Pathology_Robbins

Pathology_Robbins. Friedreich ataxia is an autosomal recessive disorder that generally manifests in the first decade of life with gait ataxia, followed by hand clumsiness and dysarthria. Most patients develop pes cavus and kyphoscoliosis, and there is a high incidence of cardiac disease and diabetes. The disease usually is caused by a GAA trinucleotide repeat expansion in the gene encoding frataxin, a protein that regulates cellular iron levels, particularly in the mitochondria. The repeat expansion results in decreased protein levels through transcriptional silencing; decreased frataxin leads to mitochondrial dysfunction as well as increased oxidative damage.


Pathology_Robbins

Pathology_Robbins. Amyotrophic lateral sclerosis (ALS) results from the death of lower motor neurons in the spinal cord and brain stem as well as upper motor neurons (Betz cells) in the motor cortex. The loss of lower motor neurons results in denervation of muscles, muscular atrophy (the “amyotrophy” of the condition), weakness, and fasciculations, while the loss of upper motor neurons results in paresis, hyperreflexia, and spasticity, along with a Babinski sign. An additional consequence of upper motor neuron loss is degeneration of the corticospinal tracts in the lateral portion of the spinal cord (“lateral sclerosis”). Sensation usually is unaffected, but cognitive impairment is not infrequent.


Pathology_Robbins

Pathology_Robbins. The disease affects men slightly more frequently than women and becomes clinically manifest in the fifth decade or later. It usually begins with subtle asymmetric distal extremity weakness. As the disease progresses, muscle strength and bulk diminish, and involuntary contractions of individual motor units, termed fasciculations, occur. The disease eventually involves the respiratory muscles, leading to recurrent bouts of pulmonary infection, which is the usual cause of death. The balance between upper and lower motor neuron involvement can vary, although most patients exhibit involvement of both. In some patients, degeneration of the lower brain stem cranial motor nuclei occurs early and progresses rapidly, a pattern of disease referred to as bulbar amyotrophic lateral sclerosis. With this disease pattern, abnormalities of swallowing and speaking dominate.


Pathology_Robbins

Pathology_Robbins. While most cases are sporadic, about 10% are familial, mostly with autosomal dominant inheritance. Familial disease begins earlier in life than sporadic disease, but once symptoms appear, the clinical course is similar in both forms. Mutations in the superoxide dismutase gene, SOD1, on chromosome 21 were the first identified genetic cause of ALS and account for about 20% of the familial forms. These mutations are thought to generate abnormal misfolded forms of the SOD1 protein, which may trigger the unfolded protein response and cause apoptotic death of neurons.


Pathology_Robbins

Pathology_Robbins. A number of other genetic loci have been identified as associated with ALS. The most common cause of familial ALS is hexanucleotide repeat expansion in a gene with the rather cumbersome name C9orf72, which is also frequently expanded in frontotemporal lobar degeneration. The protein encoded by C9orf72 associates with RNA binding proteins; notably, two other genes that when mutated may cause ALS, TDP43 (also associated with FTLD) and FUS, encode RNA binding proteins. This convergence suggests that an abnormality of RNA processing directly or indirectly contributes to the pathogenesis of ALS, but it is uncertain how mutations in SOD1 fit into this picture, and much remains to be discovered. As expected from the genetic overlap, there is some clinical overlap between ALS and FTLD, such as cognitive impairment.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Amyotrophiclateralsclerosis(ALS)isthemostcommonformofmotorneurondisease,withdiversegeneticcausesaswellassporadicforms. The annual incidence of CNS tumors ranges from 10 to 17 per 100,000 individuals for intracranial tumors and 1 to 2 per 100,000 individuals for intraspinal tumors; about one- decades of life. They usually are found in the cerebral hemispheres. The most common presenting signs and symptoms are seizures, headaches, and focal neurologic deficits related to the anatomic site of involvement. On the basis of histologic features, astrocytomas are stratified into three groups: diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV), with increasingly grim prognosis as the grade increases. There is emerging evidence that genetic subtyping provides important additional prognostic information.


Pathology_Robbins

Pathology_Robbins. There is emerging evidence that genetic subtyping provides important additional prognostic information. Diffuse astrocytomas can be static for several years, but at some point they progress; the mean survival is more than 5 years. Eventually, patients suffer rapid clinical deterioration that is correlated with the appearance of anaplastic features and more rapid tumor growth. Other patients present with glioblastoma from the outset. Once the histologic features of glioblastoma appear, the prognosis is very poor; with treatment (resection, radiotherapy, and chemotherapy), the median survival is only 15 months.


Pathology_Robbins

Pathology_Robbins. half to three-fourths are primary tumors, and the rest are metastatic. Tumors of the CNS make up a larger propor- tion of childhood cancers, accounting for as many of 20% of all pediatric tumors. Childhood CNS tumors differ from those in adults in both histologic subtype and location. In childhood, tumors are likely to arise in the posterior fossa, whereas tumors in adults are mostly supratentorial. Tumors of the nervous system have unique characteristics that set them apart from neoplastic processes elsewhere in the body. These tumors do not have morphologically evident premalignant or in situ stages comparable to those of carcinomas. Even low-grade lesions may infiltrate large regions of the brain, leading to serious clinical deficits, inability to be resected, and poor prognosis.


Pathology_Robbins

Pathology_Robbins. Even low-grade lesions may infiltrate large regions of the brain, leading to serious clinical deficits, inability to be resected, and poor prognosis. The anatomic site of the neoplasm can influence outcome independent of histologic classification due to local effects (e.g., a benign meningioma may cause cardiorespiratory arrest from compression of the medulla). Even the most highly malignant gliomas rarely spread outside of the CNS.


Pathology_Robbins

Pathology_Robbins. Even the most highly malignant gliomas rarely spread outside of the CNS. Gliomas are tumors of the brain parenchyma that have long been classified as astrocytomas, oligodendrogliomas, and ependymomas based on their morphologic resemblance to different types of glial cells. With emerging genetic information, it has become clear that the gliomas are a molecularly distinct family of neoplastic lesions, independent of the histologic patterns. Nonetheless, histologic patterns continue to inform diagnosis and guide treatment, with refinement based on molecular characterization. The diffuse gliomas constitute the vast majority of gliomas that occur in adults, and include diffuse astrocytomas and oligodendrogliomas. Astrocytomas account for about 80% of adult gliomas. They are most frequent in the fourth through the sixth GradeIIandIIIastrocytomasarepoorlydefined,gray,infiltrativetumorsthatexpandanddistorttheinvadedbrainwithoutformingadiscretemass(


Pathology_Robbins

Pathology_Robbins. Fig.23.29C Oligodendrogliomas account for 5% to 15% of gliomas and most commonly are detected in the fourth and fifth decades of life. Patients may have had several years of antecedent neurologic complaints, often including seizures. The lesions are found mostly in the cerebral hemispheres, mainly in the frontal or temporal lobes. The combination of surgery, chemotherapy, and radiotherapy yields an average survival of 10 to 20 years for well-differentiated (WHO grade II) oligodendrogliomas or 5 to 10 years for anaplastic (WHO grade III) oligodendrogliomas. http://ebooksmedicine.net Fig. 23.29 Diffuseastrocytomas.(A)GradeIIastrocytomaisseenasexpandedwhitematteroftheleftcerebralhemisphereandthickenedcorpuscallosumandfornices.(B)Glioblastomaappearingasanecrotic,hemorrhagic,infiltratingmass.(C)Glioblastomaisadenselycellulartumorwithnecrosisandpseudo-palisadingoftumorcellnucleialongtheedgeofthenecroticzone.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYWell-differentiatedoligodendrogliomas(WHOgradeII)areinfiltrativetumorsthatformgelatinous,graymassesandmayshowcysts,focalhemorrhage,andcalcification.Onmicroscopicexamination,thetumoriscomposedofsheetsofregularcellswithsphericalnucleicontainingfinelygranularchromatin(similartothatinnormaloligodendrocytes)surroundedbyaclearhaloofcytoplasm( Fig.23.30 ).Thetumortypicallycontainsadelicatenetworkofanastomosingcapillaries.Calcification,presentinasmanyas90%ofthesetumors,rangesinextentfrommicroscopicfocitomassivedepositions.Mitoticactivityusuallyislow.Ana-plasticoligodendroglioma(WHOgradeIII)isamoreaggressivesubtypewithhighercelldensity,nuclearanaplasia,increasedmitoticactivity,andoftenmicrovascularproliferation. Several classes of tumor-causing genetic alterations have been described in gliomas.


Pathology_Robbins

Pathology_Robbins. Several classes of tumor-causing genetic alterations have been described in gliomas. • Mutations in isocitrate dehydrogenase (IDH) genes are commonly observed in grade II astrocytomas and oligodendrogliomas. These mutations may occur in IDH1 or IDH2 and lead to increased production of 2-hydroxyglutarate, which interferes with the activity of several enzymes that regulate gene expression (Chapter 6). Mutations in the promoter for telomerase, which contribute to the immortalization of tumor cells (Chapter 6), are seen in glioblastomas and other astrocytic tumors. In tumors with IDH mutations, telomerase mutations are uncommon; instead, these tumors often have loss of function mutations in ATRX, which normally suppresses recombination events that can preserve telomere length, a mechanism called alternative lengthening of telomeres.


Pathology_Robbins

Pathology_Robbins. Co-deletion of 1p and 19q chromosomal segments are present in oligodendrogliomas. The mechanism through which these chromosomal alterations shape tumor morphology and response to treatment is not known. Other genetic alterations, which are also common in tumors outside the CNS, include mutations that lead to overexpression of the EGF receptor and other receptor tyrosine kinases or disable p53 or RB (Chapter 6).


Pathology_Robbins

Pathology_Robbins. Midline gliomas arise most commonly in the brain stem (specifically in the pons) and also occur in the spinal cord and thalamus. They are infiltrative and result in significant neurologic impairment because of the disruption of critical nearby structures. Although they may not show typical high-grade features such as necrosis or vascular proliferation, they often behave aggressively. These lesions typically have acquired point mutations in histone H3, the consequence of which is loss of a lysine residue that is the target of post-translational modifications that regulate gene expression, another example of oncogenesis via alteration of the cancer cell “epigenome”. Precisely how this mutation contributes to cellular transformation remains to be determined. http://ebooksmedicine.net Fig. 23.30 Inoligodendroglioma,tumorcellshaveroundnuclei,oftenwithaclearcytoplasmichalo.Bloodvesselsinthebackgroundarethinandcanformaninterlacingpattern.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 23.30 Inoligodendroglioma,tumorcellshaveroundnuclei,oftenwithaclearcytoplasmichalo.Bloodvesselsinthebackgroundarethinandcanformaninterlacingpattern. Pilocytic astrocytomas are relatively benign tumors that typically affect children and young adults. Most commonly located in the cerebellum, they also may involve the third ventricle, the optic pathways, the spinal cord, and occasionally the cerebral hemispheres. There is often a cyst associated with the tumor, and symptoms appearing after the incomplete resection of the lesions may be associated with cyst enlargement, rather than growth of the solid component. Tumors that involve the hypothalamus are especially problematic because they cannot be resected completely.


Pathology_Robbins

Pathology_Robbins. A high proportion of pilocytic astrocytomas have activating mutations or translocations involving the gene encoding the serine-threonine kinase BRAF, which result in activation of the MAPK signaling pathway. Pilocytic astrocytomas do not have mutations in IDH1 and IDH2, supporting their distinction from the low-grade diffuse gliomas. MORPHOLOGYApilocyticastrocytomaofteniscystic,withamuralnoduleinthewallofthecyst;ifsolid,itisusuallywellcircumscribed.Thetumoriscomposedofbipolarcellswithlong,thin“hairlike”processesthatareGFAP-positive.Rosenthalfibers,eosinophilicgranularbodies,andmicrocystsareoftenpresent,whilenecrosisandmitosesarerare.


