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(BQ) Part 2 book Biopsy interpretation of pediatric lesions presentation of content: Central nervous system and skeletal muscle, hematopoietic system, the heart, the lung, pancreas, adrenal, thyroid, parathyroid, and selected head and neck, breast and reproductive system, skin.
6 CENTRAL NERVOUS SYSTEM AND SKELETAL MUSCLE Peter Pytel, MD Most pediatric biopsies encountered in general practice are of lesions in the central nervous system In some instances, however, biopsies sampling peripheral nerves, skeletal muscles, or peripheral ganglion cells are received These latter biopsies are often referred for specialized processing and are only discussed briefly in this chapter Most of the chapter focuses on CNS tumors and their mimics, which are discussed separately even though the practicing pathologist will consider both of these in the differential diagnosis of any given case CENTRAL NERVOUS SYSTEM TUMORS In absolute numbers, pediatric central nervous system (CNS) tumors are relatively rare, but proportionally, they represent the most common solid neoplasm occurring in the pediatric age group They are a very diverse group of tumors complicating the classification as well as the study of these lesions.1–3 Children more commonly present with infratentorial tumors in contrast to adults in whom tumors are more often supratentorial As in adults, the anatomic location is a key consideration in the process of making a diagnosis (Table 6.1) In many cases, the received specimen does not provide any clues for determining the anatomic location of a tumor, and in many institutions, the specimen requisition forms lack detail beyond a generic description of “brain tumor.” The neuroradiology images, therefore, provide critical information for the pathologist Pediatric CNS tumors are classified according to the World Health Organization (WHO) classification.1,2 The assigned WHO grade describes the biology of the lesion, but a low grade does not always imply a good outcome In this classification system, pediatric tumors are stratified according to the same criteria as those used for adults As discussed in the following section, there are some limitations to this approach Tumors classified as glioblastoma in children may, for example, 172 Husain_Ch06.indd 172 3/3/14 4:26 PM CENTRAL NERVOUS SYSTEM AND SKELETAL MUSCLE ——— 173 TABLE 6.1 Common Tumors to Consider in the Differential Diagnosis According to Anatomic Sites Posterior Fossa/ Brainstem and Cerebellopontine Angle Sellar/ Suprasellar Pineal Region Posterior Fossa/ Cerebellum and Fourth Ventricle Craniopharyngioma Pineal parenchymal tumor Pilocytic astrocytoma Intrinsic pontine glioma Germ cell tumor Germ cell tumor Medulloblastoma Pilocytic astrocytomas Optic glioma Papillary tumor of the pineal regiona Ependymoma Epidermoid Meningiomaa Astrocytomaa Choroid plexus tumor Schwannomaa Pituitary adenomaa Hemangioblastomaa Chordomaa a Rare in children be different biologically from tumors with similar morphology found in adults (Table 6.2) Cases that defy accurate classification despite best efforts may also be more common in children Systemic metastases from brain tumors are highly unusual Thus, in most cases, the main treatment strategy is focused on preventing or delaying local recurrence or to control growth In some of the entities discussed in the following section, however, cerebrospinal fluid (CSF) dissemination is relatively common Patients with ependymomas or medulloblastomas therefore will typically have imaging studies of the entire neuro-axis Some patients including those with medulloblastoma will receive radiation treatment to the entire neuro-axis Pilocytic Astrocytoma Pilocytic astrocytoma is a WHO grade I neoplasm that is most common in the first two decades of life Common anatomic sites are the cerebellum, optic nerve/chiasm, and hypothalamus, but these tumors can be found virtually anywhere within the CNS In some cases, like a