PATHOLOGY 6020 ‐ 2002

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PATHOLOGY 6020 ‐ 2002 Powered By Docstoc
					         Pathology 6020
                         SCHEDULE 2005
Thursday November 17th

9:00-10:00 HSEB 1730     Non-neoplastic bone diseases   Dr. Rohr              1

10:00-11:00 HSEB 1730    Neoplastic bone diseases       Dr. Rohr              12

11:00-12:00 HSEB 1730    Muscle Pathology               Dr. Chin              18

1:00-3:00 HSEB 4300      Bone pathology Lab             Dr. Clayton/staff     31

                         Case Notes                                           33

   Tuesday November 22nd

   1:00-2:00 HSEB 4300 Case Presentations               Drs. Clayton /staff

   Wednesday November 23rd

   8:00-11:00am Eccles library        Examination
   11:00-2:00pm Eccles library        Examination

   Be sure to check the web for changes that may have occurred after printing
                                                                    PATHOLOGY 6020 – 2005
                                                                         BONE PATHOLOGY
                                                                            Ralph Rohr, M.D.
                                                          Thursday November 17, 9:00-11:00am
DISEASE, 7th edition, pp. 1274-1324.


Following lecture, small group and reading, the student should be able to:

1.    List the clinical and pathologic features of disorders of bone matrix: Osteogenesis
      imperfecta, achondroplasia (abnormal cartilage proliferation), and fibrous dysplasia.

2.    Describe the course, pathology, and consequences of Paget’s disease of bone

3.    List the major clinical features of osteoporosis, and differentiate osteoporosis from rickets
      and osteomalacia.

4.    Describe the features of scoliosis.

5.    Describe the clinical and pathologic features of the following bone tumors:

      Osteochondroma               Enchondroma                           Osteoid osteoma
      Chondrosarcoma               Aneurysmal bone cyst (ABC)            Giant cell tumor
      Osteosarcoma                 Ewing’s sarcoma

6.    Compare and contrast clinical and pathologic features of rheumatoid arthritis, gouty
      arthritis, osteoarthritis, and pseudogout (CPPD).

7.    Describe typical features of osteomyelitis and pyogenic arthritis, including infectious

                              NON-NEOPLASTIC BONE DISEASE

I.      Anatomy and physiology of bone and joints.

     Macro Structure:

        1. Bone Matrix: A combination of collagen (resistance to stretching) with stiffening
           minerals (calcium hydroxyapatite, Ca10(PO4)6(OH)2) that resist bending and

        2. Architecture: Mathematically determined according to lines of stress, as stated by
           Wolff‘s law, ―Every change in the function of a bone is followed by certain definite
           changes in internal architecture and external conformation in accordance with
           mathematical laws.‖

   3. Every bone has a limiting external shell of thicker (dense) cortical bone and a spongy
      lattice of internal medullary (cancellous) bone.

       a. Cortex is thick in long bones to resist bending, thin in vertebral bones where
          medullary bone structure resists compressive forces.

   4. Bone is covered by cartilage at joints, periosteum elsewhere. Periosteum forms new
      bone in fetus/child, expanding diameter; forms reactive bone in pathologic processes
      in adults.

Micro Structure:

   5. Bone matrix synthesized by osteoblasts, destroyed by osteoclasts—constant
      interplay, especially in fracture and pathologic processes.

       a. Osteoblasts become osteocytes which maintain communication through delicate
          elongated cell processes within canaliculi—coordinating network regulating
          skeletal homeostasis and repair.

       b. A vascular core, the haversian canal, supplies blood to these cells.

   6. Mature bone is lamellar with layers of collagen; immature (or reactive to injury or
      pathology) is woven without the orderly rank and file of fibers.

Joints have a living synovial membrane which lines everything except the articular

   7. Articular cartilage is hyaline cartilage, which has no nerves or blood supply. Nutrition
      is by osmosis.

   8. Hyaline cartilage consists of predominantly vertically oriented collagen fibers
      (perpendicular to joint articular surface and resisting compressive forces) with a high
      concentration of proteoglycans. Proteoglycans have overall negative charge and
      high affinity for water. The osmotic pressure of cartilage allows for its deformability
      and viscous cushioning characteristics.

Bone growth and development.

   9. A model is formed by cartilage and gradually calcified and then replaced by bone
      matrix in the fetus in a process known as enchondral (―in cartilage‖) ossification.
      This normal process continues at the ends of long bones until skeletal maturity in the
      late teens.

   10. The very earliest bone formation takes place in the periosteal membrane, but quickly
       changes over to enchondral ossification. This type of bone formation is called
       ―membranous‖ ossification and is the way that the skull and facial bones form without
       a preexisting cartilage model.

Typical long bone anatomy—three regions.

   11. Epiphysis—between the cartilaginous growth plate (physis) and joint.

   12. Metaphysis—between growth plate and shaft (alongside the physis).

   13. Diaphysis—the shaft between the ends of the bone, specifically between the

Fracture repair.

   14. Early—hemorrhage, granulation, necrosis.

   15. Mid—cartilage and immature woven bone called ―callus.‖

   16. Late—woven bone evolving into mature lamellar bone.

   17. Follows lines of force, perfectly reconstructing mature bone structure--provided there
       is proper immobilization and good vascularity.

   18. When it doesn’t proceed normally, get a ―nonunion‖ with more abundant cartilage
       which may form a pseudarthrosis (called a pseudojoint because of its abundant
       cartilage and instability).

   To right & below: a pseudoarthrosis, with cartilage

   instead of bone at the site of fracture repair.

II.       Disorders of Abnormal Bone Matrix.

       Osteogenesis imperfecta—a group of disorders of varying severity and inheritance
           patterns resulting from defective/deficient formation of collagenous matrix throughout
           the body. Type I collagen is deficient or defective.

          1. A lethal ―congenita‖ form is incompatible with postnatal survival. A less severe
             ―tarda‖ may permit normal longevity. No mental incapacity.

          2. Characterized by generalized loss of bone
             (osteopenia) with deformities of bone and
             multiple fractures.

          3. Fracture requires immobilization which leads to
             disuse osteoporosis, setting up a vicious cycle.

          4. Other collagenous abnormalities are seen in blue
             sclerae (thin of collagen in eyeball) and abnormal
             tooth formation, deafness, lax ligaments.

          To right: Skeleton of an older child with osteogenesis
              imperfecta, with severe deformation of many

       Achondroplasia (short-limbed dwarfism).

          5. Abnormal epiphyseal growth with impaired enchondral bone formation with
             shortening of long bones. Head and trunk are normal.

          6. Autosomal dominant inheritance, but also spontaneous new mutations so that family
             history may not be obtained.

          7. Normal intelligence and life span.

       Other rare bone matrix disorders include scurvy (vitamin C deficiency), Ehlers-Danlos
           syndrome (―India rubber man‖), Marfan‘s syndrome, vitamin A toxicity, and others.

III.      Paget‘s disease (osteitis deformans)—a metabolic bone disease characterized by
          excessive bone resorption and formation due to activated osteoclasts.

       Disease of elderly Caucasians, mostly males.

          1. Deformity, for instance increasing hat size.

          2. Cranial nerve palsies due to bony impingement.

          3. Monostotic and polyostotic cases.

          4. Rarely congestive heart failure due to increased circulation to polyostotic areas in the
             active mixed phase.

         5. Sarcomatous change in less than 1% of cases (osteosarcoma).

      Dense sclerotic bone radiographically and grossly.

      Hyperactive osteoblastic and osteoclastic activity with abnormal microscopic architecture in
         three phases—early, mid, late.

