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INFANTILE FIBROSARCOMA

Definition:

•

Infantile fibrosarcoma (IFS) is histologically identical to

classic fibrosarcoma of adults, but carries a much more

favourable prognosis.

•

It occurs in infants and young children, metastasizes

rarely, and has similar history of fibromatoses.

•

IFS is morphologically and genetically related to congenital

mesoblastic nephroma.

Epidemiology:

•

IFS accounts for 36%-80% of congenital cases and

36%-100% occurs in first year of life.

•

IFS is rare after 2 years of age.

•

There is slight male predominance.

Sites of involvement:

•

The superficial and deep soft tissue of the extremities,

especially distal (61%), followed by the trunk (19%) and

head and neck (16%).

Clinical findings:

•

IFS presents as a solitary enlarging, nontender mass or

swelling in the soft tissues and grows rapidly.

•

The diameter may exceed 30 cm.

Gross:

•

poorly circumscribed, lobulated mass infiltrating adjacent

soft tissue.

•

The cut surface is soft to firm, fleshy, and grey to tan with

variable areas of myxoid or mucinous change, cystic

degeneration, haemorrhage, necrosis, and yellow-red.

discoloration.

Histopathology:

•

IFS show dense cellularity composed of intersecting

fascicles of primitive ovoid and spindle cells with

herringbone pattern or forming interlacing cords, sinous

bands or sheets of cells.

•

Zonal necrosis or hemorrhage are frequent and may be

associated with dystrophic calcifications.

•

Cells show little pleomorphism.

•

Collagen production is variable, and mitotic activity is

prominent.

•

Most IFS show scattered chronic inflammatory cells and

may display focal extramedullar haematopoiesis.

•

Histological variations may show areas of

haemangipericytoma-like pattern, myxoid changes or

predominant immature ovoid cells proliferation with minimal

collagen.

•

Infiltrative growth pattern may result in entrapmet of

adipose and skeletal tissue.

Immunophenotype:

•

Positive for vimentin (100%), neuron-specific enolase NSE

(35%), smooth muscle actin (33%).

Genetics:

•

Translocation t(12;15).

Prognosis:

•

IFS has a more favourable outcome compared with adult

fibrosarcoma.

•

The mortality ranges from 4% to 25%, and the recurrence

rate is 5% to 50%.

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EMBRYONAL RHABDOMYOSARCOMA

Definition:

•

A primitive, malignant soft tissue sarcoma with phenotypic

and biological features of embryonic skeletal muscle.

Epidemiology:

•

Most common subtype of rhabdomyosarcoma, occuring in

3.0/milion U.S. children <15 years old.

•

Most (46%) of embryonal rhabdomyosarcomas occurs in

children less than five year old.

•

Male to female ratio is 1.2:1.0.

Sites of involvement:

•

Most common location head and neck (47%) followed by

genitourinary system (28%).

•

Common location in the genitourinary tract include the

urinary bladder, prostate and paratesticular soft tissues.

•

Typical sites involving head and neck area include soft

tissue surrounding the orbit and eyelid, oropharynx,

parotid, auditory canal and middle ear, pterygoid fossa,

nasopharynx, nasal passages and paranasal sinuses,

togue and cheek.

Clinical findings:

•

Clinical symptoms are associated with the affected area.

•

Head and neck lesions can cause proptosis, diplopia,

sinusitis or unilateral deafness, depending on their location.

•

Similarily, genitourinary lesions may produce scrotal mass

or urinary retention, and biliary tumors may cause

jaundice.

Gross:

•

Like most primitive pediatric tumors, embryonal

rhabdomyosarcomas form poorly circumscribed, fleshy,

pale tan masses that directly invade adjacent soft tissue.

Histopathology:

•

Embryonal rhabdomyosarcomas are composed of primitive

mesenchymal cells in various stages of myogenesis

(rhabdomyoblasts).

•

Stellate cells with lightly amphophilic cytoplasm and

central, oval nuclei represent the most primitive end of this

spectrum.

