TUMORS AND TUMOR-LIKE LESIONS

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CHAPTER 6 TUMORS AND TUMOR-LIKE LESIONS

INTRODUCTION

• Although many tumors are more common at certain sites, for ease of reference, the majority of tumors or lesions which may be resected or biopsied with a clinical suspicion of tumor, are included in this section

• Tumors which only affect a very specific site are included in their respective system chapters

• Most of the lesions covered here would be broadly considered ‘pediatric soft tissue tumors’

PEDIATRIC ‘BLASTOMAS’ / ‘SMALL ROUND CELL’ TUMORS

INTRODUCTION

• A large number of pediatric embryonal tumors share a component with a ‘small round blue cell’ phenotype (SRBCT)

• Many of the diagnostic morphological findings require assessment of overall architecture and other features which may not necessarily be present in needle core biopsy specimens

• Immunohistochemical staining and molecular techniques may be required in a large proportion of such specimens for definitive diagnosis

• A targeted immunohistochemical panel should be performed to determine appropriate positive and negative findings

• Since morphological features may be non-diagnostic, adequate clinical history, imaging and results of other investigations are essential for appropriate interpretation

• Even if a diagnosis is suggested clinically, always review all other possibilities

pediatric tumors may present in an atypical fashion at atypical sites and the apparent history submitted may be misleading

• The most immediate issues for management in most cases are the differential between leukemia / lymphoma, rhabdomyosarcoma, other high grade embryonal sarcoma such as PNET and other less aggressive tumors

• Due to their rarity, and hence potential diagnostic difficulty, in non-specialist centers, primary diagnosis of all embryonal pediatric tumors should be reviewed by a specialist center / review panel and additional investigations performed as required

HANDLING OF PEDIATRIC TUMOR SPECIMENS

• Many pediatric tumors require additional investigations for their definitive diagnosis and prognosis

molecular investigation

electron microscopy

• Optimal specimen handling makes performance and interpretation of these techniques much easier

• All diagnostic pediatric tumor specimens should be submitted to the laboratory as fresh tissue immediately following biopsy where possible

• The specimen should be divided according to predetermined standard operating procedures, with aliquots for:

formalin fixation and paraffin embedding

glutaraldehyde fixation for electron microscopy

snap freezing or storage in RNA protection medium for molecular studies such at RT-PCR

imprints / ‘dabs’ fixed for FISH in methanol

sample for cytogenetic studies

frozen for storage and subsequent analysis if required

• All laboratories providing a diagnostic pathology service for pediatric tumors should have facilities available for handling of fresh specimens and access to appropriate molecular diagnostic services

• Advances in technical aspects now mean that many molecular techniques, such as FISH and RT-PCR, may also be performed on routinely fixed paraffin embedded material

this should be carried out by centers experienced in their interpretation since the diagnostic yield is lower and technical aspects of the test performance and interpretation may require modification

Issues specific to needle core biopsy specimen interpretation in pediatric tumor diagnosis (Figs 6.1, 6.2)

• In an increasing number of centers, primary diagnostic investigation of suspected pediatric tumors is on the basis of an image guided needle core biopsy

• Limited amounts of tissue are obtained, making optimal specimen handling of importance

• A full range of ancillary investigations is possible in the vast majority of needle biopsy specimens in centers experienced in their handling

• Limited material is available for morphological analysis in such cases

many of the ‘diagnostic’ architectural features referred to in standard texts may not be applicable to the interpretation of these limited samples

extensive use of ancillary investigations such as immunostaining and molecular analysis should be carried out where required in order to reach a definitive diagnosis

• ‘Molecular profiling’ of tumors is likely to become of increasing importance for both determining diagnosis, and prognosis and management in pediatric tumors

traditional morphological characteristics may become less applicable due to changes in understanding of the biology of these tumors

• Needle biopsies are safe, with a high adequacy rate and diagnostic yield and associated low morbidity

both complication rate and adequacy are operator dependant

– ideally performed in specialist centers

• The report in such cases should provide as much information as possible, but not more

caution not to overinterpret non-diagnostic findings in limited samples

Fig 6.1 Low power scan of a glass slide with tumor core biopsies demonstrating multiple cores of tissue for diagnosis.

Fig 6.2 Low power photomicrograph of a tumor core biopsy demonstrating adequate material for diagnosis.

PERIPHERAL NEUROBLASTIC TUMORS (NTS)

• Overall around 85% are NB, 5% GNBi, <1% GN and 5–10% GNBn (Shimada et al 2003)

• May occur at wide range of sites

most commonly adrenal glands and retroperitoneal primary sites

– thoracic NTs relatively more likely to represent GNB, GN

can present with metastatic disease

• Risk stratification for prognosis and management is based on age, stage, MYCN, and Shimada pathology classification, and an increasing number of other molecular (biological) markers

NEUROBLASTOMA

• Incidence around 1 per 100,000 (Schwab et al 2003)

• 70% have metastatic disease at presentation (Ara et al 2006)

• Age, clinical stage, molecular findings and undifferentiated subtype influence overall survival (Lastowska et al 2002, Shimada et al 2001, Goto et al 2001, Ikeda et al 2002, Burgues et al 2006, Navarro et al 2006, Sano et al 2006)

Histopathological features (Figs 6.3–6.8)

• International Neuroblastoma Pathology Classification (INPC) system (Shimada et al 1999)

• By definition

Schwannian stroma comprises <50% of the tumor

• Sheets or nests of neuroblasts

varying stages of differentiation

background neurofibrillary stroma

variegated (‘salt and pepper’) chromatin pattern

Fig. 6.3

Figs 6.3–6.4 Macroscopic photographs of adrenal-associated neuroblastomas, demonstrating variable appearance from expansion of the adrenal cortex by dark tumor to nodular architecture of soft, cream-brown viable tumor.