         6. Early--vascular/osteolytic phase with increased marrow capillaries, thin bone
            trabeculae with abundant osteoclasts.

         7. Middle--mixed osteoblastic phase with abundant osteoclasts.

         8. Late--sclerotic phase with thick deformed trabeculae
            and decreased cellular components.

      Microscopically, see bizarre pattern
          with abnormal cement lines and
          collagen layers going in different
          directions, like a jigsaw puzzle.

      Near right: Abnormal cement lines in
         middle phase Paget’s.

      Far right: irregular areas of lucency
           and sclerosis in a humoral head
           in early phase Paget’s.

      Abnormal micro-architecture leads to increased fragility and deformability.

      Complications from Paget's disease include deformity, fracture, and pain.

      Many studies indicate a role for viral infectious agents, whereas others point to a recently
         identified candidate gene on chromosome 18q.

      Therapy with bisphosphonate drugs is the treatment of choice. With newer and more
          powerful agents now available, the majority of patients affected by Paget's disease can
          achieve sustained remission and avoid complications.

IV.      Disorders of Bone Stability.

      Scoliosis – lateral curvature(s) of the spine, which may progress with time and weight

         1. Complications include pain, restrictive lung disease in thoracic cases.

         2. Minor degrees of curvature are usually asymptomatic.

      Kyphosis – forward curvature of the spine producing a ―hunchback‖ appearance.

         3. Commonly related to osteoporotic compression fractures (widow’s hump).

V.      Disorders of bone mass.


        1. In elderly people, esp. women, since they enter menopause with a lower bone mass
           to start with than men, but males are also affected.

        2. Normal bone composition, but reduced amount. Normal
           serum calcium, phosphate and alkaline phosphatase.

        3. Pathogenesis includes lack of weight bearing exercise,
           decreased estrogens in women and androgens in men,
           corticosteroid therapy, and immobility.

        4. Increased risk for fractures, esp. hip, vertebra, wrist.

        5. Bone mass is evaluated with bone densitometry
           (DEXA = dual energy X-ray absorptiometry) which
           measures amount of bone per unit of area scanned.

        6. Therapy includes weight-bearing exercise, estrogen
           replacement, anti-osteoclast drugs—bisphosphonates
           like alendronate (Fosamax®).

                                                                      Above: vertebral compression
            .                                                            fractures in osteoporosis.

     Rickets—nutritional disease of children.

        7. Failure of bone mineralization due to lack of vitamin D.

        8. Excessive non-calcified bone matrix (osteoid).

        9. Widened and deformed epiphyses of growing long
           bones in children result in curved and short bowed legs.

        To right: Bowed, shortened long bones with saber shins
        in rickets.

     Osteomalacia—adult counterpart of rickets.

        10. Since epiphyses are closed, changes are more subtle
            and resemble osteoporosis

        11. Osteopenic bone more subject to fractures.

VI.      Arthritis—infectious (pyogenic, granulomatous), metabolic (gout, calcium
         pyrophosphate disease (CPPD)), aseptic (rheumatoid, degenerative).

      Rheumatoid arthritis (RA).

         1. A nonsuppurative proliferative arthritis in which pathologic findings are due to an
            immunologic reaction (IgM, RA factor, complexing IgG in an antigen-antibody type
            reaction) and to increased degradative enzymes (released from polymorphonuclear
            leukocytes drawn to antigen-antibody reaction).

            a. Increased RA factor (usually IgM) in serum, which binds to autologous IgG—―an
               antibody to an antibody‖.

            b. PMN enzymes cause necrosis of cartilage and bone.

         2. Prominent synovial proliferation with infiltration of synovium
            and bone by lymphocytes and plasma cells with formation
            of lymphoid follicles.

         3. Soft tissue necrobiotic nodules with serpiginous shapes
            (rheumatoid nodules) commonly occur subcutaneously
            overlying extensor surfaces, and sometimes in other soft
            tissues (lung, heart, GI tract, synovial membrane).

         4. 2X – 3X more common in women than men, usually
            starting about age 40 years, strong hereditary

            a. Relapsing course with progressive destruction of
               articular surfaces and bone, resulting in scarring,
               deformity and fusion of joints.

         5. Juvenile form of RA—usually less severe clinically with
            prolonged remissions, more limited joint involvement
            and less severe histologic alterations and usually
            absence of RA factor in serum.

         6. Similar histopathology in other autoimmune diseases
            (SLE, Sjögren’s).

         7. A similar polyarthritic picture is produced by Lyme
            disease, an infection by bacterium Borrelia burgdorferi,
            spread by bite of deer tick and preceded by a ring like
            rash ―erythema chronicum migrans‖ around the tick

         Top right: Cartilage erosions in RA. Middle: X-ray with bone loss,
            ulnar deviation, and subluxed distal thumb joint (at top of
            picture). Bottom: Severe hand deformation in RA, with swan
            neck deformity of distal finger joints.

   Above: rheumatoid nodule.

   Above right: histology of rheumatoid nodule, with
      necrobiotic granuloma.

   To right: necrobiotic granuloma, with area of
       fibrinoid necrosis to right, palisaded histiocytes
       in the center, and lymphocytes to the left.

Gout (hyperuricemia).

   8. Episodes of acute monoarticular pain with redness and swelling, often accompanied
      by fever, constitute acute gouty arthritis. Chronically, there may be prolonged
      asymptomatic periods and deposition of sodium urate crystals in and around joints,
      forming tophi, with joint destruction.

   9. An acute inflammatory arthritis with joint and bone destruction, but without the
      osteoporosis and joint sclerosis and fusion seen with RA. Symptoms are severe
      enough to simulate acute pyogenic infection of joint.

   10. Results from hyperuricemia. Increased serum uric acid (above 8 mg/dl) accumulates
       due to inadequate renal excretion or excessive production (myeloproliferative
       disorders, cancer, and excess cellular catabolism).

      a. Rarer is primary hyperuricemia, a inherited error of metabolism.

      b. Sodium urates deposit in joint, giving rise to neutrophilic exudates in which
         PMN’s engulf crystals. The joint fluid shows many bi-pointed negatively
         birefringent crystals. Probably facilitated by low pH in joint.

      c. In chronic tophaceous gout the urates deposit in soft tissue around joint giving
         rise to granulomatous inflammation surrounding clusters of innumerable crystals
         which look like sheaves of wheat.

          These crystals are water soluble and dissolve out readily in usual aqueous-based
             tissue fixation and processing. Use alcohol fixation and processing to
             preserve crystals in tissue for diagnosis and differentiation from pseudogout
             (calcium pyrophosphate deposition disease, CPPD or chondrocalcinosis).

          To right: Toe joint destroyed by chalky gouty

          Below: Urate granuloma with macrophages
             and giant cells surrounding the urate

          Below right: Needle shaped urate crystals in
             polarized light in gout.

   11. Calcium pyrophosphate disease (CPPD) produces granulomatous deposits and
       clinical symptoms similar to gout but is due to tissue deposits (in cartilage) of calcium
       pyrophosphate crystals

       a. Crystals are rhomboidal rather than needle-like and have positive birefringence.

       b. Most affected individuals with CPPD are asymptomatic, and incidence of disease
          is higher at autopsy than in life.

Osteoarthritis (degenerative joint disease, DJD).

   12. Increasing prevalence with age.

   13. ―Osteoarthritis is a functional disorder of joints, characterized by altered joint
       anatomy, esp. by loss of articular cartilage.‖

   14. Usually monoarticular (large joints), but rarely more erosive inflammatory form
       affecting small bones of hands as well as feet, knees, hips.