•

As these cells differentiate they progressively become

more elongated with eosinophilic cytoplasm also called

such as "tadpole", "strap", and "spider" cells.

•

Bright eosinophilia, cytoplasmic cross striations, and

multinucleation indicate terminal differentiation, and

myotube forms may be present.

•

Densely arrayed whorls of fascicles of spindle cells

constitute the spindle cell variant of embryonal

rhabdomyosarcoma.

•

These spindle cells often resemble smooth muscle cells,

with blunted central nuclei and tapered ends, but

cytoplasmic cross striations, if present, and/or broght

eosinophilia indicate striated muscle differentiation.

Immunophenotype:

•

Tumor cells are positive for desmin, myogenin and myo-D

(nuclear staining).

Genetics:

•

Alleic loss in chromosomal region 11p15, extra copies of

chromosomes 2, 8 and 13.

Prognosis:

•

Can be determined by stage, histological classification,

age , and site of origin.

•

Younger patients tend to have better prognosis.

•

Spindle cells and botryoid have better outcome.

ALVEOLAR RHABDOMYOSARCOMA

Definition:

•

Primitive, malignant , round cell neoplasm that

cytologically resembles lymphoma and show partial

skeletal muscle differentiation.

Epidemiology:

•

Occurs at all ages, more often in adolescent and young

adults.

•

Occur less frequently than embryonal rhabdomyosarcoma.

Sites of involvement:

•

Most common involvement of extremities, followed by

paraspinal and perineal regions.

Clinical findings:

•

Alveolar rhabdomyosarcoma typically present as rapidly

growing extremity masses.

•

Perirectal tumors can cause constipation.

•

Paraspinal lesionscan cause nerve root abnormalities, such

as paresthesia, hypesthesia, or paresis.

Gross:

•

Expansile, rapidly growing soft tissue tumors with a fleshy,

grey tan quality.

Histopathology:

•

three major morphological subtypes of alveolar

rhabdomyosarcoma comprise: typical alveolar, solid

pattern and mixed alveolar/embryonal. All alveolar

rhabdomyosarcomas exhibit round cell cytological features

resembling lymphoma, but with primitive myoblastic

differentiation.

Typical alveolar rhabdomyosarcomas produce fibrovascular septa that separate the tumor cells into discrete nests. These cells contain central clusters of cells with loss of cohesion at the periphery. Tumor cells align the septa in the picket fence pattern. Giant cells with rhadbomyoblastic differentiation are common.

Solid variant of ARS lack the fibrovascular stroma and form sheets of round cells with variable rhabdomyoblastic differentiation. Occasionally small nests may be seen with larger samples.

Mixed embronal/alveolar rhabdomyosarcoma contain foci with embryonal histology (mixed stroma with spindle cell myoblasts), as well as areas of alveolar histology.

Immunophenotype:

•

tumor cells are positive for desmin, myogenin, myo-D.

Genetics:

•

Most common translocation t(2;13)(q35;q14) PAX3/FKHR,

and less common t(1;13)(p36;q14) PAX7/FKHR.

Prognosis:

•

Alveolar rhabdomyosarcomas are high grade sarcomas and

are more aggressive than embryonal rhabdomyosarcoma.

•

Some data show better prognosis with t(1;13).

EMBRYONAL RHABDOMYOSARCOMA, BOTRYOID TYPE

Epidemiology:

•

Botryoid rhabdomyosarcoma accounts for approximately 6%

of all rhabdomyosarcomas.

•

Mostly young children.

Sites of involvement:

•

mostly found in mucosa-line hollow organs, such as the

nasal cavity, nasopharynx, bile duct, urinary bladder, and

vagina.

Clinical features:

•

Its unrestricted growth in body cavities or on body surfaces

accounts for its characteristic edematous and grape like

appearance (botryoid is greek name for grapes).

Gross:

•

Polypoid (grape-like) growth.