Fig. 6.5

Fig. 6.6

Fig. 6.7

Figs 6.5–6.8 Photomicrographs of cases of neuroblastoma, demonstrating tumor composed of sheets and nests of small ovoid cells within a variably prominent neurofibrillary background.

NB, undifferentiated

• No obvious morphological differentiation

no ganglion cell differentiation of neuroblasts

no definite neurofibrillary stroma on light microscopy

sheets of small round to ovoid cells

• Supplementary techniques such as immunohistochemical staining and biological marker status required for the definitive diagnosis

NB, poorly differentiated

• Morphological nests of neuroblasts

within neurofibrillary background stroma

– usually identifiable on routine light microscopy

• <5% of neuroblasts show ganglion cell differentiation

GANGLIONEUROBLASTOMA, INTERMIXED (Figs 6.11–6.14)

• Well defined nests of neuroblasts

within neurofibrillary background stroma

– intermixed / scattered throughout the lesion

usually differentiating neuroblasts within the nests

• No discreet macroscopically identifiable nodule

• <50% of the lesion represented by NB

• >50% of the lesion represented by Schwannian stroma and mature ganglion cells

Fig. 6.11

Figs 6.11–6.12 Macroscopic photographs of ganglioneuroblastoma, intermixed, demonstrating solid expansile masses with yellow cut surface. Note the area of hemorrhage in Fig 6.12 compared to the area of neuroblastomatous tissue in ganglioneuroblastoma, nodular in Fig 6.15.

Fig. 6.13

Figs 6.13–6.14 Photomicrographs of cases of ganglioneuroblastoma, intermixed, in which, overall, >50% of the lesion is represented by Schwannian stroma and mature ganglion cells, with admixed well-defined nests of neurofibrillary stroma, within which are differentiating neuroblasta.

GANGLIONEUROBLASTOMA, NODULAR (Figs 6.15–6.17)

• Macroscopic, hemorrhagic nodule within a larger bland lesion

• Surrounding areas of stroma-rich or stroma-dominant areas with mature or maturing ganglion cells

• Well demarcated nodule of Schwannian stroma-poor neuroblastomatous tissue

may be multiple

nodules morphologically those of neuroblastoma (see above)

• Outcome of GNBn

based on prognostic features of the NB component (Peuchmaur et al 2003)

– including all molecular / biological markers

Fig 6.15 Macroscopic photograph of a ganglioneuroblastoma, nodular demonstrating a uniform, bland solid yellow lesion with a macroscopically visible area of hemorrhagic neuroblastoma.

Fig. 6.16

Figs 6.16–6.17 Photomicrographs of a ganglioneuroblastoma, nodular in which most areas are composed of Schwannian stroma and mature ganglion cells, but the hemorrhagic nodule shows features indistinguishable from neuroblastoma.

NEUROBLASTIC TUMOR, UNCLASSIFIABLE

• May be used in small biopsy specimens since representativeness is unknown

NEUROBLASTOMA (SCHWANNIAN STROMA POOR), NOS

• Definite NB but subtyping not possible due to necrosis, etc

Additional investigations

• Molecular studies are mandatory in risk stratification and management planning in neuroblastic tumors

importance of optimal specimen handling to allow FISH and other molecular studies

• Current biological markers associated with adverse prognosis (Lastowska et al 2001, Schwab et al 2003) (Figs 6.21–6.23):

MYCN amplification

Fig. 6.21

Fig. 6.22

Figs 6.21–6.23 FISH studies on imprint preparations from neuroblastomas, demonstrating MYCN amplification, 1p loss and 17q gain respectively.

Pitfalls and specific issues

• NT, unclassifiable may be used in small needle biopsy specimens

in this setting biological markers become of increasing importance

• Do not diagnose as GN on a small needle biopsy

• If diagnosing tumor type from metastatic site, state this clearly on the report

• The morphological classification is based on surgical resections of pre-treatment specimens

these are almost never encountered now in the UK since initial biopsies are needle core biopsies for diagnosis

post-treatment specimens should be reported as post-treatment NTs with a description of the elements present (Figs 6.24, 6.25)

– classification above is not applicable

• MYCN status remains valid even on viable post-treatment samples

Fig 6.24 Macroscopic photograph of a post-chemotherapy neuroblastoma, demonstrating areas of hemorrhage, necrosis and dystrophic calcification.

Fig 6.25 Photomicrograph of a post-chemotherapy neuroblastoma, demonstrating changes of calcification, collections of hemosiderin-laden and foamy macrophages and reactive fibroblastic proliferation.

RHABDOMYOSARCOMA

• Malignant mesenchymal tumor with skeletal muscle differentiation

• In childhood, two main types

embryonal (eRMS)

alveolar (ARMS)

• Pleomorphic type affects adults

EMBRYONAL RHABDOMYOSARCOMA

Epidemiology

• Commonest pediatric soft tissue sarcoma

• Most <10 yrs

Genetics

• 11p15 loss well-reported

• Not diagnostically useful

• No characteristic fusion transcript

Histopathological features (Figs 6.26–6.31)

• Sheets of immature round to ovoid to spindle mesenchymal cells (rhabdomyoblasts)

• Variably cellular

• Variably loose stroma

• Variable degrees of morphological skeletal muscle differentiation

– differentiation especially prominent postchemotherapy

• May be predominantly immature mesenchymal cells morphologically

small ovoid cells (‘small round blue cells’)

• Spindle cell variant

paratesticular and head and neck

– predominant spindle cells

• Anaplastic / pleomorphic variant

nuclear enlargement, hyperchromasia and anaplasia

Fig. 6.26

Figs 6.26–6.27 Macroscopic photographs of bladder and soft-tissue rhabdomyosarcomas, demonstrating poorly circumscribed, infiltrating lesions of viable cream-colored tumor.