patient with cerebellar pilocytic astrocytoma, surgery can be curative In other patients, a hypothalamic tumor may slowly progress and ultimately be lethal This example illustrates that we may consider certain tumors low-grade but that it can be very misleading to talk about “benign” Husain_Ch06.indd 173 3/3/14 4:26 PM 174 ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS TABLE 6.2 Primary Tumors Commonly Exhibiting the Listed Individual Morphologic Feature Tumors with Desmoplasia Tumors with Large (Nonneuronal) Cells Tumors with Oligodendroglioma-like Appearance/Clear Cell Features PXA PXA DNET SEGA Clear cell ependymoma DIA/DIG a Gliosarcoma Giant cell glioblastomaa Central neurocytoma Oligodendrogliomaa Tumors with Papillary/ Pseudopapillary Features Choroid plexus tumor a Ependymoma Astroblastoma Papillary meningioma Papillary tumor of the pineal regiona a Rare in children PXA, pleomorphic xanthoastrocytoma; DNET, dysembryoplastic neuroepithelial tumor; DIA/DIG, desmoplastic infantile astrocytoma/ganglioglioma; SEGA, subependymal giant cell astrocytoma brain tumors Another uncommon but described phenomenon supporting this same point is the fact that patients with pilocytic astrocytoma may develop CSF dissemination Radiologically and grossly pilocytic astrocytomas are often associated with cyst formation On enhanced magnetic resonance images, they typically exhibit enhancement (Fig 6.1) Prototypical cases are circumscribed with an expansile growth pattern This can be a helpful diagnostic clue, but cases with more infiltrative edges are reported Typical morphologic features (Fig 6.2) of pilocytic astrocytoma include variation between dense and loose areas, presence of sometimes prominent hyalinized blood vessels, bipolar spindle cells with long processes, Rosenthal fibers, and sometimes eosinophilic granular bodies (EGBs) The presence of random atypical cells, degenerative changes with thrombosed vessels, organizing hemorrhage, necrosis, and mitotic figures may be worrisome or raise concern for other diagnoses But these changes can all be part of the spectrum of pilocytic astrocytomas Actual malignant progression in a pilocytic astrocytoma is described but highly unusual Some cases may exhibit areas mimicking oligodendroglial differentiation Husain_Ch06.indd 174 3/3/14 4:26 PM CENTRAL NERVOUS SYSTEM AND SKELETAL MUSCLE ——— 175 A B C Husain_Ch06.indd 175 FIGURE 6.1 Pilocytic astrocytoma A: This MRI shows a large mass lesion in the cerebellum with enhancement and cystic structures B: Intraoperative smear preparations show bland spindle cells C: These are associated with long, delicate “hairlike” (i.e., piloid) processes and eosinophilic Rosenthal fibers (arrow) 3/3/14 4:26 PM 176 ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS A FIGURE 6.2 Pilocytic astrocytoma A: Pilocytic astrocytoma with microcysts and solid expansile growth pattern without entrapment of preexisting structures B: Rosenthal fibers (arrows) are a helpful feature if present but are not a prerequisite Husain_Ch06.indd 176 B 3/3/14 4:26 PM CENTRAL NERVOUS SYSTEM AND SKELETAL MUSCLE ——— 177 Depending on the morphologic features exhibited in a given case, the differential diagnosis may include the following: 1) Reactive piloid gliosis adjacent to either another tumor or another lesion such as a vascular malformation 2) The glial component of a ganglioglioma may mimic pilocytic astrocytoma (see the following text) The identification of lesional dysmorphic ganglion cells allows the distinction 3) Especially in small biopsy sample, the distinction from a low-grade diffuse astrocytoma may be challenging or impossible Relative lack of clearly permeative invasive growth, presence of hyalinized blood vessels, Rosenthal fibers, EGBs, and knowledge of the radiologic appearance can all be helpful Some small biopsies may, however, be best classified descriptively as “low-grade astrocytoma.” 