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Pathology_Robbins. Fig.21.44B ).Bothdiffuseandlocalizedvariantsareheavilyinfiltratedbymacrophagescontaininghemosiderinandfoamylipid,oraremultinucleated. Diffuse tenosynovial giant cell tumor presents in the knee in 80% of cases. Affected individuals typically complain of pain, locking, and recurrent swelling similar to monoarticular arthritis. Sometimes, a palpable mass is appreciated. The localized variant manifests as a solitary, slow-growing, painless mass that frequently involves the hand. Both types are amenable to surgical excision, but recurrence is more common in the diffuse form. Clinical trials are investigating antagonists of the M-CSF signaling pathway for patients with unresectable disease.


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Pathology_Robbins. By convention, soft tissue refers to non-epithelial tissue excluding the skeleton, joints, central nervous system, hematopoietic and lymphoid tissues Although nonneoplastic conditions can involve soft tissue, they are seldom confined to this compartment, so the area of soft tissue pathology is restricted to neoplasms. With the exception of skeletal muscle neoplasms, benign soft tissue tumors outnumber their malignant counterparts, the sarcomas, by 100-fold. In the United States, the incidence of soft tissue sarcomas is approximately 12,000 per year, which is less than 1% of all cancers. Sarcomas, however, cause 2% of all cancer mortality, reflecting their aggressive behavior. Most soft tissue tumors arise in the extremities, especially the thigh. Approximately 15% arise in children but the incidence increases with age.


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Pathology_Robbins. Most sarcomas are sporadic and have no known predisposing cause. A small minority of soft tissue neoplasms are associated with germline mutations in tumor suppressor genes (neurofibromatosis 1, Gardner syndrome, Li-Fraumeni syndrome, Osler-Weber Rendu syndrome). A few tumors can be linked to known environmental exposures such as radiation, burns, or toxins. Unlike tumors such as colorectal carcinomas that usually arise from recognized precursor lesions, the origin of sarcomas is unknown. The best guess is that the tumors arise from pluripotent mesenchymal stem cells, which acquire somatic “driver” mutations. Despite heterogeneous mechanisms of tumorigenesis among sarcomas, some generalizations can be made based on their genomic complexity:


Pathology_Robbins

Pathology_Robbins. Simple karyotype (15%–20% of sarcomas): Like many leukemias and lymphomas, sarcomas are often euploid tumors with a single or limited number of chromosomal changes that occur early in tumorigenesis and are specific enough to serve as diagnostic markers. Tumors with these features most commonly arise in younger patients and tend to have a monomorphic appearance microscopically. Examples include Ewing sarcoma, described earlier, and synovial sarcoma. In some cases, the oncogenic effect of these rearrangements is reasonably well understood. In others, the mechanisms are unknown. Oncogenic tumor-specific fusion proteins represent potential molecular targets for therapy.


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Pathology_Robbins. Complex karyotype (80%–85% of sarcomas): These tumors are usually aneuploid or polyploid and demonstrate multiple chromosomal gains and losses, a feature that suggests underlying genomic instability. Examples http://ebooksmedicine.net include leiomyosarcoma and undifferentiated pleomorphic sarcoma. Such tumors are more common in adults and tend to be microscopically pleomorphic.


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Pathology_Robbins. Classification of soft tissue tumors continues to evolve as new molecular genetic abnormalities are identified. Clinically, soft tissue tumors range from benign, self-limited lesions that require minimal treatment to intermediate grade, locally aggressive tumors with minimal metastatic risk to highly aggressive malignancies with significant metastatic risk and mortality. All highly aggressive malignancies are classified as sarcomas but this term is less consistently used among the locally aggressive, rarely metastasizing category. Pathologic classification integrates morphology (e.g., muscle differentiation), immunohistochemistry, and molecular diagnostics. In addition to accurate diagnosis, grade (degree of differentiation) and stage (size and depth) are important prognostic indicators. With this as a primer, we will consider representative or especially illustrative soft tissue tumors.


Pathology_Robbins

Pathology_Robbins. With this as a primer, we will consider representative or especially illustrative soft tissue tumors. Lipoma, a benign tumor of fat, is the most common soft tissue tumor in adults. The conventional lipoma is the most common subtype, from which rare variants are distinguished according to characteristic morphologic and/or genetic features. Conventional lipoma is a well-encapsulated mass of mature adipocytes. It usually arises in the subcutis of the proximal extremities and trunk, most frequently during middle adulthood. Infrequently, lipomas are large, intramuscular, and poorly circumscribed. Most lipomas are usually cured by simple excision. Liposarcomas are malignant tumors of adipose tissue. Liposarcoma is one of the most common sarcomas of adulthood. It occurs mainly in people in their 50s to 60s in the deep soft tissues and retroperitoneum. MORPHOLOGYLiposarcomasaredividedintothreesubtypes:


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Pathology_Robbins. MORPHOLOGYLiposarcomasaredividedintothreesubtypes: Fig.21.45A ).Thetumorsharboramplificationofchromosomeregion12q13-q15,whichincludesthegeneforMDM2.YouwillrecallMDM2encodesapotentinhibitorofp53. Myxoidliposarcomacontainsabundantbasophilicextracellularmatrix,arborizingcapillaries,andprimitivecellsatvariousstagesofadipocytedifferentiationreminiscentoffetalfat( Fig.21.45B ).Thet(12;16)translocationcharacterizesmyxoidliposarcoma.Theresultantfusiongenearrestsadiposedifferentiation. Pleomorphicliposarcomaconsistsofsheetsofanaplasticcells,bizarrenuclei,andvariableamountsofimmatureadipocytes(lipoblasts).Thesetumorshavecomplexkaryotypes. All types of liposarcoma recur locally and often repeatedly unless adequately excised. The well-differentiated variant is relatively indolent, the myxoid/round cell type is intermediate in its malignant behavior, whereas the pleomorphic variant usually is aggressive and frequently metastasizes.


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Pathology_Robbins. Nodular fasciitis is a self-limited fibroblastic and myofibroblastic proliferation that typically occurs the upper extremities of young adults. A history of trauma is present in approximately 25% to 50% of cases, and the tumors grow rapidly during a period of several weeks or months. Whereas nodular fasciitis was historically considered a purely reactive lesion, identification of a t(17;22) translocation producing a MYH9-USP6 fusion gene indicates that it is a clonal, yet self-limited, proliferation. It is hypothesized that the proliferating cells lack some key hallmark of cancer, perhaps the ability to avoid senescence. Intriguingly, ABC (discussed earlier), another tumor that sits in a gray zone between reactive and neoplastic proliferations, also contains a USP6 fusion gene. Nodular fasciitis can spontaneously regress and, if excised, rarely recurs. Malignant transformation is virtually nonexistent.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYNodularfasciitisarisesinthedeepdermis,subcutis,fascia,ormuscle.Grosslythelesionislessthan5cm,circumscribed,orslightlyinfiltrative.Itishighlycellularcontainingplump,immatureappearingfibroblastsandmyofibroblastsarrangedinapatternreminiscentofculturedfibroblasts( Fig.21.46 ).Agradientofmaturation(zonation) fromcellular,loose,andmyxoidtoorganizedandfibrousistypical.Thecellsvaryinsizeandshape(spindletostellate)andhaveconspicuousnucleoli;mitoticfiguresareabundant.Lymphocytesandextravasatedredbloodcellsarecommonbutneutrophilsareunusual. Superficial fibromatosis is an infiltrative proliferation that can cause local deformity but has an innocuous clinical course. All forms of superficial fibromatosis affect males more frequently than females. They are characterized by nodular or poorly defined broad fascicles of fibroblasts in long, sweeping fascicles, surrounded by abundant dense collagen. Several clinical subtypes have been identified:


Pathology_Robbins

Pathology_Robbins. Palmar (Dupuytren contracture). Irregular or nodular thickening of the palmar fascia either unilaterally or bilaterally. Plantar. Common in young patients, unilateral and without contractures. http://ebooksmedicine.net Fig.21.45Liposarcoma.(A)Thewell-differentiatedsubtypeconsistsofmatureadipocytesandscatteredspindlecellswithhyperchromaticnuclei.(B)Myxoidliposarcomawithabundantgroundsubstanceandarichcapillarynetworkinwhichtherearescatteredimmatureadipocytesandmoreprimitiveround-tostellatecells. • Penile (Peyronie disease). Palpable induration or mass on the dorsolateral aspect of the penis. In about 20% to 25% of cases, the palmar and plantar fibromatoses stabilize and do not progress, in some instances resolving spontaneously. Some recur after excision, particularly the plantar variant.


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Pathology_Robbins. Deep fibromatoses, also called desmoid tumors, are large, infiltrative masses that frequently recur but do not metastasize. They most frequently occur in the teenage years to 30s, predominantly in women. Abdominal fibromatosis generally arises in the musculoaponeurotic structures of the anterior abdominal wall but tumors can arise in the limb girdles or the mesentery. Deep fibromatoses contain mutations in the CTNNB1 (β-catenin) or APC genes, leading to increased Wnt signaling. Most tumors are sporadic, but individuals with familial adenomatous polyposis (Gardner syndrome, Chapter 16) who have germline APC mutations are predisposed to deep fibromatosis. MORPHOLOGYFibromatosesaregray-white,firm,poorlydemarcatedmassesvaryingfrom1to15cmingreatestdiameter.Theyarerubberyandtough,andhavemarkedinfiltrationofsurroundingmuscle,nerveandfat.Cytologicallyblandfibroblastsarrangedinbroadsweepingfasciclesamiddensecollagenarethecharacteristichistologicpattern(


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Pathology_Robbins. Fig.21.47 ).Thehistologyresemblesascar. Because of the extensively infiltrative nature, complete excision is often difficult. Recent efforts have concentrated on medical therapy and radiation as alternatives to surgery. Fig.21.46Nodularfasciitiswithplump,randomlyorientedspindlecellssurroundedbymyxoidstroma.Notethemitoticactivity(arrowheads). Fig.21.47Deepfibromatosisinfiltratingbetweenskeletalmusclecells. http://ebooksmedicine.net Skeletal muscle neoplasms, in contrast to tumors of other lineages, are almost all malignant. The benign rhabdomyoma is more frequent in individuals with tuberous sclerosis.


Pathology_Robbins

Pathology_Robbins. Skeletal muscle neoplasms, in contrast to tumors of other lineages, are almost all malignant. The benign rhabdomyoma is more frequent in individuals with tuberous sclerosis. Rhabdomyosarcoma is a malignant mesenchymal tumor with skeletal muscle differentiation. Three main subtypes are recognized: alveolar (20%), embryonal (60%), and pleomorphic (20%). Rhabdomyosarcoma (alveolar and embryonal) is the most common soft tissue sarcoma of childhood and adolescence, usually appearing before age 20. Pleomorphic rhabdomyosarcoma is seen predominantly in adults. The pediatric forms often arise in the sinuses, head and neck, and genitourinary tract, locations that do not normally contain much skeletal muscle, underscoring the notion that sarcomas do not arise from mature, terminally differentiated mesenchymal cells. The embryonal and pleomorphic subtypes are genetically heterogeneous.


