A 30-year-old female presented with a swelling in her right thigh. Biopsy and histopathological examination revealed a malignant peripheral nerve sheath tumor (MPNST) with rhabdomyoblastic differentiation. MPNSTs are rare sarcomas that arise from peripheral nerves or pre-existing neurofibromas. This case demonstrated multi-lineage differentiation, with positivity for desmin and myogenin, in addition to features of MPNST. A 40-year-old female presented with fever and weight loss. Biopsies of axillary and neck swellings revealed a granulocytic sarcoma, a type of myeloid sarcoma. Immunohistochemistry showed the

1. interesting cases

2. CASE HISTORY
30 year old female
• Swelling in the right thigh X 4 months
• Gradually progressed in size & associated with pain
• Burning sensation and numbness – right lower limb X 4 months
• No H/O Diabetes, hypertension, medications or trauma

3. CLINICAL DETAILS
• Nodular swelling – anterior and lateral aspect of right thigh
• Firm, non tender, free from bone underneath
• No evidence of any other swellings / skin lesions
• No features of vascular compromise
• CLINICAL DIAGNOSIS :
• NEUROFIBROMA – RIGHT THIGH
• Lesion was excised with the surrounding skin
and sent for histopathology.
Gross: irregular skin flap (10cm) with a nodular lesion in the middle
Cut surface was tan grey, firm to hard with occasional necrotic areas.

7. MICROSCOPY
• Fascicles, nodules, whorls and diffuse distribution
• Largely monomorphic spindled to epithelioid cells with few pleomorphic
cells
• Dark hyperchromatic nucleus, inconspicuous nucleoli and pale cytoplasm
• Prominent nuclear palisades, perivascular arrangement
• Mitotic figures [25/10 HPF]
• Necrosis +
• Few round cells with eccentric nucleus & eosinophilic cytoplasm

8. Histological differentials ???
• MPNST
• Fibrosarcoma
• Synovial sarcomas
• Angiosarcoma
• Leiomyosarcoma
• Malignant fibrous histiocytoma

9. VIMENTIN

10. S-100
Positivity IN around 10% tumor cells for S-100

11. CK EMA SMA

12. DESMIN MYOGENIN

13. CD 34

14. • MPNST
• Fibrosarcoma
• Synovial sarcomas
• Angiosarcoma
• Leiomyosarcoma
• Malignant fibrous histiocytoma

15. Final diagnosis
• MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (MPNST)
• FNCLCC GRADING : GRADE III

16. ?????
• Desmin + and Myogenin + ??????
• CD 34 + ??????

17. Final diagnosis
• MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (MPNST) WITH
RHABDOMYOBLASTIC DIFFERENTIATION (MALIGNANT TRITON
TUMOR)
• [ MULTI LINEAGE DIFFERENTIATION ]
• FNCLCC GRADING : GRADE III

18. OVERVIEW
DEFINITION
•Any sarcoma with one/more of the following features:
oarising from a peripheral nerve
oarising from a pre-existing benign nerve sheath tumor
odemonstrating Schwann cell differentiation on histologic examination
•Any malignant spindled tumor in a patient with neurofibromatosis 1 (NF-1), unless proven
otherwise
EPIDEMIOLOGY
•Accounts for 5-10% of all soft tissue sarcomas
•Incidence of 0.001% in the general population
•Up to 50% occur in patients with NF-1, 10% are radiation-induced, 40% are sporadic
• NF-1 associated MPNST
•develops from existing plexiform neurofibromas, NOT superficial neurofibromas
•lifetime risk of MPNST in NF-1 patients has been reported between 5-10%
•tend to present earlier in life and with larger tumors than sporadic MPNSTs

19. CLINICAL FEATURES
•Enlarging mass
•Pain
•Paresthesias / neurologic deficits
•Most commonly occurs in or near a nerve trunk (e.g. brachial plexus,
sacral plexus, sciatic nerve)
•Local recurrence
•Hematogenous spread
• lungs - most common site of metastasis.