4) In some cases, the unusual differential diagnosis may lie between a pilocytic astrocytoma with necrosis and prominent degenerative changes and a glioblastoma Rare cases of “malignant” pilocytic astrocytoma with increased mitotic activity are described 5) Pilocytic astrocytomas may have areas mimicking oligodendroglioma Presence of areas with diagnostic morphologic features is usually key Tumors with oligodendroglial differentiation are relatively rare in children and in infratentorial locations Special studies are of limited use in pilocytic astrocytomas The lesional cells label for GFAP and S100 but these stains are rarely necessary In some cases, staining for neurofilament may be helpful by demonstrating the lack of entrapped preexisting axonal processes But this stain has to be interpreted with some caution because tumors are not always completely demarcated Variants with more distinctly infiltrative growth are described MIB-1 labeling is probably best avoided because the results may be more confusing than helpful Some cases can go along increased labeling indices of 10% or more.4,5 Recent studies have shown BRAF rearrangements with tandem duplication and BRAF-KIAA1549 fusion in pilocytic astrocytomas.6,7 These are most common in the infratentorial tumors The V600E mutation seen in melanomas is unusual in pilocytic astrocytomas but can be found in pleomorphic xanthoastrocytoma and ganglioglioma.8 In some unusual cases, fluorescence in situ hybridization (FISH) studies looking for these rearrangements may be helpful Pilomyxoid astrocytoma is closely related to pilocytic astrocytoma.9 It is most commonly found in the hypothalamus or chiasm of very young children It is characterized by prominent myxoid matrix and angiocentric arrangement of lesional cells Rosenthal fibers and EGBs are typically absent These tumors tend to be more aggressive than pilocytic astrocytomas and are graded as WHO grade II Infiltrating Astrocytomas Children, just like adults, develop tumors that are classified and graded in the WHO system as diffuse astrocytoma (WHO grade II), anaplastic astrocytoma (WHO grade III), and glioblastoma (WHO grade IV) The growth pattern of these lesions is characterized by individual cell infiltration between preexisting Husain_Ch06.indd 177 3/3/14 4:26 PM 178 ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS gray and white matter structures (Fig 6.3) Because of this growth pattern, these tumors often show up grossly and radiologically as poorly demarcated areas of mass effect that may appear to be expanding preexisting structures Enhancement is thought to often correlate with grade—it is usually absent in diffuse astrocytomas and associated with higher grade astrocytomas It is reflective of the tumor containing blood vessels lacking normal blood–brain barrier The diagnosis of these lesions often represents a two-step process First, the tumor is classified as infiltrating astrocytoma and then the tumor is graded The classification as infiltrating astrocytoma is based on the histologic growth pattern that goes along with the aforementioned entrapment of preexisting tissue elements The background matrix typically has a fibrillary appearance representative of processes belonging to preexisting cells as well as tumor cells The lesional cells morphologically exhibit features of astrocytic differentiation In some cases, cells appear to consist of A FIGURE 6.3 Infiltrating astrocytoma A: The MRI scan of this adolescent patient shows a large nonenhancing intraaxial mass lesion B: The moderately cellular tumor shows focal microcyst formation (continued) Husain_Ch06.indd 178 B 3/3/14 4:26 PM CENTRAL NERVOUS SYSTEM AND SKELETAL MUSCLE ——— 179 FIGURE 6.3 (continued) C: Neoplastic cells diffusely infiltrate between preexisting neurons (arrowhead) and axons (arrow) C basically naked-appearing elongated and irregular-shaped nuclei In other cases, cells may exhibit distinct eosinophilic and sometimes gemistocytic cytoplasm that often tapers out into processes The grading of these tumors occurs according