interesting cases

MODERATOR: Dr. Malti Kumari

Dr. A. Arun

CASE HISTORY30 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

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.

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

Histological differentials ???

• MPNST

• Fibrosarcoma

• Synovial sarcomas

• Angiosarcoma

• Leiomyosarcoma

• Malignant fibrous histiocytoma

VIMENTIN

S-100

Positivity IN around 10% tumor cells for S-100

CK SMAEMA

DESMIN MYOGENIN

CD 34

• MPNST

• Fibrosarcoma

• Synovial sarcomas

• Angiosarcoma

• Leiomyosarcoma

• Malignant fibrous histiocytoma

Final diagnosis

• MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (MPNST)

• FNCLCC GRADING : GRADE III

?????

• Desmin + and Myogenin + ??????

• CD 34 + ??????

Final diagnosis

• MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (MPNST) WITH RHABDOMYOBLASTIC DIFFERENTIATION (MALIGNANT TRITON TUMOR)

• [ MULTI LINEAGE DIFFERENTIATION ]

• FNCLCC GRADING : GRADE III

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

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.

Loss of remainingfunctional 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

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.

(adapted by Timothy Beer from Carroll S, Acta Neuropathol, 2012)

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

Pathogenesis

GROSS PATHOLOGYFEATURES•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.

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

.

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

IMMUNOHISTOCHEMISTRY

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/Positive

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

No single sensitive or specific immunohistochemical marker.

• Vimentin. Leu-7+ in 50%.• Myelin basic protein, Nestin, Sox 10, HMGA2

MPNST Neurofibroma

MALIGNANT TRITON TUMOR

IMAGINGMRI (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

Target sign. (T2-MRI)Fascicular sign. (T2-MR) Split-fat sign. (T1 MRI)

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

PROGNOSTIC FACTORS

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.

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

Differential Diagnosis

• Synovial sarcomas

• Liposarcomas

• Malignant fibrous histiocytoma

• Fibrosarcoma

• Angiosarcoma

• Leiomyosarcoma

• Malignant Melanoma

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

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.

H & E sections

Histological Differentials

• Lymphomas

• Metastasis from epithelial malignancies

• Metastasis from sarcomas

• Round cell tumors

IHC Approach LCA, CK,

Vimentin & Desmin

LCA

Vimentin

CK Desmin

PRIOR HPE: Reported as Anaplastic Large Cell Lymphoma outside

IHC A

pproac

h CD 3, CD 20 &

CD 30

CD 3

CD 20 CD 30

IHC A

pproach CD 19, CD 56

& Tdt

CD 19

CD 56 Tdt

• A PLEOMORPHIC HEMATOLOGICAL TUMOR which is

• LCA + & Vimentin +

• CD 3 –

• CD 19 & CD 20 –

• CD 30 –

• Tdt –

• CD 56 –

MPO

• GRANULOCYTIC / MYELOID SARCOMA

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

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

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

Type Morphology IHC Borislav et al

(n=13)

Pileri etal

(n=92)

ImmatureGranulocytic

sarcoma (IGC)

>90% blasts CD43, CD117,Lysozyme,MPO<10%

2 49

DifferntiatedGS (DGS)

>10% moremature neutrophils

CD43, MPO, CD15,Lysozyme, CD117

3 1

Monoblasticsarcoma(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

Gross

Granulocytic sarcoma - ovary Granulocytic sarcoma - orbit

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

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.

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