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Pathology_Robbins. Alveolar rhabdomyosarcoma frequently contains fusions of the FOXO1 gene to either the PAX3 or the PAX7 gene, rearrangements marked by the presence of (2;13) or (1;13) translocations, respectively. PAX3 is a transcription factor that initiates skeletal muscle differentiation, and it appears that the chimeric PAX3-FOXO1 fusion protein interferes with differentiation, a mechanism similar to many of the transcription factor fusion proteins that are found in acute leukemias. MORPHOLOGYEmbryonalrhabdomyosarcomapresentsasasoftgrayinfiltrativemass.Thetumorcellsmimicskeletalmuscleatvariousstagesofdifferentiationandconsistofsheetsofbothprimitiveroundandspindledcells( Fig.21.48A ).Rhabdomyoblastswithstraplikecytoplasmandvisiblecross-striationsmaybepresent.Sarcomabotryoidesisavariantofembryonalrhabdomyosarcomathatdevelopsinthewallsofhollowviscerasuchastheurinarybladderandvagina.


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Pathology_Robbins. Inalveolarrhabdomyosarcoma,anetworkoffibrousseptaedividethecellsintoclustersoraggregates,creatingacruderesemblancetopulmonaryalveoli.Thetumorcellsareuniformlyroundwithlittlecytoplasmandtheyareonlyminimallycohesive (Fig.21.48B Pleomorphicrhabdomyosarcomaischaracterizedbynumerouslarge,sometimesmultinucleated,bizarreeosinophilictumorcellsthatcanresembleotherpleomorphicsarcomas.Immunohistochemicalidentificationofmusclespecificproteinssuchasmyogeninisusuallynecessarytoconfirmrhabdomyoblasticdifferentiation. Rhabdomyosarcomas are aggressive neoplasms that are usually treated with surgery and chemotherapy, with or without radiation therapy. The botryoid variant of embryonal rhabdomyosarcoma has the best prognosis, whereas the pleomorphic subtype is often fatal.


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Pathology_Robbins. Fig.21.48Rhabdomyosarcoma.(A)Embryonalsubtypecomposedofmalig-nantcellsrangingfromprimitiveandroundtodenselyeosinophilicwithskeletalmuscledifferentiation.(B)Alveolarrhabdomyosarcomawithnumer-ousspaceslinedbydiscohesive,uniformroundtumorcells. Leiomyoma, a benign tumor of smooth muscle, is most common in the uterus but can arise in any soft tissue site. Uterine leiomyomas (Chapter 19) are common and may cause a variety of symptoms including infertility and menorrhagia. Leiomyomas also may arise from the erector pili muscles (pilar leiomyomas) in the skin and rarely in the deep somatic soft tissues or gastrointestinal tract. A germline loss-of-function mutation in the fumarate hydratase (FH) gene located on chromosome 1q42.3 leads to multiple cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma. FH is an enzyme of the Krebs cycle, and this association constitutes another intriguing example of the link between metabolic abnormalities and neoplasia.


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Pathology_Robbins. Soft tissue leiomyomas are usually 1 to 2 cm in size and are composed of fascicles of densely eosinophilic spindle cells that tend to intersect each other at right angles. The tumor cells have blunt-ended, elongated nuclei and show minimal atypia and few mitotic figures. Solitary lesions are cured with surgery. http://ebooksmedicine.net Soft tissue leiomyosarcoma accounts for 10% to 20% of soft tissue sarcomas. They occur in adults and affect women more frequently than men. Most develop in the deep soft tissues of the extremities and retroperitoneum or arise from the great vessels. Leiomyosarcomas have complex genotypes that stem from acquired defects that lead to profound genomic instability.


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Pathology_Robbins. MORPHOLOGYLeiomyosarcomaspresentaspainlessfirmmasses.Retroperitonealtumorsmaybelargeandbulkyandcauseabdominalsymptoms.Theyconsistofeosinophilicspindlecellswithblunt-ended,hyperchromaticnucleiarrangedininterweavingfascicles.Theyexpresssmoothmuscleproteins(actin,desmin,caldesmon),whichcanbedetectedbyimmunohistochemistry.Unlikeleiomyomas,mitoticactivityandnecrosisarecommoninleiomyosarcoma. Treatment depends on tumor size, location, and grade. Superficial leiomyosarcomas are usually small and have a good prognosis, whereas those of the retroperitoneum are difficult to control and cause death by both local extension and metastatic spread, especially to the lungs. Although many soft tissue tumors can be assigned to recognizable histologic types, a large proportion of tumors do not recapitulate any known mesenchymal lineage. This group includes examples with simple or complex karyotypes; one of each type is described here.


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Pathology_Robbins. Synovial sarcoma was so-named because the first described cases arose in the soft tissues near the knee joint and a morphologic relationship to synovium was postulated. However, this name is a misnomer, as these tumors can present in locations that lack synovium and their morphologic features are inconsistent with an origin from synoviocytes. Synovial sarcomas account for approximately 10% of all soft tissue sarcomas. Most occur in people in their 20s to 40s. Patients usually present with a deep-seated mass that has been present for several years. Most synovial sarcomas show a characteristic chromosomal translocation t(x;18)(p11;q11) producing fusion genes composed of portions of the SS18 gene and one of three SSX genes that encode chimeric transcription factors that derail cell cycle control. Fig.21.49Synovialsarcomashowingtheclassicbiphasicspindlecellandglandlikehistologicappearance.


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Pathology_Robbins. Fig.21.49Synovialsarcomashowingtheclassicbiphasicspindlecellandglandlikehistologicappearance. MORPHOLOGYSynovialsarcomasaremicroscopicallymonophasicorbiphasic.Monophasicsynovialsarcomaconsistsofuniformspindlecellswithscantcytoplasmanddensechromatingrowinginshort,tightlypackedfascicles.Thebiphasictypecontainsglandlikestructurescomposedofcuboidaltocolumnarepithelioidcellsinadditiontotheaforementionedspindlecellcomponent( Fig. 21.49 ).Immunohistochemistryishelpfulinidentifyingthesetumors,sincethetumorcells,especiallyinthebiphasictype,arepositiveforepithelialantigens(e.g.,keratins),differentiatingthemfrommanyothersarcomas. Synovial sarcomas are treated aggressively with limb-sparing surgery and frequently chemotherapy. The 5-year survival varies from 25% to 62%, related to stage and patient age. Common sites of metastases are the lung and, unusual for sarcomas, regional lymph nodes.


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Pathology_Robbins. Undifferentiated pleomorphic sarcoma (UPS) includes malignant mesenchymal tumors with high-grade, pleomorphic cells that cannot be classified into another category by a combination of histomorphology, immunophenotype, ultrastructure, and genetics. Most arise in the deep soft tissues of the extremity, especially the thigh of middle-aged or older adults. The diagnosis of malignant fibrous histiocytoma (MFH), sometimes used interchangeably with UPS, has fallen out of use because (1) the category included both undifferentiated tumors and others that could be reclassified with immunohistochemistry and genetics, and (2) no consensus exists for the morphologic definition of fibrohistiocytic lineage. Most tumors are aneuploid with multiple structural and numerical chromosomal changes. http://ebooksmedicine.net 832CHAPTER 21Bones,Joints,andSoftTissueTumors Fig.21.50Undifferentiatedpleomorphicsarcomashowinganaplasticspin-dledtopolygonalcells.


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Pathology_Robbins. http://ebooksmedicine.net 832CHAPTER 21Bones,Joints,andSoftTissueTumors Fig.21.50Undifferentiatedpleomorphicsarcomashowinganaplasticspin-dledtopolygonalcells. MORPHOLOGYUPSsareusuallylarge,grey-whitefleshymassesthatcangrowquitelarge(10–20cm)dependingontheanatomiccompartment.Necrosisandhemorrhagearecommon.Microscopically,theyaresomeofthemostpleomorphicmalignanciesencountered.UPSsconsistofsheetsoflarge,anaplastic,spindledtopolygonalcellswithhyperchromaticirregular,sometimesbizarrenuclei( Fig.21.50 ).Mitoticfigures,includingatypicalnonsymmetricforms,areabundantasisnecrosis.Bydefinition,tumorcellslackdifferentiationalongrecognizedlineagesorcharacteristicgeneticdefects. UPSs are aggressive malignancies that are treated with surgery and adjuvant chemotherapy and/or radiation. The prognosis is generally poor, with metastases arising in 30% to 50% of cases.


Pathology_Robbins

Pathology_Robbins. UPSs are aggressive malignancies that are treated with surgery and adjuvant chemotherapy and/or radiation. The prognosis is generally poor, with metastases arising in 30% to 50% of cases. Thecategoryofsofttissueneoplasiadescribestumorsthatarisefromnon-epithelialtissues,excludingtheskeleton,joints,centralnervoussystem,andhematopoieticandlymphoidtissues.Asarcomaisamalignantmesenchymaltumor. Althoughallsofttissuetumorsprobablyarisefrompluripotentmesenchymalstemcells,ratherthanmaturecells,theycanbeclassifiedas Tumorsthatrecapitulateamaturemesenchymaltissue(e.g.,fat).Thesecanbefurthersubdividedintobenignandmalignantforms. Tumorscomposedofcellsforwhichthereisnonormalcounterpart(e.g.,synovialsarcoma,UPS). Sarcomaswithsimplekaryotypesdemonstratereproducible,chromosomal,andmolecularabnormalitiesthatcontributetopathogenesisandaresufficientlyspecifictohavediagnosticuse. Mostadultsarcomashavecomplexkaryotypes,tendtobepleomorphic,andaregeneticallyheterogeneouswithapoorprognosis.


Pathology_Robbins

Pathology_Robbins. Mostadultsarcomashavecomplexkaryotypes,tendtobepleomorphic,andaregeneticallyheterogeneouswithapoorprognosis. We thank Dr. Andrew Rosenberg for his outstanding contribution to previous editions of this chapter. Basic Structure and Biology of Bone Kogianni G, Noble BS: The biology of osteocytes, Curr Osteoporos Rep 5:81–86, 2007. [Good review of the cellular basis of bone remodeling.] Olsen BR, Reginato AM, Wang W: Bone development, Annu Rev Cell Dev Biol 16:191–220, 2000. [Update on the molecular and genetic basis of vertebrate skeletal development.] Zaidi M: Skeletal remodeling in health and disease, Nat Med 13:791– 801, 2007. [Excellent review of the genetics and pathophysiology of skeletal diseases.] Askmyr MK, Fasth A, Richter J: Towards a better understanding and new therapeutics of osteopetrosis, Br J Haematol 140:597–609, 2008. [Nice summary of treatment options for osteoporosis including gene therapy.]


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Pathology_Robbins. Krakow D, Rimoin DL: The skeletal dysplasias, Genet Med 12:327–341, 2010. [Comprehensive summary of the dysplasias with very useful summary table.] Van Dijk FS, Pals G, Van Rijn RR, et al: Classification of Osteogenesis Imperfecta revisited, Eur J Med Genet 53:1–5, 2010. [An overview of the current classification of osteogenesis imperfecta based on clinical and molecular findings.] Mosekilde L: Mechanisms of age-related bone loss, Novartis Found Symp 235:150–166, discussion 66–71, 2001. [Nice review of relationship between remodeling and osteoporosis.] Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, et al: Multiple genetic loci for bone mineral density and fractures, N Engl J Med 358:2355–2365, 2008. [Seminal paper elucidating the molecular pathways that underly osteoporosis.]