Pathology_Robbins

Pathology_Robbins. Ependymomas most often arise next to the ependymalined ventricular system, including the central canal of the spinal cord. In the first 2 decades of life, they typically occur near the fourth ventricle and constitute 5% to 10% of the primary brain tumors in this age group. In adults, the spinal cord is their most common location; tumors in this site are particularly frequent in the setting of neurofibromatosis type 2 (Chapter 22). The clinical outcome for completely resected supratentorial and spinal ependymomas is better than for those in the posterior fossa. MORPHOLOGYInthefourthventricle,ependymomastypicallyaresolidorpapillarymassesextendingfromtheventricularfloor.Thetumorsarecomposedofcellswithregular,roundtoovalnucleiandabundantgranularchromatin.Betweenthenucleiisavariablydensefibrillarybackground.Tumorcellsmayformroundorelongatedstructures(rosettes, canals) thatresembletheembryologicependymalcanal,withlong,delicateprocessesextendingintoalumen(


Pathology_Robbins

Pathology_Robbins. Fig.23.31 );morefrequentlypresentareperivascular pseudorosettes inwhichtumorcellsarearrangedaroundvesselswithaninterveningzonecontainingthinependymalprocesses.Anaplasticependymomasshowincreasedcelldensity,highmitoticrates,necrosis,microvascularproliferation,andlessevidentependymaldifferentiation. Far less frequent than gliomas, tumors composed of cells with neuronal characteristics are typically lower-grade lesions that often present with seizures. While some neuronal differentiation can be observed in many tumors, lesions in this group are primarily composed of cells that express neuronal markers, such as synaptophysin and neurofilaments. • Central neurocytoma is a low-grade neoplasm found within and adjacent to the ventricular system (most commonly the lateral or third ventricle); it is characterized by evenly spaced, round, uniform nuclei and often islands of neuropil. Fig. 23.31 Microscopicappearanceofependymoma. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 23.31 Microscopicappearanceofependymoma. http://ebooksmedicine.net Dysembryoplastic neuroepithelial tumor is a distinctive, low-grade tumor of children and young adults that grows slowly, often manifests as a seizure disorder, and carries a favorable prognosis after resection. It typically is located in the superficial temporal lobe and consists of small, round neuronal cells arranged in columns and around central cores of processes. Gangliogliomas are tumors with a mixture of glial elements, usually a low-grade astrocytoma and mature-appearing neurons. Most of these tumors are slow growing, and often manifest with seizures. About 20% to 50% of gangliogliomas harbor point mutations in the BRAF gene.


Pathology_Robbins

Pathology_Robbins. Some tumors of neuroectodermal origin have a primitive “small round cell” appearance that is reminiscent of normal progenitor cells encountered in the developing CNS. Differentiation is often limited, but may progress along multiple lineages. The most common is the medulloblastoma, accounting for 20% of pediatric brain tumors. Medulloblastoma occurs predominantly in children and exclusively in the cerebellum. Neuronal and glial markers are nearly always expressed, at least to a limited extent. It is highly malignant, and the prognosis for untreated patients is dismal; however, medulloblastoma is exquisitely radiosensitive. With total excision, chemotherapy, and irradiation, the 5-year survival rate may be as high as 75%. There are a series of histologic patterns observed in medulloblastoma, which are informative about prognosis and correlate in part with the underlying genetics.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYInchildren,medulloblastomasarelocatedinthemidlineofthecerebellum;lateraltumorsoccurmoreofteninadults.Thetumorofteniswellcircumscribed,gray,andfriableandmaybeseenextendingtothesurfaceofthecerebellarfoliaandinvolvingtheleptomeninges( Fig.23.32A ).Medulloblastomasaredenselycellular,withsheetsofanaplastic(“smallblue”)cells(see Fig. 23.32B ).Individualtumorcellsaresmall,withlittlecytoplasmandhyperchromaticnuclei;mitosesareabundant.Often,focalneuronaldifferentiationisseenintheformofrosettes,whichcloselyresembletherosettesencounteredinneuroblastomas;theyarecharacterizedbyprimitivetumorcellssurroundingcentralneuropil(delicatepinkmaterialformedbyneuronalprocesses). Genetic analysis of medulloblastoma has revealed several subtypes associated with different clinical outcomes. Current approaches separate medulloblastoma into distinct groups with different core pathogenic pathways or driver mutations. Examples of oncogenic pathways in these tumors are the following:


Pathology_Robbins

Pathology_Robbins. Wnt pathway activation, most commonly associated with gain of function mutations in the gene for β-catenin; these have the most favorable prognosis of all of the genetic subtypes and are commonly classic-type tumors. Hedgehog pathway activation, most commonly associated with loss of function mutations in PTCH1, a negative regulator of the Hedgehog; these tumors have an intermediate prognosis, but the concomitant presence of TP53 mutation confers a very poor prognosis. MYC overexpression, due to MYC amplification as well as other changes that result in increased expression; these tumors have the poorest prognosis. Clinical trials are ongoing that seek to tailor therapy targeted to molecular alterations, with the goal of avoiding radiation therapy when possible.


Pathology_Robbins

Pathology_Robbins. Clinical trials are ongoing that seek to tailor therapy targeted to molecular alterations, with the goal of avoiding radiation therapy when possible. Primary CNS lymphoma, occurring mostly as diffuse large B-cell lymphomas, accounts for 2% of extranodal lymphomas and 1% of intracranial tumors. It is the most common CNS neoplasm in immunosuppressed individuals, in whom the tumors are nearly always positive for Epstein-Barr virus (EBV). In nonimmunosuppressed populations, the age spectrum is relatively wide, with the incidence increasing after 60 years of age. Regardless of the clinical context, primary brain lymphoma is an aggressive disease with a relatively poor response to chemotherapy as compared with peripheral lymphomas. Fig. 23.32 Medulloblastoma.(A)Sagittalsectionofabrainshowingmedulloblastomainvolvingthesuperiorvermisofthecerebellum.(B)Microscopicappearanceofmedulloblastoma,showingmostlysmall,blue,primitive-appearingtumorcells. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Patients with primary brain lymphoma often are found to have multiple tumor nodules within the brain parenchyma, yet involvement of sites outside of the CNS is uncommon. Conversely, lymphoma originating outside the CNS rarely spreads to the brain parenchyma; when this occurs, the tumor usually also involves the CSF or the meninges. MORPHOLOGYLesionsofteninvolvedeepgraystructures,aswellasthewhitematterandthecortex.Periventricularspreadiscommon.Thetumorsarerelativelywelldefinedascomparedwithglialneoplasms,buttheyarenotasdiscreteasmetastases.EBV-associatedtumorsoftenshowextensiveareasofnecrosis.ThetumorsarenearlyalwaysaggressivelargeB-celllymphomas,althoughotherhistologictypesmaybeencountered.Microscopically,malignantlymphoidcellsaccumulatearoundbloodvesselsandinfiltratethesurroundingbrainparenchyma.ThediagnosisisconfirmedbyimmunohistochemistryforBcellmarkerssuchasCD20,whichalsoisatargetoftherapeuticantibodies.


Pathology_Robbins

Pathology_Robbins. Primary brain germ cell tumors occur along the midline, most commonly in the pineal and the suprasellar regions. They account for 0.2% to 1% of brain tumors in individuals of European descent but in as many as 10% of brain tumors in individuals of Japanese ethnicity. They are a tumor of the young, with 90% occurring during the first 2 decades of life. Germ cell tumors in the pineal region show a strong male predominance. The most common primary CNS germ cell tumor is germinoma, a tumor that closely resembles testicular seminoma (Chapter 18). Secondary CNS involvement by metastatic gonadal germ cell tumors also occurs.


Pathology_Robbins

Pathology_Robbins. Meningiomas are predominantly benign tumors that arise from arachnoid meningothelial cells. They usually occur in adults and are often attached to the dura. Meningiomas may be found along any of the external surfaces of the brain as well as within the ventricular system, where they arise from the stromal arachnoid cells of the choroid plexus. They often come to attention because of vague nonlocalizing symptoms, or with focal findings referable to compression of adjacent brain. Most meningiomas are easily separable from underlying brain, but some tumors are infiltrative, a feature associated with an increased risk for recurrence. The overall prognosis is determined by the lesion size and location, surgical accessibility, and histologic grade.


Pathology_Robbins

Pathology_Robbins. When an individual has multiple meningiomas, especially in association with eighth-nerve schwannomas or glial tumors, the diagnosis of neurofibromatosis type 2 (NF2) should be considered (Chapter 22). About half of meningiomas not associated with NF2 have somatic loss-of-function mutations in the NF2 tumor suppressor gene on the long arm of chromosome 22 (22q). These mutations are found in all grades of meningioma, suggesting that they are involved in tumor initiation. Among sporadic tumors that lack mutations in NF2, several other driver mutations have been identified including in genes that regulate the Hedgehog pathway as well as in various signaling molecules and transcription factors.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Anaplastic (malignant) meningiomas (WHOgradeIII)arehighlyaggressivetumorsthatmayresembleahigh-gradesarcomaorcarcinomamorphologically.Mitoticratesaretypicallymuchhigherthaninatypicalmeningiomas. Metastatic lesions, mostly carcinomas, account for approximately one-fourth to one-half of intracranial tumors. The most common primary sites are lung, breast, skin (melanoma), kidney, and gastrointestinal tract, which together account for about 80% of cases. Metastases form sharply demarcated masses, often at the grey-white matter junction, and elicit local edema ( Fig. 23.34 ). The boundary between tumor and brain parenchyma is sharp at the microscopic level as well, with surrounding reactive gliosis.


Pathology_Robbins

Pathology_Robbins. Fig. 23.34 ). The boundary between tumor and brain parenchyma is sharp at the microscopic level as well, with surrounding reactive gliosis. In addition to the direct and localized effects produced by metastases, paraneoplastic syndromes may involve the peripheral and central nervous systems, sometimes even preceding the clinical recognition of the malignant neoplasm. Many patients with paraneoplastic syndromes have antibodies against tumor antigens. Some of the more common patterns include the following: • Subacute cerebellar degeneration resulting in ataxia, with destruction of Purkinje cells, gliosis, and a mild inflammatory infiltrate http://ebooksmedicine.net Fig. 23.33 Meningioma.(A)Parasagittalmultilobularmeningiomaattachedtothedurawithcompressionofunderlyingbrain.(B)Meningiomawithawhorled patternofcellgrowthandpsammomabodies.


Pathology_Robbins

Pathology_Robbins. Fig. 23.33 Meningioma.(A)Parasagittalmultilobularmeningiomaattachedtothedurawithcompressionofunderlyingbrain.(B)Meningiomawithawhorled patternofcellgrowthandpsammomabodies. Limbic encephalitis causing a subacute dementia, with perivascular inflammatory cells, microglial nodules, neuronal loss, and gliosis, all centered in the medial temporal lobe Subacute sensory neuropathy leading to altered pain sensation, with 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 and antibodies against the N-methyl-D-aspartate (NMDA) receptor. Several inherited syndromes caused by mutations in various tumor suppressor genes are associated with an increased risk for particular types of cancers. Those with particular involvement of the CNS are discussed here; familial syndromes associated with tumors of the peripheral nervous system are covered in Chapter 22.