Histopathology:

•

Botryoid variant of embryonal rhabdomyosarcoma show

linear aggregates of tumor cells that lightly abut an epithelial

surface. This features known as a "cambium layer" is

characteristic for this tumor.

•

The tumor cells should form a distinct zone that is several

layers thick, although the thickness of this layer may vary in

extent in different areas of the tumor.

•

The cells range from primitive small cells to cells with

clear-cut myoblastic differentiation. Cells with stellatae

cytoplasmic processes are often prominent.

•

The stroma is typically loosely cellular with myxoid

appearance, including a hypocellular zone that separates

the surface epithelium from the underlying cambium layer.

•

The surface epithelium may be hyperplastic or may undergo

squamous changes, sometimes mimicking a carcinoma.

Immunohistochemistry:

•

Positive for desmin, myogenin, myo-D

Cytogenetics:

•

Deletion of the short arm chromosome 1 and trisomies of

chromosomes 13 and 18.

Prognosis:

•

Better prognosis than other subtypes of

rhadbomyosarcoma.

RHABDOID TUMOR

Definition:

•

Malignant tumour of infants and children, characterized by

neoplastic cells with large nuclei, prominent nucleoli, and

abundant, eccentric cytoplasm with variably prominent

eosinophilic, cytoplasmic "inclusions".

Epidemiology:

•

Malignant rhabdoid tumours are well defined and

characterized entities in both the kidney and central

nervous system.

•

Tumors arising in soft tissue are confined almost

exclusively infants and children.

Sites of involvement:

•

The tumours may arise at a variety of topographic

locations, including liver,heart and gastrointestinal system.

•

Soft tissue lesions seem to arise most frequently in deep,

axial locations, including the neck and paraspinal regions.

Gross:

•

Rhabdoid tumours have been described as primarily

un-encapsulated masses, generally less than 5 cm in

greatest dimension.

•

The cut surface is soft and grey to tan in colour.

Histopathology:

•

Rhabdoid tumours are densely cellular,comprised of

sheets or solid trabeculaeof neoplastic cells with large,

vesicular,round to bean-shaped nuclei, prominent

•

Centrally located nucleoli, and abundanteccentric

cytoplasm.

•

Less common features include scattered non-neoplastic,

•

Osteoclast-like giant cells, a myxoid background, a lack of

cellular cohesiveness,and increased collagen deposition

between trabeculae of tumour cells.

•

Mitoses are frequent, averaging approximatelyone per high

power field, and necrosis is common.

•

The diagnostic hallmark of this tumour by routine

haematoxylin and eosin staining is a distinctive, globoid,

hyaline, eosinophilic,cytoplasmic inclusion.

•

While these distinctive cells are numerous in most tumors,

occasional tumors may consist primarily of primitive,

undifferentiated "small round blue cells" with only

a minority of cells having a rhabdoid phenotype.

•

In these cases, the rhabdoid cells may occur in clusters or

scattered singly throughout the tumor, highlighting a

potential diagnostic challenge in a small biopsy sample.

Immunohistochemistry:

•

Rhabdoid tumour cells are positive for vimentin, epithelial

antigens (keratin, epithelial membrane antigen and/or

CAM5.2), neuroectodermal antigens (synaptophysin,

and/or NSE), and CD 99.

•

Tumor cells are negative for desmin, myoglobin and CD34.

Prognosis:

•

Extrarenal rhabdoid tumours, like their renal and central

nervous system counterparts,are characterized by

aggressive biological behaviour and prognosis is poor.

NUEUROBLASTOMA

Definition:

•

Neuroblastomas are derived from neuroblasts that arise in

the neural crest and normally migrate downward to form

ganglion cells and chromaffin tissue.

Epidemiology:

•

Neuroblastoma is the second most common solid

malignancy of childhood after brain tumors, accounting for

7% to 10% of all pediatric neoplasms, and as many as

50% malignancies diagnosed in infancy (most common

malignant tumor of the fetus and infant).