Fig. 6.28

Fig. 6.29

Fig. 6.30

Figs 6.28–6.31 Photomicrographs of embryonal rhabdomyosarcomas, demonstrating ovoid to spindled tumor cells in a loose background stroma, with patchy and variable cytoplasmic eosinophilic rhabdomyomatous differentiation. The cellularity is often variable but is usually most marked immediately beneath the epithelial layer.

ALVEOLAR RHABDOMYOSARCOMA

• Clinically more aggressive variant of RMS

• Alveolar architecture not always present

• Characteristic gene fusion transcript in the majority of cases (see below)

• Approx 20% of all RMS

Clinical features

• Rapidly growing mass lesion

• Almost any site

extremities 40%

• Symptoms according to site

• May present with disseminated disease with or without identifiable primary site

• Bone marrow metastases

Specific issues of specimen handling

• Fusion transcript detection is of diagnostic, prognostic and therapeutic importance and molecular studies mandatory

Immunohistochemical staining (Figs 6.38–6.39)

• Myogenic markers (see eRMS)

• Diffuse, strong nuclear Myogenin+

Fig. 6.38

Figs 6.38–6.39 Photomicrographs of alveolar rhabdomyosarcomas, immunostained to demonstrate strong and diffuse nuclear expression of myogenin in the majority of tumor cells.

EXTRASKELETAL MYXOID CHONDROSARCOMA

Epidemiology

• Mainly adults

pediatric cases well reported

Genetics

• t(9;22)(q22;q12) in >50%

• t(9;17)(q22;q11) in a minority

• Diagnostic when present

Clinical features

• Mass in deep soft tissues of limbs / limb girdle

also trunk, head and neck

• 90% 5-year survival

40% long-term (15-year) mortality

• Local recurrence and metastases

Immunohistochemical staining

• Non-diagnostic

• S100, CK, EMA variable in a minority

Differential diagnoses and pitfalls

• May show focal rhabdoid phenotype but different molecular and immunostaining

• Large size, anaplasia and rhabdoid features may be associated with worse prognosis

DESMOPLASTIC SMALL ROUND CELL TUMOR

Epidemiology

• Children and young adults

Genetics

• Characteristic and diagnostic

• t(11;22)(p13;q12)

Clinical features

• Usually presents with disseminated abdominal disease

now reported at many other sites

• Presentation depends on site

EXTRARENAL MALIGNANT RHABDOID TUMOR

Epidemiology

• Infants and children

• Congenital tumors reported

• Rarely familial

• Association with family history of range of malignancies and posterior fossa tumors

Genetics

• hSNF5/INI1 gene abnormalities chromosome 22 (Uno et al 2002)

Clinical features

• Mass lesions at almost any site

• Presentation depends on site

• Aggressive, poor prognosis

improving with current chemotherapy regimes

Histopathological features (Figs 6.44–6.49)

• Small cell variant

little cytoplasm

• Some may have markedly myxoid stroma

Fig 6.44 Macroscopic photograph of primary soft-tissue malignant rhabdoid tumor demonstrating a poorly circumscribed, infiltrating lesion with hemorrhage and necrosis.

Fig. 6.45

Fig. 6.46

Fig. 6.47

Fig. 6.48

Figs 6.45–6.49 Photomicrographs of malignant rhabdoid tumors, demonstrating tumor cells with open vesicular nuclei and prominent nucleoli, with variable eosinophilic cytoplasmic ‘rhabdoid’ inclusions. Tumors may vary from highly cellular to myxoid.

Immunohistochemical staining (Figs 6.50–6.53)

• Coexpression of CK and vimentin

• Paranuclear ‘dot like’ vimentin expression highlights inclusions

• Variable non-diagnostic expression of other antibodies

• Negative INI1 nuclear expression

essentially diagnostic

hSNF5/INI1 IHC is very sensitive and highly specific for the detection of hSNF5/INI1 loss-of-function group of tumors

– some of which do not exhibit a classical rhabdoid phenotype but which behave similarly aggressively (Hoot et al 2004, Haberler et al 2006, Bourdeaut et al 2007)

Fig. 6.50

Figs 6.50–6.51 Photomicrographs of malignant rhabdoid tumors, immunostained with vimentin, demonstrating the characteristic focal expression with perinuclear cytoplasmic accentuation.

Fig. 6.52

Figs 6.52–6.53 Photomicrographs of malignant rhabdoid tumors, immunostained with INI1, demonstrating normal nuclear expression in infiltrating non-tumor cells but complete lack of expression in the tumor cells. Lack of INI1 expression now allows diagnosis of malignant rhabdoid tumors with a high degree of certainty even on small biopsies.

Special diagnostic investigations

• Electron microscopy (Fig 6.54)

diagnostic perinuclear cytoplasmic inclusions of intermediate filaments

Fig 6.54 Electron photomicrograph of a malignant rhabdoid tumor, demonstrating characteristic perinuclear whorled filaments, corresponding to the inclusions highlighted with vimentin immunostaining.

PRIMITIVE NEUROECTODERMAL TUMOR (PNET)

Introduction

• Classical pediatric ‘small round blue cell tumor’

• Definitive diagnosis now based on immunohistochemical and molecular findings

• Soft tissue counterpart of Ewing’s sarcoma of bone

• Probable neural crest derivation

Clinical features

• Soft deep mass at almost any site

Including head and neck, chest, pelvis and extremities

• Presentation depends on site

Histopathological features (Figs 6.55–6.60)

• Cellular sheets of uniform small round cell tumor

• Often thin septae separating ‘lobules’

• Round to ovoid cells

sometimes spindled or even epithelioid

• Scanty but variable cytoplasm

• Coarse or clumped chromatin

• Focal rosettes or pseudorosettes may be present

• Variable hyalinized stroma

May be especially prominent post-chemotherapy

Fig 6.55 Macroscopic photograph of post-chemotherapy PNET showing the dumbbell shaped central tumor with extensive necrosis.