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Pathology_Robbins. Weitzmann MN, Pacifici R: Estrogen deficiency and bone loss: an inflammatory tale, J Clin Invest 116:1186–1194, 2006. [Excellent review of current understanding of the relationship between estrogen and osteoporosis.] Silva BC, Bilezikian JP: Parathyroid hormone: anabolic and catabolic actions on the skeleton, Curr Opin Pharmacol 22:41–50, 2015. [Nice summary of effects of parathyroid hormone on calcium and bone metabolism.] Roodman GD, Windle JJ: Paget disease of bone, J Clin Invest 115:200– 208, 2005. [Concise, nicely illustrated, summary of clinicopathologic manifestation of Paget disease.] Singer FR: The etiology of Paget’s Disease of bone: viral and genetic interactions, Cell Metab 13:5–6, 2011. [Very good review about the viral and genetic pathways in Paget disease.] Seamon J, Keller T, et al: The pathogenesis of nontraumatic osteonecrosis, Arthritis 601763, 2012. [Summarizes recent developments regarding pathophysiology of femoral head osteonecrosis.]


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Pathology_Robbins. Seamon J, Keller T, et al: The pathogenesis of nontraumatic osteonecrosis, Arthritis 601763, 2012. [Summarizes recent developments regarding pathophysiology of femoral head osteonecrosis.] Klein MJ, Siegal GP: Osteosarcoma: anatomic and histologic variants, Am J Clin Pathol 125:555–581, 2006. [Most recent update on classification of osteosarcoma.] Wagner ER, Luther G, Zhu G, et al: Defective osteogenic differentiation in the development of osteosarcoma, Sarcoma 2011:325238, http://ebooksmedicine.net 2011. [Discusses molecular relationship between normal osteoblast development the pathogenesis of osteosarcoma.] Bovee JV, Hogendoorn PC, Wunder JS, et al: Cartilage tumours and bone development: molecular pathology and possible therapeutic targets, Nat Rev Cancer 10:481–488, 2010. [A good review of the known genetic abnormalities in these tumors]


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Pathology_Robbins. Pansuriya TC, van Eijk R, d’Adamo P, et al: Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome, Nat Genet 43:1256–1261, 2011. [Seminal article identifying IDH mutations in inherited cartilage tumors.] Wuyts W, Van Hul W: Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes, Hum Mutat 15:220–227, 2000. [Discussion of genetic basis of multiple osteochondroma syndrome.] Erkizan HV, Uversky VN, Toretsky JA: Oncogenic partnerships: EWSFLI1 protein interactions initiate key pathways of Ewing’s sarcoma, Clin Cancer Res 16:4077–4083, 2010. [Excellent summary of molecular effects of the EWS-FLI1 fusion protein found in Ewing sarcoma.] Giant Cell Tumor of Bone


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Pathology_Robbins. Giant Cell Tumor of Bone Robinson D, Einhorn TA: Giant cell tumor of bone: a unique paradigm of stromal-hematopoietic cellular interactions, J Cell Biochem 55:300– 303, 1994. [Nice discussion of molecular mechanisms underlying giant cell tumor and insight gained regarding normal bone remodeling.] Oliveira AM, Chou MM: The TRE17/USP6 oncogene: a riddle wrapped in a mystery inside an enigma, Front Biosci (Schol Ed) 4:321–334, 2012. [Excellent review of the USP6 clonal genetic rearrangement in various self-limited mesenchymal tumors.] Riminucci M, Robey PG, Saggio I, et al: Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells, J Mol Endocrinol 45:355–364, 2010. [Excellent discussion of how a mutation can affect skeletal progenitor cells and cause clinical expression of fibrous dysplasia.]


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Pathology_Robbins. Goldring MB, Goldring SR: Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis, Ann N Y Acad Sci 1192:230–237, 2010. [A succint and thoughtful presentation of the role of articular structures in the development of osteoarthritis.] Valdes AM, Spector TD: Genetic epidemiology of hip and knee osteoarthritis, Nat Rev Rheumatol 7:23–32, 2011. [Useful review of genome-wide association studies that have lead to candidate genes predisposing to osteoarthritis.] Deane KD, El-Gabalawy H: Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE, Nat Rev Rheumatol 10:212– 228, 2014. [Recent, nicely illustrated, update on pathogenesis of RA and SLE.]


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Pathology_Robbins. Scott DL, Wolfe F, Huizinga TW: Rheumatoid arthritis, Lancet 376:1094–1108, 2011. [Review of pathogenesis and treatment of the disease.] van Heemst J, Jansen DT, et al: Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis, Nat Commun 6:6681, 2015. [Describes the relationship between autoimmunity, HLA alleles and microbes.] Iliopoulou BP, Huber BT: Infectious arthritis and immune dysregulation: lessons from Lyme disease, Curr Opin Rheumatol 22:451–455, 2010. [Recent overview of immune mechanisms underlying Lyme arthritis] Marques A: Chronic Lyme disease: a review, Infect Dis Clin North Am 22:341–360, 2008. [In-depth review of Lyme disease.] Rosenthal AK: Update in calcium deposition diseases, Curr Opin Rheumatol 19:158–162, 2007. [Recent, succint, review of crystal-induced arthritis.]


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Pathology_Robbins. Rosenthal AK: Update in calcium deposition diseases, Curr Opin Rheumatol 19:158–162, 2007. [Recent, succint, review of crystal-induced arthritis.] VanItallie TB: Gout: epitome of painful arthritis, Metabolism 59(Suppl 1):S32–S36, 2010. [Excellent summary of the recent developments in the molecular and cellular biology underlying gout.] Moller E, Mandahl N, Mertens F, et al: Molecular identification of COL6A3-CSF1 fusion transcripts in tenosynovial giant cell tumors, Genes Chromosomes Cancer 47:21–25, 2008. [Seminal article identifying clonal chromosomal rearrangement in tenosynovial giant cell tumor.] Antonescu CR, Dal Cin P: Promiscuous genes involved in recurrent chromosomal translocations in soft tissue tumours, Pathology 46:105–112, 2014. [Excellent review of specificity (or lack thereof) of genetic defects in soft tissue tumors.]


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Pathology_Robbins. Fletcher CD, Gustafson P, Rydholm A, et al: Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification, J Clin Oncol 19:3045–3050, 2001. [Seminal article reassessing the diagnosis of malignant fibrous histiocytoma (MFH) allowing more specific classification.] http://ebooksmedicine.net studentconsult.com Miscellaneous Neuromuscular Junction Schwannomas and Neurofibromatosis Patterns of Peripheral Nerve Injury Patterns of Skeletal Muscle Injury and Neurofibromatosis Type 1 Inherited Disorders of Skeletal Muscle Acquired Disorders of Skeletal Muscle


Pathology_Robbins

Pathology_Robbins. Patterns of Skeletal Muscle Injury and Neurofibromatosis Type 1 Inherited Disorders of Skeletal Muscle Acquired Disorders of Skeletal Muscle The peripheral nerves and skeletal muscles permit purposeful movement and provide the brain with sensory information about our surroundings. Both the anatomic distribution of lesions and their associated signs and symptoms are helpful in classifying neuromuscular diseases. The following discussion of neuromuscular disorders is organized along anatomic lines and traces the neuromuscular system from proximal to distal by discussing disorders of peripheral nerves, neuromuscular junctions, and skeletal muscle.


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Pathology_Robbins. The two major functional elements of peripheral nerves are axonal processes and their myelin sheaths, which are made by Schwann cells. Axonal diameter and myelin thickness are correlated with each other and with conduction velocity. These characteristics are used to distinguish different types of axons, which mediate distinct sensory inputs and motor function. Light touch, for example, is transmitted by thickly myelinated large-diameter axons with fast conduction velocities, whereas temperature sensation is transmitted by slow, unmyelinated thin axons. In the case of myelinated axons, one Schwann cell makes and maintains exactly one myelin segment, or internode, along a single axon (


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Pathology_Robbins. Fig. 22.1A ). Adjacent internodes are separated by the nodes of Ranvier along which saltatory conduction occurs. Any given nerve contains axons of different sizes and axons serving different functions. These are arranged into fascicles ensheathed by a layer of perineurial cells. Perineurial cells form a barrier between endoneurium on the inside of the fascicle and epineurium on the outside. Peripheral neuropathies are often subclassified as axonal or demyelinating, even though many diseases exhibit mixed features. Axonal neuropathies are caused by insults that directly injure the axon. The entire distal portion of an affected axon degenerates. Axonal degeneration is associated with secondary myelin loss ( Fig. 22.1B). The term Wallerian degeneration is borrowed from experimental studies involving the transection of nerves to describe analogous changes observed in axonal neuropathies. Regeneration takes place through axonal regrowth and subsequent remyelination of the distal axon (


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Pathology_Robbins. Fig. 22.1C ). The morphologic hallmark of axonal neuropathies is a decrease in the density of axons, which in electrophysiologic studies correlates with a decrease in the signal strength or amplitude of nerve impulses. Demyelinating neuropathies are characterized by damage to Schwann cells or myelin with relative axonal sparing, resulting in abnormally slow nerve conduction velocities but preserved amplitude. Demyelination typically occurs discontinuously, affecting individual inter-nodes along the length of an axon in a random distribution. This process is termed segmental demyelination ( Fig. 22.1B ). Morphologically, demyelinating neuropathies show a relatively normal density of axons and features of segmental demyelination and repair. This is recognized by the presence of axons with abnormally thin myelin sheaths and short internodes ( Fig. 22.1C ). The discontinuous nature http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 22.1C ). The discontinuous nature http://ebooksmedicine.net Fig. 22.1 Patternsofperipheralnervedamage.(A)Innormalmotorunits,typeIandtypeIImyofibers(see


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net neuropathiesresultingfromvascularinjury. of damage to random internodes is best visualized when examining a series of internodes along individual axons in teased fiber preparations ( Fig. 22.2A Peripheral neuropathies exhibit several anatomic patterns. Polyneuropathies usually affect peripheral nerves in a symmetric, length-dependent fashion. Axonal loss is typically more pronounced in the distal segments of the longest nerves. Patients commonly present with loss of sensation and paresthesias that start in the toes and spread upward. By the time the sensory changes reach the level of the knees, the hands are also affected, resulting in a picture described as “stocking-and-glove” distribution. This pattern is often encountered with toxic and metabolic damage.


Pathology_Robbins

Pathology_Robbins. Mononeuritis multiplex, in which the damage randomly affects individual nerves, resulting (for example) in a right radial nerve palsy and wrist drop and, at a separate point in time, a left foot drop. Mononeuritis multiplex is often caused by vasculitis. A simple mononeuropathy only involves a single nerve and is most commonly the result of traumatic injury, entrapment (e.g., carpal tunnel syndrome), or certain infections such as Lyme disease. Many different diseases may be associated with peripheral neuropathy ( Table 22.1 ). We next discuss selected entities that are prototypical for a specific type of polyneuropathy or that are particularly common. Table 22.1 Peripheral Neuropathies InheritedCharcot-Marie-Toothneuropathy,type1,typeII,andX-linkedHereditaryneuropathywithliabilitytopressurepalsy OthersParaneoplastic,someleukodystrophies http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Guillain-Barré syndrome is a rapidly progressive acute demyelinating disorder affecting motor axons, resulting in ascending weakness that can lead to death from failure of respiratory muscles within days of onset of symptoms. It is one of the most common life-threatening diseases of the peripheral nervous system. Guillain-Barré syndrome appears to be triggered by an infection or vaccination that breaks down self-tolerance, thereby leading to an autoimmune response. Associated infectious agents include Campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus (HIV), and, most recently Zika virus. The injury is most extensive in the nerve roots and proximal nerve segments and is associated with mononuclear cell infiltrates rich in macrophages. Both humoral and cellular immune responses are believed to play a role in the disease process. Treatments include plasmapheresis (to remove offending antibodies), intravenous immunoglobulin infusions (which suppress


Pathology_Robbins

Pathology_Robbins. cellular immune responses are believed to play a role in the disease process. Treatments include plasmapheresis (to remove offending antibodies), intravenous immunoglobulin infusions (which suppress immune responses through unclear mechanisms), and supportive care, such as ventilatory support. Patients who survive the initial acute phase of the disease usually recover with time.


