TUMORS AND TUMOR-LIKE LESIONS

CHAPTER 6 TUMORS AND TUMOR-LIKE LESIONS

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

• 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.

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

Specific issues of specimen handling

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

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

Tags: Diagnostic Pediatric Surgical Pathology Expert Consult

Jun 18, 2016 | Posted by admin in PEDIATRICS | Comments Off

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