Fig. 6.56

Fig. 6.57

Figs 6.56–6.58 Photomicrographs of PNET, demonstrating sheets of uniform round to ovoid tumor cells, which may show cytoplasmic clearing, but no other specific diagnostic morphological features (the classical pediatric ‘small round blue cell tumor’).

Fig. 6.59

Figs 6.59–6.60 Photomicrographs of PNET immunostained with CD99, showing strong, uniform membranous expression.

LIPOMATOUS TUMORS

LIPOBLASTOMA / LIPOBLASTOMATOSIS

• Localized (lipoblastoma) or diffuse (lipoblastomatosis) lesions characterized by immature adipose tissue with numerous lipoblasts

Epidemiology

congenital cases reported (Singh et al 2004)

Genetics

• 8q11-13 defects

likely PLAG1 related

• Not diagnostically applicable at present

Clinical features

• Enlarging, painless mass

• Usually extremities

internal and visceral sites also well-described

• 10–20% recurrence risk

Macroscopic features

• Lobulated fatty mass

Differential diagnoses and pitfalls

• Morphologic differential with myxoid liposarcoma

age and clinical features are distinct

liposarcoma exceptionally rare in young children

LIPOMA

• Benign tumors composed of mature fat

• Most common soft tissue mesenchymal neoplasm of adults

relatively rarer in children

Genetics

• Many cytogenetic abnormalities reported

none in diagnostic use

Clinical features

• Most present as painless soft tissue masses

• Usually of small size

MYXOID LIPOSARCOMA

• Liposarcoma, all variants, are exceptionally rare in childhood

• Usually deep

• Characterized by adipocyte nuclear atypia of varying degrees.

• Myxoid / round cell liposarcoma believed to be a tumor of primitive mesenchymal cells

• Pleomorphic, mixed, dedifferentiated and well-differentiated types exceptionally rare in childhood.

Epidemiology

• Myxoid liposarcoma is least rare type in pediatric practice

usually young adults

Genetics

• Diagnostic and characteristic t(12;16)(q13;p11)>90% CHOP-TLS fusion

• t(12;22)(q13;q12) CHOP-EWS variant

Clinical features

• Painless mass

• Deep soft tissues and extremities

Immunohistochemical staining

Differential diagnoses and pitfalls

• Unfavorable outcome if localized associated with:

>5% round cell areas

p53 overexpression

• Poor prognosis if multifocal

• Outcome not related to specific molecular translocation

SPINDLE CELL TUMORS

NODULAR FASCIITIS

• Subcutaneous lesion composed of fibroblasts / myofibroblasts

characteristic ‘tissue culture’ morphology

• Intravascular fasciitis and cranial fasciitis are variants

Epidemiology

• Mainly young adults

well described in children

– cranial fasciitis in those <2 years

• Possibly initiated / stimulated by trauma

Clinical features

trunk, arm, head and neck mainly

• Rapidly growing tender mass

• Usually <5cm

Immunohistochemical staining

Differential diagnoses and pitfalls

• No metastases, recurrence is very rare

if occurs post resection, reconsider diagnosis

PROLIFERATIVE FASCIITIS / MYOSITIS

• Subcutaneous (proliferative fasciitis)

• Intramuscular (proliferative myositis)

Epidemiology

• Usually middle aged and older

reported in childhood

– much less common than nodular fasciitis

Clinical features

• Subcutaneous or intramuscular masses on extremities or trunk

• Rarely recur

• Local resection curative

Immunohistochemical staining

mainly spindle cell component

MYOSITIS OSSIFICANS

• Reactive lesion

• Fibrous tissue and bony elements

Epidemiology

peak in young adults

Clinical features

• Rapid growth of lesion

initially swollen and painful

especially those likely to undergo trauma

• Evolves to painless subcutaneous mass

Differential diagnoses and pitfalls

• May not show well-formed zonal pattern in:

digital lesions

small superficial lesions

MYOSITIS OSSIFICANS PROGRESSIVA / FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

• Aggressive fibromatosis-like condition

• Autosomal dominant

FOP gene chromosome 4 (Feldman et al 2000)

• Probably related to overexpression of BMP4

• Results in permanent fibrosis and ossification of soft tissues

Epidemiology

Histopathological features

• Fibromatosis-like morphology

• No specific diagnostic features

Special diagnostic investigations

• Radiology of hand / feet may demonstrate characteristic changes

Differential diagnoses and pitfalls

• Always consider as differential diagnosis in apparent fibromatosis-like lesions of trunk and back

FIBROUS HAMARTOMA OF INFANCY

• Benign soft tissue mass of childhood

Epidemiology

• Usually < 5 years of age,

majority < 2 years of age

– 25% congenital

Clinical features

• Trunk and limbs

usually upper arm and shoulder

• Painless solitary subcutaneous mass

• May recur locally

• Local excision treatment of choice (Carretto et al 2006)

Immunohistochemical staining

• Spindle cells vimentin+

• Scattered CD34+

Differential diagnoses and pitfalls

• Highly variable amounts of each component

• In older children lesions may show extensive sclerosis

MYOFIBROMATOSIS

• Benign myofibroblastic neoplasms

• May be isolated (myofibroma) or multiple / diffuse (myofibromatosis)

• Spectrum of morphology with infantile hemangiopericytoma

Epidemiology

• Most <2 years of age

Genetics

• Most sporadic

rare familial cases

– autosomal recessive and dominant modes suggested (Zand et al 2004)

Immunohistochemical staining

Differential diagnoses and pitfalls

• May have highly variable presentation in small infants with extensive multifocal disease