Pathology_Robbins

Pathology_Robbins. Tuberous sclerosis is an autosomal dominant syndrome characterized by the development of hamartomas and benign neoplasms involving the brain and other tissues. CNS hamartomas variously consist of cortical tubers and subependymal hamartomas, including a larger tumefactive form known as subependymal giant cell astrocytoma. Because of their proximity to the foramen of Monro, they often present acutely with obstructive hydrocephalus, which requires surgical intervention and/or therapy with an mTOR inhibitor (see later). Seizures are associated with cortical tubers and can be difficult to control with anti-epileptic drugs. Extracerebral lesions include renal angiomyolipomas, retinal glial hamartomas, pulmonary lymphangiomyomatosis, and cardiac rhabdomyomas. Cysts may be found at various sites, including the liver, kidneys, and pancreas. Cutaneous lesions include angiofibromas, leathery thickenings in localized patches (shagreen patches), hypopigmented areas (ash leaf patches), and


Pathology_Robbins

Pathology_Robbins. sites, including the liver, kidneys, and pancreas. Cutaneous lesions include angiofibromas, leathery thickenings in localized patches (shagreen patches), hypopigmented areas (ash leaf patches), and subungual fibromas.


Pathology_Robbins

Pathology_Robbins. Tuberous sclerosis results from disruption of either TSC1, which encodes hamartin, or TSC2, which encodes tuberin. The two TSC proteins form a dimeric complex that negatively regulates mTOR, a kinase that “senses” the cell’s nutrient status and regulates cellular metabolism. Loss of either protein upregulates mTOR activity, which disrupts normal feedback mechanisms that restrict uptake of nutrients and leads to increased cell growth. MORPHOLOGYCortical hamartomas arefirmerthannormalcortexandhavebeenlikenedinappearancetopotatoes—hencetheappellationtubers. Theyarecomposedofhaphazardlyarrangedlargeneuronsthatlackthenormalcorticallaminararchitecture.Thesecellsmayexhibitamixtureofglialandneuronalfeatures,havinglargevesicularnucleiwithnucleoli(likeneurons)andabundanteosinophiliccytoplasm.Similarabnormalcellsarepresentinsubependymal nodules, inwhichlargeastrocytelikecellsclusterbeneaththeventricularsurface. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net In this autosomal dominant disorder, affected individuals develop hemangioblastomas within the cerebellar hemispheres, retina, and, less commonly, the brain stem, spinal cord, and nerve roots. Patients also may have cysts involving the pancreas, liver, and kidneys and have an increased propensity to develop renal cell carcinoma. The disease frequency is 1 in 30,000 to 40,000. Therapy is directed at the symptomatic neoplasms, including surgical resection of cerebellar tumors and laser ablation of retinal tumors.


Pathology_Robbins

Pathology_Robbins. The affected gene, the tumor suppressor VHL, encodes a protein that is part of a ubiquitin-ligase complex that degrades the transcription factor hypoxia-inducible factor (HIF). Tumors arising in patients with von Hippel–Lindau disease generally have lost all VHL protein function. As a result, the tumors express high levels of HIF, which drives the expression of VEGF, various growth factors, and sometimes erythropoietin; the latter effect may produce a paraneoplastic form of polycythemia.


Pathology_Robbins

Pathology_Robbins. McKee AC, Cairns NJ, Dickson DW, et al: The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy, Acta Neuropathol 131(1):75–86, 2016. [The first effort to define objectively the neuropathologic changes which define CTI.] McKee AC, Stein TD, Kiernan PT, et al: The neuropathology of chronic traumatic encephalopathy, Brain Pathol 25(3):350–364, 2015. [A summary of much of the descriptive work laying the basis for the emergence of CTE as a tauopathy associated with prior brain trauma.] Guemez-Gamboa A, Coufal NG, Gleeson JG: Primary cilia in the developing and mature brain, Neuron 82(3):511–521, 2014. [A discussion of the role of primary cilia in brain development, particularly the posterior fossa, as well as consideration of malformations that accompany disorders of this cilium.]


Pathology_Robbins

Pathology_Robbins. Guerrini R, Dobyns WB: Malformations of cortical development: clinical features and genetic causes, Lancet Neurol 13(7):710–726, 2014. [A clear review of many of the biological mechanisms that underlie cortical development as well as the genetic disorder that disrupt the process.] Infections of the Nervous System Clifford DB: Neurological immune reconstitution inflammatory response: riding the tide of immune recovery, Curr Opin Neurol 28(3):295–301, 2015. [Discusses the clinical and pathological aspects of the inflammatory syndrome which can accompany initiation of HAART as a result of recovery of aspects of the immune system.] Saylor D, Dickens AM, Sacktor N, et al: HIV-associated neurocognitive disorder—pathogenesis and prospects for treatment, Nat Rev Neurol 12(4):234–248, 2016. [Summary of the underlying mechanisms for HIV-induced neurologic dysfunction and the impact of existing therapies on these complications of infection.]


Pathology_Robbins

Pathology_Robbins. Dendrou CA, Fugger L, Friese MA: Immunopathology of multiple sclerosis, Nat Rev Immunol 15(9):545–558, 2015. [While the immune basis of MS has been accepted for many years, it has become clear that there are increasing complexities of this injury to myelin, axons, and oligodendrocytes than previously assumed.] Podestà MA, Faravelli I, Cucchiari D, et al: Neurological counterparts of hyponatremia: pathological mechanisms and clinical manifestations, Curr Neurol Neurosci Rep 15(4):18, 2015. [The mechanistic relationship between alterations in serum osmolality and acute injury to myelin remains complex but is partially addressed in this discussion.] Yang X, Ransom BR, Ma JF: The role of AQP4 in neuromyelitis optica: More answers, more questions, J Neuroimmunol 298:63–70, 2016. [While the presence of antibodies to aquaporin-4 helped clarify the syndrome of neuromyelitis optica, it remains a more complex disease than a simple autoimmune disorder.]


Pathology_Robbins

Pathology_Robbins. Barker RA, Williams-Gray CH: Review: the spectrum of clinical features seen with alpha synuclein pathology, Neuropathol Appl Neurobiol 42(1):6–19, 2016. [Aggregation of α-synuclein marks several neurodegenerative diseases, and this review considers shared and distinct aspects of the pathologic findings.] Colonna M, Wang Y: TREM2 variants: new keys to decipher Alzheimer disease pathogenesis, Nat Rev Neurosci 17(4):201–207, 2016. [One of the strongest links between Alzheimer disease and microglia is the risk associated with variants of TREM2 on the surfaces of microglia.] Ling SC, Polymenidou M, Cleveland DW: Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis, Neuron 79(3):416–438, 2013. [A clear summary of mechanisms associated with neurodegeneration that can be linked to the consequences of altered RNA dynamics within cells and the consequence of this for proteins.] http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Mackenzie IR, Neumann M: Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies, J Neurochem 138(Suppl 1):54–70, 2016. [A consideration of the complex family of disorders that give rise to frontotemporal lobe degenerations, with different clinical pictures as well as different histologic findings and associated mechanisms.] Selkoe DJ, Hardy J: The amyloid hypothesis of Alzheimer’s disease at 25 years, EMBO Mol Med 8(6):595–608, 2016. [A current summary of the relationship of Aβ to the pathogenesis of Alzheimer disease.]


Pathology_Robbins

Pathology_Robbins. Louis DN, Perry A, Reifenberger G, et al: The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary, Acta Neuropathol 131(6):803–820, 2016. [A concise summary of the most recent classification of brain tumors, including the concept of “layer” diagnoses that incorporate histologic findings as well as multiple types of molecular information in order to predict course and guide therapy.] http://ebooksmedicine.net studentconsult.com Skin diseases are common and diverse, ranging from irritating acne to life-threatening melanoma. Many are intrinsic to the skin, but some are manifestations of diseases involving many tissues, such as systemic lupus erythematosus or genetic syndromes such as neurofibromatosis. In this sense, the skin is a uniquely accessible “window” through which numerous disorders can be recognized.


Pathology_Robbins

Pathology_Robbins. Skin is not a mere protective mantle but rather a complex organ, actually the largest in the body. It is constantly exposed to microbial and nonmicrobial antigens from the environment. Given this, it is not surprising that the skin is an active participant in immune responses. Environmentally derived antigens are processed by intraepithelial Langerhans cells, which bear their antigenic cargo to regional lymph nodes and initiate immune responses. Squamous cells (keratinocytes) help maintain skin homeostasis by providing a physical barrier to environmental insults and by secreting a plethora of cytokines that influence both the squamous and dermal microenvironments. The dermis contains resident populations of CD4+ helper and CD8+ cytotoxic T lymphocytes, some of which home to the skin by virtue of specialized receptors such as cutaneous lymphocyte antigen, as well as memory T cells, regulatory T cells (Tregs) and occasional B cells. The epidermis contains intraepithelial lymphocytes,


Pathology_Robbins

Pathology_Robbins. virtue of specialized receptors such as cutaneous lymphocyte antigen, as well as memory T cells, regulatory T cells (Tregs) and occasional B cells. The epidermis contains intraepithelial lymphocytes, including γ/δ T cells, while the dermis contains perivascular mast cells and scattered macrophages, all components of the innate immune system. Responses involving these immune cells and locally released cytokines account for the morphologic patterns and clinical expressions of inflammatory and infectious skin disorders.


Pathology_Robbins

Pathology_Robbins. This chapter focuses on common and pathogenically illustrative skin diseases. In considering these diseases, it is important to appreciate that the practice of The contributions of Dr. George Murphy to this chapter in previous editions are gratefully acknowledged. dermatopathology relies on close interactions with clinicians, particularly dermatologists, as the clinical history, gross appearance, and distribution of lesions are often as important as the microscopic findings in arriving at a specific diagnosis. Diseases of the skin can be confusing for the student, in part because dermatologists and dermatopathologists communicate using a large, “skin-specific” lexicon that students must become familiar with in order to understand skin diseases. The most important of these terms and definitions are listed in Table 24.1


Pathology_Robbins

Pathology_Robbins. Table 24.1 Thousands of inflammatory dermatoses exist, challenging the diagnostic acumen of even experienced clinicians. In general, acute lesions, defined as days to several weeks in duration, are characterized by inflammation, edema, and sometimes epidermal, vascular, or subcutaneous injury. Acute dermatoses are often marked by infiltrates consisting of mononuclear cells rather than neutrophils, unlike acute inflammatory disorders at most other sites. Some acute lesions may persist, transitioning to a chronic phase, while others are self-limited. Urticaria (“hives”) is a common disorder mediated by localized mast cell degranulation, which leads to dermal microvascular hyperpermeability. The resulting erythematous, edematous, and pruritic plaques are termed wheals. In most cases, urticaria stems from an immediate (type 1) hypersensitivity reaction (Chapter 5), in which antigens trigger mast cell degranulation by binding to http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. In most cases, urticaria stems from an immediate (type 1) hypersensitivity reaction (Chapter 5), in which antigens trigger mast cell degranulation by binding to http://ebooksmedicine.net Table 24.1 Nomenclature of Skin Lesions ExcoriationTraumaticlesionbreakingtheepidermisandcausingarawlineararea(i.e.,deepscratch);oftenself-inflicted LichenificationThickened,roughskin(similartoalichenonarock);usuallytheresultofrepeatedrubbing Macule,patchCircumscribed,flatlesiondistinguishedfromsurroundingskinbycolor.Maculesare5mmindiameterorless,whilepatchesaregreaterthan5mminsize. Papule,noduleElevateddome-shapedorflat-toppedlesion.Papulesare5mmindiameterorless,whilenodulesaregreaterthan5mminsize. PlaqueElevatedflat-toppedlesion,usuallygreaterthan5mmindiameter(maybeformedbycoalescenceofpapules) PustuleDiscrete,pus-filled,raisedlesion ScaleDry,horny,platelikeexcrescence;usuallytheresultofimperfectcornification


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. ParakeratosisRetentionofnucleiinthestratumcorneumofasquamousepithelium.Onmucousmembranes,parakeratosisisnormal. immunoglobulin E (IgE) antibodies attached to the mast cell surface through their Fc receptor. Responsible antigens include viruses, pollens, foods, drugs, and insect venom. IgE-independent urticaria also can result from exposure to substances that directly incite mast cell degranulation, such as opiates and certain antibiotics. In the vast majority of cases, no clinical cause is discovered even with extensive investigation. MORPHOLOGYThehistologicfeaturesofurticariaoftenaresubtle.Thereisusuallyasparsesuperficialperivenularinfiltrateofmononuclearcells,rareneutrophils,andsometimeseosinophils.Superficialdermaledemacausessplayingofcollagenbundles,makingthemappeartobemorewidelyspacedthannormal.Degranulationofmastcells,whichresidearoundsuperficialdermalvenules,isdifficulttoappreciatewithroutinehematoxylin-eosin(H&E)stainsbutcanbehighlightedusingaGiemsastain.