   15. Pathogenesis: aging, wear & tear, acute/chronic trauma, neurologic. Probably a
       wide variety of disease processes with common manifestations.

          16. Pathology: fibrillation, cracking, erosion of cartilage (eburnation--polished marble-like
              bony joint surface), subchondral bony sclerosis and cysts, new bone formation by
              enchondral ossification of pre-existing or new reparative cartilage (osteophytes).

              a. Absence of significant inflammation.

          17. Clinically there is ―morning stiffness and pain‖
              which eases with movement but increasing pain
              later in the day with prolonged or heavy joint

          Below: Femoral head with severe osteoarthritis, with loss of the
             cartilaginous surface over part of it.

          To right: Fibrillated cartilage in early osteoarthritis.

          Below right: Severe loss of cartilage, with a subchondral cyst.

VII.      Osteomyelitis—bacterial infections of bone marrow.

       Routes of infection:

          1. Hematogenous—sepsis, IV drug abuse.

          2. Contiguous—soft tissue infections/abscesses.

          3. Traumatic—compound fractures, orthopedic surgery

       Pyogenic (Staphylococcus, Pseudomonas, Salmonella)--bone centered.

       Granulomatous (tuberculous, fungal)--joint centered.

          4. Pott’s disease is tuberculosis of the spine; originally described by Pott in 1779, it
             included paraplegia due to collapse of infected, destroyed vertebrae.

          5. Neisseria gonorrhoeae may produce an acute bacterial pyogenic arthritis.

Bone marrow may contain passing bacteria and no osteomyelitis develops. Accessory
   factors--systemic disease, trauma, surgical or other tissue damage.


   6. Abscesses in bone, mixed acute and chronic inflammation, fibrosis, bony destruction.

   7. Localized Brodie’s abscess.

   8. Dead bone (sequestrum) surrounded by new bone (involucrum).

   To right: osteomyelitis, with surrounding
       area of dense, reactive new bone.

   Below right: there are inflammatory
      cells, either neutrophils or plasma
      cells with lymphocytes, granulation
      tissue, and reactive woven bone

                                 NEOPLASTIC BONE DISEASE

I.   Primary bone tumors.

     Arise from mesenchymal tissues: bone (osteoblasts and osteoclasts), cartilage
         (chondroblasts & chondrocytes), fibrous tissue (fibroblasts and fibrocytes), blood
         vessels (endothelial cells).

     If malignant, they are called ―sarcomas‖: osteosarcoma, chondrosarcoma, etc.

     If benign, they are designated as ―omas‖: osteomas, chondromas, etc.

     Are rather rare--2000 new cases per year compared with 168,000 lung cancers, 181,000
         breast cancers, 156,000 colon cancers, 190,000 prostate cancers, etc.

     Majority arise in young people. A frequent location is around the knee (a rapid bone growth

II. Metastatic bone tumors.

     Far more common than primary bone malignancies (seen in about 15% of cancer cases
        clinically and 30% at autopsy).

     Most are adenocarcinomas: prostate, breast, kidney, thyroid, lung are the most common
        primaries—acronym of ―PB KTL‖ (lead kettle).

     Usually seen in persons over age 40, though thyroid may occur in 3rd decade, and lung and
        kidney are not uncommon in 4th decade.

     Most common metastatic sites are axial skeleton (spine, pelvis) and proximal femur;
        metastases distal to elbow or knee are rare.

III. Multiple myeloma--a neoplastic proliferation of plasma cells in bone marrow produces bone
     destruction; this was discussed in the hematology organ system along with lymphomas and
     leukemias. Myelomas are the most common neoplasm in bone. These tumors often produce
     discrete ―punched out‖ lytic lesions, but can also cause indistinct lytic lesions. Vertebrae,
     ribs, skull, and pelvis are the most common sites, but long bone lesions also must be looked
     for to avoid pathologic fractures.

IV. The radiographic appearance of a bone lesion is extremely important in diagnosis
    and must be correlated with the pathology. Bone lesions often have both a characteristic
    location and characteristic radiographic appearance. Examining the histology without
    radiographic correlation can result in a mistaken diagnosis.

                                   Benign Primary Bone Tumors
I.   Osteoid osteoma--‖oma‖ (tumor) of the ―osteo‖ (bone) producing ―osteoid‖ (bone-like

     Seen in first two decades, male predominance (3:1); diaphyseal &
        metaphyseal location.

     Painful, waking from sleep at night, responsive to aspirin.

     Pathologic appearance is that of a central nidus of irregular                well
        vascularized osteoid surrounded by a shell of sclerotic                bone;
        rarely more than 1.5 cm size.

     When located near a joint may produce arthritic symptoms.

     It is important to extirpate the nidus to stop the pain.

     Osteoblastoma is a similar looking lesion pathologically,                     but
         is much larger and more aggressive in radiographic
         appearance, resembling osteosarcoma.

     To right: resected osteoid osteoma, with dark nidus at right side.

     Above right: osteoid osteoma of distal femur.

II. Osteochondroma (exostosis).

   Not a true neoplasm, but a projection of the
      cartilaginous growth plate.

   Most are solitary, on long bones (primarily                                           femur)
      and composed of a bony stalk
      capped by cartilage.

   If multiple, may be part of an hereditary
       condition termed osteochondromatosis.

   Rarely may develop chondrosarcoma in                                                       a
      persistent cartilaginous cap.

   Top right: Osteochondroma of proximal femur.
       Lower right: Osteochondroma with cartilage
       cap at top. Below: Histology of osteochondroma
       with osteocartilaginous growth plate.

III. Enchondroma—tumor of cartilage in (―en‖) bone.

   Proliferation of mature hyaline cartilage within bone medullary cavity.

   Usually solitary, but may be multiple within small bones of hands and feet.

   If multiple, may be part of a hereditary condition (enchondromatosis or Ollier’s disease) with
       multiple cartilaginous tumors in a single extremity.

   Does not expand or erode the bone or cause pain (such features suggest malignancy in
      cartilage tumor).

IV. Giant cell tumor (―osteoclastoma‖).

   Benign but locally aggressive, tending to recur; rarely metastasizes; treated with surgical
      curettage and sclerosis of residual cavity; radiation may induce malignant
      transformation; most often seen between ages of 20 and 40.

   Arise in the epiphysis of long bones with a ―soap bubble‖ radiographic
       appearance, extending ―to the end of the bone‖ (right down to joint).

   Histologically are composed of giant cells with stroma in which the stromal
       nuclei look like the giant cell nuclei; many nuclei in giant cells (50-100).

   Differential diagnosis includes aneurysmal bone cyst, which can appear
       very similar histologically but is more of a hemorrhagic cyst surrounded
       by an ―eggshell‖ of periosteal new bone; aneurysmal bone cysts occur in
       the metaphysis, most often in vertebrae, and occur in first two decades.
       Above right: Giant cell tumor, a lytic lesion of the tibial epiphysis, extends
       to the joint. Below right: gross of that lesion. Below: Giant cell tumor,
       with abundant giant
       cells with nuclei like
       the stroma cell

V. Aneurysmal bone cyst (ABC).

   Deforms the bone in aneurysmal fashion; metaphyseal location.

   Produces pain and/or swelling clinically. Can fracture.

   May occur on top of another bone tumor.

   Histologically consists of hemorrhagic cysts with
       giant cells & cellular fibroblastic tissue with
       surrounding ―eggshell‖ of new woven bone.

   Most frequent in first two decades.

   To right: radiograph and gross of aneurysmal bone cyst.