Pathology_Robbins

Pathology_Robbins. CIDP is the most common chronic acquired inflammatory peripheral neuropathy, characterized by symmetrical mixed sensorimotor polyneuropathy that persists for 2 months or more. Both motor and sensory abnormalities are common, such as weakness, difficulty in walking, numbness, and pain or tingling sensations. Like Guillain-Barré syndrome, CIDP is immune mediated. But in contrast to Guillain-Barré syndrome, CIDP follows a chronic, relapsing-remitting, or progressive course. It occurs with increased frequency in patients with other immune disorders, such as systemic lupus erythematosus and HIV infection. The peripheral nerves show segments of demyelination and remyelination (


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Pathology_Robbins. Fig. 22.2A ). In long-standing cases, repeated activation and proliferation of Schwann cells with episodes of regeneration result in the concentric arrangement of multiple Schwann cells around individual axons to produce multilayered structures likened to onion bulbs. Treatment includes plasmapheresis and administration of immunosuppressive agents. Some patients recover completely, but more often recurrent bouts of symptomatic disease lead to permanent loss of nerve function. Diabetes is the most common cause of peripheral neuropathy, usually developing with long-standing disease. Diabetic neuropathies include several forms that can occur singly or together. Autonomic neuropathy is characterized by changes in bowel, bladder, cardiac, or sexual function. Lumbosacral radiculopathy usually manifests with asymmetric pain that can progress to lower extremity weakness and muscle atrophy.


Pathology_Robbins

Pathology_Robbins. Lumbosacral radiculopathy usually manifests with asymmetric pain that can progress to lower extremity weakness and muscle atrophy. Distal symmetric sensorimotor polyneuropathy is the most common form of diabetic neuropathy. Sensory axons are more severely affected than motor axons, resulting in a clinical presentation dominated by paresthesias and numbness. This form of diabetic polyneuropathy results from the length-dependent degeneration of peripheral nerves and does not neatly fit into the axonal or demyelinating category but instead often exhibits features of both. The pathogenesis of diabetic neuropathy is complex; accumulation of advanced glycosylation end products resulting from hyperglycemia, increased levels of reactive oxygen species, microvascular changes, and changes in axonal metabolism, all have been implicated. Strict glycemic control is the best form of therapy. Toxic,Vasculitic, and Inherited Forms of Peripheral Neuropathy


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Pathology_Robbins. Toxic,Vasculitic, and Inherited Forms of Peripheral Neuropathy There are diverse other causes of peripherlal neuropathy ( Table 22.1 ), some of which merit brief discussion. Drugs and environmental toxins that interfere with axonal transport or cytoskeletal function often produce peripheral neuropathies. The longest axons are most susceptible, hence symptoms appear first and are most pronounced in the distal extremities. Peripheral nerves are damaged in many different forms of systemic vasculitis (


Pathology_Robbins

Pathology_Robbins. Peripheral nerves are damaged in many different forms of systemic vasculitis ( Fig. 22.2B ) (Chapter 10), including polyarteritis nodosa, Churg-Strauss syndrome, and polyangiitis with granulomatosis. Overall, peripheral nerve damage is seen in about a third of all patients with vasculitis at the time of presentation. The most common clinical picture is that of mononeuritis multiplex with a painful asymmetric mixed sensory and motor peripheral neuropathy. Patchy involvement also is apparent at the microscopic level, as single nerves may show considerable interfascicular variation in the degree of axonal damage ( Fig. 22.2C


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Pathology_Robbins. Fig. 22.2C Inherited diseases of peripheral nerves are a heterogeneous but relatively common group of disorders, with a prevalence of 1 to 4 in 10,000. They can be demyelinating or axonal. Many such disorders manifest in adulthood and follow a slowly progressive course that may mimic that of acquired polyneuropathies. The most common causes are mutations in the genes encoding myelin-associated proteins. Peripheralneuropathiesmayresultinweaknessand/orsensorydeficitsinpatternsdescribedaspolyneuropathy,mononeuritismultiplex,andmononeuropathy. Axonalanddemyelinatingperipheralneuropathiescanbedistinguishedonthebasisofclinicalandpathologicfeatures.Somedisordersareassociatedwithamixedpatternofinjury. Diabetesisthemostcommoncauseofperipheralneuropathy. Guillain-Barrésyndromeandchronicidiopathicdemyelinatingpolyneuropathyareimmune-mediateddemyelinatingdiseasesthatfollowacuteandchroniccourses,respectively.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The neuromuscular junction is a complex specialized structure located at the interface of motor nerve axons and skeletal muscle that serves to control muscle contraction. Here the distal ends of peripheral motor nerves branch into small processes that terminate in bulbous synaptic boutons. Nerve impulses depolarize the presynaptic membrane, stimulating calcium influx and the release of acetylcholine into the synaptic cleft. Acetylcholine diffuses across the synaptic cleft to bind its receptor on the postsynaptic membrane, leading to depolarization of the myofiber and contraction through electromechanical coupling. Often disorders of the neuromuscular junction produce functional deficits in the absence of any significant alterations in morphology beyond ultrastructural changes. Considered in this section are some of the more common or pathogenically interesting disorders that disrupt the transmission of signals across the neuromuscular junction.


Pathology_Robbins

Pathology_Robbins. Myasthenia gravis is an autoimmune disease with fluctuating muscle weakness that is caused by autoantibodies that target the neuromuscular junction. The most common antigenic target is the postsynaptic acetylcholine receptor (AChR). Other pathogenic antibodies recognize muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein (LRP4). These antibodies lead to loss of receptors and damage to the structure of the junctions. The disease has an incidence of approximately 2 in 100,000 persons. Anti-AChR mediated cases have bimodal age distribution with somewhat distinctive clinical features. Early onset before age 50 years is more common in females and is frequently associated with enlargement of the thymus due to the presence of B cell follicles and germinal centers (follicular thymic hyperplasia). Late-onset cases show a more equal gender distribution and are associated with thymoma (Chapter 12), a neoplasm derived from thymic epithelium. Both of these thymic


Pathology_Robbins

Pathology_Robbins. (follicular thymic hyperplasia). Late-onset cases show a more equal gender distribution and are associated with thymoma (Chapter 12), a neoplasm derived from thymic epithelium. Both of these thymic lesions are believed to perturb tolerance to self-antigens, setting the stage for the generation of autoreactive T and B cells.


Pathology_Robbins

Pathology_Robbins. Clinically, myasthenia gravis frequently manifests with ptosis (drooping eyelids) or diplopia (double vision) because of weakness in the extraocular muscles. This pattern of weakness is distinctly different from that of most primary myopathic diseases, in which there is relative sparing of facial and extraocular muscles. The severity of the weakness often fluctuates rapidly, sometimes over periods of a few minutes. Characteristically, repetitive firing of muscles makes the weakness more severe, whereas cholinesterase inhibitors improve strength markedly, features that are are diagnostically useful. Effective treatments include cholinesterase inhibitors, immunosuppression, plasmapheresis, and (in patients with thymic lesions) thymectomy. These interventions have improved the 5-year survival rate to greater than 95%.


Pathology_Robbins

Pathology_Robbins. Lambert-Eaton syndrome is caused by autoantibodies that inhibit the function of presynaptic calcium channels, thereby reducing the release of acetylcholine into the synaptic cleft. Patients with Lambert-Eaton syndrome experience improvement in weakness with repetitive stimulation, in contrast to those suffering from myasthenia gravis. Repetitive stimulation serves to build up sufficient intracellular calcium to facilitate acetylcholine release. Lambert-Eaton syndrome often arises as a paraneoplastic disorder, particularly in patients with small cell lung carcinoma. Cholinesterase inhibitors are not effective, and therapy is therefore directed toward reducing the titer of causative antibodies, through either plasmapheresis or immunosuppression. The prognosis is worse than that of myasthenia gravis because of the frequent coexistence of an underlying malignancy. Several other neuromuscular junction disorders merit brief mention.


Pathology_Robbins

Pathology_Robbins. Several other neuromuscular junction disorders merit brief mention. Congenital myasthenic syndromes comprise a heterogeneous group of diseases that result from mutations that disrupt the function of various neuromuscular junction proteins. Depending on the affected protein, the defects may occur at the level of acetylcholine release (presynaptic), the transport of acetylcholine across the synaptic cleft (synaptic), or the responsiveness of skeletal muscle (postsynaptic). Hence they may present with symptoms mimicking Lambert-Eaton syndrome or myasthenia gravis. Some forms respond to treatment with acetylcholinesterase inhibitors.


Pathology_Robbins

Pathology_Robbins. Infections with exotoxin-producing bacteria may be associated with defects in neural transmission and muscle contraction. Clostridium tetani and Clostridium botulinum (Chapter 9) both release extremely potent neurotoxins that interfere with neuromuscular transmission. Tetanus toxin (known as tetanospasmin) blocks the action of inhibitory neurons, leading to the increased release of acetylcholine and sustained muscle contraction and spasm (tetanus). Botulinum toxin, by contrast, inhibits acetylcholine release, producing a flaccid paralysis. The purified toxin (Botox) is remarkably stable after injection, an attribute that has led to its widespread use as an antidote for wrinkles and a variety of other conditions associated with unwanted muscular activity (e.g., blepharospasm and strabismus). Disordersofneuromuscularjunctionsmanifestwithweaknessthatoftenaffectsfacialandextraocularmusclesandmayshowrapidfluctuationinseverity.


Pathology_Robbins

Pathology_Robbins. Disordersofneuromuscularjunctionsmanifestwithweaknessthatoftenaffectsfacialandextraocularmusclesandmayshowrapidfluctuationinseverity. BothmyastheniagravisandLambert-Eatonsyndrome,whicharethemostcommonforms,areimmunemediated,beingcausedbyantibodiesthattypicallytargetpostsynapticacetylcholinereceptorsandpresynapticcalciumchannels,respectively. http://ebooksmedicine.net Myastheniagravisoftenisassociatedwiththymichyperplasiaorthymoma.Lambert-Eatonsyndromeisaparaneoplasticdisorderinthemajorityofthecases;thestrongestassociationiswithsmallcelllungcancer. Geneticdefectsinneuromuscularjunctionproteinsandbacterialtoxinsalsocancausesymptomaticdisturbancesinneuromusculartransmission. The principal component of the motor system is the motor unit, which is composed of one lower motor neuron together with the associated axon, its neuromuscular junctions, and the skeletal muscle fibers it innervates.