Pathology_Robbins

Pathology_Robbins. Urticaria typically affects individuals between 20 and 40 years of age, but no age is immune. Individual lesions usually develop and fade within hours, but episodes can persist for days or even months. Lesions range in size and nature from small, pruritic papules to large, edematous, erythematous plaques. They may be localized to a particular part of the body or generalized. In a specific type of urticaria termed pressure urticaria, lesions are found only in areas exposed to pressure (such as the feet or buttocks). Although not life-threatening, severe pruritus and the social embarrassment of urticaria can compromise quality of life. Most cases respond to antihistamines, but more severe, refractory disease may require treatment with leukotriene antagonists, monoclonal antibodies that block the action of IgE, or immunosuppressive drugs.


Pathology_Robbins

Pathology_Robbins. Eczema is a clinical term that embraces a number of conditions with varied underlying etiologies. New lesions take the form of erythematous papules, often with overlying vesicles, which ooze and become crusted. Pruritus is characteristic. With persistence, these lesions coalesce into raised, scaling plaques. The nature and degree of these changes vary among the clinical subtypes, which include the following: Allergic contact dermatitis—stems from topical exposure to an allergen and is caused by delayed hypersensitivy reactions. Atopic dermatitis—formerly attributed to allergen exposure, now thought to often stem from defects in keratinocyte barrier function, defined as skin with increased permeability to substances to which it is exposed, such as potential antigens Drug-related eczematous dermatitis—hypersensitivity reaction to a drug Photoeczematous dermatitis—appears as an abnormal reaction to UV or visible light


Pathology_Robbins

Pathology_Robbins. Drug-related eczematous dermatitis—hypersensitivity reaction to a drug Photoeczematous dermatitis—appears as an abnormal reaction to UV or visible light Primary irritant dermatitis—results from exposure to substances that chemically, physically, or mechanically damage the skin While atopic dermatitis reflects a genetic predisposition and can persist for years or decades, other forms of eczematous dermatitis resolve completely when the offending stimulus is removed or exposure is limited, stressing the importance of investigating the underlying cause. Only the most common form, contact dermatitis, is considered here.


Pathology_Robbins

Pathology_Robbins. Allergic contact dermatitis is triggered by exposure to an environmental contact-sensitizing agent, such as poison ivy, that chemically reacts with self-proteins, creating neoantigens that can be recognized by the T cell http://ebooksmedicine.net arm of the adaptive immune system. The self-proteins modified by the agent are processed by epidermal Langerhans cells, which migrate to draining lymph nodes and present the antigen to naïve T cells. This sensitization event leads to acquisition of immunologic memory; on reexposure to the antigen, the activated memory CD4+ T lymphocytes migrate to the affected skin sites during the course of normal circulation. There they release cytokines that recruit additional inflammatory cells and also mediate epidermal damage, as in any delayed-type hypersensitivity reaction (Chapter 5). MORPHOLOGYAsthenameimplies,skininvolvementincontactdermatitisislimitedtositesofdirectcontactwiththetriggeringagent(


Pathology_Robbins

Pathology_Robbins. Lesions of acute eczematous dermatitis are pruritic, edematous, oozing plaques, often containing vesicles and bullae. With persistent antigen exposure, lesions may become scaly (hyperkeratotic) as the epidermis thickens (acanthosis). Some changes are produced or exacerbated by scratching of the lesion (see “ ”, discussed later). The clinical causes of eczema are sometimes divided into “inside jobs”—reaction to an internal circulating antigen (such as an ingested food or drug)— and “outside jobs”—disease resulting from contact with an external antigen (such as poison ivy).


Pathology_Robbins

Pathology_Robbins. Susceptibility to atopic dermatitis is often inherited; the disorder is concordant in 80% of identical twins and 20% of fraternal twins. It usually appears in early childhood and remits spontaneously as patients mature into adults. Children with atopic dermatitis often have asthma and allergic rhinitis, termed the atopic triad. Recent genetic studies have identified polymorphisms associated with increased risk in genes that encode proteins involved in keratinocyte barrier function, innate immunity, and T cell function.


Pathology_Robbins

Pathology_Robbins. Erythema multiforme is characterized by epithelial injury mediated by skin-homing CD8+ cytotoxic T lymphocytes. It is an uncommon, usually self-limited disorder that appears to be a hypersensitivity response to certain infections and drugs. Antecedent infections include those caused by herpes simplex, mycoplasma, and some fungi, while implicated drugs include sulfonamides, penicillin, salicylates, hydantoins, and anti-malarials. The cytotoxic T cell attack is focused on the basal cells of cutaneous and mucosal epithelia, presumably due to recognition of still unknown antigens. Certain human lymphocyte antigen (HLA) haplotypes are associated with the disease. Fig. 24.1 Eczematousdermatitis.(A)Patternederythemaandscalestem-mingfromanickel-inducedcontactdermatitisproducedbyanecklace. (B)Microscopically,thereisaccumulationoffluid(spongiosis)betweenepidermalcells,whichmayprogresstofrankblisterformation.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 24.2 Erythemamultiforme.(A)Targetlikelesionsconsistingofapalecentralblisterorzoneofepidermalnecrosissurroundedbymacularery-thema.(B)Earlylesionsshowlymphocytesalongthedermoepidermaljunc-tion(interfacedermatitis)associatedwithscatteredapoptotickeratinocytes,markedbydarkshrunkennucleiandeosinophiliccytoplasm. Erythema multiforme has a broad range of severity. The forms associated with infection (most often herpesvirus) are less severe. Erythema multiforme caused by medications may progress to more serious eruptions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis. These forms can be life-threatening, as they may cause sloughing of large portions of the epidermis, resulting in fluid loss and infections complications similar to those seen in burn-injured patients.


Pathology_Robbins

Pathology_Robbins. Chronic inflammatory dermatoses are persistent skin conditions that exhibit their most characteristic features over many months to years, although they may begin with an acute stage. The skin surface in some chronic inflammatory dermatoses is roughened as a result of excessive or abnormal scale formation and shedding (desquamation). Psoriasis is a common chronic inflammatory dermatosis, affecting 1% to 2% of individuals residing in the United States. Recent epidemiologic studies have shown that psoriasis is associated with an increased risk for heart attack and stroke, a relationship that may be related to a chronic inflammatory state. Psoriasis also is associated in up to 10% of patients with arthritis, which in some cases may be severe.


Pathology_Robbins

Pathology_Robbins. Psoriasis is a T cell-mediated inflammatory disease, presumed to be autoimmune in origin, although the antigens are not well described. Both genetic (HLA types and other susceptibility loci) and environmental factors contribute to the risk. It is unclear whether the inciting antigens are self-antigens, environmental antigens, or some combination of the two. Sensitized populations of T cells home to the dermis, including CD4+ TH17 and TH1 cells and CD8+ T cells, and accumulate in the epidermis. These cells secrete cytokines and growth factors that induce keratinocyte hyperproliferation, resulting in the characteristic lesions. Psoriatic lesions can be induced in susceptible individuals by local trauma (Koebner phenomenon), which may induce a local inflammatory response that promotes lesion development. Genome-wide association studies (GWAS) have linked an increased risk for psoriasis to polymorphisms in HLA loci and genes affecting antigen presentation, TNF signaling, and skin barrier


Pathology_Robbins

Pathology_Robbins. development. Genome-wide association studies (GWAS) have linked an increased risk for psoriasis to polymorphisms in HLA loci and genes affecting antigen presentation, TNF signaling, and skin barrier function. Several loci also are associated with the development of psoriatic arthritis, a more severe complication of this disease.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYThetypicallesionisawell-demarcated, pink to salmon– colored plaque covered by loosely adherent silver-white scale ( Fig.24.3A ).Thereismarkedepidermalthickening(acanthosis), withregulardownwardelongationofthereteridges(see Fig.24.3B ).Thepatternofthisdownwardgrowthhasbeenlikenedto“testtubesinarack.”Increasedepidermalcellturnoverandlackofmaturationresultsinloss of the stratum granulosum and extensive parakeratotic scale. Alsoseenisthinningoftheepidermalcelllayeroverlyingthetipsofdermalpapillae(suprapapillaryplates),anddilatedandtortuousbloodvesselswithinthepapillae.Thesevesselsbleedreadilywhenthescaleisremoved,givingrisetomultiplepunctatebleedingpoints(Auspitz sign). Neutrophilsformsmallaggregateswithinboththespongioticsuperficialepidermisandtheparakeratoticstratumcorneum.Similarchangescanbeseeninsuperficialfungalinfections,whichneedtobeexcludedwithappropriatespecialstains.


Pathology_Robbins

Pathology_Robbins. Psoriasis most frequently affects the skin of the elbows, knees, scalp, lumbosacral areas, intergluteal cleft, glans penis, and vulva. Nail changes on the fingers and toes occur in 30% of cases. In most cases psoriasis is limited in distribution, but it can be widespread and severe. The clinical subtypes are defined by pattern of involvement and severity. Treatment is aimed at preventing the release or actions of inflammatory mediators. Mild disease is treated topically with ointments containing corticosteroids or other immunomodulatory agents, whereas more severe disease is treated with phototherapy (which has immunosuppressive effects) or systemic therapy with immunosuppressive agents such as methotrexate or TNF antagonists. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 24.3 Chronicpsoriasis.(A)Erythematouspsoriaticplaquescoveredbysilvery-whitescale.(B)Microscopicexaminationshowsmarkedepidermalhyperplasia,downwardextensionofreteridges(psoriasiformhyperplasia),andprominentparakeratoticscalewithinfiltratingneutrophils. “Pruritic, purple, polygonal, planar papules, and plaques” are the tongue-twisting Ps that describe this disorder of skin and squamous mucosa. The lesions may result from a CD8+ T cell–mediated cytotoxic response against antigens in the basal cell layer and the dermoepidermal junction that are produced by unknown mechanisms, perhaps as a consequence of a viral infection or drug exposure. MORPHOLOGYCutaneouslesionsoflichenplanusconsistofpruritic, violaceous, flat-topped papules thatmaycoalescefocallytoformplaques(


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYCutaneouslesionsoflichenplanusconsistofpruritic, violaceous, flat-topped papules thatmaycoalescefocallytoformplaques( Fig.24.4A ).ThesepapulesarehighlightedbywhitedotsorlinestermedWickham striae. Hyperpigmentationmayresultfrommelaninlossintothedermisfromdamagedkeratinocytes.Microscopically,lichenplanusisaprototypicalinterface dermatitis, socalledbecausetheinflammationanddamageareconcentratedattheinterfaceofthesquamousepitheliumandpapillarydermis.Thereisadense,continuousinfiltrateoflymphocytesalongthedermoepidermaljunction(see


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig. 24.4 Lichenplanus.(A)Flat-toppedpink-purplepolygonalpapulewithwhitelacelikemarkingsreferredtoasWickham striae. (B)Microscopicexaminationshowsabandlikeinfiltrateoflymphocytesalongthedermoepi-dermaljunction,hyperkeratosis,hypergranulosis,andpointedreteridges(“sawtoothing”),whichresultsfromchronicinjuryofthebasalcelllayer. http://ebooksmedicine.net Lichen planus is an uncommon disorder that usually presents in middle-aged adults. The cutaneous lesions are multiple and are usually symmetrically distributed, particularly on the extremities, and often occur around the wrists and elbows and on the vulva and glans penis. Approximately 70% of cases also involve the oral mucosa, where the lesions manifest as white papules with a reticulate or netlike appearance. The cutaneous lesions of lichen planus usually resolve spontaneously within 1 to 2 years, but the oral lesions may persist and be of sufficient severity to interfere with food intake.


