patoloji-ders-notlari

Title

Serdar Balcı

SSS Tümörleri

Dr. Serdar BALCI

SSS Tümörleri

• SSS tümörlerinin yıllık insidansı
  • 10-17/100,000 intrakraniyel tümörler
  • 1-2/100,000 intraspinal tümörler
• 1/2-2/3 primer tümörler
• Diğerleri metastatik
• Pediatrik tümörlerin %20’si
  • Daha çok posterior fossada
• Erişkinlerde tümörler daha çok supratentorial

SSS Tümörlerinin Özellikleri

• Karsinomlar gibi önceden tespit edilebilen in situ ya da premalign evreleri yok
• Düşük dereceli lezyonlar beynin geniş alanlarını infiltre edebilir
  • Ciddi klinik defisit, rezekte edilemez ve kötü prognoz
• Histolojik sınıflamadan bağımsız olarak anatomik lokalizasyon klinik gidişi etkiler
  • Lokal kitle etkisi
    • Benign meningiom medullada kardiyorespiratuar arreste neden olur
  • Rezektabilite
    • Beyin kökü gliomları rezeke edilemez
• En malign gliomlar bile nadiren SSS dışına çıkar
  • Lokal infiltrasyon
  • Subaraknoid alana yayılım

SSS Tümörleri

• SSS tümörleri hemen tüm hücre tiplerinden köken alır
• Beyin zarları
  • Meningiom
• Beyin
  • Gliom, nöronal tümörler, koroid pleksus tümörleri
• Diğer hücre popülasyonları
  • Primer SSS lenfomaları, germ hücre tümörleri
• Diğer organlardan
  • Metastaz

SSS Tümörleri Sınıflaması

Hücre orijinine göre sınıflama

Ayırıcı tanı için en önemli özellikler

Lokalizasyon, lokalizasyon, lokalizasyon…

Yaş

Radyolojik özellikler

Histomorfolojik özellikler

Genetik özellikler

SSS tümörlerinin lokalizasyonu

• Spesifik tümörler spesifik lokalizasyonlarda olur
  • Serebellum → Medulloblastom
  • İntraventriküler → Santral Nörositom
• Spesifik yaş grupları
  • Pediatrik → Medulloblastom, Pilositik astrositom
  • İleri yaş → Glioblastom, Lenfoma

SSS tümörlerinin yayılımı

Beyin tümörlerinin diğer bölgelere yayılımı çok nadir

Spinal subaraknoid tümör yayılımı (ekilimi, seeding)

Autopsy Pathology: A Manual and Atlas

SSS tümörlerinin derecelendirilmesi

Derecelendirme histolojik alt tipe göre yapılır

Grade I tümörler

Grade II tümörler

Grade III tümörler

Grade IV tümörler

Benign, Resection is cure

Progression can be seen

GLIOMLAR

Gliomlar

• Beyin parankim tümörleri
• Glial hücelere benzerliklerine göre
  • Astrositom
  • Oligodendrogliom
  • Ependimom
• Diffüz, infiltratif gliomlar
  • En sık görülen tipler
  • Astrositik, oligodendroglial ve mikst formlar
• Ependimomlar solid kitleler oluştururlar

Grading of CNS gliomas

Increasing tumor malignancy is associated with more cytologic anaplasia, increased cell density, necrosis, and mitotic activity

Grade I tumors

Grade II tumors

Grade III tumors

Grade IV tumors

Astrositomlar

• Pilositik astrositomlar
  • Derece I
• İnfiltratif gliomlar
  • Diffüz Astrositom, Derece II
    • Atipik nükleer özellikler
    • İnfiltrasyon
  • Anaplastik Astrositom, Derece III
    • Artmış mitoz
  • Glioblastom, Derece IV
    • Nekroz
    • Mikrovasküler (endotelial) proliferasyon

Pilositik Astrositom, Derece I

• Benign tümör
• Çocuklar ve genç erişkinler
• Lokalizasyon
  • En sık serebellum
  • 3. ventrikül
  • Optik yolak
  • Spinal kord
  • Serebral hemisferler
• Tümör ile ilişkili kist
  • Rekürrens olurs da kistik komponentin genişlemesi ile olur
• Hipotalamik tümörler problemli çünkü tümüyle rezeke edilemez

