Mesenchymal tumors, neuroectodermal tumors, pigmented skin lesions Ondrej Soucek, MD Leos Kren, MD, Ph.D. Should you decide to remember just two slides…basics from the terminology of “cancers“ •Epithelial tumors: •Benign: adenoma (glandular epi), papiloma (surface epi (incl. urothel!)) •Malignant: carcinoma (adenocarcinoma, papilocarcinoma…exc. squamous cell ca, basal cell ca). Carcinoma in situ: malignant cells did not perforate basal membrane of the particular epithelium (usually “B9“, exc. urothelial ca in situ) • •Mesenchymal tumors: •Benign: tissue + oma (lipoma, fibroma, myoma, hemangioma, chondromaosteoma…) •Malignant: tissue + sarcoma (liposarcoma, fibrosarcoma…) •No “sarcoma in situ“. •(Exc. Lymphoma, melanoma... Also no “sarcoma in situ“.) • Mesenchymal tumors •Mesenchymal tumors (“soft tissue tumors“) are neoplasms that arise in mesodermal tissues of the body, including skeletal muscle, fat, fibrous tissue, blood vessels and lymphatics •Malignant are rare, accounting for less than 1% of all malignancies •Benign are 100 times more common than malignant ones Mesenchymal tumors •Arise from multipotential mesenchymal stem cells that reside in soft tissues and are classified according to the phenotype they exhibit. Lipomatous tumors •Lipoma –Most common soft tissue tumor –Composed of well-differentiated adipocytes –Can originate at any site in the body that contains adipose tissue –Lipomas are seen mainly in adults •Liposarcoma –Second most common sarcoma in adults –20% of all malignant soft tissue tumors –After age 50 years and is most common in the deep thigh and retroperitoneum –Tend to grow slowly but may become extremely large Lipomatous tumors •Lipoma –Encapsulated, soft, yellow lesions that vary in size and may become very large –Deeper tumors are often poorly circumscribed –Histologically indistinguishable from normal adipose tissue – •Liposarcoma –Typically measure 5 to 10 cm in diameter –Gross appearances vary depending on the proportions of adipose, mucinous and fibrous tissue –Lipoblast - a malignant-appearing cell with univacuolated or multivacuolated cytoplasmic fat vesicles indenting the nucleus, that essentially defines a tumor as a liposarcoma – Lipomatous tumors NEO031 Výsledek obrázku pro LIPOBLAST Skeletal muscle tumors •Rhabdomyoma –Extremely rare, usually in heart (+ myxoma – USMLE!) •Rhabdomyosarcoma –Malignant tumor that displays features of striated muscle differentiation –Most frequent soft tissue sarcoma of children and young adults, uncommon in adults Skeletal muscle tumors •Rhabdomyoma – •Rhabdomyosarcoma –Most of these tumors probably derive from primitive mesenchyme that has retained the capacity for skeletal muscle differentiation –4 subtypes: embryonal, botryoid (sarcoma botryoides, urinary bladder, genitalia) alveolar, pleomorphic) Skeletal muscle tumors Skeletal muscle tumors alv200 Smooth muscle tumors •Leiomyoma –Usually arises in subcutaneous tissues, or from blood vessel walls in deep somatic tissues, or in myometrium –Painful lesions that appear as firm, gray-white, well-circumscribed nodules –Microscopically composed of perpendicular fascicles of relatively uniform spindled cells with cigar-shaped nuclei and very low mitotic activity – •Leiomyosarcoma –Uncommon tumor of adults that typically arises from the wall of blood vessels in the soft tissue of the extremities or in retroperitoneum or in myometrium –Differentiated from leiomyoma mainly by necroses and high mitotic activity –Most leiomyosarcomas eventually metastasize, although dissemination may occur as late as 15 or more years after resection of the primary tumor Smooth muscle tumors leimyo400xx FEM033 Blood vessels tumors •Hemangioma –Usually occur in the skin but may also be found in internal organs –Capillary hemangioma •Composed of vascular channels with the size and structure of normal capillaries, var. pyogenic granuloma –Arteriovenous hemangioma •Composed of arteries and veins, in skin and meninges, can lead to Kasabach Meritt sy –Cavernous hemangioma •Made of large vascular channels, the liver – •Hemangiosarcoma –Rare, occur in either sex and at any age –The most common locations are skin, soft tissue, breast, bone, liver and spleen –Display varying degrees of differentiation, ranging from those composed mainly of distinct vascular elements to undifferentiated tumors with few recognizable blood channels –Kaposi sarcoma (AIDS, HHSV 8) – – Blood vessel tumors Blood vessel tumors Lymphatic vessels tumors •Lymphangioma •Capillary, cavernous • •Lymphangiosarcoma Bone tumors •Osteoma –Benign, slow-growing tumor composed of cortical-type dense bone –Multiple osteomas are associated with colonic familial adenomatous polyposis in Gardner syndrome •Osteoid osteoma –Composed of