Sites of involvement:

•

About 40% of neuroblastomas arise in adrenal medulla.

•

The reminder occur anywhere along the sympathetic chain,

with the most common location being the paravertebral

region of the abdomen (25%) and posterior mediastinum

(15%).

Clinical findings:

•

In young children, under age 2 years, neuroblastomas

generally present with large abdominal masses, fever and

weight loss.

•

In older patients they may not come to attention until

metastasize and produce manifestations like bone pain,

respiratory symptoms, or gastrointestinal complaints.

Histopathology:

•

Neuroblastomas are composed of small, primitive-appearing

cells with dark nuclei, scant cytoplasm, and poorly defined

cell borders growing in solid sheets.

•

Mitotic activity, nuclear breakdown ("karyorrhexis"), and

pleomorphism may be prominent.

•

The background often demostrates a eosinophilic fibrillary

material (neuropil) that corresponds to neuritic process of

the primitive neuroblasts.

•

Typically, rosettes (Homer-Wright pseudorosettes, tumor

cells are concentrically arranged around central space filled

with neuropil) can be found.

Neuroblastoma differentiation:

•

Classic (undifferentiated) neuroblastoma: grade III/IV ,

stroma-poor, 5% or less of tumor has features of

differentiation towards, ganglion cells with vesicular nuclei

and prominent nucleoli no/minimal ganglioneuromatous

stroma

•

Differentiating neuroblastoma: 6-49% of tumor cells show

ganglionic differentiation (abundant eosinophilic or

amphophilic cytoplasm, large eccentric nuclei with

vesicular chromatin and single prominent nucleoli), often at

periphery of tumor if 50% or more differentiation

ganglioneuroblastoma,

•

Intermixed; usually abundant neuropil

Immunohistochemistry:

•

Positive for chromogranin, synaptophysin, vimentin,

neurofilament, neuron-specific enolase

Staging of neuroblastomas:

•

I - tumor confined to structure or organ of origin

•

II - tumor extends in continuity beyond structure or organ of

origin, doesn't cross midline, variable ipsilateral nodal

metastases

•

III - tumor extends in continuity beyond midline; variable

bilateral nodal metastases

•

IV - tumor metastatic to viscera, distal lymph nodes, soft

tissue, skeleton

•

IV-S (special) - stage I or II with remote disease in liver,

skin, bone marrow (with no bony destruction)

•

Stage IV-S (4S): small/undetectable primaries with disease

involving liver, skin or bone marrow; survival of 60-90%;

median age 4 months, primary usually adrenal (also

retroperitoneum, mediastinum); usually have favorable

histology; patients dying of progressive disease have either

unfavorable histology or N-myc amplification

Prognosis:

Poor prognostic indicators:

•

1p36.33 deletion (subtelomeric region, may be site of

•

differentiation associated genes)

•

N-myc amplification (>10 copies, is associated with 1p36

•

deletion)

•

14p deletion

•

diploidy

•

low expression of TrkA gene (maturation factor)

•

undifferentiated morphology

•

high mitotic rate-karyorrhexis index

•

age 1 year old or more (this group has a 5% cure rate)

•

17q+, elevated serum ferritin (> 150 ng/mL)

Favorable prognostic indicators:

•

age < 1 year regardless of stage

•

hyperdiploid / near-triploid

•

high levels of TrkA gene (associated with lack of N-myc

•

amplification)

•

stages 1, 2 or 4S versus stages 3 or 4

WILMS TUMOR

Definition:

•

Triphasic tumor, with undifferentiated blastema,

fibroblast-like stroma and epithelium also called

nephroblastoma,

•

Usually seen in children

Epidemiology:

•

Most common kidney tumor of childhood, affecting 1 per

8-10,000 children; 500 new cases/year in US.

•

There is no gender preference.

•

About 90% of cases occur before age 6 years, only rarely

congenital.

•

Associated with WAGR, Denys-Drash and Beckwith-

Wiedemann syndromes and nephroblastomatosis

•

WAGR syndrome: Wilms’ tumor, Aniridia, Genitourinary

anomalies, mental Retardation.

