA

38. EWINGS SARCOMA

39. EWING’S -PAS positivity

40. • CD99 &FLI-1, seen in 90% of these tumors, but not
specific for EFT. Hence other antibodies also should be
used to exclude hematolymphoid, neuroblastic and
myogenic tumors.
• Lymphoblastic lymphoma is notorious for its mimicry
of EFT, since it displays the uniform strong
membranous reactivity of CD99 and nuclear reactivity
of FLI-1.
Another prob is, they can also be negative for CD45(LCA).
• So a large panel of antibodies are reqd for its diffl
diagnosis.

41. ALL-FLI1 positivity

42. ALL- CD99 positivity

44. Desmoplastic round cell tumor (DRCT)
• Highly aggressive, well-defined entity, mainly of
young adults, and also in children.
• Displays striking diversity in location, and so, in
clinical presentation.
• Has wide histological spectrum, with several
morphological variants and polyphenotypic
immunoreactivity.
• In difficult cases, confirmation of the specific
chromosomal rearrangement and chimeric
transcript is done by FISH & RT-PCR.

45. DRCT

46. DSRCT- CK20 positivity

47. DSRCT- CD56 positivity

48. DSRCT- MAP2 POSITIVITY

49. DSRCT-DESMIN positivity

51. MALIGNANT RHABDOID TUMOR(MRT)
• Very aggressive neoplasm of infancy and childhood,
with tendency for wide spread metastasis. Difft
locations are – Renal, CNS, etc.
• Hallmark ‘ rhabdoid cell’ has large, round or oval
nuclei, with distinct central eosinophilic nucleoli &
abundant cytoplasm, with sometimes, paranuclear
cytoplasmic globules.
• Typical arrangement – Patternless sheets or cords.
• Variety of morphological patterns can occur. Complex
immunophenotype is present.
• Most specific antibody is INI1/BAF1, to differentiate
from other similar appearing tumors.

52. MRT

53. MRT - lung

55. ADULT TYPE NRSTS
• Heterogenous group of tumors, and includes the
entities, usually seen in adults.
• Synovial sarcoma(SS) : In extremitis & also in
visceral sites like mediastinum.MPNST is the most
impt tumor in the D/D of biphasic SS, since it also
shows glandular diffn.
• A characteristic feature of MPNST is the presence
of intestinal-type epith diffn with goblet-cells and
microvilli in glands, not seen in SS.

56. • The monophasic spindle-cell type of SS should be difftd
from MPNST & fibrosarcoma, which can be v.difficult.
• Epith component and foci of calcification are more
common in SS than in fibrosarcoma. CK/EMA positivity in
both the spindle and epith cells is the most reliable
indicator of SS, in this context.
• Poorly difftd variant of SS has to be difftd from
SRCTs/MPNST.
• Myxoid variant of SS has to be difftd from ERMS.
• HPCmatous variant of SS has to be difftd from Infantile HPC.
• Specific translocation in SS is t(X;18), which has to be
demonstrated.

57. Synovial sarcoma

58. Synovial sarcoma - biphasic

59. MPNST
• An impt tumor to consider in the D/D of pediatric
MPNST is – plexiform(multinodular) cellular
schwannoma, which is a rare type of peripheral
nerve sheath tumor, mistaken as malignancy, due
to its rapid growth & locally aggressive behaviour.
• Plexiform schwannomas occur most commonly in
the first decade, No a/w NF1, superficial location,
in subcutis of extremities, uniform positivity for
S100 and no p53 positivity.
• E/M shows uniform popln of wd schwann cells.

60. MPNST- spindle cells, storiform,
glandular, neuroendocrine

61. PLEXIFORM SCHWANNOMA –
discontiguous encapsulated nodules,
with typical schwannoma pattern

62. PLEXIFORM SCHWANNOMA

63. SARCOMAS MISDIAGNOSED AS
BENIGN LESIONS
• Myxoid tumors are the most vulnerable group, for
misdiagnosis in pediatric soft tissue tumors.
• MYXOFIBROSARCOMA: It is the malignant
myofibroblastic tumor, and rare in children.
Arises in bone/soft tissue, mostly in head/neck region.
Metastasis can occur after a very long period of
primary occurrence.
Infiltrative pattern of spindle cells, in a herring-bone
pattern, in a collagenous background. Low to high
grade cytomorphology. Just like in ERMS, foci of low
cellularity may be misleading to know the grade.

64. MYXOFIBROSARCOMA

65. MYXOFIBROSARCOMA

66. MYXOFIBROSARCOMA

67. Low grade Fibromyxoid
sarcoma(LGFMS)
Along with the entity, ‘Hyalinising spindle cell
tumor with giant rosettes’(HSCTWGR) – Both are
intermediate-grade tumors, of the same entity.
Have a common translocation, t(7;16)(q34;p11).
Present as slow growing deep soft tissue mass,
commonly in shoulder/extremity.
Late metastasis is impt feature.
Mixture of fibrous/myxoid tissue; swirling pattern;
Impt feature is arcades of curvilinear blood
vessels.

68. • LGFMS shows a bland appearance due to low
cellularity, infrequent mitosis & absence of nuclear
pleomorphism; well-circumscribed borders .
Hence, deceptively appear benign due to resemblance to
benign tumors like nodular fascitis / benign nerve
sheath tumor.
• Lack of awareness of LGFMS and its rarity contribute to
its misdiagnosis.
• Deep location and size(9-10cms) are pointers towards
high-grade sarcoma;
• Also chimeric FUS/CREB3L2 gene & its transcripts
detected by RT-PCR.

69. LGFMS

70. LGFMS

71. HSCTWGR – large confluent collagen
rosettes with intervening spindle cells

72. HSCTWGR

73. NON STTs MISDIAGNOSED AS STS
• JUVENILE XANTHOGRANULOMA(JXG): Most common non-
Langerhan’s histiocytic disorder.
• Occurs mostly as solitary/multiple skin lesions in
head/neck; also in subcut/parenchymal organs.
• Deep JXG is a benign self-limited lesion.
• Lipidised & non-lipidised, multinucleated Touton cells &
inflam cells.
• Difficulty in diagnosis is, when it is located in deep soft
tissues/skeletal muscle; where they are poorly
circumscribed, grow rapidly, and mimic a sarcoma.
• Hence, JXG should be kept in mind, in infants & children,
with a histiocytic lesion in soft tissues. CD68/FXIIa is
helpful.

74. JXG

75. JXG

76. HEMATOLYMPHOID MALIGNANCIES
• Extranodal non-Hodgkin’s lymphomas are
more common in children, in contrast to
adults.
• Extramedullary myeloid tumors are also more
common in children.
• Hence these should be considered in D/D of
round cell tumors, to avoid pitfalls in the
diagnosis.