• Zonal pattern may not be apparent on a small needle core biopsy

JUVENILE HYALINE FIBROMATOSIS

• Systemic disorder

• Multiple abnormal tumorous masses

due to extracellular collections of amorphous matrix-like material

• Overlap with infantile systemic hyalinosis (Antaya et al 2007)

Epidemiology

• Initially presents in infancy

Genetics

• Autosomal recessive defect in collagen production

no currently available routine diagnostic test

• Germline mutations in capillary morphogenesis gene-2 (CMG2) responsible for both JHF and ISH (Dowling et al 2003, Antaya et al 2007)

Clinical features

• Multiple superficial and deep nodular tumors

especially head and neck, gingiva, soft tissue and bone

• Recurrence and new lesions develop

Immunohistochemical staining

• Spindle cells vimentin+

Special diagnostic investigations

• Electron microscopy

fibroblasts with abnormal membrane bound vacuoles containing matrix like material

Differential diagnoses and pitfalls

• Probable continuum with infantile systemic hyalinosis

INCLUSION BODY FIBROMATOSIS

• Characteristic lesions affecting digits of children with intracytoplasmic inclusions (infantile digital fibromatosis)

Epidemiology

• Infants and young children

Clinical features

• Painless swellings usually on dorsum of digits of infants

usually ulnar digits

• Rapid growth

• Now reported at other sites in soft tissues also, hence current name

Immunohistochemical staining

Special diagnostic investigations

• Electron microscopy

intracytoplasmic filamentous inclusions

Differential diagnoses and pitfalls

• Inclusions present only in minority of cells

often much easier to identify with Trichrome stain

CALCIFYING APONEUROTIC FIBROMA

• Painless spindle cells nodule usually affecting of palms and soles

Epidemiology

Clinical features

• Palms, soles, wrists and ankles mainly

reported at many other sites near tendons / aponeuroses

• Small, non-tender nodular mass

• 50% recurrence risk

Immunohistochemical staining

Differential diagnoses and pitfalls

• Lesions may be more cellular and less mineralized in young children

SUPERFICIAL FIBROMATOSES

• Infiltrative fibroblastic proliferations

• Palmar and plantar recognized specific types

• Pediatric superficial fibromatoses NOS probably also represent members of this group

Clinical features

• Firm, painless nodules

• Palmar and plantar cases have median age of 9 years in childhood (Fetsch et al 2005)

plantar more common in children

• One-third to one-half associated with family history

• Local recurrence common

Immunohistochemical staining

• Variable SMA+

Differential diagnoses and pitfalls

• Remains uncertain whether superficial infantile / juvenile fibromatoses NOS are best regarded in this group or as members of the aggressive / desmoid-type fibromatosis group

beta-catenin data suggests superficial and deep fibromatoses are biologically different entities

DESMOID-TYPE (AGGRESSIVE) FIBROMATOSIS

• Deep, infiltrative fibroblastic lesions

Epidemiology

Differential diagnoses and pitfalls

• Desmoid type fibromatosis in childhood may indicate APC abnormalities and be associated with familial polyposis

• Trunk fibromatoses may also be part of myositis ossificans progressiva

LIPOFIBROMATOSIS

• Fibrofatty tumor of distal extremities

Epidemiology

Clinical features

• Painless mass affecting forearms, hands, feet

rarely other sites

• May be congenital

• 70% recurrence (Fetsch et al 2000)

Immunohistochemical staining

• BCL2, S100, CD34±

Differential diagnoses and pitfalls

• May initially look like a ‘deep’ fibrous hamartoma of infancy but does not have an immature mesenchymal element

GARDNER FIBROMA

• Benign collagenous subcutaneous lesion associated with desmoid fibromatosis and Gardner syndrome / polyposis colli

Epidemiology

Genetics

• Associated with Gardner syndrome, familial adenomatous polyposis

APC mutations

Clinical features

• Plaque-like superficial and deep painless lesions

affecting trunk, head and neck and extremities

– 60% on back and paraspinal areas

• 70% have known FAP at presentation

• Remainder first presentation with fibroma should indicate patient and familial colonic screening

Histopathological features

• Poorly circumscribed lesion

• Bland hypocellular proliferation of haphazardly arranged coarse collagen fibers

• Hypocellular proliferation of spindle cells

• Scattered small blood vessels

• Sparse mast cell infiltrate

• Entraps fat and muscle at periphery

Immunohistochemical staining

• 60% nuclear beta-catenin+ (Coffin et al 2007)

Differential diagnoses and pitfalls

• Lesions which look like nuchal-type fibroma in childhood may be Gardner fibromas

INFLAMMATORY MYOFIBROBLASTIC TUMOR

• Soft tissue or visceral lesion composed of admixed myofibroblasts and inflammatory cells

• Unclear whether all cases are neoplastic versus reactive (inflammatory pseudotumor / plasma cell granuloma)

Epidemiology

• Mean 10 yrs

Genetics

• ALK rearrangements in a proportion

genetic analysis not used diagnostically

– although immunostaining may be useful (see below)

Histopathological features (Figs 6.87–6.91)

• Composed of a mixture of:

inflammatory cells

• Stroma may be:

variably collagenous and even fibromatosis-like

• Small vessels surrounded by plump spindled myofibroblasts

• Variable inflammatory infiltrate

mainly lymphocytes, plasma cells and eosinophils

• Increased recurrence risk if:

presence of ganglion like cells

Fig. 6.87

Figs 6.87–6.88 Macroscopic photographs of inflammatory myofibroblastic tumors, showing a solid infiltrating pattern of growth.

Fig. 6.89

Fig. 6.90

Figs 6.89–6.91 Photomicrographs of cases of inflammatory myofibroblastic tumors, demonstrating the characteristic combination of proliferating spindled myofibroblastic cells with admixed, predominantly mononuclear, inflammatory cells.