Sites of involvement:

•

Kidney, occasionally extrarenal (retroperitoneum,

sacrococcygeal region, testis, uterus, inguinal canal,

mediastinum).

Clinical findings:

•

Usually presents as large abdominal mass felt by mother

holding child.

Gross:

•

Large, solitary, well-circumscribed mass (10% bilateral or

multicentric), soft, homogenous, tan-gray.

•

May show hemorrhage, necrosis, cysts and lobular pattern.

Histopathology:

•

Triphasic with undifferentiated blastema (cellular with small

blue primitive cells with scanty cytoplasm, nuclei are

overlapping with finely dispersed chromatin; patterns are

diffuse, nodular, cordlike or basaloid), fibroblast-like stroma

and epithelium (abortive tubules, glomeruli with

elongate/ovoid nuclei having molded/wedged shapes).

•

May show additional findings of smooth muscle, cartilage,

adipose tissue, squamous or mucinous epithelium, bone,

neural tissue.

•

Anaplastic cells may be found in 5% of cases and are

associated with worse prognosis.

Immunohistochemistry:

•

Positive for WT1, desmin and focally vimentin.

Genetics:

•

Abnormal expression of WT1 (11p13).

Staging (National Wilms Tumor Study Group)

•

Stage I (43%): tumor limited to kidney and completely resected, renal capsule intact, tumor not ruptured or biopsied prior to removal, no residual tumor beyond margins of resection, no tumor within renal vein (tumor within intrarenal vessels is OK), no nodal involvement or distant metastases

•

Stage II (23%): tumor extends beyond kidney but is completely resected, regional extension of tumor (vascular invasion outside of renal parenchyma or within the renal sinus, or capsular penetration but with negative surgical margin), operative tumor spill confined to flank (no peritoneal contamination), tumor biopsy (except FNA) prior to surgery

•

Stage III (23%): nonhematogenous metastases to abdomen only (such as regional lymph nodes), including tumor implants in or penetrating peritoneum; gross or microscopic tumor present postoperatively (i.e. positive resection margins), tumor spill before or during surgery not confined to flank, removal of tumor in > 1 piece

•

Stage IV (10%): hematogenous metastases or nodal metastases outside of abdominopelvic region (e.g. lung, liver or elsewhere beyond renal drainage system)

•

Stage V (5%) bilateral renal involvement at diagnosis (but each side should be staged separately as I-IV above)

Prognosis:

Poor prognostic factors:

•

anaplasia in stage II-IV tumors

•

high stage (most epithelial-predominant tumors are stage I;

•

most blastema-predominant tumors are stage III/IV)

•

age >2 years

•

large size

RETINOBLASTOMA

Definition:

•

Most common small blue cell intraocular tumor of

children.

Epidemiology:

•

May be congenital, and not be recognized until 6 momths

of life. Incidence of 1 per 20,000 live births.

•

Represent 60% sporadic, and 40% familial

(autosoma dominant) cases.

•

Sites of involvement: eye. About 30% of cases are

bilateral.

Clinical findings:

•

White reflex (leukokoria) present in affected eye; also

retinal detachment.

Histopathology:

•

Sheets, trabeculae and nests of small blue cells with

scant cytoplasm, hyperchromatic nuclei and scanty

stroma.

•

May show frequent necrosis of tumor cells away from

vessels and calcification.

•

Additional findings are : Flexner-Wintersteiner rosettes

(cells line up around empty lumen delineated by a

distinct eosinophilic circle composed of terminal bars

analogous to outer limiting membrane of normal retina),

Homer-Wright rosettes (nuclei are displaced away from

lumen), fluerettes (tumor cells arranged side by side

which show differentiation towards photoreceptors).

•

There are also frequent Azzopardi phenomena

(basophilic deposits around blood vessels, also seen in

small cell carcinoma), mitotic figures and variable

apoptotic cells.