osseous tissue (the nidus) surrounded by a halo of reactive bone formation –Very painful •Osteoblastoma –Histologically similar to osteoid osteoma, but larger and not painful •Osteosarcoma –Most common primary malignant bone tumor –Represents one fifth of all bone cancers and is most frequent in adolescents between 10 and 20 years old, affecting boys more often than girls (2:1) –Highly malignant –Often arise near the knee, in the lower femur or upper tibia/fibula –75% arise adjacent to the knee or shoulder –Osteoplastic, chondroplastic, fibroplastic variant –Codman triangle Bone tumors WHO-Bone Tumours_08 Tumors of cartilage •Chondroma –Most solitary chondromas occur in the metacarpals and phalanges of the hands, the remainder being in almost any other tubular bone –On gross examination, solitary chondromas have the semitranslucent appearance of hyaline cartilage, often with a few calcified areas •Chondroblastoma –Uncommon, chondrogenic tumor with predilection for the proximal femur, tibia and humerus, mostly in young (5-25 yrs) •Chondrosarcoma –Malignant tumor of cartilage that arises from a preexisting cartilage rest or chondroma –Chondrosarcoma is the second most common primary malignant bone tumor and is more common in men than in women (2:1) –Central chondrosarcoma, peripheral chondrosarcoma, juxtacortical chondrosarcoma –Older patients than osteosarcoma, hip joint Tumors of cartilage Chordoma •NOT chondroma – malignant tumor from the rest of notochord – localised in base of skull, sacral area. • • Neuroectodermal tumors •Tumors of central nervous system (CNS) •Tumors of peripheral nervous system (PNS) •Pigmented skin lesions Tumors of CNS •Primary CNS cancers account for about 1.5% of all primary malignant tumors •Metastatic tumors to the CNS are far more common than primary tumors and are a major problem in clinical management •The broad spectrum of cellular constituents of the CNS (all of the diverse cell types in the CNS) is mirrored by the wide range of tumor types that arise within the brain, spinal cord and their overlying meninges (over 130 different types of CNS neoplasms are recognized and formally codified by the WHO) Tumors of CNS •Most brain tumors arise in adults, but some are more common in childhood (the most prominent being medulloblastoma, pilocytic astrocytoma and diffuse pontine astrocytoma) •In adults, the most common types are meningiomas and gliomas Tumors of CNS Tumors of CNS •Diagnosis –Generating a preoperative differential diagnosis of the most likely possibilities based on the patient’s clinical information (gender, age, anatomic location) –Biopsy or resection of the lesion to obtain a definitive tissue-based diagnosis upon which further clinical management depends •Clinical signs and symptoms –Long history (e.g. several years of poorly controlled seizures, favors more indolent or low-grade disease) –Relatively brief history (2-week history of headache, nausea and emesis and localizing signs) favors a higher grade and more aggressively expanding lesion Tumors of CNS •Grading –Tumor grades according to WHO criteria range from I through IV (I being the lowest grade and IV being the most malignant) –Subjective and ill-defined term “benign” should be used with extreme caution, if at all (even WHO grade I tumors can result in a clinical course that entails considerable morbidity and even mortality - anatomic location, growth pattern etc.) Tumors of CNS •Meningiomas •Diffuse astrocytic and oligodendroglial tumors (astrocytomas, oligodendrogliomas) •Other astrocytic tumors (pilocytic astrocytomas) •Ependymal tumors •Embryonal tumors Meningioma •Meningiomas are derived from arachnoid (meningothelial) cells that form the outer boundary of the subarachnoid space •These tumors can arise at any CNS site where arachnoid cells are present Meningioma •Meningiomas typically arise in one of three settings: –Sporadic – most common –Iatrogenic—usually associated with prior cranial irradiation –Associated with tumor predisposition syndrome—most commonly neurofibromatosis type 2 (NF2) Meningioma •Grade I – „benign“ –Meningothelial, fibrous, transitional, psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte rich, metaplastic •Grade II – atypical –Chordoid, clear cell •Grade III – malignant (anaplastic) –Rhabdoid, papillary – Meningioma •The indolent growth of most meningiomas enables these tumors to enlarge very slowly for years before becoming symptomatic, during which time they displace the brain but do not infiltrate it •Patients frequently have seizures (particularly with tumors at parasagittal sites over the convexity of the hemispheres) and/or „site-specific signs“ (e.g. tumors of the olfactory groove produce anosmia) Meningioma •Invasion of cranial bone is