VI. Fibrous dysplasia.

   Abnormal persistence of fibrous tissue in bone; bone arises in it by ―metaplasia‖;
      occasionally may have cartilage within it.

   Commonly in skull, ribs, jaws, neck of femur; usually 2nd & 3rd decades.

   X-ray shows a hazy ground glass-like quality.

   May thin the bone cortex with bowing (―shepherd’s crook‖ deformity) and fracture.

   Usually is asymptomatic incidental finding on X-ray.

   Histologically consists of misshapen bone trabeculae (like Chinese characters) arising
       directly out of fibrous tissue without osteoblastic rimming.

                               Malignant Primary Bone Tumors
VII. Osteosarcoma.

   Most common primary malignant bone tumor; arise
      in the metaphysis of long bones (most often knee
      area); most often males; most often in teenagers
      and young adults when primary (later in life if
      due to a disease such as Paget’s); increased risk
      in persons with retinoblastoma gene.

   Histologically, the hallmark is formation of osteoid                                 (bone-
       like matrix) by spindle-shape malignant cells.

   Very aggressive and causes bone destruction with                                      pain;
      often high-grade histology and can spread                                          locally
      or metastasize to lungs.

   Treated with wide resection and chemotherapy.

   Several different types depending on main mesen-
      chymal tissue type (osteoblastic, fibroblastic,
      chondroblastic, telangiectatic).

   Above right: Osteosarcoma radiographs, showing mineralizing tumor that
      extends out of distal femur. Below right: resected tumor. Below:
      malignant spindled cells forming stroma and bone-like material.

VIII.   Chondrosarcoma.

    The second most common primary malignant bone
       tumor; tends to arise in central skeleton (trunk,
       proximal humerus, proximal femur); cartilaginous
       tumors of small bones of hands and feet are almost
       always benign.

    Appear in a broad age range including older adults;
       some arise in conjunction with enchondromatosis
       or osteochondromatosis.

    Tend to be lower grade, less aggressive, slower                      growing
       neoplasms that may recur locally but are                         less likely to

    Expand bone, erode cortex, and produce pain.

    Above right: low grade chondrosarcoma of proximal
       femur. The tumor expands the bone, has a typical
       pattern of calcification, and erodes the
       cortex. To right: Intermediate grade
       chondrosarcoma, a cellular tumor with
       cartilage and spindled cells.

IX. Ewing‘s sarcoma.

    Appears in children and teenagers; arises                                     in
       the diaphysis of long bones.

    Histologically a ―small round blue                                           cell

    Very aggressive and destructive, with                                    local
       pain and fever.

    Treated with combination chemotherapy,                                  surgery,
       and radiation.

    May arise in soft tissue.

    To right: Radiograph of Ewing’s sarcoma showing ill-defined lytic
defect and periosteal thickening. The tumor cells are round, have              round
nuclei, and invade skeletal muscle.

PATHOLOGY 6020, Year 2005

    Steven S. Chin, M.D., Ph.D.
    November 17, 2005; Thursday 11-12 am

DISEASE, 7th edition, pp. 1325-1346.

   1. To provide an overview of the common pathologic changes seen in peripheral
      neuropathies and myopathies

   2. To describe the pathologic features of myelinopathies and axonopathies

   3. To distinguish the pathologic features of neurogenic and myopathic disorders of
      skeletal muscle

   4. To discuss the pathologic features of Duchenne muscular dystrophy,
      polymyositis, and mitochondrial myopathies

    Neuromuscular diseases are caused by dysfunction of motor nerve cells, peripheral
nerve and skeletal muscle. Weakness is the chief symptom, but peripheral neuropathies
can also produce sensory and autonomic symptoms with or without motor dysfunction.

     The Motor Unit
     Motor units consist of two major functional types, one composed of fast-twitch
muscle fibers and the other slow-twitch fibers. The two different fiber types can be
distinguished and visualized in tissue sections by histochemical stains. The
histochemical stain for myosin ATPase is the standard method for evaluating fiber
types in human neuromuscular disease. Type 1 fibers are pale in the ATPase reaction
(performed at pH 9.4), rich in mitochondria and dependent on oxidative
phosphorylation as a chief source of energy. The fibers contract slowly and resist
fatigue with repetitive contractions. Their major functions are maintenance of posture
and prolonged, low-intensity motor activity as in jogging. Type 2 fibers are dark with the
ATPase reaction (performed at pH 9.4) and poor in mitochondria, and they use chiefly
anaerobic glycolysis for generating energy. These fibers are used during vigorous
motor activity such as sprinting or lifting heavy weights with maximal exertion. They
contract quickly and fatique more rapidly than type 1 fibers. In contrast to some
mammalian species, each human muscle is composed of both fiber types, intermingled
in a mosaic pattern in transverse sections stained for ATPase. The muscle fibers of a
single motor unit are not grouped together but normally are widely distributed over a
large area of muscle. All of the fibers of the unit have the same histochemical type, an
expression of the capacity of motor neurons to determine muscle fiber type.

     The peripheral nervous system and skeletal muscle has substantial capacity
to regenerate axons, Schwann cells and muscle fibers in response to injury. Two
different forms of regeneration occur in the axons: 1) The well-known regenerative
response of axons proximal to the site of axotomy. 2) Sprouting of terminal axons of
intact motor units, a process that can be induced locally by denervation of neighboring
muscle fibers, a phenomenon known as collateral reinnervation. Schwann cells and
muscle satellite cells act as the cellular basis of regeneration of myelin sheaths and
muscle fibers.

     Classification of Neuromuscular Diseases
     Classification of neuromuscular disorders is based largely on which populations of
cells are affected morphologically and clinically. Neuromuscular disorders have been
separated into five general categories: myelinopathies, neuronopathies, axonopathies,
disorders of neuromuscular transmission, and myopathies. The disorders discussed in
this lecture have been selected to illustrate basic pathologic principles of disease in
three of these categories. Disorders of neuronopathies and neuromuscular
transmission, myasthenic syndromes, will not be discussed.

      Neuropathies are disorders that primarily affect the PNS, which include all neural
processes, nerve cells, and their supporting elements that lie outside the entry and exit
zones of the spinal and cranial nerve roots. The Schwann cells and their ganglionic
counterparts, the satellite cells, further distinguish it from the central nervous system.
Hence, the first and second cranial nerves are excluded, as they are extensions of the
brain and are composed of cells of central neural origin. Using this narrow definition, the
peripheral neuropathies do not include diseases of the motor neurons (for example
ALS). The distinction between motor neuron diseases and peripheral neuropathies is
artificial, however, and overlap exists in the functional and structural features of both
classes. For this reason, some investigators consider ALS and other motor neuron
diseases as forms of neuropathy.

    Symptoms and signs of peripheral neuropathy often begin distally in the extremities
and later involve proximal regions of limbs if the disease progresses. The cause of the
distal distribution is not understood in detail, but there is presumably more than one
mechanism. If multifocal lesions of nerves are random, then the longer nerve fibers,
which serve the distal regions of limbs, have a greater probability of being affected than
shorter fibers. Examples include the axonopathy of vasculitic neuropathy and the
myelinopathy of Guillain-Barré syndrome. In distal axonopathies (dying back
neuropathy), interference with axonoplasmic flow may account for the greater
dysfunction of the longest nerve fibers. This pattern of degeneration typifies many toxic,
metabolic and genetic disorders of the PNS.