to the same criteria as in adults Increased proliferative activity with mitotic figures is required for a diagnosis of anaplastic astrocytoma Endothelial proliferation or necrosis is required for classification as glioblastoma The necrosis is often but not always pseudopalisading (Figs 6.4 and 6.19) A Husain_Ch06.indd 179 FIGURE 6.4 Glioblastoma multiforme A: Intraoperative frozen section shows a cellular tumor associated with necrosis (continued) 3/3/14 4:26 PM 180 ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS B FIGURE 6.4 (continued) B: Intraoperative frozen section shows a cellular tumor associated with necrosis C: On the permanent sections, the tumor is seen as cellular lesion composed of pleomorphic mitotically (arrows) active cells Samples from the center of the lesion may give the false impression of a solid neoplasm Examination of the edges showing individual cell infiltration similar to that seen in Figure 6.3C can be helpful C In some cases, MIB-1 labeling and p53 staining may provide some prognostic information Special stains are of limited use in establishing the lineage of differentiation Often, the tumor cells label for GFAP and S100 It is, however, important to remember that absence of GFAP expression does not exclude the diagnosis of glioblastoma Neuronal markers such as neurofilament stain preexisting tissue elements In some cases, negative staining for other Husain_Ch06.indd 180 3/3/14 4:26 PM CENTRAL NERVOUS SYSTEM AND SKELETAL MUSCLE ——— 181 markers can be helpful in excluding other entities that may be considered in the differential diagnosis, including lymphoma, systemic metastasis, or neuronal neoplasm The differential diagnosis varies depending on the grade of the tumor Other high-grade tumors, such as primitive neuroectodermal tumors and atypical teratoid rhabdoid tumor, may be considered in the differential diagnosis of glioblastoma In some cases, pleomorphic xanthoastrocytoma and pilocytic astrocytoma may mimic glioblastoma by showing pleomorphism, necrosis, or even mitotic activity The final diagnosis in those cases rests on immunohistochemical and, in some cases, molecular studies Reactive gliosis and other low-grade tumors including ganglioglioma may be considered in the differential diagnosis for low-grade lesions The distinction of reactive gliosis may be difficult on biopsy samples A history of disease processes that could illicit reactive gliosis or morphologic features of the same can be helpful Uniform spacing of glial cells, lack of frank atypia, reactive vascular changes, and macrophage infiltration can be suggestive of reactive etiology When grading and classifying astrocytomas, we often treat pediatric patients like little adults Molecular studies suggest that this approach has limitations Glioblastomas in children are associated with different molecular changes than those typically seen in their adult counterparts.10 There may even be differences between glioblastomas of early childhood and older children In adult patients, studies looking for isocitrate dehydrogenase (IDH)1/IDH2 mutations and epidermal growth factor receptor (EGFR) amplification are sometimes employed IDH1/IDH2 mutations and EGFR amplification are rare in pediatric astrocytomas.11 Plateletderived growth factor receptor, ␣-polypeptide (PDGFRA) amplification is relatively common in pediatric glioblastomas but rare in adult cases Recent data suggests that about a third of pediatric glioblastomas show mutations in the H3F3A gene encoding the replication-independent histone variant H3.3.11,12 This leads to a unique methylation signature in the cancer genome.11 Oligodendroglioma In adults, oligodendrogliomas are a well-defined group of tumors that exhibit an infiltrating growth pattern similar to that seen in infiltrating astrocytomas but distinctly different cytomorphologic features The lesional cells show round regular nuclei On paraffin sections, they often show perinuclear halos as a processing artifact lacking