Pilositik Astrositom

Autopsy Pathology: A Manual and Atlas

Pilositik Astrositom

• BRAF (serin-threonin kinaz) aktivasyon mutasyonları
  • Tandem duplikasyon
  • Nokta mutasyonu (V600E)
• IDH1 ve IDH2 mutasyon yok

Kistik

Kist duvarında mural nodül

Eğer solid ise, iyi sınırlı

Bipolar hücreler, ince saçsı uzantılar

GFAP-pozitif

Rozental lifler, eozinofilik granüler cisimcikler, mikrokist

Nekroz ve mitoz çok çok nadir

Diffüz astrositomlar

• Erişkin gliomların %80’i
• 4-6. dekad
• Genellikle serebral hemisferlerde
• Klinik bilgi ve bulgular
  • Nöbet
  • Başağrısı
  • Lokalizasyona bağlı nörolojik defisitler

Diffuse Astrocytoma

• Spectrum of histologic differentiation that correlates well with clinical course and outcome
  • well-differentiated astrocytoma (grade II/IV)
  • anaplastic astrocytoma (grade III/IV)
  • glioblastoma (grade IV/IV)

Infiltrating pontine glioma (astrocytoma)

Autopsy Pathology: A Manual and Atlas

Diffüz infiltratif astrositom

Autopsy Pathology: A Manual and Atlas

İyi diferansiye astrositomlar belirsiz sınırlı, gri, infiltratif tümörlerdir. Ayrı bir kitle oluşturmadan infiltratif oalrak büyür ve normal dokuların yapısını ortadan kaldırır

Robbins Basic Pathology

Makroskopik olarak görünen sınır ötesine de uzanım mutlaka vardır

Kesit yüzü sert, yumuşak veya jelatinöz

Kistik dejenerasyon görülebilir

Robbins Basic Pathology

Clinical Neuropathology Text and Color Atlas

Practical Surgical Neuropathology

Brain Tumor Pathol (2011) 28:177–183

Diffüz astrositom

• İyi diferansiye astrositomlar uuzn yıllar statik kalabilir
  • Progresyon olduğunda, ortalama sağkalım 5 yıldan fazla
• Hızlı klinik bozulma, anaplastik özelliklerin ortaya çıkması ve hızlı tümör büyümesi ile korele
• Tümörlerin dereceleri artabilir
  • İyi diferansiye, Grade II → Anaplastik astrositom, grade III → Glioblastom, grade IV
• Glioblastoma ait histolojik özellikler belirgin olduğunda sağkalım çok kötü
  • Rezeksiyon, radyoterapi ve kemoterapi ile ortanca sağkalım 15 ay

Brain Tumor Pathol (2011) 28:177–183

Defects in tricyclic carbon cycle

Isocitrate dehydrogenase mutasyonları yan ürünlerin birikimine neden olur

SSS tümörlerinde yakın zamanda bulunan en önemli mutasyon

Cancer Cell. 2010 Jan 19;17(1):7-9

N Engl J Med 2009;360:765-73.

İyi diferansiye astrositom

Glial hücre sayısında hafif orta artış

Değişken nükleer pleomorfizm

Zeminde ince, GFAP pozitif gliofibriler ağ

Normal doku ve tümör geçişi net değil

Neoplastik hücreler ana tümör kitlesinin santimetrelerce uzağında olabilir

Anaplastik astrositomlar, Derece III

Selülarite daha belirgin

Daha belirgin nükleer pleomorfizm

Mitotik figürlerin görülmesi

Practical Surgical Neuropathology

Glioblastom, Derece IV

• p53 ve Rb tümör süpresör yolaklarında fonksiyon kaybı mutasyonları
• Onkojenik PI3K yolaklarında fonksiyon kazanıkm mutasyonları
• Düşük dereceli astrositomlarda ve bunlardan gelişen glioblastomlarda isocitrate dehydrogenase (IDH1 and IDH2) mutasyonları
  • İmmünohistokimya ile tanısal olarak da kullanılıyor