Pathology_Robbins

Pathology_Robbins. Lichen simplex chronicus manifests as roughening of the skin, which takes on an appearance reminiscent of lichen on a tree. It is a response to local repetitive trauma, usually from rubbing or scratching. Nodular forms exist that are referred to as prurigo nodularis. The pathogenesis of lichen simplex chronicus is not understood, but the trauma probably induces epithelial hyperplasia and eventual dermal scarring. MORPHOLOGYLichensimplexchronicusischaracterizedbyacanthosis, hyperkeratosis, andhypergranulosis. Alsoseenareelongationofthereteridges,fibrosisofthepapillarydermis,andadermalchronicinflammatoryinfiltrate( Fig.24.5 ).Ofinterest,theselesionsaresimilarinappearancetonormalvolar(palmsandsoles)skin,inwhichskinthickeningservesasanadaptationtorepetitivemechanicalstress.


Pathology_Robbins

Pathology_Robbins. Fig.24.5 ).Ofinterest,theselesionsaresimilarinappearancetonormalvolar(palmsandsoles)skin,inwhichskinthickeningservesasanadaptationtorepetitivemechanicalstress. The lesions often are raised, erythematous, and scaly and can be mistaken for keratinocytic neoplasms. Lichen simplex chronicus can be superimposed on and mask another (often pruritic) dermatosis. It is therefore important to rule out an underlying cause while recognizing that the lesion may be entirely trauma-related. Fig. 24.5 Lichensimplexchronicus.Notethedistinctiveacanthosis,hyper-keratosis,andhypergranulosis.Superficialdermalfibrosisandvascularectasia,bothcommonfeatures,alsoarepresent. ManyspecificinflammatorydermatosesexistandcanbemediatedbyIgEantibodies(urticaria),antigen-specificTcells(eczema,erythemamultiforme,andpsoriasis),ortrauma(lichensimplexchronicus). Underlyinggeneticsusceptibilityplaysaroleinatopicdermatitisandpsoriasis.


Pathology_Robbins

Pathology_Robbins. Underlyinggeneticsusceptibilityplaysaroleinatopicdermatitisandpsoriasis. Thesedisorderscanbegroupedbasedonpatternsofinflammation(e.g.,interfacedermatitisinlichenplanusanderythemamultiforme). Clinicalcorrelationisessentialtodiagnosespecificskindiseases,sincemanyhaveoverlapping,nonspecifichistologicfeatures. Numerous bacterial infections occur in skin. These range from superficial infections known as impetigo, to deeper dermal abscesses associated with puncture wounds that are caused by bacteria such as Pseudomonas aeruginosa. The pathogenesis is similar to that for microbial infections elsewhere (Chapter 9). Only impetigo is discussed here. MORPHOLOGYImpetigoischaracterizedbyanaccumulationofneutrophilsbeneaththestratumcorneumthatoftenproducesasubcornealpustule.Nonspecificreactiveepidermalalternationandsuperficialdermalinflammationaccompanythesefindings.BacterialcocciinthesuperficialepidermiscanbedemonstratedbyGramstain.


Pathology_Robbins

Pathology_Robbins. Impetigo, one of the most common bacterial infections of the skin, is seen primarily in children. The causative organism is usually Staphylococcus aureus or, less commonly, Streptococcus pyogenes, and is typically acquired through direct contact with a source. Impetigo often begins as a single small macule, usually on the extremities or the face near the nose or the mouth, which rapidly evolves into a larger lesion ( Fig. 24.6 ), often with a honey-colored crust of dried serum. Individuals who are colonized by S. aureus or S. pyogenes (usually nasal or anal) are more likely to be affected. A less common bullous form of childhood impetigo may mimic an autoimmune blistering disorder. Fungal infections are varied, ranging from superficial infections with Tinea or Candida spp. to life-threatening http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fungal infections are varied, ranging from superficial infections with Tinea or Candida spp. to life-threatening http://ebooksmedicine.net Fig. 24.6 Impetigo.Achild’sarminvolvedbyasuperficialbacterialinfectionshowingthecharacteristicerythematousscablikelesionscrustedwithdriedserum.(Courtesy of Dr.Angela Wyatt,Bellaire,Texas.) Aspergillus spp. infections in immunosuppressed individuals. Fungal infections can be superficial (stratum corneum, hair, and nails), deep (dermis or subcutis), or systemic, the last type arising through hematogenous spread, often in an immunocompromised patient. MORPHOLOGYThehistologicappearancevariesdependingontheorganism,hostresponse,anddegreeofsuperinfection.Superficialinfectionsareoftenassociatedwithaneutrophilicinfiltrateintheepidermis.Deepfungalinfectionsproducegreatertissuedamageandoftenelicitagranulomatousresponse.Aspergillus canbeangioinvasive.Periodicacid–Schiff(PAS)andGomorimethenaminesilverstainsarehelpfulinidentifyingthefungalorganisms.


Pathology_Robbins

Pathology_Robbins. Superficial infections usually produce erythematous macules with superficial scale that can be pruritic, while deeper infections such as those seen with Aspergillus spp. are erythematous and often nodular and sometimes associated with local hemorrhage. Superficial fungal infections may have an annular appearance. However, they also may induce lesions that mimic other psoriasiform or eczematous dermatoses, so it is important to consider the possibility of fungal infection when these conditions are in the differential diagnosis. Verrucae are proliferative lesions of squamous epithelial cells that are caused by human papillomavirus (HPV). They are most common in children and adolescents, but may be encountered in any age group. HPV infection usually stems from direct contact with an infected individual or autoinoculation. Verrucae generally are self-limited, most often regressing spontaneously within 6 months to 2 years.


Pathology_Robbins

Pathology_Robbins. While some members of the HPV family are associated with preneoplastic and invasive cancers of the anogenital region (Chapters 6 and 18), cutaneous warts are mainly caused by low-risk HPV subtypes that lack transforming potential. Like high-risk HPV, low-risk viruses express viral E6 and E7 oncoproteins that lead to dysregulated epidermal cell growth and increased survival. Why low-risk viruses cause warts instead of cancer is likely due to structural variation in E6 and E7 proteins that affect their interactions with host proteins. Because the growth of warts is normally halted by the immune response, immunodeficiency is associated with more numerous and larger verrucae. MORPHOLOGYDifferentkindsofwartsareidentifiedonthebasisoftheirgrossappearanceandlocationandgenerallyarecausedbydistinctHPVsubtypes.Verruca vulgaris (


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYDifferentkindsofwartsareidentifiedonthebasisoftheirgrossappearanceandlocationandgenerallyarecausedbydistinctHPVsubtypes.Verruca vulgaris ( Fig.24.7A ),themostcommontypeofwart,canoccuranywherebutisfoundmostfrequentlyonthehands,particularlyonthedorsalsurfacesandperiungualareas,whereitappearsasagray-whitetotan,flattoconvex,0.1-to1-cmpapulewitharough,pebblelikesurface.Verruca plana, orflat wart, iscommononthefaceordorsalsurfacesofthehands.Thesewartsareflat,smooth,tanmacules.Verruca plantaris andverruca palmaris occuronthesolesandpalms,respectively.Theserough,scalylesionscanreach1to2cmindiameterandmaycoalescetoformasurfacethatcanbeconfusedwithordinarycalluses.Condyloma acuminatum (venereal wart) occursonthepenis,femalegenitalia,urethra,andperianalareas(Chapters18and19).Histologicfeaturescommontoverrucaeincludeepidermal hyperplasia, whichisoftenundulantincharacter(so-calledverrucous orpapillomatous epidermal hyperplasia)(


Pathology_Robbins

Pathology_Robbins. Fig.24.7B ,top panel),andcytoplasmicvacuolization(koilocytosis), whichpreferentiallyinvolvesthemoresuperficialepidermallayers,producinghalosofpallorsurroundinginfectednuclei.Infectedcellsalsomaydemonstrateprominentkeratohyalingranulesandjaggedeosinophilicintracytoplasmicproteinaggregatesasaresultofimpairedmaturation( Fig.24.7B , bottom panel). Although vesicles and bullae (blisters) occur as secondary phenomena in several unrelated conditions (e.g., herpes-virus infection, spongiotic dermatitis), there is a group of disorders in which blisters are the primary and most distinctive feature. Blistering in these diseases tends to occur at specific levels within the skin, a morphologic distinction that is critical for diagnosis ( Fig. 24.8 Pemphigus is an uncommon autoimmune blistering disorder resulting from loss of normal intercellular attachments within the epidermis and the squamous mucosal epithelium. There are three major variants: Pemphigus vulgaris (the most common type)


Pathology_Robbins

Pathology_Robbins. Pemphigus vulgaris (the most common type) The last entity is associated with internal malignancy and is not discussed here. http://ebooksmedicine.net Fig. 24.7 Verrucavulgaris.(A)Multiplewarts,withcharacteristicrough,pebblelikesurfaces.(B)Microscopically,commonwartscontainzonesofpapillaryepidermalproliferationthatoftenradiatesymmetricallylikethepointsofacrown(top). Pallororhalosaroundnuclei,prominentkeratohyalingranules,andrelatedcytopathicchangesareseenathighermagnification (bottom).


Pathology_Robbins

Pathology_Robbins. Pemphigus vulgaris and pemphigus foliaceus are autoimmune diseases caused by antibody-mediated (type II) hypersensitivity reactions (Chapter 5). The pathogenic antibodies are IgG autoantibodies that bind to intercellular desmosomal proteins (desmoglein types 1 and 3) found in the skin and mucous membranes. The antibodies disrupt the intercellular adhesive function of desmosomes and may activate intercellular proteases as well. The distribution of desmoglein proteins within the epidermis determines the location of the lesions. By direct immunofluorescence study, lesional sites show a characteristic fishnet-like pattern of intercellular IgG deposits ( Fig. 24.9 ). As with many other autoimmune diseases, pemphigus is associated with particular HLA alleles.


Pathology_Robbins

Pathology_Robbins. Fig. 24.9 ). As with many other autoimmune diseases, pemphigus is associated with particular HLA alleles. MORPHOLOGYPemphigus vulgaris involvesbothmucosaandskin,especiallyonthescalp,face,axillae,groin,trunk,andpointsofpressure.Thelesionsaresuperficialflaccidvesiclesandbullaethatruptureeasily,leavingdeepandoftenextensiveerosionscoveredwithaserumcrust( Fig.24.10A ).Pemphigus foliaceus, arare,milderformofpemphigus,resultsinbullaethataremainlyconfinedtotheskin,withonlyinfrequentinvolvementofmucousmembranes.Theblistersinthisdisorderaresuperficial,suchthatmorelimitedzonesoferythemaandcrustingofrupturedblistersareseen( Fig.24.11A Thecommonhistologicdenominatorinallformsofpemphigusisacantholysis, lysisoftheintercellularadhesivejunctionsbetweenneighboringsquamousepithelialcellsthatresultsintheroundingupofdetachedcells.Inpemphigusvulgaris,acantholysisselectivelyinvolvesthelayerofcellsimmediatelyabovethebasalcelllayer,givingrisetoasuprabasal acantholytic blister ( Fig.