20. Loss of remaining
functional NF-1 gene ↑Ras, cAMP, Ca2+
↑EGFR, Kit-L, TGFβ1
↓p53, p16INK4A, p19ARF, Rb
↑EGFR, ErbB2, c-KIT, c-MET
HGF, PDGF
A B
C
D
E
PATHOGENESIS
(adapted by Timothy Beer from Carroll S, Acta Neuropathol, 2012)
Model for the pathogenesis of plexiform neurofibroma development and subsequent
malignant transformation to malignant peripheral nerve sheath tumor (MPNST).
The NF-1 gene  neurofibromin  tumor suppressor function.

21. Absence of the second
functional NF-1 gene
de-regulation of several
intracellular signaling
cascades like RAS & cAMP
increases in secretion of the
factors like Kit ligand (Kit-L)
& TGFβ1
NEUROFIBROMA
Decreased/absent expression
of tumor suppressor proteins
p53, p16INK4A, p19ARF & Rb
further increased expression
of EGFR, ErbB2, c-KIT, c-MET,
HGF and PDGF.
MPNST

22. GROSS PATHOLOGY
FEATURES
• Shape  globoid or fusiform
•Mean size  10-15 cm in greatest dimension.
• Consistency Fleshy and firm to hard
• Color  tan-gray on cut section, but may include a wide variety of colors
• Necrosis  present, either focally or extensively
• Fibrous pseudocapsule, gross invasion into surrounding soft tissues maybe seen
•Entering and exiting nerve segments may be thickened due to spread along the epineurium and perineurium
•May be surrounded by portions of plexiform neurofibroma which have not yet undergone malignant
transformation
Retroperitoneal MPNST. MPNST adherent to psoas
muscle.
MPNST of the right arm.

23. MICROSCOPIC PATHOLOGY
FEATURES
•“Marbled” pattern of hypercellular fascicles
interrupted by hypocellular myxoid areas.
• Long, wavy/“serpentine” nuclei.
• “punched out” nuclei
•Perivascular hypercellularity & indentation of
cells into vascular lumens, is characteristic
•High-grade tumors - high mitotic activity
and necrosis.
•Geographic necrosis with palisading of
tumor cells
.

24. MICROSCOPIC VARIANTS
•MPNST – highly heterogenous tumor.
•MPNSTs can exhibit variable
differentiation.
[Rhabdomyoblastic, Epithelioid,
Glandular, Melanocytic, Endothelial,
Osseous, cartilaginous,
Neuro- endocrine, smooth muscle]
•EPITHELIOID MALIGNANT MPNST
•MALIGNANT TRITON TUMOR
•PERINEURIAL MPNST

25. IMMUNOHISTOCHEMISTRY
No single sensitive or specific immunohistochemicalmarker.
IHC Classical MPNST Aberrations
S100 FOCAL
POSITIVITY IN
50%
STRONG S-100 POSITIVITY IN EPITHELIOID
VARIANTS
CK, CEA Negative POSITIVE IN MPNST with GLANDULAR
DIFFERENTIATION
Desmin, myogenin Negative POSITIVE IN MALIGNANT TRITON TUMOR
CD 34 Negative/Positiv
e
POSITIVE IN MPNST with ENDOTHELIAL OR
PERINEURIAL DIFFERENTIATION
HMB45 Negative POSITIVE IN MPNST with MELANOCYTIC
DIFFERENTIATION
EMA Negative POSITIVE IN MPNST with PERINEURIAL/
GLANDULAR DIFFERENTIATION
• Vimentin. Leu-7+ in 50%.
• Myelin basic protein, Nestin, Sox 10, HMGA2
MPNST Neurofibroma
MALIGNANT TRITON TUMOR