Glioblastom

• Anaplastik astrositom özellikleri VE
• Nekroz
  • Psödopalizatlanma
  • Coğrafi
• Vasküler proliferasyon
  • Mikrovasküler proliferasyon
  • Vasküler endotelyal proliferasyon
  • Glomeruloid vasküler proliferasyon

Glioblastom

Nekrotik, hemorajik, infiltratif kitle

• Makroskopik görünümde bölgesel farklılıklar karakteristiktir:
• Sert ve beyaz
• Yumuşak ve sarı
  • Nekroz
• Kistik dejenerasyon ve kanama

Robbins Basic Pathology

Glioblastoma multiforme

Autopsy Pathology: A Manual and Atlas

Glioblastom

Selüler tümör, nekroz ve psödopalizatlanma dizilimi

Robbins Basic Pathology

Clinical Neuropathology Text and Color Atlas

Practical Surgical Neuropathology

Practical Surgical Neuropathology

OLIGODENDROGLIOM

Oligodendrogliom

• Gliomların %5-15’i
• 4-5. dekad
• Uzun yıllar süren nörolojik bulgular, sıklıkla nöbet
• Çoğunlukla serebral hemisferlerde
  • Frontal ve temporal lob

Oligodendrogliom: Tümör hücreleri yuvarlak oval çekirdekli, sitoplazmik halo

Damarlar ince

Robbins Basic Pathology

• Benzer dereceli astrositomdan daha iyi prognozlu
• Cerrahi, kemoterapi ve radyoterapi sonrası
  • İyi diferansiye (WHO grade II) oligodendrogliomlarda ortalama sağkalım 10-20 yıl
  • Anaplastik (WHO grade III) oligodendrogliomlarda 5-10 yıl

1p ve 19q kromozomların kaybı

1p ve 19q kaybı tipik olarak birlikte olur

1p ve 19q kaybı gösteren tümörlerde kemoterapi ve radyoterapiye cevap çok daha iyi

İyi diferansiye oligodendrogliomlar(WHO grade II/IV)

• Infiltratif tümörler
• Jelatinöz, gri kitleler
• Kist, fokal kanama ve kalsifikasyon
• Tabakalar halinde regüler hücreler
  • Oligodendroglial hücrelere benzer yuvarlak nükleus, ince granüler görünümde kromatin
  • Şeffaf sitoplazmik halo
• İnce anastomoz yapan kapillerler
• Kalsifikasyon
  • Tümörlerin %90’ında var
  • Mikroskopik ve makroskopik birikimler
• Mitozu genelde tespit etmek zor

Anaplastic oligodendroglioma (WHO grade III/IV)

More aggressive subtype

Higher cell density

Nuclear anaplasia

Mitotic activity

EPENDİMOM

Ependimom

• Oluşum yeri
  • Ependim döşeli ventriküler sistem
  • Central canal
• İlk iki dekad
  • 4. ventrikül
  • Bu yaş grubundaki beyin tümörlerinin %5-10’u
• Erişkinler
  • Spinal kord en sık oluşum yeri
  • Nörofibromatozis tip 2
• Tümüyle çıkarılan supratentoryal ve spinal ependimomların prognozu posterior fossa tümörlerinden daha iyi

4. ventrikül

Solid veya papiller kitle

Ventrikül tabanından köken alır

Ependymoma

• Cells with regular, round to oval nuclei and abundant granular chromatin
• Between the nuclei a variably dense fibrillary background
• Round or elongated structures
  • rosettes, canals
  • resemble the embryologic ependymal canal
• Long, delicate processes extending into a lumen
• Perivascular pseudorosettes
  • tumor cells are arranged around vessels with an intervening zone containing thin ependymal processes

Anaplastic ependymoma

Increased cell density

High mitotic rates

Necrosis

Less evident ependymal differentiation

Robbins Basic Pathology

NEURONAL TUMORS

Neuronal Tümörler

Santral Nörositom

Gangliogliom

Dysembryoplastic neuroepithelial tumor (DNET)