    Acute Inflammatory Polyneuropathy (Guillain-Barré Syndrome)

     Acute inflammatory polyneuropathy (AIP) is an acute or subacute monophasic
illness characterized by multiple foci of segmental demyelination (a myelinopathy) and
mononuclear inflammatory cells in the peripheral nervous system. AIP is believed to
be an autoimmune disorder of myelin, often triggered by an acute respiratory or
gastrointestinal infection, but the pathogenesis of nerve fiber injury is not well

     Clinical features: AIP is the most common acute or subacute neuropathy (0.6-1.9
cases/100,000 population worldwide). It occurs in people of all ages but is most
common after the fourth decade. Two-thirds of patients suffer an acute infectious
illness, often with influenza-like symptoms or diarrhea, one to six weeks prior to the
onset of AIP. Most of these infections are caused by viruses (CMV, EBV, etc.) and
Campylobacter jejuni, a bacteria that causes diarrhea. Other illnesses, surgery, and
pregnancy can also precede the neuropathy. Most cases are sporadic, but several
epidemics of AIP have occurred. A widely publicized epidemic of Guillain-Barre
syndrome developed in the United States in 1976 as a result of widespread vaccination
with swine influenza virus. No association with specific HLA haplotypes has been
reported in most studies.

    AIP usually begins with weakness in the lower extremities and then spreads over
hours and days to involve symmetrically the arms, axial musculature, face, and
occasionally, the extraocular and pharyngeal muscles. Sensory and autonomic
manifestations are less prominent as a rule. Electrophysiological studies of the PNS
usually demonstrate slow motor conduction velocity and conduction block of the
nerve action potentials. Clinical recovery usually begins two to four weeks after onset of
symptoms and continues over the ensuing weeks or months. Patients respond to
treatment by plasmapheresis or intravenous gamma immunoglobulin. About 5% of
patients die of their disease and another 5% are permanently handicapped. A smaller
percentage develops a chronic or relapsing form of the illness.

    Pathology: The chief histopathological feature of AIP is the presence in peripheral
nerves of foci of perivenular infiltration with lymphocytes and monocytes associated with
segmental demyelination of nerve fibers. Remyelination occurs later as the patient
recovers. Immune complexes composed of IgM and C3 have been observed at the
margin of myelin sheaths during the early stage of the disease.

     Axons are typically spared, but a variable degree of Wallerian degeneration of nerve
fibers may occur in some cases. The cause of this axonal degeneration is not known. In
some instances, it may be a secondary or bystander effect of the inflammatory
response. The loss of axons is thought to be responsible for the permanent weakness in
5% of patients who have Guillian-Barre syndrome.

     The earliest pathological event is the migration of lymphocytes across the walls of
venules into the endoneurium, where they transform into ―activated‖ lymphocytes and
attract blood-borne monocytes. The monocytes, rather than lymphocytes, attack the
myelin sheaths based on electron microscopic examination. The myelin sheath is
stripped away and the myelin fragments are phagocytosed by the monocytes, acquiring
the morphological features of macrophages. After about one week, the Schwann cells
begin to form new myelin sheaths along the denuded segments. The new myelin
internodes are generally shorter and thinner than those they replace. The conduction of
action potentials in these nerve fibers is slower than normal but is not associated with
detectable weakness. Weakness correlates with conduction block and axonal
degeneration in this disorder.

    Below left: routine light microscopic section of nerve in AIP, showing a lymphocyte
and monocyte infiltrate. Below right top: a plastic embedded section showing, in the
center, a large, thinly myelinated axon. This indicates that there has been demyelination
then remyelination. Below right bottom: electron micrograph showing a macrophage
invading and destroying the axonal sheath.

    Recently, a rare axonal form of Guillain-Barré syndrome has been defined by
pathological studies of the PNS. Peripheral nerves in these cases show axonal
degeneration with little or no pathological signs of segmental demyelination. Deposits of
C3 and IgG have been observed at the nodes of Ranvier in the initial phase of this
disease. The macrophages first appear in the periaxonal space between the axon and
the myelin sheath, and later contain cellular debris as the axons and myelin sheaths
begin to degenerate.

    Pathogenesis: The pathogenesis of AIP is not understood in detail, but an
autoimmune response to myelin is thought to be important because:
   1. A clinically and pathologically similar disease known as experimental allergic
      neuritis (EAN) can be induced by inoculation of animals with a homogenate of
      peripheral nerve myelin or purified myelin glycoproteins (P0, P2, or PMP22) and
      Freund’s adjuvant.

  2. Circulating autoantibodies to myelin are found in patients during the active stage
     of disease. A minority of the patients have antibodies that recognize specific
     glycoproteins (P0, P2 or PMP22) or gangliosides (GM1) that are expressed in
     myelin of peripheral nerve. GM1 ganglioside is also expressed in the axolemma,
     and high titers of anti-GM1 or GD1a antibodies have been found in the axonal
     variant of Guillain-Barré syndrome.

  3. The chemical structure of a carbohydrate group in lipopolysaccharide of
     Campylobacter jejuni closely resembles the oligosaccharide chains of GM1
     ganglioside. This molecular mimicry suggests that the immune response to the
     bacterium could potentially produce pathogenic antibodies that crossreact and
     attack carbohydrate epitopes of GM1, other glycolipids and glycoproteins of

  4. Patients respond to plasmapheresis or intravenous gamma globulin when
     treatment is started early in the course of the illness.

     Chronic Inflammatory Demyelinating Polyneuropathy (CIDP; Chronic Guillain-
Barré Syndrome)
     Chronic inflammatory demyelinating polyneuropathy (CIDP) resembles AIP, but
differs in several respects:

  1. The clinical course of CIDP is multiphasic (relapsing, or stepwise) or slowly

  2. A recognized antecedent viral illness is uncommon in CIDP.

  3. An association of CIDP with HLA haplotypes (A1, B8, DRw3, and Dw3) has been

  4. Hypertrophic changes (―onion bulbs‖) may be present in peripheral nerves in

  5. The disorder responds to plasmapheresis and intravenous gamma globulin, but
     treatment with glucocorticoids is often recommended for long-term treatment
     because it is less expensive.

     In CIDP, the peripheral nerve shows segmental demyelination, segmental
remyelination, and a characteristic structure known as an ‗onion bulb‘. This structure
consists of a remyelinated segment of a
nerve fiber surrounded by one or more
concentric layers of redundant Schwann
cell processes, when viewed in transverse
section. Onion bulbs are produced by
repeated cycles of segmental demyelin-
ation and remyelination occurring over a
period of months or years. Inflammatory
cells are often sparse or absent in CIDP

    To right: ―Onion bulbs‖ in a plastic
section, in a case of CIDP.

     Charcot-Marie-Tooth Disease (Hereditary Motor and Sensory Neuropathy)
     Charcot-Marie-Tooth disease (CMT) is the most common hereditary neuropathy, a
clinically and genetically heterogenous disorder. The characteristic clinical features
include a childhood onset of weakness in distal leg muscles, very slow progression,
atrophy of leg muscles (stork leg or inverted champagne bottle appearance) and foot
deformity (pes cavus and hammer toes). The most frequent type of CMT I (HMSN I)
consists of palpably enlarged nerves (hypertophic neuropathy), slowed nerve
conduction velocity and pathological features of a chronic myelinopathy including
prominent onion bulbs. This disorder is usually inherited in an autosomal dominant
pattern. Mutations of three genes have been identified and linked to the syndrome to
date. The most commonly affected gene encodes a protein expressed in peripheral
myelin, known as PMP22.