Pathology_Robbins

Pathology_Robbins. Skeletal muscle consists of different fiber types broadly classified as slow twitch type I and fast twitch type II fibers ( Table 22.2 ). The fiber type is dependent on the innervation. All myofibers of a motor unit therefore share the same fiber type. Normally the fibers of different types are distributed in checkerboard patterns ( Fig. 22.1A ). A number of proteins and protein complexes are crucial for the unique structure and function of skeletal muscles. These include proteins that make up the sarcomeres and the dystrophinglycoprotein complex ( Fig. 22.3 ), as well as enzymes that allow muscle to meet it unusual metabolic requirements. Primary muscle diseases or myopathies have to be distinguished from secondary neuropathic changes caused by disorders that disrupt muscle innervation. Both are associated with altered muscle function and morphology, but each has distinctive features (


Pathology_Robbins

Pathology_Robbins. Fig. 22.4 ). Myopathic conditions are often associated with segmental necrosis and regeneration of individual muscle fibers ( Fig. 22.4B ). Some myopathies are also associated with other morphologic features, such as inflammatory infiltrates or intracellular inclusions. Disruption of muscle by endomysial fibrosis and fatty replacement is reflective of disease chronicity that can occur both in myopathic as well as neuropathic conditions. Both neuropathic and myopathic processes cause muscle fiber atrophy. However, certain disorders are associated with particular patterns of atrophy, as follows: • Neuropathic changes. Loss of innervation causes atrophy of myofibers. The two main morphologic hallmarks of neurogenic changes, grouped atrophy and fiber type grouping ( Fig. 22.4C ), are the result of multiple rounds of denervation and reinnervation. Loss of an axon or lower motor neuron results in atrophy of the myofibers that are part of this motor unit (


Pathology_Robbins

Pathology_Robbins. Fig. 22.4C ), are the result of multiple rounds of denervation and reinnervation. Loss of an axon or lower motor neuron results in atrophy of the myofibers that are part of this motor unit ( Fig. 22.4C2 ). Atrophic myofibers can be reinnervated by axonal branches from adjacent motor units, increasing the size of these motor units and returning trophic input to the atrophic myofibers ( Fig. 22.4C3 ). Multiple rounds of denervation and reinnervation result in a dwindling number of motor units of increasingly larger size. In this setting loss of innervation will therefore produce large clusters of atrophic myofibers, grouped atrophy ( Fig. 22.4C5 ). Because


Pathology_Robbins

Pathology_Robbins. Fig. 22.4C5 ). Because Fig. 22.3 Thedystrophin-glycoproteincomplex(DGC).Thiscomplexofglycoproteinsservestocouplethecellmembrane(thesarcolemma)toextracellularmatrixproteinssuchaslaminin-2andtheintracellularcytoskeleton.Akeysetofconnectionsismadebydystrophin,ascaffoldingproteinthattethersthemyofibrillarcytoskeletontothetransmembranedystroglycansandsarcoglycans,andalsobindssignalingcomplexescontainingdystrobrevin,syntrophin,neuronalnitricoxidesynthetase(nNOS),andcaveolin.MutationsindystrophinareassociatedwithX-linkedDuchenneandBeckermusculardystrophies;mutationsincaveolinandthesarcoglycanproteinswithautosomallimb-girdlemusculardystrophies;andmutationsinα2laminin(merosin)withaformofcongenitalmusculardystrophy. Table 22.2 Muscle Fiber Types EnergymetabolismLowglycolyticHighglycolyticcapacity,highcapacity,lowoxidativecapacityoxidativecapacity MyosinheavychainMYH7 MYH2,MYH4,geneexpressed http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. EnergymetabolismLowglycolyticHighglycolyticcapacity,highcapacity,lowoxidativecapacityoxidativecapacity MyosinheavychainMYH7 MYH2,MYH4,geneexpressed http://ebooksmedicine.net Fig. 22.4 Patternsofskeletalmuscleinjury.(A)Normalskeletalmusclehasrelativelyuniformpolygonalmyofiberswithperipherallyplacednucleithataretightlypackedtogetherintofasciclesseparatedbyscantconnectivetissue.Aperimysialinterfascicularseptumcontainingabloodvesselispresent(top center).


Pathology_Robbins


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Pathology_Robbins. andtypeII(dark) fibersonthisATPasereaction(pH9.4),correspondingtofindingsin(A).(C5)Clusteredflattened“angulated”atrophicfibers(grouped atrophy) areatypicalfindingassociatedwithdisruptedinnervation.(C6)Withongoingdenervationandreinnervation,largeclustersoffibersappearthatallsharethesamefibertype(fiber type grouping).


Pathology_Robbins

Pathology_Robbins. myofiber type depends on the innervating motor unit, reinnvervated fibers may change from type I to type II and vice versa. The presence of increasingly larger motor units alters the normal checkerboard type distribution of fibers by producing large clusters of the same type, fiber type grouping ( Fig. 22.4C6). • Prolonged disuse of muscles from any cause (e.g., prolonged bed rest in the sick, casting of a broken bone) may cause focal or generalized muscle atrophy, which tends to affect type II fibers more than type I fibers. • Glucocorticoid exposure, whether exogenous or endogenous (e.g., in Cushing syndrome), also may cause muscle atrophy. Proximal muscles and type II myofibers are affected preferentially in this setting. Inherited mutations are responsible for a diverse collection of disorders marked by defects in skeletal muscle. In some of these disorders, skeletal muscle is the main site of disease, while in others multiple organs are involved. Of http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Dystrophinopathies: Duchenne and the other organs involved, the heart is of particular impor- tance, because cardiac involvement is common and is often life-limiting. Included in this group of inherited muscular disorders are the following: Muscular dystrophies are associated with progressive muscle injury in patients who have normal muscle function at birth. Congenital muscular dystrophies, by contrast, are progressive, early-onset diseases. Some are also associated with malformations of the central nervous system. Congenital myopathies typically present in infancy with muscle defects that tend to be static or to even improve with time. They are often associated with distinct structural abnormalities of the muscle.


Pathology_Robbins

Pathology_Robbins. The discussion of muscular dystrophies may at first glance appear confusing because of different classification systems and terminologies. This is reflective of our evolving understanding of these diseases, from a description based on phenotype and inheritance pattern, to one based on underlying genetic mutations. An additional layer of complexity stems from the fact that there is not a simple one-to-one correspondence between genotypes and phenotypes. Instead mutations in several different genes can, for example, present as autosomal recessive limb-girdle muscular dystrophy; conversely different mutations in a single gene (such as dystrophin) can lead to very different clinical phenotypes, as illustrated by Duchenne and Becker types of muscular dystrophy.


Pathology_Robbins

Pathology_Robbins. The most common muscular dystrophies are X-linked and are caused by mutations that disrupt the function of a large structural protein called dystrophin. As a result, these diseases are referred to as dystrophinopathies. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the two most important diseases in this group. DMD has an incidence of about 1 per 3500 live male births and follows an invariably fatal course. It becomes clinically evident in early childhood; most patients are wheelchair-bound by the time they are teenagers and are dead of their disease by early adulthood. The Becker type of muscular dystrophy is less common and less severe. MORPHOLOGYThehistologicalterationsinskeletalmusclesaffectedbyDMDandBMDaresimilar,exceptthatthechangesaremilderinBMD(


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Both DMD and BMD are caused by mutations disrupting the function of the dystrophin gene located on the short arm of the X chromosome (Xp21). Dystrophin is a very large protein (427 kD in molecular weight) found in skeletal and cardiac muscle, brain, and peripheral nerves; it is part of the dystrophin-glycoprotein complex ( Fig. 22.3 ). This complex stabilizes the muscle cell during contraction and may be involved in cell signaling through interactions with other proteins. Dystrophin-glycoprotein complex defects are thought to make muscle cells vulnerable to transient membrane tears during contraction that lead to calcium influx, and they may also disrupt intracellular signaling. The result is myofiber degeneration that with time out-paces the capacity for repair. The dystrophin-glycoprotein complex also is important for cardiac muscle function; this explains why cardiomyopathy eventually develops in many patients.


Pathology_Robbins

Pathology_Robbins. The dystrophin gene spans roughly 2.4 megabases (about 1% of the X chromosome), making it one of the largest human genes. Its enormous size may make it more prone to sporadic mutations, which all things being equal are more likely by chance to affect large genes. The most common mutations are deletions, followed by frameshift and point mutations. Patient with DMD usually have either of the first two and show complete absence of dystrohpin on a muscle biopsy. Patients with BMD often have point mutations and make residual but defective forms. The severity of disease therefore correlates with genotype and extent of dystrohpin deficiency.


Pathology_Robbins

Pathology_Robbins. Often the first symptoms of DMD are clumsiness and an inability to keep up with peers because of muscle weakness. The weakness typically begins in the pelvic girdle and next involves the shoulder girdle. Enlargement of the calves, termed pseudohypertrophy, is an early physical finding. The increased muscle bulk initially stems from myofiber hypertrophy, but as myofibers progressively degenerate, an increasing part of the muscle is replaced by adipose tissue and endomysial fibrosis. Cardiac muscle damage and fibrosis may lead to heart failure and arrhythmias, which may prove fatal. Although no structural abnormalities in the central nervous system have been described, cognitive impairment also may occur and may be severe enough to be classified as mental retardation. Owing to ongoing muscle degeneration, high serum creatine kinase levels are present at birth and persist through the first decade of life but fall as muscle mass is lost as the disease progresses. Death results from


Pathology_Robbins

Pathology_Robbins. muscle degeneration, high serum creatine kinase levels are present at birth and persist through the first decade of life but fall as muscle mass is lost as the disease progresses. Death results from respiratory insufficiency, pneumonia, and cardiac decompensation.


Pathology_Robbins

Pathology_Robbins. BMD becomes symptomatic later in childhood or adolescence and progresses at a slower and more variable rate. Many patients live well into adulthood and have a nearly normal life span. Cardiac involvement may be the dominant clinical feature and may result in death, even in the absence of significant skeletal muscle weakness.


Pathology_Robbins

Pathology_Robbins. Treatment of patients with dystrophinopathies is challenging. Current treatment consists primarily of supportive care. Definitive therapy requires restoration of dystrophin levels in skeletal and cardiac muscle fibers. Genetic approaches to accomplish this are being tested in clinical trials. One strategy involves the expression of anti-sense RNAs that alter RNA splicing so as to cause “skipping” of exons containing deleterious mutations, thus permitting the expression of a truncated, but partially functional, dystrophin protein. A second strategy involves the use of drugs that promote ribosomal “read-through” of stop codons, another ploy that may enable the synthesis of some functional dystrophin protein. Other forms of muscular dystrophy share features with DMD and BMD but have distinct clinical, genetic, and pathologic features.


Pathology_Robbins

Pathology_Robbins. • Myotonic dystrophy. Myotonia, the sustained involuntary contraction of a group of muscles, is the cardinal neuromuscular symptom in myotonic dystrophy. Patients often complain of stiffness and difficulty in relaxing their grip, for example, after a handshake. Myotonic dystrophy is a nucleotide repeat expansion disease (Chapter 7) that is inherited as an autosomal dominant trait. More than 95% of patients with myotonic dystrophy have mutations in the gene that encodes the dystrophia myotonica protein kinase (DMPK). In normal subjects, this gene contains 5 to 37 CTG repeats, whereas affected patients usually carry 45 to several thousand. As with other nucleotide repeat expansion diseases, myotonic dystrophy exhibits anticipation, characterized by worsening of the disease manifestations with each passing generation because of further trinucleotide repeat expansion. The CTG repeat is located in the 3′ untranslated region of the DMPK mRNA. Experimental studies suggest that the skeletal


Pathology_Robbins

Pathology_Robbins. each passing generation because of further trinucleotide repeat expansion. The CTG repeat is located in the 3′ untranslated region of the DMPK mRNA. Experimental studies suggest that the skeletal muscle phenotype stems from a “toxic” gain-of-function caused by the triplet repeat expansion. The mutant DMPK mRNA with the resulting CUG expansions sequesters muscleblindlike proteins involved in RNA splicing. This functional depletion of proteins involved in RNA splicing disrupts normal gene expression patterns and alters the function of diseased tissues like skeletal and cardiac muscle. Myotonic dystrophy often manifests in late childhood with gait abnormalities due to weakness of foot dorsiflexors, with subsequent progression to weakness of the intrinsic muscles of the hands and wrist extensors, atrophy of the facial muscles, and ptosis. Involvement of other organ systems results in potentially fatal cardiac arrhythmias, cataracts, early frontal balding, endocrinopathies, and testicular


Pathology_Robbins

Pathology_Robbins. atrophy of the facial muscles, and ptosis. Involvement of other organ systems results in potentially fatal cardiac arrhythmias, cataracts, early frontal balding, endocrinopathies, and testicular atrophy.