Central neurocytoma

Low-grade neoplasm

Within and adjacent to the ventricular system

Most commonly the lateral or third ventricles

Evenly spaced, round, uniform nuclei

Islands of neuropil

Ganglioglioma

• Manifest with seizures
• Slow-growing
• Mixed tumor
  • glial elements
    • low-grade astrocytoma
  • mature-appearing neurons
• Glial component occasionally becomes anaplastic
  • then progresses rapidly

Dysembryoplastic neuroepithelial tumor (DNET)

• Low-grade childhood tumor
• Grows slowly
• Relatively good prognosis after resection
• Often manifests as a seizure disorder
• Typically located in the superficial temporal lobe
• Consists of small round neuronal cells
  • arranged in columns
  • around central cores of processes
• Typically form multiple discrete intracortical nodules
  • myxoid background
• Well-differentiated “floating” neurons within pools of mucopolysaccharide-rich myxoid fluid

EMBRİYONAL (PRIMITIF) NEOPLAZİLER

Embryonal (Primitive) Neoplasms

• Neuroectodermal origin
• Primitive “small round cell” appearance
  • reminiscent of normal progenitor cells encountered in the developing CNS
• Differentiation is often limited
• May progress along multiple lineages

Medulloblastom

En sık embriyonel tümör

Pediatrik beyin tümörlerinin %20’si

Serebellum

Küçük yuvarlak hücreli malign tümör

• Most common Embryonal (Primitive) Neoplasm
• 20% of pediatric brain tumors
• Cerebellum
• Neuronal and glial markers are nearly always expressed
• Highly malignant
  • Prognosis for untreated patients is dismal
  • Exquisitely radiosensitive
  • Total excision, chemotherapy, and irradiation, the 5-year survival rate may be as high as 75%
• Primitive neuroectodermal tumors (PNETs)
  • Tumors of similar histologic type and a poor degree of differentiation elsewhere in the nervous system

Located in the midline of the cerebellum

Lateral tumors occur more often in adults

Often well circumscribed, gray, and friable

May extend to the surface of the cerebellar folia and involve the leptomeninges

Robbins Basic Pathology

Autopsy Pathology: A Manual and Atlas

Extremely cellular

Sheets of anaplastic (small blue) cells

Small, with little cytoplasm

Hyperchromatic nuclei

Abundant mitosis

Robbins Basic Pathology

Focal neuronal differentiation

Homer Wright or neuroblastic rosette

Resembles the rosettes in neuroblastomas

Primitive tumor cells surrounding central neuropil

-delicate pink material formed by neuronal processes

Medulloblastom genetiği

• MYC amplifikasyonu
  • Kötü klinik gidiş
• WNT sinyal yolağı
  • Daha iyi gidiş
• Sonic hedgehog (shh) yolağı
  • Klinik gidişle ilişkisi net değil

Genetic of medulloblastoma

• Morphologically similar tumors commonly exhibit distinct alterations
• There is a relationship between the underlying mutations and outcome
• MYC amplification
  • associated with poor outcomes
• WNT signaling pathway
  • have a more favorable course
• Sonic hedgehog (shh) pathway
  • has a critical role in tumorigenesis but an uncertain relationship to outcome

LENFOMALAR

Primary CNS Lymphoma

• Mostly diffuse large B cell lymphoma
• 2% of extranodal lymphomas
• 1% of intracranial tumors
• Most common CNS neoplasm in immunosuppressed persons
  • nearly always positive for the oncogenic Epstein-Barr virus
• Nonimmunosuppressed populations
  • age spectrum is relatively wide
  • incidence increasing >60 years of age
• Aggressive disease
  • relatively poor response to chemotherapy compared with peripheral lymphomas

Primer SSS lenfoması

Çoğunlukla diffüz büyük B hücreli lenfoma

Primary CNS Lymphoma

• Multiple tumor nodules within the brain parenchyma
• Involvement outside of the CNS is an uncommon late complication
• Lymphoma originating outside the CNS rarely spreads to the brain parenchyma
  • when it happens, within the CSF or involvement of the meninges
• Often involve deep gray structures
• Also white matter and the cortex
• Periventricular spread is common
• Relatively well defined as compared with glial neoplasms
  • not as discrete as metastases
• EBV-associated tumors
  • extensive areas of necrosis
• Nearly always aggressive large B-cell lymphomas
  • rarely other histologic types
• Malignant cells accumulate around blood vessels
• Infiltrate the surrounding brain parenchyma