    Wallerian degeneration

    If a nerve trunk is severed, conduction of an action potential distal to the site of
transaction fails in three to four days and both axons and myelin sheaths degenerate.
During the first hour after transaction, terminal loops of myelin retract causing the nodal
gap to widen (paranodal demyelination). By two or three days, myelin sheaths and
corresponding axons begin to separate into trains of myelin ovoids (myelin debris).
Macrophages appear in large numbers derived largely from blood-borne monocytes.
By the fourth day, Schwann cells begin to proliferate and line up within the tube formed
by the basal lamina remnant of the degenerating nerve fiber. These longitudinal arrays
of Schwann cells are known as the bands of Bungner. Myelin debris is slowly removed
and, if regeneration is prevented, bands of Bungner are eventually replaced by
connective tissue.

    Within hours, axonal sprouts appear at the cut end of the proximal stump. If these
regenerating axons reach the bands of Bungner, they then grow at an average rate of 1-
2 mm per day within the old basal lamina sheath. Axonal contact with the proliferated
Schwann cells inhibits further mitotic activity and induces the cells to form a series of
new myelin internodes, which are shorter and thinner than normal internodes. More
than one axonal sprout grows down a single band of Bungner, eventually producing a
regenerative cluster of thinly myelinated fibers within the original basal lamina.

    In comparison with remyelination, axonal regeneration is slow and often incomplete.
The extent of functional recovery depends on the age of the individual and the degree to
which the transected ends are approximated. The more distal the site of transection, the
better the functional outcome.

    During the first few days after transaction of a motor axon, the body of the nerve cell
begins to undergo axonal reaction or central chromatolysis. The cell swells, contours
become rounded, the nucleus migrates to the periphery, and Nissl substance becomes
dispersed centrally leaving a peripheral rim of Nissl granules. The changes reach a
maximum at two to three weeks after transaction and persist until regeneration is
complete. If regeneration of axons is prevented, the cell body of the motor neuron will
eventually disappear after months or years.

     Below left: Wallerian degeneration, H&E stain. Below right: Wallerian degeneration
in a plastic section, showing regenerative clusters – small clusters of newly formed
axons replacing a transected axon.

    Distal axonopathies
    Exogenous toxins, metabolic dysfunction and certain hereditary disorders cause
distal axonopathies most commonly. The onset of sensory dysfunction and weakness
begins distally and progresses slowly. If toxic exposure or metabolic disorder can be
recognized early and eliminated, progression can be reversed with gradual, often
complete recovery.

    The pathologic changes consist of degeneration of the distal portion of an axon. The
degeneration appears in teased myelinated fibers as a linear train of myelin ovoids,
indistinguishable from Wallerian degeneration. The proximal surviving part of the axon
often develops segmental demyelination and remyelination. The effect on the myelin
sheath is presumably secondary to the abnormality of the axon. Exposure to acrylamide
and hexacarbon solvents (n-hexane, methyl n-butyl ketone) produces a distal
axonopathy associated with accumulation of neurofilaments in axons of large
myelinated nerve fibers. Similar pathological findings occur in the CNS.

    How toxins cause neuropathy is not known, but abnormalities of axon transport may
cause preferential degeneration of the distal part of long or large diameter axons.
Degeneration advances proximally (dying back phenomenon) until exposure to the toxic
substance is eliminated and the axon is allowed to regenerate. If toxins affect the
central nervous system as well, neurological deficits may persist after toxic exposure is
eliminated, because of the limited capacity of the CNS to regenerate.


    Special stains used to evaluate muscle biopsies

   H&E – this stain differentiates nuclei and is helpful for the recognition of
degenerating and regenerating fibers.

    Modified Gomori’s trichrome – this stain will differentiate collagen and will also stain
clumps of mitochondria within the muscle cells.

     NADH-TR – this stain localizes oxidative enzymes within myofibers and reveals
internal architectural changes. This and the ATPase require frozen sections – muscle
biopsies must not be just put in formalin.

     ATPase pH 9.4 – this stain differentiates type 1 and type 2 myofibers. The type 1
fibers stain light tan and the type 2 fibers stain dark brown.

     Neurogenic Disorders of Muscle
     Weakness and wasting of muscles are characteristic signs of motor neuron
diseases and motor neuropathies, but the clinical features cannot be distinguished
reliably from the weakness that occurs in primary disease of muscle (myopathy).
However, the pathologic findings in muscle in lower motor neuron disease are so
distinctive that they can be used for diagnosis in muscle biopsies. The cardinal features
of a neurogenic disorder include groups of atrophic muscle fibers (group atrophy),
groups of fibers of the same histochemical type (fiber type grouping), and target
fibers. These pathologic alterations are found in diseases that evolve over a period of
weeks or longer. In most of these diseases, motor neurons and motor axons are not
affected simultaneously but some degenerate while others are spared. By comparison,

interruption of all motor nerve fibers to a muscle, a common maneuver in experimental
studies, causes atrophy of all fibers. In this case, the mosaic pattern of type 1 and type
2 fibers in ATPase stains are retained for weeks in the denervated state when
regeneration of nerve is prevented.

     Fiber type grouping and group atrophy of muscle
fibers are believed to occur as a result of collateral
reinnervation. By gradual remodeling of the motor unit,
a single neuron can innervate many contiguous muscle
fibers. Because the nerve supply determines the
histochemical type of a muscle fiber, remodeling of
motor units eventually yields fiber type grouping. If
subsequently, the axon of such an altered motor unit
undergoes degeneration, then the corresponding
muscle fibers will undergo atrophy as a group.

     Top left: normal innervation of muscle.
     Top right: early denervation.
     Bottom left: reinnervation with fiber type grouping, a
finding that indicates neurogenic injury.
     Bottom right: with continued denervation, there is
group atrophy of the muscle fibers, also indicating                            neurogenic

    To right: fiber type groups indicating chronic
neurogenic disease. In normals, the dark and pale fibers
are mixed together instead of in clumps. ATPase stain

    Below: grouped atrophy, H&E stain.

    The myopathies are disorders that exhibit muscle dysfunction without evidence of
denervation. The cause of the disease may reside in the muscle fibers themselves, as
in most inherited myopathies, or it may be intrinsic to muscle, as in the myopathies
caused by various endocrine diseases. The muscle biopsy may show a selective
atrophy of type 2 muscle fibers as the only abnormality in Cushing’s syndrome,
hyperparathyroidism and other disorders with muscle weakness. A large group of
myopathies are characterized by necrotic fibers and regenerating fibers, and these
abnormalities are attended by fibrosis of the endomysium when the disorder is chronic.

    Duchenne Muscular Dystrophy

    Clinical features: Duchenne muscular dystrophy (DMD) is an X-linked, recessive
disorder and the most common inherited myopathy of children. The affected gene
in Duchenne dystrophy encodes a 427-kD protein known as dystrophin. The disease
begins with progressive weakness of proximal limb muscles early in childhood. Mild
enlargement of calf muscle is usually observed. Patients become confined to a
wheelchair by age 12, and they usually die by the middle of the third decade as
respiratory muscles become progressively involved. Serum activity of creatine kinase
is markedly elevated, even during infancy before the onset of clinical symptoms. A
milder variant of the disease, known as Becker muscular dystrophy, is an allelic form of

     Pathology: Muscle biopsy shows
necrotic muscle fibers, groups of
regenerating fibers, and hypercontracted
(hyaline) fibers. As the disease
progresses, there is excessive variation
in muscle fiber size and increased
fibrous connective tissue and adipose
tissue. These non-muscle tissues can
eventually replace all of the muscle
fibers at the end-stage of disease. To right:
H&E stain of DMD. Notice the variation in
fiber size, fibrosis, and early fatty replacement. Below left: dystrophin stain in DMD,
which is negative. Below right: dystrophin stain in normal control. Note that the fibers
have peripheral dark (or brown) staining that is absent in DMD.