Pathology_Robbins

Pathology_Robbins. Limb-girdle muscular dystrophies. These muscular dystrophies preferentially affect the proximal musculature of the trunk and limbs. Their genetic basis is heterogeneous. The growing list includes at least 7 dominant subtypes and 15 autosomal recessive subtypes. Some of the responsible mutations affect components of the dystrophin-glycoprotein complex other than dystrophin. Others affect proteins involved in vesicle transport and repair of cell membrane after injury (caveolin-3 and dysferlin), cytoskeletal proteins, or posttranslational modification of dystroglycan, a component of the dystrophin-glycoprotein complex.


Pathology_Robbins

Pathology_Robbins. Emery-Dreifuss muscular dystrophy (EMD) is a genetically heterogeneous disorder caused by mutations http://ebooksmedicine.net affecting structural proteins found in the nucleus. An X-linked form results from mutations in the gene encoding the protein emerin, whereas an autosomal dominant form is caused by mutations in the gene encoding lamin A/C. It is hypothesized that defects in these proteins compromise the structural integrity of the nucleus in cells that are subjected to repetitive mechanical stress (e.g., cardiac and skeletal muscle). These proteins may also regulate chromatin structure and thereby affect gene expression patterns. The clinical picture is characterized by progressive muscle weakness and wasting, contractures of the elbows and ankles, and cardiac disease. The cardiac involvement is severe, being associated with cardiomyopathy and arrhythmias that lead to sudden death in up to 40% of patients.


Pathology_Robbins

Pathology_Robbins. • Facioscapulohumeral dystrophy is an autosomal dominant form of muscular dystrophy that is caused by complex genetic changes that allow expression of the transcription factor DUX4 that is normally repressed in mature tissues. It is thought that the disease is caused by over expression of DUX4 target genes, many of which are involved in the normal function of skeletal muscles. Most patients become symptomatic by the age of 20 years, usually owing to weakness in the facial muscles and the shoulder. Patients also exhibit weakness in the lower trunk and the dorsiflexors of the foot. Most affected persons have a normal life expectancy. Channelopathies, Metabolic Myopathies, and Mitochondrial Myopathies Other important inherited disorders of skeletal muscle are the result of defects in ion channels (channelopathies), metabolism, and mitochondrial function.


Pathology_Robbins

Pathology_Robbins. • Ion channel myopathies are a group of familial disorders caused by inherited defects in ion channels that are characterized by myotonia, relapsing episodes of hypotonic paralysis associated with abnormal serum potassium levels, or both. Hyperkalemic periodic paralysis results from mutations in the gene encoding the skeletal muscle sodium channel SCN4A, which regulates sodium entry during contraction. Malignant hyperthermia is a rare syndrome characterized by tachycardia, tachypnea, muscle spasms, and hyperpyrexia. It is triggered when patients carrying mutations in the ryanodine receptor RYR1, a calcium efflux channel, receive halogenated anesthetic agents or succinylcholine during surgery. On exposure to anesthetic, the mutated receptor leads to increased efflux of calcium from the sarcoplasmic reticulum, producing tetany and excessive heat production. There is some evidence that people carrying RYR1 mutations also are unusually susceptible to exertional hyperthermia (heat stroke).


Pathology_Robbins

Pathology_Robbins. • Myopathies due to inborn errors of metabolism include disorders of glycogen synthesis and degradation (Chapter 7) and lipid handling. The latter include disorders of the carnitine transport system and deficiencies of the mitochondrial dehydrogenase enzyme system, both of which can lead to accumulation of lipid in myocytes (lipid myopathies). These storage disorders may manifest as systemic disease or as a muscle-specific phenotype. Some are associated with muscle damage and weakness. Others manifest with recurring episodes of exerciseor fasting-induced muscle damage, which if severe may lead to necrosis of myoctyes (rhabdomyolysis), myoglobulinuria and acute renal failure.


Pathology_Robbins

Pathology_Robbins. • Mitochondrial myopathies can stem from mutations in either the mitochondrial or nuclear genomes because both encode proteins and RNAs that are critical for mitochondrial function. The variants caused by mitochondrial mutations show maternal inheritance (Chapter 7). Mitochondrial myopathies usually manifest in early adulthood with proximal muscle weakness and sometimes with severe involvement of the ocular musculature (external ophthalmoplegia). There may also be neurologic signs and symptoms, lactic acidosis, endocrinopathy, peripheral neuropathy, and cardiomyopathy. Some mitochondrial diseases are associated with normal muscle morphology, whereas others show aggregates of abnormal mitochondria; the latter impart a blotchy red appearance in special stains—hence the term ragged red fibers. On ultrastructural examination, these correspond to abnormal aggregates of mitochondria with abnormal shape and size, some containing crystalline inclusions.


Pathology_Robbins

Pathology_Robbins. A diverse group of acquired disorders may manifest with muscle weakness, muscle cramping, or muscle pain. These include inflammatory myopathies, toxic muscle injuries, postinfectious rhabdomyolysis, and muscle infarction in the setting of diabetes. In most instances these are disorders of adults with acute or subacute onsets. Polymyositis, dermatomyositis, and inclusion body myositis represent the traditional triad of inflammatory myopathies. This triad is a simplified view of complex diseases with variable phenotypes that are not always as well delineated as outlined here. Nevertheless, this approach still helps to outline key principles. Polymyositis is an autoimmune disorder associated with increased expression of MHC class I molecules on myofibers and predominantly endomysial inflammatory infiltrates containing CD8+ cytotoxic T cells. The autoimmune attack leads to myofiber necrosis and subsequent regeneration (


Pathology_Robbins

Pathology_Robbins. Fig. 22.6A ). Patients with polymyositis are often successfully treated with corticosteroids or other immunosuppressive agents. Dermatomyositis is the most common inflammatory myopathy in children, in whom it appears as an isolated entity. In adults, it often manifests as a paraneoplastic disorder. In both contexts, it is believed to have an autoimmune basis. The disease is typically associated with skin manifestations, as implied by the name, and may also have systemic manifestations such as interstitial lung disease. On microscopic examination and ultrastructural studies, it is associated with perivascular mononuclear cell infiltrates with plasma cells, “dropout” of capillaries, the presence of so-called “tubuloreticular inclusions” in endothelial cells, and myofiber damage in a paraseptal or perifascicular pattern ( Fig. 22.6B http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 22.6B http://ebooksmedicine.net Fig. 22.6 Inflammatorymyopathies.(A)Polymyositisischaracterizedbyendomysialinflammatoryinfiltratesandmyofibernecrosis(arrow).(B)Dermatomyositisoftenshowsprominentperifascicularandparaseptalatrophy.(C)Inclusionbodymyositis,showingmyofiberscontainingrimmedvacuoles(arrows).ModifiedGomoritrichromestain. As with some other autoimmune diseases such as SLE (Chapter 5), type 1 interferon-induced gene products are strongly upregulated in affected muscles. Some patients have autoantibodies that are relatively specific for dermatomyositis; these include antibodies against Mi-2 (a nuclear helicase) and p155 and p140, proteins with uncertain functions.


Pathology_Robbins

Pathology_Robbins. • Inclusion body myositis is the most common inflammatory myopathy in patients older than 60 years of age. It is grouped with other forms of myositis, but it has yet to be determined whether inflammation is a cause or an effect in this disorder. The morphologic hallmark of inclusion body myositis is the presence of rimmed vacuoles (


Pathology_Robbins

Pathology_Robbins. Fig. 22.6C ) that contain aggregates of the same proteins that accumulate in the brains of patients with neurodegenerative diseases—hyperphosphorylated tau, amyloid derived from β-amyloid precursor protein, and TDP-43 (Chapter 23)—leading some to speculate that this is a degenerative disorder of aging. Other features typical of chronic inflammatory myopathies, including myopathic changes, mononuclear cell infiltrates, endomysial fibrosis, and fatty replacement, also are evident. The disease follows a chronic, progressive course and generally does not respond well to immunosuppressive agents, another feature suggesting that inflammation is a secondary event. A number of insults can cause toxic muscle injury, including intrinsic factors (e.g., thyroxine) and extrinsic factors (e.g., acute alcohol intoxication, various drugs).


Pathology_Robbins

Pathology_Robbins. A number of insults can cause toxic muscle injury, including intrinsic factors (e.g., thyroxine) and extrinsic factors (e.g., acute alcohol intoxication, various drugs). Thyrotoxic myopathy may take the form either of acute or chronic proximal muscle weakness, and it can be the first indication of thyrotoxicosis. Histologic findings include myofiber necrosis and regeneration. Ethanol myopathy occurs after an episode of binge drinking. The degree of rhabdomyolysis may be severe, sometimes leading to acute renal failure secondary to myoglobinuria. Patients usually complain of acute muscle pain, which may be generalized or confined to a single muscle group. Microscopically, there is myocyte swelling, necrosis, and regeneration.


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Pathology_Robbins. • Drug myopathy can be produced by a variety of agents. For example, myopathy is the most common complication of statins (e.g., atorvastatin, simvastatin, pravastatin), occurring in approximately 1.5% of users. Two forms of statin associated myopathy are recognized: (1) toxicity of the drug and (2) statin-induced HMG-CoA reductase autoantibodies causing an immune mediated myopathy. Tumors of Skeletal Muscles These are discussed in Chapter 21 along with other tumors of soft tissues. Skeletalmusclefunctioncanbeimpairedbyaprimary(inheritedoracquired)myopathyorsecondarilybecauseofproblemswithmuscleinnervation. Thegeneticformsofmyopathyfallintoseveralfairlydistinctclinicalphenotypes,includingmusculardystrophy,congenitalmyopathy,andcongenitalmusculardystrophy. DystrophinopathiesareX-linkeddisorderscausedbymutationsinthedystrophingeneanddisruptionofthedystrophinglycoproteincomplex.Dependingonthetypeofmutation,thediseasemaybesevere,suchasDMD,ormild(e.g.,Beckerdystrophy).


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Pathology_Robbins. Acquiredmyopathieshavediversecauses,includinginflammationandtoxicexposures. http://ebooksmedicine.net A number of different tumors arise from peripheral nerves. Such tumors may manifest as soft tissue masses, with pain or loss of function related to impingement on nerves or other surrounding structures. In most peripheral nerve tumors, the neoplastic cells show evidence of Schwann cell differentiation. These tumors usually occur in adults and include both benign and malignant variants. An important feature is their frequent association with the familial tumor syndromes neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2).


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Pathology_Robbins. Schwannomas are benign encapsulated tumors that may occur in soft tissues, internal organs, or spinal nerve roots. The most commonly affected cranial nerve is the vestibular portion of the eighth nerve. Tumors arising in a nerve root or the vestibular nerve may be associated with symptoms related to nerve root compression, which includes hearing loss in the case of vestibular schwannomas.