GERM CELL TUMORS

Primary brain germ cell tumors

• Occur along the midline
  • Most commonly in the pineal and the suprasellar regions
• 0.2-1% of brain tumors in European
• 10% of brain tumors in Japanese
• Young
  • 90%, during the first 2 decades of life
• Pineal region show a strong male predominance
• Germinoma
  • Most common primary CNS germ cell tumor
  • resembles testicular seminoma
• Metastatic gonadal germ cell tumors also occur

MENINGIOM

Meningioma

Benign

Araknoid meningotelyal hücre kökenli

Duraya yapışık

• Predominantly benign tumors
• Arise from arachnoid meningothelial cells
• Usually occur in adults
• Often attached to the dura
• Found along any of the external surfaces of the brain
• Within the ventricular system
  • arise from the stromal arachnoid cells of the choroid plexus
• Sympotoms
  • vague nonlocalizing symptoms
  • focal findings compression of adjacent brain
• Most meningiomas are easily separable from underlying brain
  • some tumors infiltrate the brain
  • increased risk of recurrence
• Overall prognosis
  • lesion size and location
  • surgical accessibility
  • histologic grade
• Neurofibromatosis type 2 (NF2)
  • Multiple meningiomas
  • eighth-nerve schwannomas
  • glial tumors
• Half of meningiomas not associated with NF2
  • acquired loss-of-function mutations in the NF2 TSG on 22q
• Mutations found in all grades of meningioma
  • involved with tumor initiation
• Mutations in NF2 are more common in:
  • fibroblastic, transitional, and psammomatous growth pattern

Meningioma

WHO grade I/IV

well-defined dura-based masses

compress the brain but do not invade it

Extension into the overlying bone may be present

Robbins Basic Pathology

Parasagittal meningioma

Autopsy Pathology: A Manual and Atlas

Intraosseous meningioma

Autopsy Pathology: A Manual and Atlas

Histologic patterns of Meningioma

• Syncytial
  • whorled clusters of cells without visible cell membranes that sit in tight groups
• Fibroblastic
  • elongated cells and abundant collagen deposition between them
• Transitional
  • shares features of the syncytial and fibroblastic types
• Psammomatous
  • numerous psammoma bodies
• Secretory
  • gland-like PAS-positive eosinophilic secretions known as pseudopsammoma bodies

Robbins Basic Pathology

Atypical meningiomas(WHO grade II/IV)

prominent nucleoli

increased cellularity

pattern-less growth

higher mitotic rate

More aggressive local growth

Higher rate of recurrence

Require therapy in addition to surgery

Anaplastic (malignant) meningiomas(WHO grade III/IV)

Highly aggressive tumors

May resemble a high-grade sarcoma or carcinoma

usually some histologic evidence of a meningothelial cell origin

METASTATIK TÜMÖRLER

Metastatic Tumors

Mostly carcinomas

1/4-1/2 of intracranial tumors

Most common primary sites

Lung, breast, skin (melanoma), kidney, and gastrointestinal tract

Form sharply demarcated masses

Often at the gray-white junction, and elicit edema

The boundary between tumor and brain parenchyma is sharp at the microscopic level as well, with surrounding reactive gliosis

Direct and localized effects

#

Metastatic spread of brain tumors to other regions of the body is rare

Brain is not protected against spread of distant tumors

Carcinomas are the dominant type of systemic tumors that metastasize to the nervous system

Metastatic melanoma

Metastatic lesions are distinguished grossly from most primary central nervous system tumors by their multicentricity and well-demarcated margins

The dark color of the tumor nodules in this specimen is due to the presence of melanin