    Pathogenesis: Dystrophin protein is located chiefly at the surface membrane of
muscle fibers. It is thought to link actin with the surface membrane and the extracellular
matrix by binding and acting through a membrane complex of dystrophin-associated
glycoprotein and proteins. Dystrophin is absent or barely detectable in muscle fibers of
DMD patients, presumably interrupting the linkage of the cytoskeletal proteins to
extracellular proteins. This idea is supported by mutations of genes that encode certain
dystrophin-associated proteins, which produce a phenotype that can resemble
Duchenne dystrophy or Becker dystrophy.

    Serum levels of creatine kinase and other enzymes of muscle seem unusually high
in Duchenne dystrophy in comparison to a rather low proportion of muscle fibers that
have necrosis. This observation suggested that the function of the surface membrane is
abnormally leaky. The membrane abnormality is thought to cause muscle cell
dysfunction and death of muscle fibers, probably triggered by influx of extracellular
calcium into the sarcoplasm.


    Clinical features: Polymyositis is a common acquired myopathy in adults.
Weakness affects proximal limb muscles more than distal muscle, and it progresses
slowly for several weeks or months. Some of the patients have muscle aches. Serum
creatine kinase activity is usually moderately elevated. A characteristic electromyogram
helps to confirm the diagnosis. Most patients are treated with steroids or some other
immunosuppressive agent and about 70% improve or recover. Mortality rate varies
widely in different studies but is about 30% in those reported recently.

     Pathology: Characteristic findings in the
muscle biopsy include scattered necrotic fibers,
regenerating fibers, and mononuclear
inflammatory cells, chiefly lymphocytes. The
inflammatory cells are located around muscle
fibers and small blood vessels. Fibrosis occurs
between muscle fibers, becoming more prominent
when disease is chronic. Inflammatory cells are
absent in about one third of biopsies and the
muscle is normal in a few percent of them.
These atypical biopsies might be a consequence
of focal expression of pathologic changes in
polymyositis. They might also occur because the
syndrome is heterogeneous in etiology and include
cases that are not inflammatory.
     Above right: polymyositis, showing an endomysial chronic inflammatory infiltrate
and chronic myopathic changes.

     Pathogenesis: The etiology and cause of muscle fiber necrosis in this disorder are
not understood. Lymphocyte marker studies have indicated that most of the
mononuclear cells in the tissue are cytotoxic T-cells, and some of them invade muscle
fibers before they become frankly necrotic. This observation and the clinical response of
patients to immunosuppressive agents suggest that the disorder is autoimmune, as
postulated for other collagen vascular diseases.

    Mitochondrial diseases

     Inherited defects of mitochondrial metabolism are an uncommon but conceptually
important group of disorders. Historically, mitochondrial diseases of muscle were
recognized first and designated as mitochondrial myopathies, but others affect the
CNS as well as muscle and are known as the mitochondrial encephalomyopathies.
The nervous system, skeletal muscle, heart, kidney and other organs can be affected in
different combinations as part of a multisystem disease.

    Nuclear DNA (nDNA) encodes most mitochondrial proteins, but mitochondrial
DNA (mtDNA) specifies 13 of the 80 or so polypeptide subunits of the electron transport
chain. The inherited diseases of mitochondria can be classified genetically into two
broad groups, defects of nDNA and defects of mtDNA. Point mutations, deletions and
duplications of mtDNA have been identified and linked to several syndromes of the
mitochondrial encephalomyopathies.

      The diseases of mtDNA defects have a maternal pattern of inheritance in contrast
to the Mendelian pattern of nDNA mutations. All of the mtDNA of the zygote are derived
from the oocyte. Each cell has many mitochondria, and each mitochondrion contains
several copies of the mitochondrial genome. If some copies of the mtDNA of a zygote
have a mutation, they are passed on randomly to subsequent generations of cells. At
birth or later, it is probable that some cells would contain only mutant genomes (mutant
homoplasmy) and others would have only normal genomes (wild-type homoplasmy).
Still others would receive a mixed population of mutant and normal mtDNA
(heteroplasmy). If the mutation is deleterious and impairs oxidative phosphorylation,
then clinical expression will depend on the balance of normal and mutated genomes in
each cell.

     The pathological signature of a mtDNA mutation is accumulation of
mitochondria in muscle fibers. The excessive organelles are expressed as aggregates
of reddish granular material in the sarcoplasm demonstrable by the modified Gomori
trichrome stain. The abnormality is termed a ragged red fiber because of the irregular
contour of the reddish deposits at the fiber periphery. Deletions and point mutations of
mtDNA in these diseases often impair the activity of complex IV (cytochrome c
oxidase or COX), a multiunit protein that is encoded in part by mtDNA. Histochemical
stains for ragged red fibers are often deficient for COX activity. By contrast, the ragged
red fibers stain intensely for succinate dehydrogenase (SDH, complex II), a complex
that is exclusively encoded by nDNA. The increased activity of SDH reflects the

proliferation of mitochondria, which is one of the many proteins that are synthesized in
the cytoplasm and imported into the mitochondrion. The impairment of oxidative
phosphorylation causes dysfunction of myofibers. Death of nerve cells and astrocytosis
occurs in the CNS.

    There is a bewildering variety of syndromes associated with mitochondrial disorders
and clinical phenotypes include myopathy, encephalomyopathy, neuropathy,
cardiomyopathy, stroke-like disease, deafness, renal disease, anemia, liver disease.
Limb weakness, exercise intolerance, and fatigue are common complaints of patients
with mitochondrial myopathies.

    Below left: modified trichrome stain showing dark, mitochondria-rich ragged red fibers.
    Below upper right: SDH stain, showing increased (dark) staining of the abnormal fibers.
    Below lower right: COX stain showing abnormal very pale fibers lacking that enzyme.

Access labs at:

                       Musculoskeletal Pathology Cases

Musculoskeletal Pathology Cases

Laboratory I Thursday November 17, 2005 1:00-3:00pm

Laboratory II Tuesday November 22 2005 1:00-2:00pm

    About the cases:
    These cases were developed for the Musculoskeletal Organ System Course by Dr. Juliana
    Szakacs and Yasuko Erickson, MSIV in the Department of Pathology at the University of
    Utah for use in the Pathology laboratory. Olympus and RadWeb are the electronic record
    systems of the University Hospital and are restricted to physicians and care givers with
    passwords. Please respect the privacy and confidentiality of patients at all times following
    HIPPA guidelines. The cases published on this web-site contain no personal identifiers.

    Instructions for Medical Students:
    1. The initial cases will guide you through the use of the electronic medical record and
    reference sources at the Medical Library.
    2. Computer access will be available in the lab and in the library. If you have your own
    laptop and wireless card you can bring them to the lab.
    3. Go through part by part of each of the assigned Cases and review the gross materials at
    your lab station during the first lab period. Discussion of each of the questions in small
    group format is encouraged.
    4. Groups of students will be assigned one case to present at the next lab meeting.
    During the week between the first and second lab sessions review the comprehensive case
    materials linked to the last part of the case, complete your research on the disease entity
    being presented in the case, and answer the questions in the last part of the case. Prepare
    a 5 minute oral presentation as you would for attending rounds. This includes a brief
    summary of the chief complaint, pertinent history, labs, X-rays and hospital course; pay
    close attention to how the diagnosis was made and the outcome. Be sure to reference the
    data you give in answering the questions of the last part of the case.
    5. A written copy of your presentation with the answers to the questions at the end of the
    case must be turned in to your facilitator during the second lab; your report will be
    graded. If you worked with other students in the class on one case, you may turn in one
    report with all the names and you will each receive the same grade.