on frozen sections Sometimes, cells with round regular nuclei but distinct eosinophilic cytoplasm are seen, so-called mini-gemistocytes Oligodendrogliomas show a strong association with codeletion of 1p and 19q—some would argue they are defined by these molecular changes Sometimes, prototypical oligodendrogliomas with 1p/19q codeletion are seen in older children In younger patients, these tumors are uncommon Rare tumors in these patients with oligodendroglioma morphology typically lack the 1p/19q codeletion Husain_Ch06.indd 181 3/3/14 4:26 PM THE LUNG ——— 1 eTABLE 9.1 Differential Diagnosis for Hyphal Structures in Lung Biopsy Width Walls Branching Septa Zygomycosis 10–25 mm Irregular “ribbonlike” 90 degrees Rare Septate molds (Aspergillus) 3–6 mm Parallel Acute Regular, straight, not occur at branch points Candida pseudohyphae 3–5mm Constrictions where cells join May have buds at tips Curved, may occur at branch points ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS eTABLE 9.2 Differential Diagnosis of Common Yeast Forms Cryptococcus Typical Clinical History Most Classic Histologic Pattern Spread from lung to meninges No inflammation if immunocompromised Halo Mucin (usually) Fontana-Masson Size and Shape Variable size (2–20 mm) G R Pleomorphic: spherical to oval Rare pseudohyphae V d ti e n U Narrow-based budding Usually systemic infection with hematologic spread, rarely due to aspiration of oral material 9 - 2–6 mm (yeast) 2–10 mm (width of pseudohyphae) Oval with pseudohyphae (constriction at point of “septae”) Rare true hyphae Southwestern United States and Central/ South America Variable: pneumonia to granulomas 1/2 necrosis Endospores: 2–4 mm May involve skin, soft tissue, bone, meninges Spherules with endospores or free endospores Spherule: thick refractile wall full of endospores Ohio and Mississippi river valley May disseminate from lung to lymph nodes, liver, spleen, bone marrow via macrophages Spherules: 10–200 mm r i h ta Histoplasma Often neutrophilic inflammation Can have budding Granulomas 1/2 necrosis Coccidioides Basophilic yeast and pseudohyphae Frequent colonizer—must identify fungus in tissue with inflammation Candida Intra- and extracellular forms Often in clusters Retraction artifact may mimic halo 2–5 mm Oval, often pointed at one end Can have central dot Rare pseudohyphae Narrow-based budding ——— THE LUNG eTABLE 9.2 Differential Diagnosis of Common Yeast Forms (Continued) Southeastern and Midwestern United States Blastomycosis May disseminate to skin or bones Mixed neutrophilic and histiocytic response with giant cells Organisms inside giant cells or free 8–20 mm Round Nuclear material inside Thick, refractile wall (double contoured) G R Broad-based budding V d ti e n U Diffuse, bilateral infiltrates Pneumocystis Extracellular frothy clusters in alveoli 4–7 mm (cysts) Round, helmet/ cup shaped If collapsed, both ends pointed Intracystic dots or “commas” r i h ta 9 - ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS eTABLE 9.3 Viral Inclusions in Lung Tissue Histology Smudgy, basophilic fills entire nucleus None G R Inclusions in epithelial cells at edge of necrosis Necrotizing bronchiolitis V d ti e n U Small Small Eosinophilic Eosinophilic May be multiple May be multiple None Small Diffuse alveolar damage Early inclusions may have clearing and marginated chromatin similar to herpes Diffuse alveolar damage Measles Cytoplasmic Inclusions Necrotizing bronchiolitis Adenovirus Nuclear Inclusions Possible multinucleated cells Necrotizing bronchiolitis RSV Eosinophilic (very subtle) Interstitial pneumonia - Possible multinucleated cells Necrotizing bronchiolitis 9 Parainfluenza None 1/2 Indistinct, eosinophilic One per nucleus Multiple small, basophilic Interstitial pneumonia r i h ta Possible multinucleated cells Hemorrhage, necrosis with or without inflammation CMV Cells with markedly enlarged nucleus and cytoplasm Up to 20 mm Amphophilic Halo and rim of compressed chromatin After treatment