Robbins Basic Pathology

Paraneoplastic syndromes

• Subacute cerebellar degeneration
  • result in ataxia
  • destruction of Purkinje cells, gliosis, and a mild inflammatory infiltrate
• Limbic encephalitis
  • subacute dementia
  • perivascular inflammatory cells, microglial nodules, some neuronal loss, and gliosis, all centered in the medial temporal lobe
• Subacute sensory neuropathy
  • altered pain sensation
  • loss of sensory neurons from dorsal root ganglia, in association with inflammation
• Syndrome of rapid-onset psychosis, catatonia, epilepsy, and coma
  • associated with ovarian teratoma
  • antibodies against the N-methyl-d-aspartate (NMDA) receptor

AILESEL TÜMÖR SENDROMLARI

Ailesel tümör sendromları

• Tuberous Sclerosis (TSC)
  • Kortikal tüberler
• von Hippel–Lindau Hastalığı
  • Serebellar Hemanjioblastomlar

Tuberous Sclerosis (TSC)

• Autosomal dominant
• Development of hamartomas and benign neoplasms involving the brain and other tissues
• CNS hamartomas
  • cortical tubers
  • subependymal hamartomas
  • tumefactive form known as subependymal giant cell astrocytoma
• Proximity to the foramen of Monro
  • present acutely with obstructive hydrocephalus
  • requires surgical intervention and/or therapy with an mTOR inhibitor
• Seizures
  • associated with cortical tubers
  • difficult to control with antiepileptic drugs
• Extracerebral lesions
  • renal angiomyolipomas
  • retinal glial hamartomas
  • pulmonary lymphangiomyomatosis
  • cardiac rhabdomyomas
  • Cysts
    • liver, kidneys, and pancreas
  • Cutaneous lesions
    • angiofibromas, leathery thickenings in localized patches (shagreen patches), hypopigmented areas (ash leaf patches), and subungual fibromas
• TSC1
  • encodes hamartin
• TSC2
  • encodes tuberin
• Two TSC proteins form a dimeric complex
  • negatively regulates mTOR, a kinase that “senses” the cell’s nutrient status and regulates cellular metabolism
• Loss of either protein leads to increased mTOR activity
  • Disrupts nutritional signaling and increases cell growth
• Cortical hamartomas
• Firmer than normal cortex
• Likened in appearance to potatoes
  • “tubers”
• Composed of haphazardly arranged large neurons
• Lack the normal cortical laminar architecture
• Cells exhibit a mixture of glial and neuronal features
  • large vesicular nuclei with nucleoli (like neurons)
  • abundant eosinophilic cytoplasm (like gemistocytic astrocytes)
  • Similar cells are present in the subependymal nodules

von Hippel–Lindau Disease

• Autosomal dominant disorder
• Hemangioblastoma
  • cerebellar hemispheres, retina, and, less commonly, the brain stem, spinal cord, and nerve roots
• Cysts
  • pancreas, liver, and kidneys
• Renal cell carcinoma
• Frequency is 1/30,000-40,000
• Therapy is directed at the symptomatic neoplasms
  • surgical resection of cerebellar tumors and laser ablation of retinal tumors
• Tumor suppressor VHL
• Encodes a protein that is part of a ubiquitin-ligase complex
• Targets the transcription factor hypoxia-inducible factor (HIF) for degradation
• Lost all VHL protein function
• Express high levels of HIF
• Expression of VEGF, various growth factors
• Expression of erythropoietin
  • paraneoplastic polycythemia
• Cerebellar capillary hemangioblastoma
  • Highly vascular neoplasm
  • Mural nodule
  • Large, fluid-filled cyst
  • Numerous capillary-sized or somewhat larger thin-walled vessels
  • Intervening stromal cells with vacuolated, lightly PAS-positive, lipid-rich cytoplasm

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Distribution of CNS Tumors

**A pilocytic astrocytoma of the cerebellum in a child. **

Glioma of the brainstem – pilocytic astrocytoma

GBM. Note the prominent vascularity as well as the area of necrosis at the left with neoplastic cells palisading around it (pseudopalisading necrosis*).

Here is an ependymoma arising from the ependymal lining of the fourth ventricle above the brainstem and bulging toward the cerebellum.

This horizontal (CT scan) section of the brain reveals a large ependymoma of the fourth ventricle.

Irregular posterior fossa mass (medulloblastoma) - near the midline of the cerebellum and extending into the fourth ventricle above the brainstem