relatively common (even in grade I meningiomas) and growth through the calvarium may create a tumor mass beneath the scalp •In contrast, invasion of the underlying brain by meningiomas is rare, and such aggressive behavior warrants upgrading to WHO grade II (atypical) Meningioma •Usually well-circumscribed dura-based masses of variable size that compress, but do not invade, underlying brain •Cut surface is fleshy and tan •Classic histologic hallmark of meningiomas is a whorled pattern, often in association with psammoma bodies (laminated, spherical calcospherites) Meningioma Meningioma Meningioma 29 Astrocytic tumors •Tumors of astrocytic derivation (astrocytomas) are the most common primary brain tumors –Diffuse astrocytoma (grade II) –Anaplastic astrocytoma (grade III) –Glioblastoma (grade IV) –Pilocytic astrocytoma (grade I) • Diffuse astrocytoma •WHO - …“typically affects young adults and is characterized by a high degree of cellular differentiation and slow growth; the tumour occurs throughout the CNS but is preferentially located supratentorially and has an intrinsic tendency for malignant progression to anaplastic astrocytoma and, ultimately, glioblastoma“... Diffuse astrocytomas •Ability of individual tumor cells to infiltrate widely through brain and spinal cord parenchyma •This property reaches its extreme in “gliomatosis cerebri“ (WHO grade III), in which infiltrating glioma cells involve at least three cerebral lobes (and often more) with infiltration into both hemispheres, the brainstem, the cerebellum and even the spinal cord Diffuse astrocytoma Diffuse astrocytoma Diffuse astrocytoma 2749-05,HE400 Diffuse astrocytoma •The mean survival time after surgical intervention is in the range of 6-8 years, with marked individual variation •Young age at diagnosis has been consistently predictive of a more favourable clinical course, while large tumour size appears to be a negative predictor Anaplastic astrocytoma •WHO - …“a diffusely infiltrating malignant astrocytoma that primarily affects adults, is preferentially located in the cerebral hemispheres, and is histologically characterized by nuclear atypia, increased cellularity and significant proliferative activity. The tumour may arise from diffuse astrocytoma WHO grade II or de novo, i.e. without evidence of a less malignant precursor lesion, and has an inherent tendency to undergo progression to glioblastoma“… Anaplastic astrocytoma Glioblastoma •WHO - …“the most frequent primary brain tumor and the most malignant neoplasm with predominant astrocytic differentiation; histopathological features include nuclear atypia, cellular pleomorphism, mitotic activity, vascular thrombosis, microvascular proliferation and necrosis. It typically affects adults and is preferentially located in the cerebral hemispheres. Most glioblastomas manifest rapidly de novo, without recognizable precursor lesions (primary glioblastoma). Secondary glioblastomas develop slowly from diffuse astrocytoma WHO grade II or anaplastic astrocytoma (WHO grade III). Due to their invasive nature, glioblastomas cannot be completely resected, and despite progress in radio/chemotherapy, less than half of patients survive more than a year, with older age as the most significant adverse prognostic factor“… Glioblastoma •The vast majority of glioblastomas are sporadic, but a minority arise in the setting of a genetic tumor predisposition syndrome –neurofibromatosis type 1 and Turcot type 1 syndrome (mismatch repair [MMR]/hereditary nonpolyposis colon cancer [HNPCC]– associated Turcot) Pilocytic astrocytoma •In contrast to diffuse astrocytomas, pilocytic astrocytomas do not infiltrate brain or spinal cord parenchyma diffusely and are not prone to undergo anaplastic progression to higher-grade tumors •Common anatomic locations include the cerebellum, brainstem, optic nerves and third ventricular region Pilocytic astrocytoma •WHO - …“a relatively circumscribed, slowly growing, often cystic astrocytoma occurring in children and young adults, histologically characterized by a biphasic pattern with varying proportions of compacted bipolar cells associated with Rosenthal fibers and loose-textured multipolar cells associated with microcysts and eosinophilic granular bodies/hyaline droplets“... Pilocytic astrocytoma 236-06,HE200x Oligodendroglial tumors •Oligodendroglioma (grade II) •Anaplastic oligodendrolioma (grade III) Oligodendroglioma •WHO - …“a diffusely infiltrating, well-differentiated glioma of adults, typically located in the cerebral hemispheres, composed of neoplastic cells morphologically resembling oligodendroglia and harbouring deletions of chromosomal arms 1p and 19q“… Oligodendroglioma •Like diffuse astrocytomas, oligodendrogliomas are highly infiltrative