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. The 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.
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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RHABDOMYOSARCOMA
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. The greatest proportion (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.
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. They 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).
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.
Definition: malignant tumour of infants and children, characterizedby 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. Tumours 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 unencapsulated 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 mosttumours, occasional tumours may consistprimarily of primitive, undifferentiated
"small round blue cells" with only a minorityof cells having a rhabdoid phenotype.In these cases, the rhabdoid cells
may occur in clusters or scattered singlythroughout the tumour, 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.
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
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
Clinical findings: usuallypresents 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
1) anaplasia in stage II-IV tumors
2) high stage (most epithelial-predominant tumors are stage I;
most blastema-predominant tumors are stage III/IV)
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 (autosomal 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