Pathology_Robbins

Pathology_Robbins. Fig. 24.10B ).Inpemphigusfoliaceus,acantholysisselectivelyinvolvesthesuperficialepidermisatthelevelofthestratumgranulosum( Fig.24.11B ).Variablesuperficialdermalinfiltratescomposedoflymphocytes,macrophages,andeosinophilsaccompanyallformsofpemphigus. Pemphigus vulgaris is a rare disorder that occurs most commonly in older adults and more often in women than in men. Lesions are painful, particularly when ruptured, and frequently develop secondary infections. Most affected patients have oropharyngeal involvement at some point in their course. The mainstay of treatment is immunosuppressive therapy, sometimes for life. Medications can induce pemphigus, more often pemphigus foliaceus than pemphigus vulgaris. There is also an unusual endemic form of pemphigus foliaceus in South America (fogo selvagem) that is putatively associated with the bite of a black fly. Bullous pemphigoid is another distinctive acquired blistering disorder with an autoimmune basis.


Pathology_Robbins

Pathology_Robbins. Bullous pemphigoid is another distinctive acquired blistering disorder with an autoimmune basis. Blistering in bullous pemphigoid is triggered by the linear deposition of autoreactive IgG antibodies and complement in the epidermal basement membrane ( Fig. 24.12A ). Reactivity also occurs in the basement membrane attachment plaques (hemidesmosomes), where most bullous pemphigoid antigen (most commonly type XVII collagen) is located. The proteins that are recognized by the autoantibodies have structural roles in dermoepidermal adhesion. IgG autoantibodies to hemidesmosome components fix complement and cause tissue injury by recruiting neutrophils and eosinophils. Bullous pemphigoid and pemphigus vulgaris are thus caused by similar pathogenic http://ebooksmedicine.net Fig. 24.8 Levelsofblisterformation.(A)Subcorneal(asinpemphigusfoliaceus).(B)Suprabasal(asinpemphigusvulgaris).(C)Subepidermal(asinbullouspemphigoidordermatitisherpetiformis).


Pathology_Robbins

Pathology_Robbins. Fig. 24.8 Levelsofblisterformation.(A)Subcorneal(asinpemphigusfoliaceus).(B)Suprabasal(asinpemphigusvulgaris).(C)Subepidermal(asinbullouspemphigoidordermatitisherpetiformis). mechanisms, but differ in their clinical presentation and course due to variation in the location of the target antigen (hemidesmosomes in bullous pemphigoid, desmosomes in pemphigus). Fig.24.12B ).Theoverlyingepidermischaracteristicallylacksacantholysis.Earlylesionsshowvariablenumbersofeosinophilsatthedermal-epidermaljunction,occasionalneutrophils,superficialdermaledema,andassociatedbasalcelllayervacuolization.Thevacuolatedbasalcelllayereventuallygivesrisetoafluid-filledblister( Fig.24.12C ).Theblisterroofconsistsoffull-thicknessepidermiswithintactintercellularjunctions,akeydistinctionfromtheblistersseeninpemphigus.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. The lesions of bullous pemphigoid do not rupture as readily as in pemphigus and, if uncomplicated by infection, heal without scarring. The disease tends to follow a remitting and relapsing course and responds to topical or systemic immunosuppressive agents. Gestational pemphigoid (also known as herpes gestationis, a misnomer since there is no viral etiology) is a clinically distinct subtype that appears suddenly during the second or third trimester of pregnancy. It also is caused by autoantibodies against bullous pemphigoid antigen. Gestational pemphigoid typically resolves after childbirth, but may recur with subsequent pregnancies. Fig. 24.10 Pemphigusvulgaris.(A)Anerosiononthelegarisingfromcoalescenceofagroupof“unroofed”blisters.(B)Suprabasalintraepidermalblisterinwhichrounded,dissociated(acantholytic)keratinocytesareplenti-ful(inset). http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 24.11 Pemphigusfoliaceus.(A)Atypicalblister,whichismoresuperfi-cialthanthoseseeninpemphigusvulgaris.(B)Microscopicappearanceofacharacteristicsubcornealblister. Dermatitis herpetiformis is an autoimmune blistering disorder associated with gluten sensitivity that is characterized by extremely pruritic grouped vesicles and papules. The disease affects predominantly males, often in the third and fourth decades of life. Up to 80% of cases are associated with celiac disease; conversely, only a small fraction of patients with celiac disease develop dermatitis herpetiformis. Like celiac disease, dermatitis herpetiformis responds to a gluten-free diet.


Pathology_Robbins

Pathology_Robbins. The strong association of dermatitis herpetiformis with celiac disease provides a clue to its pathogenesis. Geneti-cally predisposed individuals develop IgA antibodies to dietary gluten (derived from the wheat protein gliadin) as well as IgA autoantibodies that cross-react with endomysium and tissue transglutaminases, including epidermal transglutaminase expressed by keratinocytes. By direct immunofluorescence, the skin shows discontinuous, granular deposits of IgA selectively localized in the tips of dermal papillae ( Fig. 24.13A ). The resultant injury and inflammation produce a subepidermal blister. Fig. 24.12 Bullouspemphigoid.(A)DepositionofIgGantibody(detectedbydirectimmunofluorescence)inthesubepidermalbasementmembrane(epidermisisontheleftsideofthefluorescentband).(B)Grossappearanceofcharacteristictense,fluid-filledblisters.(C)Subepidermalvesiclewithaneosinophil-richinflammatoryinfiltrate.(C, Courtesy of Dr. Victor G. Prieto, Houston,Texas.) http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. BullouspemphigoidisassociatedwithIgGautoantibodiestobasementmembraneproteins(partofthehemidesmosome)andproducesasubepidermalblister. DermatitisherpetiformisisassociatedwithIgAautoantibodiestotransglutaminase,andalsoischaracterizedbysubepidermalblisters. Benign epithelial neoplasms are common and probably arise from stem cells residing in the epidermis and hair follicles. These tumors grow to a limited size and generally do not undergo malignant transformation. These common pigmented epidermal tumors occur most frequently in middle-age or older individuals. They arise spontaneously and are particularly numerous on the trunk, although the extremities, head, and neck also may be sites of involvement.


Pathology_Robbins

Pathology_Robbins. Fig. 24.13 Dermatitisherpetiformis.(A)CharacteristicselectivedepositionofIgAautoantibodyatthetipsofthedermalpapillae.(B)Lesionsconsistofintactanderoded(usuallyscratched)erythematousblisters,oftengrouped(seenhereonelbowsandarms).(C)Blistersassociatedwithbasalcelllayerinjury,initiallycausedbyaccumulationofneutrophils(microabscesses)atthetipsofthedermalpapillae.(A, Courtesy of Dr.Victor G. Prieto, Houston,Texas.)


Pathology_Robbins

Pathology_Robbins. Seborrheic keratoses are caused by acquired activating mutations in growth factor signaling pathways. A significant fraction of these tumors harbor activating mutations in fibroblast growth factor receptor 3 (FGFR3), which possesses a tyrosine kinase activity that stimulates RAS and the PI3K/AKT pathway, while others have activating mutations in downstream pathway components such as RAS and PI3K. Except for cosmetic concerns, seborrheic keratoses are usually of little clinical importance. However, in rare patients hundreds of lesions may appear suddenly as a paraneoplastic syndrome (sign of Leser-Trelat). Patients with this presentation may harbor internal malignancies, most commonly gastrointestinal tract carcinomas, which produce growth factors that stimulate epidermal proliferation. MORPHOLOGYSeborrheickeratosesareround, exophytic, coinlike plaques thatvaryindiameterfrommillimeterstocentimetersandhavea“stuck-on” appearance(


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYSeborrheickeratosesareround, exophytic, coinlike plaques thatvaryindiameterfrommillimeterstocentimetersandhavea“stuck-on” appearance( Fig.24.14 ,inset).Theyaretantodarkbrownandhaveavelvety-togranular-appearingsurface.Occasionally,theirdarkcolorissuggestiveofmelanoma,leadingtosurgicalremoval. Microscopically,seborrheickeratosesarecomposedofmonotonoussheetsofsmallcellsthatresemblethebasalcellsofthenormalepidermis(see Fig.24.14 ).Variablemelaninpigmentationispresentwithinthesebasaloidcells,accountingforthebrowncolorationseengrossly.Hyperkeratosisoccursatthesurface,andthepresenceofsmallkeratin-filledcysts(horncysts)anddowngrowthofkeratinintothemaintumormass(pseudo–horncysts)arecharacteristicfeatures. Actinic keratosis is a premalignant lesion caused by UV-induced DNA damage that is associated with mutations in TP53 and other genes that also are frequently mutated in squamous cell carcinoma of the skin. Because such lesions usually are the result of chronic exposure to


Pathology_Robbins

Pathology_Robbins. Fig. 24.14 Seborrheickeratosis.Acharacteristicroughened,brown,waxylesionthatappearstobe“stuckon”theskin(inset). Microscopicexaminationshowsanorderlyproliferationofuniform,basaloidkeratinocytesthattendtoformkeratinmicrocysts(horncysts). sunlight and are associated with hyperkeratosis, they are called actinic (sun-related) keratoses. The rate of progression to squamous cell carcinoma is small, varying from 0.1% to 2.6% per year. Most regress or remain stable. MORPHOLOGYActinickeratosesusuallyarelessthan1cmindiameter,tan-brownorred,andrough(sandpaper-like)tothetouch (Fig. 24.15A ).Microscopically,lowerportionsoftheepidermisshowcytologic atypia, oftenassociatedwithhyperplasiaofbasalcells(see


Pathology_Robbins

Pathology_Robbins. 24.15A ).Microscopically,lowerportionsoftheepidermisshowcytologic atypia, oftenassociatedwithhyperplasiaofbasalcells(see Fig.24.15B )orwithatrophyanddiffusethinningoftheepidermalsurface.Thedermiscontainsthickened,blue-grayelasticfibers(solarelastosis),theresultofchronicsundamage.Thestratumcorneumisthickenedandshowsabnormalretentionofnuclei(parakeratosis).Uncommonly,full-thicknessepidermalatypiaisseen;suchlesionsareconsideredsquamouscellcarcinomainsitu( Fig.24.15C Actinic keratoses are very common in fair-skinned individuals and increase in incidence with age and sun exposure. As would be expected, there is a predilection for sun-exposed areas (face, arms, dorsum of the hands). Despite the low risk for malignant progression, actinic keratoses are often treated, either to prevent progression or for cosmetic reasons. Local eradication with cryotherapy (superficial freezing) or topical agents is effective and safe.


Pathology_Robbins

Pathology_Robbins. Seborrheic keratosis: Round,flatplaquesmadeupofproliferatingmonotonousepidermalbasalcells,whichsometimescontainmelanin.Hyperkeratosisandkeratin-filledcystsarecharacteristic. Actinic keratosis: Presentonsun-exposedskin,theselesionsshowcytologicatypiainlowerpartsoftheepidermisandinfrequentlyprogresstocarcinomainsitu. Althoughbothoftheselesionsareassociatedwithoncogenicmutations,malignanttransformationisexceedinglyrareinseborrheickeratosesandoccursinonlyasmallsubsetofactinickeratoses. Squamous cell carcinoma is a common tumor that typically arises on sun-exposed sites in older adults. These tumors have a higher incidence in men than in women.