Differential diagnoses and pitfalls

• No good morphological predication of behavior

CONGENITAL / INFANTILE FIBROSARCOMA

Epidemiology

40–80% congenital

• Rare after age 2

Histopathological features (Figs 6.93–6.95)

• Infiltrative, lobulated, poorly circumscribed mass

• Highly cellular

• Interlacing fascicles of plump spindle-ovoid cells

may show focal ‘herringbone pattern’

– rarely seen on needle biopsy

• Focal necrosis / hemorrhage

• Focal hemangiopericytoma like vascular pattern

may be prominent

• Minimal atypia

rarely high grade pleomorphic areas

• Mitoses numerous

• May show inflammatory cells and hematopoiesis

Fig. 6.93

Fig. 6.94

Figs 6.93–6.95 Photomicrographs of cases of molecular proven congenital-infantile fibrosarcoma, demonstrating fascicles of plump spindle-ovoid cells, with variable admixed inflammatory cells. Some cases may show a typical ‘fibrosarcoma’ pattern, whilst others show only a hemangiopericytoma-like appearance with plump ovoid cells.

Immunohistochemical staining

• Non-diagnostic

• Variable expression of most other markers

Special diagnostic investigations

• RTPCR is diagnostic in the appropriate clinical context and is required for definitive diagnosis on needle core biopsy

Differential diagnoses and pitfalls

• May appear as a vascular lesion on initial imaging studies and prominent vascular pattern also histologically

LOW GRADE FIBROMYXOID SARCOMA

Epidemiology

• Rare, usually adults

20% in childhood / adolescence (Billings et al 2005)

Genetics

• Characteristic t(7;16)(q33;p11)–FUS-CREB3L2 fusion (Mertens et al 2005, Matsuyama et al 2006)

detectable by RT-PCR

Clinical features

• Painless, deep, slowly growing soft tissue mass on trunk

superficial or deep on extremities

• 10% recurrence

• 5% metastases

• 2% mortality

Immunohistochemical staining

• Focal expression of SMA, CD68, EMA

Differential diagnoses and pitfalls

• Nuclei look very bland

architectural pattern and molecular findings are important

SMOOTH MUSCLE TUMORS IN IMMUNOCOMPROMISED PATIENTS

Epidemiology

• More common in immunocompromised children than adults

HIV or post-transplant

Clinical features

• Usually visceral lesions rather than soft tissue

Immunohistochemical staining

Special diagnostic investigations

• EBV-related

Differential diagnoses and pitfalls

• Smooth muscle tumors in general are much rarer in children than adults

leiomyoma / leiomyosarcoma in childhood, consider underlying immunodeficiency

FETAL-TYPE RHABDOMYOMA

Epidemiology

Genetics

• None diagnostic

• ?PTCH and nevoid basal cell carcinoma syndrome associated

Clinical features

• Head and neck

• Soft tissue mass

Immunohistochemical staining

Differential diagnoses and pitfalls

• Main differential in childhood is embryonal rhabdomyosarcoma

site is superficial in rhabdomyoma

no atypia in rhabdomyoma

less cellular and more differentiation in rhabdomyoma

[/level-membership-for-pathology-category][not-level-membership-for-pathology-category]

CHAPTER 6 TUMORS AND TUMOR-LIKE LESIONS

INTRODUCTION

• Although many tumors are more common at certain sites, for ease of reference, the majority of tumors or lesions which may be resected or biopsied with a clinical suspicion of tumor, are included in this section

• Tumors which only affect a very specific site are included in their respective system chapters

• Most of the lesions covered here would be broadly considered ‘pediatric soft tissue tumors’

PEDIATRIC ‘BLASTOMAS’ / ‘SMALL ROUND CELL’ TUMORS

INTRODUCTION

• A large number of pediatric embryonal tumors share a component with a ‘small round blue cell’ phenotype (SRBCT)

• Many of the diagnostic morphological findings require assessment of overall architecture and other features which may not necessarily be present in needle core biopsy specimens

• Immunohistochemical staining and molecular techniques may be required in a large proportion of such specimens for definitive diagnosis

• A targeted immunohistochemical panel should be performed to determine appropriate positive and negative findings

• Since morphological features may be non-diagnostic, adequate clinical history, imaging and results of other investigations are essential for appropriate interpretation

• Even if a diagnosis is suggested clinically, always review all other possibilities

pediatric tumors may present in an atypical fashion at atypical sites and the apparent history submitted may be misleading

• The most immediate issues for management in most cases are the differential between leukemia / lymphoma, rhabdomyosarcoma, other high grade embryonal sarcoma such as PNET and other less aggressive tumors

• Due to their rarity, and hence potential diagnostic difficulty, in non-specialist centers, primary diagnosis of all embryonal pediatric tumors should be reviewed by a specialist center / review panel and additional investigations performed as required

HANDLING OF PEDIATRIC TUMOR SPECIMENS

• Many pediatric tumors require additional investigations for their definitive diagnosis and prognosis

molecular investigation

electron microscopy

• Optimal specimen handling makes performance and interpretation of these techniques much easier

• All diagnostic pediatric tumor specimens should be submitted to the laboratory as fresh tissue immediately following biopsy where possible

• The specimen should be divided according to predetermined standard operating procedures, with aliquots for:

formalin fixation and paraffin embedding

glutaraldehyde fixation for electron microscopy

snap freezing or storage in RNA protection medium for molecular studies such at RT-PCR

imprints / ‘dabs’ fixed for FISH in methanol

sample for cytogenetic studies

frozen for storage and subsequent analysis if required

• All laboratories providing a diagnostic pathology service for pediatric tumors should have facilities available for handling of fresh specimens and access to appropriate molecular diagnostic services