26. IMAGING
MRI (with and without contrast)
• Imaging modality of choice for peripheral nerve sheath tumors
• Differentiates MPNST from benign plexiform neurofibromas (see table)
• Magnetic resonance neurography (MRN) offers superior visualization and delineation of peripheral nerves from surrounding soft tissue
• CT scan - All patients with MPNSTs should receive CT of the chest to assess for pulmonary metastases
MRI CHARACTERISTICS OF BENIGN AND MALIGNANT PERIPHERAL NERVE SHEATH TUMORS
CHARACTERISTIC BPNST MPNST
Fusiform shape with tapered ends Present Present
Oriented longitudinally along direction of peripheral nerve Present Present
Fascicular sign: multiple ring-like structures with peripheral hyperintensity on T2 weighted MR Present Absent
Target sign: hyperintense periphery surrounding a hypointense center on T2 weighted MR Present Absent
Split-fat sign: rim of fat surrounding the neurovascular bundle (and lesion) on T1 weighted MR Present Absent
Fascicular sign. (T2-MR) Target sign. (T2-MRI) Split-fat sign. (T1 MRI)

27. PROGNOSTIC FACTORS
FAVORABLE PROGNOSTIC FACTORS IDENTIFIED IN 11 REVIEWS OF MPNST
PUBLICATION n SIGNIFICANT RELATIVELY FAVORABLE POSTOPERATIVE PROGNOSTIC FACTORS*
Anghileri (2006) 205 smaller tumor size, lack of local recurrence, extremity location
Stucky (2012) 175 tumor size < 5 cm, lack of local recurrence, low histologic grade, extremity location
Zou (2009) 140 tumor size < 10 cm, low intensity p53 staining, positive S-100 staining
Wong (1999) 134 smaller tumor size, low histologic grade, perineural histologic subtype
Brekke (2009) 64 tumor size < 8 cm, complete surgical resection, lower intensity p53 staining
Okada (2006) 56 tumor size < 7 cm
Baehring (2003) 54 complete surgical resection, young age, radiation therapy, lack of chemotherapy
Gousias** (2010) 43 gross total resection
Kar (2006) 25 lower histologic grade, greater cellular differentiation
Romanathan (1999) 23 tumor size < 10 cm, low histologic grade
Zhu** (2012) 16 low histologic grade
* For studies that performed both univariate and multivariate analyses, only those risk factors found to be significant on multivariate analysis are
included here. Metastasis at time of presentation is a uniformly poor prognostic factor and therefore was not evaluated in most studies
** Zhu series included only spinal tumors and Gousias series included only intracranial tumors
SUMMARY
• Evidence overwhelmingly supports tumor size and local recurrence as important postoperative prognostic factors.
By extension, because lack of local recurrence by definition requires complete surgical resection, complete surgical
resection is likely also an important prognostic factor..
• Evidence is suggestive, but not conclusive, that tumor location (extremity vs. trunk, head and neck) and histologic
grade are also important prognostic factors.
• Further analysis is needed to determine whether factors such as p53 expression, radiation therapy, histologic
subtype and S-100 staining are significant prognostic factors.

28. Differential Diagnosis
• Synovial sarcomas
• Liposarcomas
• Malignant fibrous histiocytoma
• Fibrosarcoma
• Angiosarcoma
• Leiomyosarcoma
• Malignant Melanoma

29. GENERAL MANAGEMENT
Complete surgical excision is required for cure
SURGICAL RESECTION
•Often requires en-bloc resection of major nerves and acceptance of potentially significant functional loss
•Complete resectability rates are determined primarily by neuroanatomic location
• Reported to be around 95% for extremity lesions and 20% for paraspinal lesions
•Most cases of extremity MPNST can be completely resected without amputation
RADIOTHERAPY (ADJUVANT OR NEOADJUVANT)
• Found to improve local control and reduce local recurrence rates in many series
• However, most series have found no benefit with respect to overall survival
CHEMOTHERAPY (ADJUVANT)
• Has NOT been shown in any large studies to significantly improve survival

30. Case 2
• 40 year female
• Fever on & off
• Generalised weakness & weight loss
• Swelling in the axilla and neck X 2 months
• Progressed to > 2cm in size. Not associated with pain / discharge
• Tru cut biopsy cores were received from both the swelling, processed and
stained.