Pathology_Robbins

Pathology_Robbins. Squamous cell carcinoma is a common tumor that typically arises on sun-exposed sites in older adults. These tumors have a higher incidence in men than in women. Cutaneous squamous cell carcinoma is mainly caused by UV light exposure, which leads to widespread DNA damage and extremely high mutational loads (Chapter 6). As one might imagine, patients with the rare disorder xeroderma pigmentosum, which disrupts repair of UV-induced DNA damage, are at an exceptionally high risk. TP53 mutations are common, as are activating mutations in RAS and loss-of-function mutations in Notch receptors, which transmit signals that regulate the orderly differentiation of normal squamous epithelia.


Pathology_Robbins

Pathology_Robbins. Fig. 24.15 Actinickeratosis.(A)Red,rough(sandpaper-like)lesionsowingtoexcessivescalearepresentonthecheekandnose.(B)Basalcelllayeratypia(dysplasia)withepithelialbudsassociatedwithmarkedhyperkeratosis,parakeratosis,anddermalsolarelastosis(asterisk). (C)Squamouscellcarcinomainsitulesionshowingfull-thicknessepithelialatypia. Immunosuppression, particularly in organ transplant recipients, is associated with an increased incidence of cutaneous squamous cell carcinomas that are likely to be associated with HPV infection. Other predisposing factors include industrial carcinogens (tars and oils), chronic non-healing ulcers, old burn scars, ingestion of arsenicals, and ionizing radiation.


Pathology_Robbins

Pathology_Robbins. Fig.24.16B Invasive squamous cell carcinomas of the skin often are discovered while small and resectable. Less than 1% will have metastasized to regional lymph nodes at diagnosis. The likelihood of metastasis is related to the thickness of the lesion and degree of invasion into the subcutis. Tumors arising from actinic keratoses may be locally aggressive but generally metastasize only after long periods of time, while those arising in burn scars, ulcers, and non–sun-exposed skin often behave more aggressively. Squamous cell carcinomas arising at internal sites (oropharynx, lung, esophagus, anus) are generally invasive and aggressive, possibly because (unlike in the skin) early lesions go unrecognized. Fig. 24.16 Invasivesquamouscellcarcinoma.(A)Anodular,hyperkeratoticlesionoccurringontheear,associatedwithmetastasistoaprominentpostauricularlymphnode(arrow). (B)Tumorinvadesthedermalsofttissueasirregularprojectionsofatypicalsquamouscellsexhibitingacantholysis.


Pathology_Robbins

Pathology_Robbins. Basal cell carcinoma is a common slow-growing cancer that rarely metastasizes. It tends to occur at sites subject to chronic sun exposure and in lightly pigmented individuals.


Pathology_Robbins

Pathology_Robbins. The molecular hallmark of basal cell carcinoma is loss-offunction mutations in PTCH1, a tumor suppressor gene that negatively regulates Hedgehog signaling; hence, tumors exhibit constitutive Hedgehog pathway activation. Excessive activation of Hedgehog in turn activates a host of downstream genes implicated in cell growth and survival and other phenotypes linked to malignant transformation. In sporadic basal cell carcinoma, PTCH1 mutations bear the telltale signs of UV light–induced DNA damage. The central role of increased Hedgehog signaling in basal cell carcinoma is further emphasized by Gorlin syndrome, an autosomal dominant disorder caused by inherited defects in PTCH1 that is associated with familial basal cell carcinoma. The Hedgehog pathway is an important regulator of embryonic development, and patients with Gorlin syndrome also often manifest subtle developmental anomalies. Mutations in TP53 caused by UV light–induced damage also are common in both familial and sporadic


Pathology_Robbins

Pathology_Robbins. development, and patients with Gorlin syndrome also often manifest subtle developmental anomalies. Mutations in TP53 caused by UV light–induced damage also are common in both familial and sporadic tumors.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig.24.17B ).Peripheraltumorcellnucleialignintheoutermostlayer(apatterntermedpalisading),whichoftenseparatesfromthestroma,creatingacharacteristiccleft( Fig.24.17C It is estimated that more than 1 million basal cell carcinomas are treated in the United States annually. By far the most important risk factor is cumulative sun exposure; basal cell carcinoma is more common in warm southern regions of the United States, and its incidence is 40-fold higher in sunny climates near the equator, such as Australia, than it is in Northern European locales. Individual tumors usually are cured by local excision, but approximately 40% of patients develop another basal cell carcinoma within 5 years. Advanced lesions may ulcerate, and extensive local invasion of bone or facial sinuses may occur if the lesions are neglected. Metastasis is exceedingly rare. Hedgehog pathway inhibitors are used to treat locally advanced or metastatic tumors.


Pathology_Robbins

Pathology_Robbins. Fig. 24.17 Basalcellcarcinoma.(A)Aprototypicalpearly,smooth-surfacedpapulewithtelangiectaticvessels.(B)Tumoriscomposedofnestsofbasaloidcellsinfiltratingafibroticstroma.(C)Tumorcellswithscantcytoplasmandsmallhyperchromaticnucleithatpalisadeontheoutsideofthenest.Thecleftbetweenthetumorcellsandthestromaisahighlycharacteristicartifactofsectioning. The incidence of both basal cell and squamous cell carcinomais strongly correlated with increasing lifetime sun exposure. Risk factors for cutaneous squamous cell carcinoma includefair skin, UV light exposure, exposure to carcinogenic chemicals, chronic skin inflammation and scarring, and HPV infection(in the setting of immunosuppression). Cutaneous squamous cell carcinoma has the potential for metastasis but usually is recognized and excised before it does so. Basal cell carcinoma, the most common malignancy worldwide, is a locally aggressive tumor associated with mutations in theHedgehog pathway. Metastasis is very rare.


Pathology_Robbins

Pathology_Robbins. Basal cell carcinoma, the most common malignancy worldwide, is a locally aggressive tumor associated with mutations in theHedgehog pathway. Metastasis is very rare. Strictly speaking, the term nevus denotes any congenital lesion of the skin. Melanocytic nevus, however, refers to any benign congenital or acquired neoplasm of melanocytes.


Pathology_Robbins

Pathology_Robbins. Melanocytic nevi are benign neoplasms caused by somatic gain-of-function mutations in BRAF or RAS. Nevi are derived from melanocytes, pigment-producing cells with dendritic projections that are normally interspersed among basal keratinocytes. You will recall that BRAF encodes a serine/threonine kinase that lies downstream of RAS in the extracellular regulated kinase (ERK) pathway. Experimental evidence suggests that unbridled BRAF/RAS signaling initially induces melanocytic proliferation followed by senescence. How these opposing effects are coordinated is unclear, but it is believed that the “brake” on proliferation provided by induced senescence explains why very few nevi transform into malignant melanomas. Indeed, the growth and migration of nevus cells from the dermoepidermal junction into the underlying dermis is accompanied by morphologic changes that are taken as evidence of cellular senescence (


Pathology_Robbins

Pathology_Robbins. Fig. 24.18 ). Superficial nevus cells are larger and tend to produce melanin pigment and grow in nests; deeper nevus cells are smaller, produce little or no pigment, and grow in cords or single cells. The deepest nevus cells have fusiform contours and grow in fascicles. This sequence of morphologic changes is of diagnostic importance, since they are absent from melanomas. Common melanocytic nevi are tan-to-brown, uniformly pigmented, small papules (5 mm or less across) with well-defined, rounded borders ( Fig. 24.19A ). Early lesions are composed of round to oval cells that grow in “nests” along the dermoepidermal junction. Nuclei are uniform and round, and contain inconspicuous nucleoli with little or no mitotic activity. Such early-stage lesions are called junctional nevi. Eventually, most junctional nevi grow into the underlying dermis as nests or cords of cells (compound nevi), and in older lesions the epidermal nests may be lost entirely, creating intradermal nevi (


Pathology_Robbins

Pathology_Robbins. Fig. 24.19B There are numerous types of melanocytic nevi, with varied appearances. Although these lesions usually are of only cosmetic concern, they may cause irritation or mimic melanoma, requiring their surgical removal. Compound and intradermal nevi often are more elevated than junctional nevi. Dysplastic nevi may be sporadic or familial. The latter are important clinically because they identify individuals who Fig. 24.18 Possible steps in the development of melanocytic nevi. (A) Normal skin shows only scattered melanocytes. (B) Junctional nevus. (C) Compound nevus. (D) Intradermal nevus. (E) Intradermal nevus with extensive cellular senescence. Fig. 24.19 Melanocyticnevus.(A)Melanocyticneviarerelativelysmall,symmetric,anduniformlypigmented.(B)Anevuscomposedofmelanocytesthatlosepigmentationandbecomesmallerandmoredispersedastheyextendintothedermis—allsignsthatspeaktothebenignnatureoftheproliferation.


Pathology_Robbins

Pathology_Robbins. have an increased risk of developing melanoma. As with conventional melanocytic nevi, activating RAS or BRAF mutations are commonly found in dysplastic nevi and are believed to have a pathogenic role. MORPHOLOGYDysplasticneviarelargerthanmostacquirednevi(oftenmorethan5mmacross)andmay number in the hundreds ( Fig. 24.20A ).Theyareflatmaculestoslightlyraisedplaques,witha“pebbly”surface.Theyusuallyhavevariablepigmentation(variegation)andirregularborders( Fig.24.20A , inset). Microscopically,dysplasticneviaremostlycompoundnevithatexhibitbotharchitecturalandcytologicevidenceofabnormalgrowth.Nevuscellnestswithintheepidermismaybeenlargedandexhibitabnormalfusionorcoalescencewithadjacentnests(bridging).Aspartofthisprocess,singlenevuscellsbegintoreplacethenormalbasalcelllayeralongthedermoepidermaljunction,producingso-called“lentiginous hyperplasia”( Fig.24.20B ).Cytologicatypiaconsistingofirregular,oftenangulated,nuclearcontoursandhyperchromasiaisfrequentlyobserved(


Pathology_Robbins

Pathology_Robbins. Unlike ordinary nevi, dysplastic nevi have a tendency to occur on body surfaces not exposed to the sun as well as on sun-exposed sites. Familial dysplastic nevus syndrome is strongly associated with melanoma, as the lifetime risk for the development of melanoma in affected individuals is close to 100%. In sporadic cases, only individuals with 10 or more dysplastic nevi appear to be at an increased risk for melanoma. Transformation of dysplastic nevus to melanoma has been documented, both clinically and histologically. However, such cases are the exception, as most melanomas appear to arise de novo and not from a preexisting nevus. Thus, the likelihood that any particular nevus, dysplastic or otherwise, will develop into melanoma is low, and these lesions are best viewed as markers of melanoma risk.


Pathology_Robbins

Pathology_Robbins. Melanoma is less common but much more deadly than basal or squamous cell carcinoma. Today, as a result of increased public awareness of the earliest signs of skin melanomas, most melanomas are cured surgically. Nonetheless, the incidence of these lesions has increased dramatically over the past several decades, at least in part as a result of increasing sun exposure and/or higher detection rates resulting from vigorous surveillance.