• Advances in technical aspects now mean that many molecular techniques, such as FISH and RT-PCR, may also be performed on routinely fixed paraffin embedded material

this should be carried out by centers experienced in their interpretation since the diagnostic yield is lower and technical aspects of the test performance and interpretation may require modification

Issues specific to needle core biopsy specimen interpretation in pediatric tumor diagnosis (Figs 6.1, 6.2)

• In an increasing number of centers, primary diagnostic investigation of suspected pediatric tumors is on the basis of an image guided needle core biopsy

• Limited amounts of tissue are obtained, making optimal specimen handling of importance

• A full range of ancillary investigations is possible in the vast majority of needle biopsy specimens in centers experienced in their handling

• Limited material is available for morphological analysis in such cases

many of the ‘diagnostic’ architectural features referred to in standard texts may not be applicable to the interpretation of these limited samples

extensive use of ancillary investigations such as immunostaining and molecular analysis should be carried out where required in order to reach a definitive diagnosis

• ‘Molecular profiling’ of tumors is likely to become of increasing importance for both determining diagnosis, and prognosis and management in pediatric tumors

traditional morphological characteristics may become less applicable due to changes in understanding of the biology of these tumors

• Needle biopsies are safe, with a high adequacy rate and diagnostic yield and associated low morbidity

both complication rate and adequacy are operator dependant

– ideally performed in specialist centers

• The report in such cases should provide as much information as possible, but not more

caution not to overinterpret non-diagnostic findings in limited samples

Fig 6.1 Low power scan of a glass slide with tumor core biopsies demonstrating multiple cores of tissue for diagnosis.

Fig 6.2 Low power photomicrograph of a tumor core biopsy demonstrating adequate material for diagnosis.

PERIPHERAL NEUROBLASTIC TUMORS (NTS)

• Overall around 85% are NB, 5% GNBi, <1% GN and 5–10% GNBn (Shimada et al 2003)

• May occur at wide range of sites

most commonly adrenal glands and retroperitoneal primary sites

– thoracic NTs relatively more likely to represent GNB, GN

can present with metastatic disease

• Risk stratification for prognosis and management is based on age, stage, MYCN, and Shimada pathology classification, and an increasing number of other molecular (biological) markers

NEUROBLASTOMA

• Incidence around 1 per 100,000 (Schwab et al 2003)

• 70% have metastatic disease at presentation (Ara et al 2006)

• Age, clinical stage, molecular findings and undifferentiated subtype influence overall survival (Lastowska et al 2002, Shimada et al 2001, Goto et al 2001, Ikeda et al 2002, Burgues et al 2006, Navarro et al 2006, Sano et al 2006)

Histopathological features (Figs 6.3–6.8)

• International Neuroblastoma Pathology Classification (INPC) system (Shimada et al 1999)

• By definition

Schwannian stroma comprises <50% of the tumor

• Sheets or nests of neuroblasts

varying stages of differentiation

background neurofibrillary stroma

variegated (‘salt and pepper’) chromatin pattern

Fig. 6.3

Figs 6.3–6.4 Macroscopic photographs of adrenal-associated neuroblastomas, demonstrating variable appearance from expansion of the adrenal cortex by dark tumor to nodular architecture of soft, cream-brown viable tumor.

Fig. 6.5

Fig. 6.6

Fig. 6.7

Figs 6.5–6.8 Photomicrographs of cases of neuroblastoma, demonstrating tumor composed of sheets and nests of small ovoid cells within a variably prominent neurofibrillary background.

NB, undifferentiated

• No obvious morphological differentiation

no ganglion cell differentiation of neuroblasts

no definite neurofibrillary stroma on light microscopy

sheets of small round to ovoid cells

• Supplementary techniques such as immunohistochemical staining and biological marker status required for the definitive diagnosis

NB, poorly differentiated

• Morphological nests of neuroblasts

within neurofibrillary background stroma

– usually identifiable on routine light microscopy

• <5% of neuroblasts show ganglion cell differentiation

GANGLIONEUROBLASTOMA, INTERMIXED (Figs 6.11–6.14)

• Well defined nests of neuroblasts

within neurofibrillary background stroma

– intermixed / scattered throughout the lesion

usually differentiating neuroblasts within the nests

• No discreet macroscopically identifiable nodule

• <50% of the lesion represented by NB

• >50% of the lesion represented by Schwannian stroma and mature ganglion cells

Fig. 6.11

Figs 6.11–6.12 Macroscopic photographs of ganglioneuroblastoma, intermixed, demonstrating solid expansile masses with yellow cut surface. Note the area of hemorrhage in Fig 6.12 compared to the area of neuroblastomatous tissue in ganglioneuroblastoma, nodular in Fig 6.15.

Fig. 6.13

Figs 6.13–6.14 Photomicrographs of cases of ganglioneuroblastoma, intermixed, in which, overall, >50% of the lesion is represented by Schwannian stroma and mature ganglion cells, with admixed well-defined nests of neurofibrillary stroma, within which are differentiating neuroblasta.

GANGLIONEUROBLASTOMA, NODULAR (Figs 6.15–6.17)

• Macroscopic, hemorrhagic nodule within a larger bland lesion

• Surrounding areas of stroma-rich or stroma-dominant areas with mature or maturing ganglion cells

• Well demarcated nodule of Schwannian stroma-poor neuroblastomatous tissue

may be multiple

nodules morphologically those of neuroblastoma (see above)

• Outcome of GNBn

based on prognostic features of the NB component (Peuchmaur et al 2003)

– including all molecular / biological markers

Fig 6.15 Macroscopic photograph of a ganglioneuroblastoma, nodular demonstrating a uniform, bland solid yellow lesion with a macroscopically visible area of hemorrhagic neuroblastoma.