31. H & E sections

32. Histological Differentials
• Lymphomas
• Metastasis from epithelial malignancies
• Metastasis from sarcomas
• Round cell tumors

33. LCA, CK,
Vimentin &
Desmin
LCA Vimentin CK Desmin

34. PRIOR HPE: Reported as Anaplastic Large Cell Lymphoma outside

35. CD 3, CD 20
&
CD 30
CD 3 CD 20 CD 30

36. CD 19, CD 56
&
Tdt
CD 19 CD 56 Tdt

37. • A PLEOMORPHIC HEMATOLOGICAL TUMOR which is
• LCA + & Vimentin +
• CD 3 –
• CD 19 & CD 20 –
• CD 30 –
• Tdt –
• CD 56 –

38. MPO

40. • GRANULOCYTIC / MYELOID SARCOMA

41. Discussion
• Definition
• ‘Is a pathologic diagnosis for extramedullary proliferation of blasts of one or
more myeloid lineages that disrupts the normal architecture of the tissues in
which it is found’
• Leukemia cutis
• Meningeal leukemia
• Extramedullary myeloid tumour
• Myeloblastoma

42. History
• ‘Chloroma’
• Burns A. Observations of surgical anatomy, in Head and Neck. London, England, Royce,
1811, p. 364
• King A. A case of chloroma. Monthly J Med 17:17, 1853.
• ‘Granulocytic sarcoma’
• Rappaport H. Tumors of the hematopoietic system, in Atlas of Tumor Pathology, Section III,
Fascicle 8. Armed Forces Institute of Pathology, Washington DC, 1967, pp. 241‐247
• ‘Granulocytic Leukemia and Reticulum Cell Sarcoma’ John Laszlo and Harvey E Grode.
Cancer April 1967.
• FAB classification (1976) – does not specify
• WHO classification (2001) – Included under ‘AML not otherwise categorized’
• WHO Classification (2008) – separate entity in classification of AML

43. Types of presentation
• De novo – 27%
• Concurrent with AML, MPD or MDS – 35%
• Previous H/O AML, MDS, MPN – 38%
• Initial manifestation of relapse in AML in remission
• Evolution to AML in known MDS or MDS/MPN
• Blast transformation in MPN

45. Type Morphology IHC Borislav
et al
(n=13)
Pileri et
al
(n=92)
Immature
Granulocytic
sarcoma (IGC)
>90% blasts CD43, CD117,
Lysozyme,
MPO<10%
2 49
Differntiated
GS (DGS)
>10% more
mature neutrophils
CD43, MPO, CD15,
Lysozyme, CD117
3 1
Monoblastic
sarcoma
(MBLS)
>80% monoblast CD43, Lysozyme,
CD68, CD163,
CD34 neg
4 20
Monocytic sarcoma
(MCS)
More mature
monocytes
CD 43, CD68, CD163,
variable MPO
1 2
Myelomonocytic
sarcoma (MMS)
Mixed granulocytes
and monocytes
Both myeloid and
monocytic markers
3 20

46. Gross

47. Granulocytic sarcoma - ovary Granulocytic sarcoma - orbit

48. Differential Diagnosis
• Haematopoietic:
• Lymphoblastic,
• Diffuse large B cell Lymphoma
• Anaplastic Large Cell Lymphoma
• Burkitts,
• Non haematopoietic :
• Small round cell tumour (neuroblastoma, rhabdomyosarcoma, Ewing Sarcoma/PNET,
medulloblastoma)
• Undifferentiated carcinomas
Immunophenotyping is mandatory.
Misdiagnosed 50% of the times if IPT is not done

51. Treatment
• No definite guidelines
• Complex issue – depends on type of presentation
• Various modalities
• Surgery
• Radiotherapy
• Chemotherapy
• Anti‐AML therapy - less intense /more intense therapy?
• Combined therapy:
• EFS and OS of the MS patients vs AML patients matched for age, PS, Cytogenetics,
time of treatment.