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Pathology_Robbins. Most schwannomas are sporadic, but about 10% are associated with familial neurofibromatosis type 2 (NF2). NF2 patients are at risk of developing multiple schwannomas, meningiomas, and ependymomas (the latter are described in Chapter 23). The presence of bilateral vestibular schwannomas is a hallmark of NF2; despite the name, neurofibromas (described later) are not found in NF2 patients. Affected patients carry a dominant loss of function mutation of the merlin gene on chromosome 22. Merlin is a cytoskeletal protein that functions as a tumor suppressor by facilitating E-cadherin–mediated contact inhibition (Chapter 6). With loss of merlin function, the tumor cells proliferate because contact inhibition is lost. Of note, merlin expression also is disrupted in sporadic schwannomas, possibly because of somatic mutations.


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Pathology_Robbins. MORPHOLOGYMostschwannomasappearascircumscribedmassesabuttinganadjacentnerve.Onmicroscopicexamination,thesetumorsoftenshowanadmixtureofdenseandlooseareasreferredtoasAntoniAandB,respectively( Fig.22.7A–B).They arecomprisedofauniformproliferationofneoplasticSchwanncells.InthedenseAntoni A areas,blandspindlecellswithbucklednucleiarearrangedintointersectingfascicles.Thesecellsoftenaligntoproducenuclearpalisading,resultinginalternatingbandsofnuclearandanuclearareascalledVerocaybodies.Axonsarelargelyexcludedfromthetumor.Intheloose,hypocellularAntoni B areas,thespindlecellsarespreadapartbyaprominentmyxoidextracellularmatrix.Thick-walledhyalinizedvesselsoftenarepresent.Hemorrhageorcysticchangesalsoaresometimesseen. Neurofibromas are benign peripheral nerve sheath tumors. Three important subtypes are recognized:


Pathology_Robbins

Pathology_Robbins. Neurofibromas are benign peripheral nerve sheath tumors. Three important subtypes are recognized: Localized cutaneous neurofibromas arise as superficial nodular or polypoid tumors. These occur either as solitary sporadic lesions or often as multiple lesions in the context of neurofibromatosis 1 (NF1). Plexiform neurofibromas grow diffusely within the confines of a nerve or nerve plexus. Surgical enucleation of such lesions is therefore difficult and is often associated with lasting neurologic deficits. Plexiform neurofibromas are virtually pathognomonic for NF1 (discussed later). Unlike other benign nerve sheath tumors, these tumors are associated with a small but real risk of malignant transformation. Diffuse neurofibromas are infiltrative proliferations that can take the form of large, disfiguring subcutaneous masses. These also are often associated with NF1.


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Pathology_Robbins. Diffuse neurofibromas are infiltrative proliferations that can take the form of large, disfiguring subcutaneous masses. These also are often associated with NF1. MORPHOLOGYUnlikeschwannomas,neurofibromasarenotencapsulated.Theymayappearcircumscribed,asinlocalized cutaneous neurofibromas, ormayexhibitadiffuselyinfiltrativegrowthpattern.Alsoincontrasttoschwannomas,theneoplasticSchwanncellsinneurofibromaareadmixedwithothercelltypes,includingmastcells,fibroblastlikecells,andperineurial-likecells.Thebackgroundstromaoftencontainsloosewavycollagenbundlesbutalsocanbemyxoidorcancontaindensecollagen( Fig.22.7D ).Plexiform neurofibromas involvemultiplefasciclesofindividualaffectednerves( Fig.22.7C ).Diffuse neurofibromas showanextensiveinfiltrativepatternofgrowthwithinthedermisandsubcutisoftheskin.


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Pathology_Robbins. NF1 is an autosomal dominant disorder caused by mutations in the tumor suppressor neurofibromin, encoded on the long arm of chromosome 17 (17q). Neurofibromin is a negative regulator of the potent oncoprotein Ras (Chapter 6). Loss of neurofibromin function and the resulting Ras hyperactivity appear to be a cardinal feature of NF1associated tumors. As would be anticipated for a tumor suppressor gene, the sole normal NF1 allele is mutated or silenced in tumors arising in the setting of NF1. These include neurofibromas of all three main types, malignant peripheral nerve sheath tumors, “optic gliomas,” and other glial tumors. In addition, patients with NF1 exhibit learning disabilities, seizures, skeletal abnormalities, vascular abnormalities with arterial stenoses, pigmented nodules of the iris (Lisch nodules), and pigmented skin lesions (axillary freckling and café-au-lait spots) in various degrees.


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Pathology_Robbins. Malignant peripheral nerve sheath tumors are neoplasms seen in adults that typically show evidence of Schwann cell derivation and sometimes a clear origin from a peripheral nerve. They may arise from transformation of a neurofibroma, usually of the plexiform type. About one-half of such tumors arise in patients with NF1, and 3% to 10% of all patients with NF1 develop a malignant peripheral http://ebooksmedicine.net Fig. 22.7 Schwannomaandplexiformneurofibroma.(A–B)Schwannoma.Asseenin(A),schwannomasoftencontaindensepinkAntoniAareas(left) andloose,paleAntoniBareas(right),aswellashyalinizedbloodvessels(right).(B)AntoniAareawiththenucleioftumorcellsalignedinpalisadingrows.(C–D)Plexiformneurofibroma.Multiplenervefasciclesareexpandedbyinfiltratingtumorcells(C),whichathigherpower(D)areseentoconsistofblandspindle cellsadmixedwithwavycollagenbundleslikenedtocarrotshavings.


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Pathology_Robbins. nerve sheath tumor during their lifetimes. Histologically, these tumors are highly cellular and exhibit features of overt malignancy, including anaplasia, necrosis, infiltrative growth pattern, pleomorphism, and high proliferative activity. Traumatic neuroma is a nonneoplastic proliferation associated with a previous injury leading to transection of a peripheral nerve. Such injuries activate a regenerative program (see Fig. 22.1 ) characterized by sprouting and elongation of processes from the proximal axonal stump. With severe injuries that disrupt the perineurial sheath, these new processes may “miss” their target, the distal end of the transected nerve. The misguided elongating axonal processes can induce a reactive proliferation of Schwann cells, leading to the formation of a painful localized nodule that consists of a haphazard mixture of axons, Schwann cells, and connective tissue. Inmostperipheralnervesheathtumors,theneoplasticcellsshowevidenceofSchwanncelldifferentiation.


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Pathology_Robbins. Inmostperipheralnervesheathtumors,theneoplasticcellsshowevidenceofSchwanncelldifferentiation. PeripheralnervesheathtumorsareimportantfeaturesofthefamilialtumorsyndromesNF1andNF2. Schwannomasandneurofibromasarebenignnervesheathtumors. Schwannomasarecircumscribed,usuallyencapsulatedtumorsthatabutthenerveoforiginandareafeatureofNF2. Neurofibromasmaymanifestasasporadicsubcutaneousnodule,asalarge,poorlydefinedsofttissuelesion,orasagrowthwithinanerve.NeurofibromasareassociatedwithNF1. About50%ofmalignantperipheralnervesheathtumorsoccurdenovoinotherwisenormalpersons,whereastheremainderarisefromthemalignanttransformationofapreexistingNF1associatedneurofibroma. http://ebooksmedicine.net Berrih-Aknin S, Le Panse R: Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms, J Autoimmun 52:90–100, 2014. [Review of subtypes and etiology of myasthenia gravis.]


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Pathology_Robbins. Briemberg HR: Peripheral nerve complications of medical disease, Semin Neurol 29:124, 2009. [Review of the ways medical diseases including diabetes, connective tissue diseases, cancer, and infections affect peripheral nerves.] Dalakas MC: Inflammatory muscle diseases, N Engl J Med 372:18, 2015. [Discussion of current concepts on the pathophysiology of idiopathic inflammatory myopathies.] Falzarano MS, Scotton C, Passarelli C, et al: Duchenne muscular dystrophy: from diagnosis to therapy, Molecules 20:18168, 2015. [Molecular techniques for the diagnosis and treatment of this disease.] Habib AA, Brannagan TH III: Therapeutic strategies for diabetic neuropathy, Curr Neurol Neurosci Rep 10:92, 2010. [Review focused especially on clinical features and therapy of diabetic neuropathy.] Kang PB, Griggs RC: Advances in muscular dystrophies, JAMA 72:741, 2015. [An update on the molecular pathogenesis of muscular dystrophies and their treatment.]


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Pathology_Robbins. Kang PB, Griggs RC: Advances in muscular dystrophies, JAMA 72:741, 2015. [An update on the molecular pathogenesis of muscular dystrophies and their treatment.] Mahadeva B, Phillips LH, Juel VC: Autoimmune disorders of neuromuscular transmission, Semin Neurol 28:212, 2008. [Review of myasthenia gravis and Lambert-Eaton syndrome.] McClatchey AI: Neurofibromatosis, Annu Rev Pathol 2:191, 2007. [Review of features that distinguish neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis, with a focus on the genetics.] Obrosova IG: Diabetes and the peripheral nerve, Biochim Biophys Acta 1792:931, 2009. [Detailed discussion of the pathophysiology of diabetic neuropathy.] Petrilli AM, Fernández-Valle C: Role of Merlin/NF2 inactivation on tumor biology, Oncogene 35:537–548, 2016. [Mechanisms of action of the NF2 gene in the pathogenesis of neuronal tumors.]


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Pathology_Robbins. Petrilli AM, Fernández-Valle C: Role of Merlin/NF2 inactivation on tumor biology, Oncogene 35:537–548, 2016. [Mechanisms of action of the NF2 gene in the pathogenesis of neuronal tumors.] Ravenscroft G, Laing NG, Bönnemann CG: Pathophysiological concepts in the congenital myopathies: blurring the boundaries, sharpening the focus, Brain 138:246, 2015. [A review of the overlapping and nonoverlapping genetic lesions in congenital myopathies.] Tawil R, van der Maarel SM, Tapscott SJ: Facioscapulohumeral dystrophy: the path to consensus on pathophysiology, Skelet Muscle 4:12, 2014. [Review of FSHD including a discussion of the complex genetics.] van Adel BA, Tarnopolsky MA: Metabolic myopathies: update 2009, J Clin Neuromuscul Dis 10:97, 2009. [Review of metabolic myopathies.]


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Pathology_Robbins. Vrablik M, Zlatohlavek L, Stulc T, et al: Statin-associated myopathy: from genetic predisposition to clinical management, Physiol Res 63(Suppl 3):S327, 2014. [A discussion of the risk factors for statininduced myopathy and its therapy.] Wang ET, Cody NA, Jog S, et al: Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins, Cell 150:710–724, 2012. [Study of the transcriptional changes with myotonic dystrophy.] http://ebooksmedicine.net studentconsult.com Edema,Herniation,andHydrocephalus Hypoxia, Ischemia, and Infarction


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Pathology_Robbins. Degenerative, inflammatory, infectious, vascular, and neoplastic disorders of the central nervous system (CNS) are some of the most serious diseases of mankind. These diseases have many unique features that reflect the highly specialized structure and functions of the CNS. The principal functional unit of the CNS is the neuron. Neurons of different types and in different locations have distinct properties, including functional roles, distribution of their connections, neurotransmitters used, metabolic requirements, and levels of electrical activity at a given moment. A set of neurons, not necessarily clustered together in a region of the brain, may thus show selective vulnerability to various insults because it shares one or more of these properties. Since different regions of the brain participate in different functions, the pattern of clinical signs and symptoms that follow injury depend as much on the region of brain involved as on the pathologic process. Mature neurons are


Pathology_Robbins

Pathology_Robbins. brain participate in different functions, the pattern of clinical signs and symptoms that follow injury depend as much on the region of brain involved as on the pathologic process. Mature neurons are incapable of cell division, so destruction of even a small number of neurons essential for a specific function may leave the individual with a neurologic deficit. In addition to neurons the CNS contains other cells, such as astrocytes and oligodendrocytes, which make up the glia. The components of the CNS are affected by a number of unique neurologic disorders and also respond to common insults (e.g., ischemia, infection) in a manner that is distinct from other tissues.