Pathology_Robbins

Pathology_Robbins. As with other cutaneous malignancies, melanoma is mainly caused by UV light–induced DNA damage that leads to the stepwise acquisition of driver mutations. The incidence is highest in sun-exposed skin and in geographic locales such as Australia, where sun exposure is high and much of the population is fair-skinned. Intense intermittent exposure at an early age is particularly harmful. Hereditary predisposition also plays a role in an estimated 5% to 10% of cases, as already discussed under familial dysplastic nevus syndrome. For example, germ-line mutations in the CDKN2A locus (located on 9p21) are found in as many as 40% of the rare individuals who suffer from familial melanoma. This complex locus encodes two tumor suppressors: p16, a cyclin-dependent kinase inhibitor that regulates the G1-S transition of the cell cycle by maintaining the retinoblastoma (RB) tumor suppressor protein in its active state; and p14, which augments the activity of the p53 tumor suppressor by preventing its


Pathology_Robbins

Pathology_Robbins. transition of the cell cycle by maintaining the retinoblastoma (RB) tumor suppressor protein in its active state; and p14, which augments the activity of the p53 tumor suppressor by preventing its degradation.


Pathology_Robbins

Pathology_Robbins. Key phases of melanoma development are marked by radial and vertical growth. The earliest recognizable phase of melanoma development is proposed to consist of lateral expansion of melanocytes along the dermoepidermal junction (lentiginous hyperplasia and lentiginous compound nevus; Fig. 24.21A-C ). This then progresses to the phase of melanoma in situ, which is marked by radial growth within the epidermis, often for a prolonged period ( Fig. 24.21D ). During this stage, melanoma cells do not have the capacity to invade and metastasize. With time, a vertical growth phase supervenes, in which the tumor grows downward into the deeper dermal layers as an expansile mass lacking cellular maturation ( Fig. 24.21E ). This event often is heralded by the development of a nodule in a previously flat lesion and correlates with the emergence of metastatic potential.


Pathology_Robbins

Pathology_Robbins. Fig. 24.21E ). This event often is heralded by the development of a nodule in a previously flat lesion and correlates with the emergence of metastatic potential. DNA sequencing of familial and sporadic cases, including cases that appear to have arisen from benign nevi, has provided important insights into the molecular pathogenesis of melanoma ( Fig. 24.22 ). The initiating event appears to be an activating mutation in BRAF or (less commonly) RAS. In the vast majority of cases, this produces only a benign nevus unless other mutations are superimposed. Sequencing of nevi with “atypical” morphologic features suggestive of melanoma as well as melanomas in the radial phase of growth (melanoma in situ) has shown that they commonly harbor mutations that activate the expression of telomerase, which is proposed to serve as an antidote to senescence (the usual fate of benign nevi). With additional mutations or epigenetic aberrations that lead to loss of


Pathology_Robbins

Pathology_Robbins. Fig. 24.21 Possible steps in the development of melanoma. (A) Normal skin shows only scattered melanocytes. (B) Lentiginous melanocytic hyperplasia. (C) Lentiginous compound nevus with abnormal architecture and cytologic features (dysplastic nevus). (D) Early or radial growth phase melanoma (large dark cells in epidermis) arising in a nevus. (E) Melanoma in vertical growth phase with metastatic potential. Note that no melanocytic nevus precursor is identified in most cases of melanoma. They are believed to arise de novo, perhaps all using the same pathway. Telomerase Loss of Loss of activation p16 p53, PTEN Melanoma, Melanoma, (e.g., nevus) atypia


Pathology_Robbins

Pathology_Robbins. Telomerase Loss of Loss of activation p16 p53, PTEN Melanoma, Melanoma, (e.g., nevus) atypia Fig. 24.22 Molecularevolutionofcutaneousmelanoma.Themostimportantdrivermutationsandtheoverallmutationalburden(pointmutationsandgenomiccopy-numbervariations)atvarioushistologicphasesofmelanocyticlesionprogressionareindicated.Notethatasthetumormetastasizestointernalsites,UVlight–inducedDNAdamageleadingtopointsubstitutionsceases,andcopynumberchangesrelatedtoaneuploidyincrease.


Pathology_Robbins

Pathology_Robbins. CDNK2A and its encoded tumor suppressor p16, the tumor shifts to the invasive vertical phase of growth. Throughout this cutaneous phase of tumor evolution, exposure to UV light adds to the mutational burden and increases the chances of tumor progression. Finally, with additional mutations in genes such as tumor suppressors TP53 and PTEN, the tumor acquires the capacity for metastasis. This phase is marked by the appearance of aneuploidy and genomic copy number alterations, which add to the genetic heterogeneity of the evolving tumor. By contrast, the less common melanomas that arise in non–sun-exposed acral and mucosal sites follow different molecular courses. The most common initiating mutation in these tumors is a gain-of-function mutation in the KIT receptor tyrosine kinase. Similarly, melanomas arising the uvea of the eye also have a distinct set of driver gene mutations, most notably mutually exclusive mutations that activate the GTP-binding proteins GNAQ or GNA11.


Pathology_Robbins

Pathology_Robbins. In addition, it has long been speculated that melanomas express neoantigens that should be subject to recognition by the immune system. It follows that for melanoma to develop, tumor cells must acquire the ability to either suppress or evade the host immune response. The importance of immune evasion has been proven by the response of many advanced melanomas to immune checkpoint inhibitors, agents that unleash muzzled melanoma-specific T cells, allowing them to attack the tumor (described later). MORPHOLOGYUnlikebenignnevi,melanomasoftenexhibitstriking variations in pigmentation, includingshadesofblack,brown,red,darkblue,andgray( Fig.24.23A ).Theborders are irregular andoften“notched.”Microscopically,malignantcellsgrowaspoorlyformednestsorasindividualcellsatalllevelsoftheepidermis(pagetoidspread)andinexpansiledermalnodules;theseconstitutetheradialandverticalgrowthphases,respectively(


Pathology_Robbins

Pathology_Robbins. Fig.24.23B-C ).Ofnote,superficialspreadingmelanomasareoftenassociatedwithabrisklymphocyticinfiltrate( Fig.24.23B ),afeaturethatmayreflectahostresponsetotumor-specificantigens.Increasing thickness strongly correlates with worse biologic behavior of melanomas (termed Breslow thickness). Byrecordingandusingtheseandothervariablesinaggregate,accurateprognosticationispossible. Individualmelanomacellsusuallyareconsiderablylargerthannevuscells.Theyhavelargenucleiwithirregularcontours,chromatinthatischaracteristicallyclumpedattheperipheryofthenuclearmembrane,andprominent“cherryred”eosinophilicnucleoli( Fig.24.23D ).Immunohistochemicalstainscanbehelpfulinidentifyingmetastaticdeposits( Fig.24.23D , inset). Although most of these lesions arise in the skin, they also may occur in the oral and anogenital mucosal surfaces, the esophagus, the meninges, and the eye. The following discussion applies to cutaneous melanomas.


Pathology_Robbins

Pathology_Robbins. Melanoma of the skin usually is asymptomatic, although pruritus may be an early manifestation. The most important clinical sign is a change in the color or size of a pigmented lesion. The main clinical warning signs are as follows: 1. Rapid enlargement of a preexisting nevus 2. 3. Development of a new pigmented lesion during adult life 4. Irregularity of the borders of a pigmented lesion 5. Variegation of color within a pigmented lesion These principles are expressed in the so-called “ABCs” of melanoma: asymmetry, border, color, diameter, and evolution (change of an existing nevus). It is vitally important to recognize melanomas and intervene as rapidly as possible. The vast majority of superficial lesions are curable surgically, while metastatic melanoma has a very poor prognosis.


Pathology_Robbins

Pathology_Robbins. The probability of metastasis is predicted by measuring the depth of invasion in millimeters of the vertical growth phase nodule from the top of the granular cell layer of the overlying epidermis (Breslow thickness). Metastasis risk also is increased in tumors with a high mitotic rate and in those that fail to induce a local immune response. When metastases occur, they involve not only regional lymph nodes but also liver, lungs, brain, and virtually any other site that can be seeded hematogenously. Sentinel lymph node biopsy (of the first draining node[s] of a primary melanoma) at the time of surgery provides additional information on biologic aggressiveness.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Agents that selectively inhibit mutant BRAF and KIT have produced dramatic responses in patients with metastatic tumors with BRAF and KIT mutations, respectively, an encouraging development in a previously hopeless disease. More recently, immune checkpoint inhibitors have been shown to be effective at stabilizing metastatic disease and in some instances causing remarkable tumor regression and even clinical remissions. Immune checkpoint inhibitors are antibodies that interfere with the function of proteins found on the surface of T lymphocytes that abrogate cytotoxic T cell responsiveness. By blocking these pathways, checkpoint inhibitors reactivate the host T-cell response, which otherwise is held at bay. Current efforts are focused on building upon these successes by using combinations of different checkpoint inhibitors, as well as checkpoint inhibitors together with other targeted therapies such as BRAF inhibitors. MELANOCYTICLESIONS,BENIGNANDMALIGNANT


Pathology_Robbins

Pathology_Robbins. MELANOCYTICLESIONS,BENIGNANDMALIGNANT Mostmelanocytic nevi haveactivatingmutationsinBRAF orlessoftenNRAS, butthevastmajorityneverundergoesmalignanttransformation. Mostsporadicdysplastic nevi arebestregardedasmarkersofmelanomariskratherthanpremalignantlesions.Theyarecharacterizedbyarchitecturaldisorderandcytologicatypia. Melanoma isahighlyaggressivemalignancy;tumorsonlyafewmillimetersinthicknesscangiverisetodeadlymetastases. Inmostcases,melanomaprogressesfromanintraepithelial(insitu)toaninvasive(dermal)form.Characteristicsofthedermaltumorsuchasdepthofinvasionandmitoticactivitycorrelatewithsurvival. Bastian BC: The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia, Ann Rev Pathol 9:239, 2014. [A modified classification of melanoma based on both clinical and genetic features. Such molecular classification schemes are critical for progress in targeted therapy.]


Pathology_Robbins

Pathology_Robbins. Cancer Genome Atlas Network: Genomic classification of cutaneous melanoma, Cell 161:1681, 2015. [A genomic study of cutaneous melanoma that highlights the different molecular subtypes and common pathogenic pathways.] Elder DE: Dysplastic nevi: an update, Histopathology 56:112, 2010. [A balanced presentation of the histology and pathogenesis of dysplastic nevi and their relationship to melanoma.] Epstein EH: Basal cell carcinomas: attack of the hedgehog, Nat Rev Cancer 8:743, 2008. [A succinct review of the epidemiology, clinical presentation, molecular pathogenesis, and novel treatment options for basal cell carcinoma.] Nestle FO, Kaplan DH, Barker J: Psoriasis, N Engl J Med 361:496, 2009. [A discussion of the pathogenesis, clinical features, and targeted treatment options for psoriasis.]


Pathology_Robbins

Pathology_Robbins. Nestle FO, Kaplan DH, Barker J: Psoriasis, N Engl J Med 361:496, 2009. [A discussion of the pathogenesis, clinical features, and targeted treatment options for psoriasis.] Ratushny V, Gober MD, Hick R, et al: From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma, J Clin Invest 122:464, 2012. [Models of human epidermal carcinogenesis indicate that multiple mutations in specific pathways are required for malignant transformation.] Ujiie H, Shibaki A, Nishie W, et al: What’s new in bullous pemphigoid, J Dermatol 37:194, 2010. [A review of bullous pemphigoid pathogenesis.] Wargo JA, Cooper ZA, Flaherty KT: Universes collide: combining immunotherapy with targeted therapy for cancer, Cancer Discov 4:1377, 2014. [A presentation of melanoma signaling pathways with therapeutic interventions and the role of the immune system.]


Pathology_Robbins

Pathology_Robbins. Yokoyama T, Amagai M: Immune dysregulation of pemphigus in humans and mice, J Dermatol 37:205, 2010. [A review of immune disturbances that may underlie pemphigus.]