may be smudgy and eosinophilic May not be present PAS1, GMS1 ——— THE LUNG eTABLE 9.3 Viral Inclusions in Lung Tissue (Continued) Intraalveolar fibrinous debris Glassy amphophilic Frequent necrosis Does not enlarge the nucleus Tracheobronchial ulcers None HSV/VZV In nonsquamous epithelium, may not see typical multinucleation, margination, and molding V d ti e n U G R 1/2 Cowdry type A (eosinophilic) RSV, respiratory syncytial virus; CMV, cytomegalovirus; PAS, periodic acid–Schiff; GMS, Gomori methenamine-silver; HSV, herpes simplex virus; VZV, varicella-zoster virus r i h ta 9 - ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS Acute Rejection (A) Endothelialitis Eosinophils Extension into Alveolar Septa eTABLE 9.4 2007 Consensus Lung Transplant Grading Criteria Description A0 – None 2 Normal A1 – Minimal 2 Scattered circumferential perivenular infiltrates (two to three rings of lymphocytes) A2 – Mild 1/2 1/2 G R V d ti e n U More frequent and larger perivascular infiltrates, easily recognized at low power Often with airway inflammation A4 – Severe 1 9 Dense perivascular cuffing extending to septa with possible intraalveolar macrophages and reactive pneumocytes Diffuse perivascular, interstitial, and airspace infiltrates with evidence of parenchymal injury (necrosis, hyaline membranes, hemorrhage, neutrophils) Epithelial Damage Fibrosis B0 – None 2 No bronchiolar inflammation B1R – Low grade 2 Scattered or bandlike mononuclear cells in submucosa B2R – High grade 1 Variable degree of epithelial damage (metaplasia to ulceration) Airway Inflammation (B) Intraepithelial Lymphocytes r i h ta - A3 – Moderate Increased eosinophils and plasmacytoid cells ——— THE LUNG eTABLE 9.4 2007 Consensus Lung Transplant Grading Criteria (Continued) Absence of bronchioles, infection, or artifact preclude grading BX – Ungradeable Chronic Airway Rejection (C) (Obliterative Bronchiolitis) G R – Absent – Present r i h ta 9 - V d ti e n U ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS eTABLE 9.5 Common Differential Diagnosis for Histology Patterns of Nonimmunosuppressed Lung Biopsies NSIP Obliterative Bronchiolitis Follicular Bronchiolitis Organizing Pneumonia Surfactant disorders Previous viral infection Viral infection Infection Connective tissue disease Aspiration Connective tissue disease Connective tissue disease Hypersensitivity Immunodeficiency Drug reaction Drug reaction V d ti e n U NSIP, nonspecific interstitial pneumonia r i h ta 9 - G R ——— THE LUNG eTABLE 9.6 Developmental Disorders and Growth Abnormalities Histologic Features Presents at birth with severe refractory respiratory failure Arrest at pseudoglandular/ canalicular stage Acinar dysplasia Clinical Never reported in biopsies Diagnosis made at autopsy G R Respiratory failure in early neonatal period requiring ventilator support Diffuse developmental arrest at late canalicular/ saccular stage Alveolar capillary dysplasia with misalignment of pulmonary veins Persistent pulmonary hypertension and progressive respiratory failure beginning in hours to weeks after birth Decreased capillary density V d ti e n U Often with other congenital malformations Associated with FoxF1 mutations r i h ta 9 - Congenital alveolar dysplasia Small pulmonary veins adjacent to pulmonary arteries Pulmonary artery medial hypertrophy and muscularization of arterioles Lobular simplification and alveolar widening Lymphangiectasis 10 ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS eTABLE 9.7 Surfactant Disorders Common Patterns of Histologya Electron Microscopy Autosomal recessive CAP Absence of mature lamellar bodies Infants with refractory respiratory distress IHC negative for SPB Complex lamellar/ multivesicular bodies Autosomal dominant CPI Usually normal Infants, children, or young adults CAP Clinical Surfactant protein B Surfactant protein C DIP G R DIP V d ti e n U NSIP UIP (adults) Autosomal recessive CAP Infants or children NSIP DIP Dense inclusions in abnormal lamellar bodies ABCA3 