Pathology_Robbins

Pathology_Robbins. Before delving into specific disorders, we will briefly review the characteristic morphologic changes that are often seen in the CNS in the setting of injury or infection. Features of Neuronal Injury. Inresponsetoinjury,anumberofchangesoccurinneuronsandtheirprocesses(axonsanddendrites).Within12hoursofanirreversiblehypoxic-ischemicinsult,neuronal injury becomesevidentonroutinehematoxylinandeosin(H&E)staining( Fig.23.1A ).Thereisshrinkageofthecellbody,pyknosisofthenucleus,disappearanceofthenucleolus,lossofNisslsubstance,andintenseeosinophiliaofthecytoplasm(“redneurons”).Axonalinjuryalsoleadstocellbodyenlargementandrounding,peripheraldisplacementofthenucleus,enlargementofthenucleolus,andperipheraldispersionofNisslsubstance(central chromatolysis). Inaddition,acuteinjuriestypicallyresultinbreakdownoftheblood-brainbarrierandvariabledegreesofcerebraledema(discussedlater).


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig.23.1C ).Similarcollectionscanbefoundcongregatingaroundandphagocytosinginjuredneurons(neuronophagia). Ependymal cells linetheventricularsystemandthecentralcanalofthespinalcord.Certainpathogens,particularlycytomegalovirus(CMV),canproduceextensiveependymalinjury,withtypicalviralinclusions.Choroid plexus isincontinuitywiththeependyma,anditsspecializedepithelialcoveringisresponsibleforthesecretionofcerebrospinalfluid(CSF). EDEMA,HERNIATION,ANDHYDROCEPHALUS


Pathology_Robbins

Pathology_Robbins. EDEMA,HERNIATION,ANDHYDROCEPHALUS The brain and spinal cord are encased within the skull and spinal canal, with nerves and blood vessels passing through specific foramina. The advantage of housing the delicate CNS within hard, rigid structures is obvious, but this arrangement provides little room for expansion of the brain in disease states. As a result, virtually any increase in the volume of the skull contents brings with it an increase in intracranial pressure. Substantial increases in the intracranial pressure compromise the ability of the cardiovascular system to deliver blood to the brain, resulting in decreased brain perfusion, with serious or fatal consequences. Disorders that may cause dangerous increases in the volume of intracranial contents include generalized cerebral edema, hydrocephalus, hemorrhages, ischemia, and mass lesions such as tumors.


Pathology_Robbins

Pathology_Robbins. Cerebral edema is the accumulation of excess fluid within the brain parenchyma. There are two types, which often occur together, particularly after generalized injury. Vasogenic edema occurs when the integrity of the normal blood-brain barrier is disrupted, allowing fluid to shift from the vascular compartment into the extracellular spaces of the brain. Vasogenic edema can be localized (e.g., the result of increased vascular permeability due to inflammation or in tumors) or generalized. Cytotoxic edema is an increase in intracellular fluid secondary to neuronal and glial cell injury, as might follow generalized hypoxic or ischemic insult or exposure to certain toxins. The edematous brain is softer than normal and often appears to “overfill” the cranial vault. In generalized edema, the gyri are flattened, the intervening sulci are narrowed, and the ventricular cavities are compressed ( Fig. 23.2 http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 23.2 http://ebooksmedicine.net Fig. 23.2 Cerebraledema.Thesurfacesofthegyriareflattenedasaresultofcompressionoftheexpandingbrainbytheduramaterandinnersurfaceoftheskull.Suchchangesareassociatedwithadangerousincreaseinintra-cranialpressure. After being produced by the choroid plexus within the ventricles, CSF circulates through the ventricular system and flows through the foramina of Luschka and Magendie into the subarachnoid space, where it is absorbed by arachnoid granulations. The balance between rates of generation and resorption regulates CSF volume.


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Pathology_Robbins. Hydrocephalus refers to an increase in the volume of the CSF within the ventricular system. This disorder most often is a consequence of impaired flow or decreased resorption of CSF. If there is a localized obstacle to CSF flow within the ventricular system, then a portion of the ventricles enlarges while the remainder does not. This pattern is referred to as noncommunicating hydrocephalus and most commonly is caused by masses obstructing the foramen of Monro or compressing the cerebral aqueduct. In communicating hydrocephalus, the entire ventricular system is enlarged; it is usually caused by reduced CSF resorption. If hydrocephalus develops in infancy before closure of the cranial sutures, the head enlarges. Once the sutures fuse, hydrocephalus causes ventricular expansion and increased intracranial pressure, but no change in head circumference (


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Pathology_Robbins. Fig. 23.3 ). In contrast to these disorders, in which increased CSF volume is the primary process, a compensatory increase in CSF volume (hydrocephalus ex vacuo) may occur secondary to a loss of brain volume from any underlying cause (e.g., infarction, neurodegenerative disease). In such settings, the hydrocephalus merely reflects the primary disorder and is of no clinical significance. Herniation is the displacement of brain tissue from one compartment to another in response to increased intra-cranial pressure. The intra-cranial compartment is divided by rigid dural folds (falx and tentorium). If the pressure is sufficiently high, portions of the brain are displaced across these rigid structures. This herniation often leads to compromise of the blood supply to compressed tissue, producing infarction, additional swelling, and further herniation. There are three main types of herniation ( Fig. 23.4


Pathology_Robbins

Pathology_Robbins. There are three main types of herniation ( Fig. 23.4 Subfalcine (cingulate) herniation occurs when unilateral or asymmetric expansion of a cerebral hemisphere displaces the cingulate gyrus under the edge of the falx. This may compress the anterior cerebral artery.


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Pathology_Robbins. Transtentorial (uncinate) herniation occurs when the medial aspect of the temporal lobe is compressed against the free margin of the tentorium. As the temporal lobe is displaced, the third cranial nerve is compromised, resulting in pupillary dilation and impaired ocular movements on the side of the lesion (“blown pupil”). The posterior cerebral artery may also be compressed, resulting in ischemic injury to tissue supplied by that vessel, including the primary visual cortex. With further displacement of the temporal lobe, pressure on the mid-brain may compress the contralateral cerebral peduncle against the tentorium, resulting in hemiparesis ipsilateral to the side of the herniation. The compression of the peduncle creates a deformation known as Kernohan’s notch. Compression of the midbrain and the ascending reticular activating system with transtentorial herniation leads to depressed consciousness. Progression of transtentorial herniation is often accompanied by linear or


Pathology_Robbins

Pathology_Robbins. the midbrain and the ascending reticular activating system with transtentorial herniation leads to depressed consciousness. Progression of transtentorial herniation is often accompanied by linear or flame-shaped hemorrhages in the midbrain and pons, termed Duret hemorrhages (


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Pathology_Robbins. Fig. 23.5 ). These lesions usually occur in the midline and paramedian regions and are believed to be the result of tearing of penetrating veins and arteries supplying the upper brain stem. Tonsillar herniation refers to displacement of the cerebellar tonsils through the foramen magnum. This type of herniation causes brain stem compression and compromises vital respiratory and cardiac centers in the medulla, and is often fatal. Fig. 23.3 Hydrocephalus.Dilatedlateralventriclesseeninacoronalsectionthroughthemid-thalamus. http://ebooksmedicine.net Fig. 23.4 Herniationsyndromes.Displacementofbrainparenchymaacrossfixedbarrierscanbesubfalcine,transtentorial,ortonsillar(intotheforamenmagnum). EDEMA,HERNIATION,ANDHYDROCEPHALUS Cerebraledemaistheaccumulationofexcessfluidwithinthebrainparenchyma.HydrocephalusisdefinedasanincreaseinCSFvolumewithinallorpartoftheventricularsystem.


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Pathology_Robbins. Cerebrovascular diseases are brain disorders caused by pathologic processes involving blood vessels. They are a major cause of death in the developed world and are the most prevalent cause of neurologic morbidity. The three main pathogenic mechanisms are (1) thrombotic occlusion, (2) embolic occlusion, and (3) vascular rupture. Stroke is the clinical designation applied to all of these conditions when symptoms begin acutely. Thrombosis and embolism have similar consequences for the brain: loss of oxygen and metabolic substrates, resulting in infarction or ischemic injury of regions supplied by the affected vessel. Similar injury occurs globally when there is complete loss of perfusion, severe hypoxemia (e.g., hypovolemic shock), or profound hypoglycemia. Hemorrhage accompanies rupture of vessels and leads to direct tissue damage as well as secondary ischemic injury. Traumatic vascular injury is discussed separately in the context of trauma. Hypoxia,Ischemia,andInfarction


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Pathology_Robbins. Hypoxia,Ischemia,andInfarction The brain is a highly oxygen-dependent tissue that requires a continual supply of glucose and oxygen from the blood. Although it constitutes no more than 2% of body weight, the brain receives 15% of the resting cardiac output and is responsible for 20% of total body oxygen consumption. Cerebral blood flow normally remains stable over a wide range of blood pressure and intracranial pressure because of autoregulation of vascular resistance. The brain may be deprived of oxygen by two general mechanisms: Functional hypoxia, caused by a low partial pressure of oxygen (e.g., high altitude), impaired oxygen-carrying capacity (e.g., severe anemia, carbon monoxide poisoning), or toxins that interfere with oxygen use (e.g., cyanide poisoning) Ischemia, either transient or permanent, due to tissue hypoperfusion, which can be caused by hypotension, vascular obstruction, or both


Pathology_Robbins

Pathology_Robbins. Widespread ischemic-hypoxic injury can occur in the setting of severe systemic hypotension, usually when systolic pressures fall below 50 mm Hg, as in cardiac arrest and shock. The clinical outcome varies with the severity and duration of the insult. When the insult is mild, there may be only a transient postischemic confusional state, with eventual complete recovery. Neurons are more susceptible to hypoxic injury than are glial cells, and the most susceptible neurons are the pyramidal cells of the hippo-campus and neocortex and Purkinje cells of the cerebellum. In some individuals, even mild or transient global ischemic insults may cause damage to these vulnerable areas. In severe global cerebral ischemia, widespread neuronal death occurs irrespective of regional vulnerability. Patients who survive often remain severely impaired neurologically and in a persistent vegetative state. Other patients meet the clinical criteria for so-called “brain death,” in which all voluntary and reflex


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Pathology_Robbins. survive often remain severely impaired neurologically and in a persistent vegetative state. Other patients meet the clinical criteria for so-called “brain death,” in which all voluntary and reflex brain and brain stem function is absent, including respiratory drive. When patients with this form of irreversible injury are maintained on mechanical ventilation, the brain gradually undergoes autolysis, resulting in the so-called “respirator brain.” http://ebooksmedicine.net


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Pathology_Robbins. Fig.23.6B ).Repair, seenafter2weeks,ischaracterizedbyremovalofnecrotictissueandgliosis(see Fig.23.6C Border zone (“watershed”) infarcts occurinregionsofthebrainandspinalcordthatlieatthemostdistalportionsofarterialterritories.Theyareusuallyseenafterhypotensiveepisodes.Inthecerebralhemispheres,theborderzonebetweentheanteriorandthemiddlecerebralarterydistributionsisatgreatestrisk.Damagetothisregionproducesawedge-shapedbandofnecrosisoverthecerebralconvexityafewcentimeterslateraltotheinterhemisphericfissure.