tumors. However, their response to treatment and attendant overall survival are much more favorable than for diffuse astrocytomas of comparable grade •Majority of oligodendrogliomas arise in adults in the fourth and fifth decades, largely in the white matter of cerebral hemispheres Oligodendroglioma 24 Glioblastoma 22 Anaplastic oligodendroglioma •WHO - …“an oligodendroglioma with focal or diffuse histological features of malignancy and a less favourable prognosis“… Anaplastic oligodendroglioma Ependymal tumors •Ependymoma (grade II) •Anaplastic ependymoma (grade III) WHO revision 2016 for tumors of astrocytic and oligodendroglial lineage •Concept of “integrated diagnosis“ •Evaluation of IDH (isocitrate dehydrogenase) 1,2 expression (both in astrocytomas and in oligodendrogliomas) •ATRX (ataxia telangiectasia retardation X-linked) i astrocytomas •Co-deletion 1p19q in oligodendrogliomas Ependymoma •WHO - …“a generally slowly growing tumor of children and young adults, originating from the wall of the ventricles or from the spinal canal and composed of neoplastic ependymal cells“… Ependymoma •Ependymomas grow as relatively circumscribed masses, and so are amenable to surgical resection •Their primary histologic hallmark is the perivascular pseudorosette, a perivascular cuff of radiating tumor cell cytoplasmic processes • Ependymoma 500-07,HE200x Ependymoma 3723-06,HE400x Anaplastic ependymoma •WHO - …“a malignant glioma of ependymal differentiation with accelerated growth and unfavourable clinical outcome, particularly in children; histologically characterized by high mitotic activity, often accompanied by microvascular proliferation and pseudopalisading necrosis“… Embryonal tumors: medulloblastoma •WHO - …“a malignant, invasive embryonal tumour of the cerebellum with preferential manifestation in children, predominantly neuronal differentiation, and an inherent tendency to metastasize via CSF pathways“… • “drop metastases“ •Grade IV Medulloblastoma •Peak incidence is at 7 years, but it can also affect adults in the 20- to 45-year old age group •Childhood medulloblastomas commonly arise in the midline vermis, often expanding to fill the fourth ventricle •Adult tumors prefer the cerebellar hemispheres Medulloblastoma •About one third of patients have leptomeningeal spread at the time of presentation, which is a negative prognostic factor: “drop metastasis“ •Medulloblastoma is thought to arise from stem cells of the fetal external granular layer and/or the periventricular germinal matrix Medulloblastoma 5983-03,HE Medulloblastoma 3097-06,HE200x • • • • • • • •Other than medulloblastoma, which tu is the most likely to be in posterior fossa in a kid? •Is medulloblastoma and neuroblastoma the same tumor? •Which “blastomas“ are benign? Tumors of PNS •Primary PNS tumors are of neuronal or nerve sheath origin •The most common nerve sheath tumors are schwannoma and neurofibroma •Neuronal tumors usually arise from the adrenal medulla or sympathetic ganglia (neuroblastoma and ganglioneuroma) Schwannoma •Schwannomas are benign, slowly growing, typically encapsulated neoplasms of Schwann cells that originate in cranial nerves, spinal roots or peripheral nerves •These tumors usually are seen in adults and only very rarely undergo malignant transformation • Schwannoma •Vestibular (acoustic) schwannoma –Intracranial schwannomas account for 8% of all primary intracranial tumors –Most arise from the vestibular branch of the eighth cranial nerve within the internal auditory canal –Most vestibular schwannomas are unilateral and are not associated with NF –Bilateral vestibular schwannomas are a defining feature of NF2 •Spinal and peripheral schwannoma –Spinal schwannomas are intradural, extramedullary tumors that arise most often from the dorsal (sensory) spinal roots –More peripherally located schwannomas usually arise on nerves of the head, neck and extremities Schwannoma •The proliferating Schwann cells form two distinctive histologic patterns –Antoni A pattern – interwoven fascicles of spindle cells with elongated nuclei, eosinophilic cytoplasm and indistinct cytoplasmic borders. Nuclei may palisade in areas to form structures known as Verocay bodies –Antoni B pattern – spindle or oval cells with indistinct cytoplasm in a loose, vacuolated background Schwannoma 3 Neurofibroma •Neurofibromas are benign, slowly growing tumors of peripheral nerve, composed of Schwann cells, perineurial-like cells and fibroblasts •Schwann cells are the neoplastic cells in neurofibromas • Can be associated with NF1 and have a potential for sarcomatous degeneration to malignant peripheral nerve sheath tumor Neurofibroma •Neurofibromas may be solitary or multiple and may arise on any nerve •They occur in both children and adults •Most commonly, they involve skin, subcutis, major nerve plexuses, large deep nerve trunks, retroperitoneum and gastrointestinal tract • Neurofibroma •Most solitary cutaneous neurofibromas occur outside the context of NF1 and do not have the potential for sarcomatous transformation •The presence of multiple neurofibromas or one large plexiform neurofibroma is strongly suggestive of NF1 and should prompt a careful search for other stigmata of the disease Neurofibroma 4 Neuroblastoma (not medulloblastoma!) •Embryonal malignancy of neural crest origin composed of neoplastic neuroblasts •Neuroblasts arise from primitive sympathogonia and are intermediates in the development of sympathetic ganglion neurons •Neuroblastomas are the most common solid extracranial neoplasms of childhood, accounting for up to 10% of all childhood cancers and 15% of cancer deaths in children •Overall incidence is 1 in 7000, the peak incidence is in the first 3 years Neuroblastoma •One third of tumors are in the adrenal, another third elsewhere in the abdomen and 20% in the posterior mediastinum •Neuroblastomas readily infiltrate surrounding structures and metastasize to regional lymph nodes, liver, lungs, bones and other sites •Localized neuroblastomas are treated by surgery alone, disseminated tumors require chemotherapy and sometimes irradiation Neuroblastoma 1 Ewing sarcoma •Primitive neuroectodermal tumor in childhood •Uncommon malignant bone tumor composed of small, uniform, round cells •Represents only 5% of all bone tumors and is found in children and adolescents, with two thirds of cases occurring in patients younger than 20 years •Primarily a tumor of the long bones (humerus, tibia and femur) •Prognosis used to be dismal, but with current use of chemotherapy plus radiation and/or surgery, 5-year disease-free survival is between 60% and 75% Ewing sarcoma WHO-Bone Tumours_11 Pigmented skin lesions •Ephelides (freckles) •Lentigo simplex •Acquired melanocytic nevus (mole) •Dysplastic nevus •(Malignant) melanoma See the source image Acquired melanocytic nevus •Localized benign neoplastic proliferations of melanocytes within the epidermis and/or dermis •Most people, regardless of skin color, develop 10 to 50 nevi on their skin •Except for occasional cosmetic significance, nevi are important mainly in relation to melanoma, as markers of individuals at increased risk of developing melanoma and as potential precursors of melanoma Acquired melanocytic nevus •A majority of nevi have recently been found to have an activating mutation of the gene encoding the oncogene BRAF, which can lead to growth stimulation through the mitogen-activated protein kinase (MAPK) pathway •After an initial period of growth, nevi are stable lesions that may regress Acquired melanocytic nevus • Junctional nevus –melanocytes form nests at the tips of epidermal rete ridges. They tend to lose their dendritic morphology and retain pigment in their cytoplasm • Compound nevus –nests of melanocytes are seen in the epidermis and some of the cells have migrated into the dermis • Dermal nevus –intraepidermal melanocytic growth has ceased and melanocytes are present only in the dermis Compound melanocytic nevus 5 Intradermal melanocytic nevus nevus-id-7463-00-he-10x Blue nevus • Dysplastic nevus •Some common acquired nevi do not follow the differentiation described above, and are termed “dysplastic nevi” •These nevi may show foci of aberrant melanocytic growth and become larger and somewhat irregular peripherally •Patients with dysplastic nevi are at increased risk of developing melanoma Dysplastic nevus •Combination of architectural disorder and cytologic atypia constitutes a dysplastic nevus Melanoma •Malignant neoplasm of melanocytes •The term “melanoma” in current practice is synonymous with previous “malignant melanoma” •Although not one of the most common cancers overall, it is one of leading causes of cancer mortality in young adults Malignant melanoma •Melanomas may evolve through two major stages of progression – –Radial growth phase - the lesion spreads along the radii of an imperfect circle in the skin but remains superficial –Vertical growth phase - focal area in which the lesion expands in a more or less spherical manner to form a tumor mass, with increasing thickness Malignant melanoma •Superficial spreading melanoma (primarily radial growth) •Nodular melanoma (primarily vertical growth) •Lentigo maligna melanoma (melanoma in situ on sun damaged skin) •Acral lentiginous melanoma (most common melanoma in dark skinned people) (Malignant) melanoma •Melanoma staging –Clark level (anatomic) –Breslow thickness (mm) Malignant melanoma Malignant melanoma • Malignant melanoma ssm-4852-96-he-2,5x Malignant melanoma mm-nodul-799-93-he-1,25x