Fig. 6.16

Figs 6.16–6.17 Photomicrographs of a ganglioneuroblastoma, nodular in which most areas are composed of Schwannian stroma and mature ganglion cells, but the hemorrhagic nodule shows features indistinguishable from neuroblastoma.

NEUROBLASTIC TUMOR, UNCLASSIFIABLE

• May be used in small biopsy specimens since representativeness is unknown

NEUROBLASTOMA (SCHWANNIAN STROMA POOR), NOS

• Definite NB but subtyping not possible due to necrosis, etc

Additional investigations

• Molecular studies are mandatory in risk stratification and management planning in neuroblastic tumors

importance of optimal specimen handling to allow FISH and other molecular studies

• Current biological markers associated with adverse prognosis (Lastowska et al 2001, Schwab et al 2003) (Figs 6.21–6.23):

MYCN amplification

Fig. 6.21

Fig. 6.22

Figs 6.21–6.23 FISH studies on imprint preparations from neuroblastomas, demonstrating MYCN amplification, 1p loss and 17q gain respectively.

Pitfalls and specific issues

• NT, unclassifiable may be used in small needle biopsy specimens

in this setting biological markers become of increasing importance

• Do not diagnose as GN on a small needle biopsy

• If diagnosing tumor type from metastatic site, state this clearly on the report

• The morphological classification is based on surgical resections of pre-treatment specimens

these are almost never encountered now in the UK since initial biopsies are needle core biopsies for diagnosis

post-treatment specimens should be reported as post-treatment NTs with a description of the elements present (Figs 6.24, 6.25)

– classification above is not applicable

• MYCN status remains valid even on viable post-treatment samples

Fig 6.24 Macroscopic photograph of a post-chemotherapy neuroblastoma, demonstrating areas of hemorrhage, necrosis and dystrophic calcification.

Fig 6.25 Photomicrograph of a post-chemotherapy neuroblastoma, demonstrating changes of calcification, collections of hemosiderin-laden and foamy macrophages and reactive fibroblastic proliferation.

RHABDOMYOSARCOMA

• Malignant mesenchymal tumor with skeletal muscle differentiation

• In childhood, two main types

embryonal (eRMS)

alveolar (ARMS)

• Pleomorphic type affects adults

EMBRYONAL RHABDOMYOSARCOMA

Epidemiology

• Commonest pediatric soft tissue sarcoma

• Most <10 yrs

Genetics

• 11p15 loss well-reported

• Not diagnostically useful

• No characteristic fusion transcript

Histopathological features (Figs 6.26–6.31)

• Sheets of immature round to ovoid to spindle mesenchymal cells (rhabdomyoblasts)

• Variably cellular

• Variably loose stroma

• Variable degrees of morphological skeletal muscle differentiation

– differentiation especially prominent postchemotherapy

• May be predominantly immature mesenchymal cells morphologically

small ovoid cells (‘small round blue cells’)

• Spindle cell variant

paratesticular and head and neck

– predominant spindle cells

• Anaplastic / pleomorphic variant

nuclear enlargement, hyperchromasia and anaplasia

Fig. 6.26

Figs 6.26–6.27 Macroscopic photographs of bladder and soft-tissue rhabdomyosarcomas, demonstrating poorly circumscribed, infiltrating lesions of viable cream-colored tumor.

Fig. 6.28

Fig. 6.29

Fig. 6.30

Figs 6.28–6.31 Photomicrographs of embryonal rhabdomyosarcomas, demonstrating ovoid to spindled tumor cells in a loose background stroma, with patchy and variable cytoplasmic eosinophilic rhabdomyomatous differentiation. The cellularity is often variable but is usually most marked immediately beneath the epithelial layer.

ALVEOLAR RHABDOMYOSARCOMA

• Clinically more aggressive variant of RMS

• Alveolar architecture not always present

• Characteristic gene fusion transcript in the majority of cases (see below)

• Approx 20% of all RMS

Clinical features

• Rapidly growing mass lesion

• Almost any site

extremities 40%

• Symptoms according to site

• May present with disseminated disease with or without identifiable primary site

• Bone marrow metastases

Specific issues of specimen handling

• Fusion transcript detection is of diagnostic, prognostic and therapeutic importance and molecular studies mandatory

Immunohistochemical staining (Figs 6.38–6.39)

• Myogenic markers (see eRMS)

• Diffuse, strong nuclear Myogenin+

Fig. 6.38

Figs 6.38–6.39 Photomicrographs of alveolar rhabdomyosarcomas, immunostained to demonstrate strong and diffuse nuclear expression of myogenin in the majority of tumor cells.

EXTRASKELETAL MYXOID CHONDROSARCOMA

Epidemiology

• Mainly adults

pediatric cases well reported

Genetics

• t(9;22)(q22;q12) in >50%

• t(9;17)(q22;q11) in a minority

• Diagnostic when present

Clinical features

• Mass in deep soft tissues of limbs / limb girdle

also trunk, head and neck

• 90% 5-year survival

40% long-term (15-year) mortality

• Local recurrence and metastases

Immunohistochemical staining

• Non-diagnostic

• S100, CK, EMA variable in a minority

Differential diagnoses and pitfalls

• May show focal rhabdoid phenotype but different molecular and immunostaining

• Large size, anaplasia and rhabdoid features may be associated with worse prognosis

DESMOPLASTIC SMALL ROUND CELL TUMOR

Epidemiology

• Children and young adults

Genetics

• Characteristic and diagnostic

• t(11;22)(p13;q12)

Clinical features

• Usually presents with disseminated abdominal disease

now reported at many other sites

• Presentation depends on site

Immunohistochemical staining (Figs 6.42, 6.43)

• Polyphenotypic expression of nest cells

· dot-like intracytoplasmic

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