Immunohistochemistry:

•

Positive for neuron-specific enolase, synaptophysin,

S100, Leu7, GFAP, myelin basic protein, p53; high Ki-67

Prognosis:

•

5 year survival: 90% if unilateral, slightly less if bilateral

•

Poor prognostic factors:

•

invasion of optic nerve

•

invasion of uveal tract or sclera

•

seeding of vitreous

•

involvement of anterior segment

LEIOMYOSARCOMA OF SOFT TISSUE

Definition:

Malignant tumour composed of cells with smooth muscle features.

Epidemiology:

leiomyosarcoma usually occurs in middle-aged or older persons

very rare in infantile or young children

represent significant percentage of retroperitoneal sarcomas and is the predominant sarcoma

arising from larger blood vessels.

Sites of involvement:

most common location of soft tiss is the retroperitoneum, including the pelvis.

may arise in large blood vessels, most commonly the inferior vena cava and thelarge veins of the lower extremity.

Third group include nonretroperitoneal soft tissue sites constitute most frequently involving lower extremities

Clinical features:

generally presents as a mass lesion

retroperitoneal tumors may present with pain

leiomyosarcoma involving upper portoion of vena cava may obstruct hepatic veins and produce Budd-Chari syndrome with hepatomegaly

Macroscopy:

typicall forms a fleshy mass, grey to white to tan

whorled character

may display haemorrhage, necrosis, or

cystic change

frequently appears well circumscribed

Histopathology:

histological pattern show intersecting,sharply marginated groups of spindle cells

occasionally there may be focal storiform,

palisaded, or haemangiopericytoma-like

arrangement.

usuall compactly cellular, but fibrosis or myxoid

change may be present and may show microcystic pattern

hyalinized, hypocellular zones and coagulative tumour necrosisare frequent in larger leiomyosarcomas.

tumour cell nuclei are characteristically

elongated and blunt-ended (cigar shape) and

may be indented or lobated.

nuclear hyperchromatism and pleomorphism

may be seen

increased mitotic activity

cytoplasm varies from typically eosinophilic to pale,

cytoplasmic vacuolation may be seen

Immunophenotype:

positive for SMA, desmin and h-caldesmon

may be focally positive for keratin, EMA, CD34, and S100 protein.

Ultrastructure:

cytoplasmic filament with densities

cell junctions,

pinocytotic vesicles

basement membrane

Genetics:

most karyotypes are complex

no specific abberation

most common lost chromosome regions include 3p21-23, 8p21-pter, 13q12-13, 13q32-qter, whereas the

1q21-31 region is often gained

Comparative genomic hybridization (CGH) has confirmed frequent numerical changes, like gain of material from

chromosomes 1, 15, 17, 19, 20, 22 and X and loss from

1q, 2, 4q, 9p, 10, 11q, 13q and 16

size-related abberation: gain of 16p and 17p with

smaller tumours and gain of 6q and 8q with larger

tumours

Molecular genetics:

Loss of RB1 gene (chromosome 13)

frequent abnormalities in the Rb-cyclinD pathway (RB1,

CDKN2A, CCND1, and CCND3)

Prognostic factors:

Soft tissue leiomyosarcomas may recurre locally and metastasize

important prognostic are tumor location and size

retroperitoneal leiomyosarcomas are more aggressive and in most of the time large (over 10 cm), difficult to get good margins

large vessels leiomyosarcomas tend toi have a poor prognosis, although local control is better

Nonretroperitoneal soft tissue leiomyosarcomas are generally smaller and better to manage locally

Local recurrences and metastases of soft tissue leiomyosarcoma usually reccur in first few yaers, however they may appear after 10 years

most common sites for metastasis are lung andliver, whereas lung is more common

Ref.Leiomyosarcoma of soft tissue in children: clinicopathologic analysis of 20 cases.

de Saint Aubain Somerhausen N, Fletcher CD.

Am J Surg Pathol. 1999 Jul;23(7):755-63