mutations UIP PAP CSF2RA X-linked PAP Profound immunosuppression or autoimmune disease Secondary pulmonary alveolar proteinosis 9 a - See Table 9.2 for histologic patterns CAP, congenital alveolar proteinosis; DIP, desquamative interstitial pneumonia; IHC, immunohistochemistry; CPI, chronic pneumonitis of infancy; NSIP, nonspecific interstitial pneumonia; UIP, usual interstitial pneumonia of Liebow; PAP, pulmonary alveolar proteinosis r i h ta ——— 11 THE LUNG eTABLE 9.8 Differential Diagnosis of Common Patterns in Immunocompetent Lung Biopsies Diffuse Alveolar Damage Pleuritis Follicular Bronchiolitis Organizing Pneumonia SLE SLE Infection Dermato-/ polymyositis Dermato-/ polymyositis Rheumatoid arthritis Drug reaction Drug reaction NSIP SLE G R Systemic sclerosis Dermato-/ polymyositis Drug reaction V d ti e n U NSIP, nonspecific interstitial pneumonia; SLE, systemic lupus erythematosus r i h ta 9 - 12 ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS eTABLE 9.9 Heath-Edwards Grading of Pulmonary Hypertension in Congenital Heart Disease Muscular hypertrophy of arteries and muscularization of arterioles Intimal fibrosis Concentric intimal fibrosis with near complete occlusion Plexiform lesions Plexiform lesions with associated angiomatoid dilation Fibrinoid necrosis of vessel wall r i h ta 9 - V d ti e n U G R — PANCREAS, ADRENAL, THYROID, PARATHYROID, AND SELECTED HEAD AND NECK eTABLE 10.1 Neuroblastic Family of Tumors Classification of Neuroblastic Family of Tumors Neuroblastoma (Schwannian stroma poor) Undifferentiated: tumor cells lacking cytologic differentiation, no neuropil and none to minimal Schwannian stroma Poorly differentiated: ,5% of tumor cells with differentiation toward ganglion cells, neuropil present, and none to minimal Schwannian stroma G R Differentiating: $5% of tumor cells with differentiation toward ganglion cells, neuropil present, and none to minimal to ,50% Schwannian stroma Ganglioneuroblastoma (Schwannian stroma rich) V d ti e n U Intermixed (Schwannian stroma rich): ganglioneuromatosis component 50% with well-delineated microscopic foci of neuroblastomatous component Nodular (composite, Schwannian stroma rich/stroma dominant and stroma poor): grossly visible single nodule, multiple nodules or large nodule of neuroblastomatous component (usually hemorrhagic or congested) with ganglioneuromatous component peripheral to nodule, multinodules, or large nodule with abrupt transition between neuroblastic nodule or multinodules and adjacent ganglioneuromatous component; neuroblastic component composed of undifferentiated, poorly differentiated, or differentiating tumor cells No nodule but with metastatic disease: primary tumor with features of intermixed ganglioneuroblastoma or ganglioneuroma with neuroblastomatous metastasis to lymph node, bone, or other sites 9 - Ganglioneuroma (Schwannian stroma dominant) Maturing: few scattered poorly delineated foci of differentiating neuroblasts, neuropil unassociated with neuroblasts (naked neuropil), and mature ganglion cells in predominant ganglioneuromatous background r i h ta Mature: tumor composed of exclusively ganglioneuromatous component with ganglion cells and NO evidence of immaturity or atypia of cellular elements Favorable Histology Group Neuroblastoma (Schwannian stroma poor), poorly differentiated and low or intermediate MKI: age ,1.5 years Neuroblastoma (Schwannian stroma poor), differentiating, and low MKI: age 1.5 to ,5 years) Ganglioneuroma, maturing and mature: any age Ganglioneuroblastoma, intermixed (Schwannian stroma rich): any age Ganglioneuroblastoma, nodular (single nodule [classical], multiple nodules, or large nodule) Age ,1.5 years: nodule with poorly differentiated or differentiating neuroblastoma and low or intermediate MKI Age 1.5–5.0 years: nodule with differentiating neuroblastomas and low MKI continued ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS eTABLE 10.1 Neuroblastic Family of Tumors (Continued) Unfavorable Histology Group Neuroblastoma (Schwannian stroma poor), undifferentiated, and any MKI: any age Neuroblastoma (Schwannian stroma poor), poorly differentiated, or differentiating and high MKI: age ,1.5 years G R Neuroblastoma (Schwannian stroma poor), poorly differentiated, and any MKI: age 1.5 to ,5 years Neuroblastoma (Schwannian stroma-poor), differentiating, and intermediate or high MKI: age 1.5 to ,5 years V d ti e n U Neuroblastoma (Schwannian stroma-poor), any subtype, and any MKI: age $5 years Ganglioneuroblastoma, nodular (single nodule [classical], multiple nodules, or large nodule) Age ,1.5 years: nodule with undifferentiated neuroblastoma and high MKI Age 1.5 to years: nodule with undifferentiated or poorly differentiated neuroblastoma with intermediate to high MKI Age years: all nodular ganglioneuroblastomas Mitotic–Karyorrhexis Index (MKI) Low MKI: ,100 mitotic and karyorrhectic cells per 5,000 tumor cells or ,2% of tumor consisting of cells with mitoses or karyorrhexis - Intermediate MKI: 100 to 200 mitotic and karyorrhectic cells per 5,000 tumor cells or 2%–4% of tumor consisting of cells with mitoses or karyorrhexis 9 r i h ta High MKI: 200 mitotic and karyorrhectic cells per 5,000 tumor cells or 4% of tumor consisting of cells with mitoses or karyorrhexis International Neuroblastoma Staging System Localized tumor with complete gross excision with or without Stage 1: microscopic residual disease and negative nonadherent ipsilateral lymph nodes (Lymph nodes attached to or adjacent lymph nodes removed with tumor may be positive.) Stage 2A: Localized tumor with incomplete gross excision and representative negative ipsilateral nonadherent lymph nodes Stage 2B: Localized tumor with or without complete gross excision and positive ipsilateral nonadherent lymph nodes but negative contralateral lymph nodes Stage 3: Unresectable unilateral tumor infiltrating across midline with or without positive regional lymph node; or localized unilateral tumor with positive contralateral regional lymph nodes; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement with midline defined as vertebral column Tumor originates on one side and infiltrates or extends beyond the opposite side of the vertebral column — PANCREAS, ADRENAL, THYROID, PARATHYROID, AND SELECTED HEAD AND NECK eTABLE 10.1 Neuroblastic Family of Tumors (Continued) Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, or other organs except as defined for stage 4S Stage 4: Stage 4S: Localized tumor (stage 1, 2A, 2B) with dissemination limited to skin, liver, and/or bone marrow (limited to infants ,1 year of age) Minimal marrow involvement (,10% of nucleated cells in marrow) More extensive marrow disease considered to be stage MIBG scans should be negative for disease in bone marrow Risk Categories: Biologic and Clinical Factors Low Intermediate High MYCN status Normal Ploidy Hyperdiploid Near triploid 17q gain Rare 11q, 14q LOH Rare 1p LOH Rare TRK A High TRK B Truncated TRK C High Age Usually ,1 year 9 Stage r i h ta 3-year survival 1, 2, 4S 90% - G R V d ti e n U Normal Amplified (.10 copies) Near diploid Near diploid Near tetraploid Near tetraploid Common Common Common Rare Uncommon Common Low or absent Low or absent Low or absent Low or absent Low of absent Low or absent Usually ,1 year Usually 1–5 years Usually or Usually or 30%–50% ,20% ... Husain_Ch06.indd 20 1 3/3/14 4 :27 PM 20 2 ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS A FIGURE 6 .22 Focal cortical dysplasia Some variants include cortex with altered architectural arrangement of neurons... vimentin, and actin This tumor is associated with loss of chromosome 22 or part of chromosome 22 that goes along with deletion of INI1 on 22 q11 .2 Nowadays, the more common diagnostic test is immunohistochemical... pattern of distribution seen with pediatric brain tumors, Husain_Ch06.indd 197 3/3/14 4 :26 PM 198 ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS A FIGURE 6.18 Craniopharyngioma A: The hallmarks of