    Goals and Objectives:

    Following the participation in lab sessions one and two the student will be able to:
    1. Use the electronic medical record and or computer to gather data on patients
    2. Use the library electronic reference system to research data on diseases, therapies and
    3. Understand the basic pathology, presentation, and treatment of bone disorders including:

   a. Osteomyelitis
   b. Osteonecrosis
   c. Osteosarcoma
   d. Fractures
   e. Metastatic disease
   f. Multiple Myeloma
   g. Osteochondroma
   h. Chondrosarcoma
   i. Osteoporosis

4. Understand the basic pathology, presentation, and treatment of muscle disorders
   a. Rhabdomyosarcoma
   b. Rhabdomyolysis

5. Compile data on a patient and present it in the form of a Clinical Pathological Correlation.

                                                  Case Notes
Case 1

Part 1

1. What is your initial differential diagnosis?

Part 2

1. What is your differential diagnosis for his sudden generalized weakness?

Part 3

1. Why does the nuclear medicine scan "light-up" in the right pelvic region?

2. Have the lab data helped to narrow the diagnosis

Part 4

1. What is your diagnosis?

Part 5

Using all of the information you have gathered from the chart, prepare a presentation about this
case as you would for attending rounds with a concise summary of the history, physical findings,
labs and x-rays. Your presentation should be about 5 minutes long. A copy of your presentation
needs to be handed in to your facilitator by the end of the lab on 11/22/04.

Incorporate the following into your report:

1. How was the necrotic bone diagnosed?

2. What is avascular- or osteonecrosis?

3. What is the treatment for osteonecrosis?

4. What are the most common infectious agents associated with osteomyelitis?

5. How do organisms reach the bone to infect it?

6. How is osteomyelitis diagnosed?

7. What is the outcome of osteomyelitis?

Case 3

Part 1

1. What concerns do you have for this patient?

Part 2

1. Where is the CPK coming from?

2. Why is the urine brown?

Part 3

1. What is the significance of the elevated white count?

2. Why would this woman have a hematocrit of >50%?

1. What is your diagnosis?

Part 4

1. Why did the white count fall?

2. What is the most likely route of colonization in this patient?

Part 5

Using all of the information you have gathered from the chart, prepare a presentation about this
case as you would for attending rounds with a concise summary of the history, physical findings,
labs and x-rays. Your presentation should be about 5 minutes long. A copy of your presentation
needs to be handed in to your facilitator by the end of the lab on 11/22/04.

Incorporate the following into your report:

1. What is rhabdomyolysis?

2. How is the diagnosis of rhabdomyolysis made?

3. What are the clinical symptoms of rhabdomyolysis?

4. How does rhabdomyolysis cause renal failure?

5. What does the pathologist see on a section of skeletal muscle from a patient with

6. What is the treatment of rhabdomyolysis?

7. What laboratories do you need to follow in a patient with rhabdomyolysis?

Case 4

Part 1

1. What are the causes of hypercalcemia?

2. What causes increased creatinine?

Part 2

1. What is your differential diagnosis?

2. What diagnostic test would you order?

3. How would you determine the extent of disease?

Part 3

1. What cells are present in the biopsy?

2. Do these lesions explain the patient’s pain?

3. What type of lesions are these by radiographic imaging?

4. Does this explain the hypercalcemia?

Part 4

1.What was the final cause of death

Part 5

Using all of the information you have gathered from the chart, prepare a presentation about this
case as you would for attending rounds with a concise summary of the history, physical findings,
labs and x-rays. Your presentation should be about 5 minutes long. A copy of your presentation
needs to be handed in to your facilitator by the end of the lab on 11/22/04.

Incorporate the following into your report:

1. What is multiple myeloma?

2. What is the incidence of multiple myeloma?

3. What is the genetic disorder in multiple myeloma?

4. What bones are most affected by multiple myeloma?

5. How is the diagnosis of multiple myeloma made?

6. What does an X-ray of multiple myeloma demonstrate?

7. What type of renal disease do patients with multiple myeloma get?

8. What is seen on electrophoresis in multiple myeloma patients?

9. What are the symptoms of multiple myeloma?

10. What is the prognosis for patients with multiple myeloma?

Case 5

Part 1

1. What is your differential diagnosis?

Part 2

1. What is your diagnosis?

Part 3

1. What is your diagnosis?

Part 4

1. What is enoxaparin and why was it important for him to get a dose before getting on the plane
to go home?

Part 5

Using all of the information you have gathered from the chart, prepare a presentation about this
case as you would for attending rounds with a concise summary of the history, physical findings,
labs and x-rays. Your presentation should be about 5 minutes long. A copy of your presentation
needs to be handed in to your facilitator by the end of the lab on 11/22/04.

Incorporate the following into your report:

1. What is a Pathologic Fracture?

2. How is the diagnosis of metastatic disease to the bone made?

3. What type of malignancies metastasize to the bone?

4. What is the difference between lytic and sclerotic metastases to bone?

5. What are the symptoms of metastatic bone disease?

6. How can the Oncologist follow his patient to determine if bone metastases are developing?

7. What is the treatment for bone metastases?

Case 6

Part 1

1. What is your differential diagnosis?

Part 2

1. What is your differential based on the X-ray?

Part 3

1. What is the diagnosis?

2. What is the difference between Chondrosarcoma and Osteochondroma?

3. What is this patient’s prognosis?

Part 4

1. Has the lesion been completely excised and is this important?

Part 5

Using all of the information you have gathered from the chart, prepare a presentation about this
case as you would for attending rounds with a concise summary of the history, physical findings,
labs and x-rays. Your presentation should be about 5 minutes long. A copy of your presentation
needs to be handed in to your facilitator by the end of the lab on 11/22/04.

Incorporate the following into your report:

1. What is an osteochondroma?

2. What type of patients get osteochondroma?

3. What is the heredity pattern of osteochondroma?

4. How does an osteochondroma form?

5. What is chondrosarcoma?

6. Where do chondrosarcomas arise?

7. What type of patient would develop a chondrosarcoma?

8. How would the clinician diagnose chondrosarcoma?

9. How is the pathologic diagnosis of chondrosarcoma made?

Case 7

Part 1

1. What is the differential diagnosis?

2. Why might the lesion have reopened after 1 month?

Part 2

1. What is your differential diagnosis for the knee mass now?

Part 3

1. What is your differential diagnosis?

Part 4

1. What is your diagnosis?

Part 5

Using all of the information you have gathered from the chart, prepare a presentation about this
case as you would for attending rounds with a concise summary of the history, physical findings,
labs and x-rays. Your presentation should be about 5 minutes long. A copy of your presentation
needs to be handed in to your facilitator by the end of the lab on 11/22/04.

Incorporate the following into your report:

1. What is the difference between sarcoma and carcinoma?

2. What is an osteosarcoma and why might the first biopsy have been confused with this

3. What is rhabdomyosarcoma?

4. What are the four main types of rhabdomyosarcoma?

5. How is the diagnosis of rhabdomyosarcoma made?

6. What genetic alterations are associated with rhabdomyosarcoma?

7. What is the treatment for rhabdomyosarcoma?

Case 8

Part 1

1. What is the differential diagnosis for joint pain in an 84 year old?

Part 2

1. Where are the fractures?

2. What do you notice about the bone density:

3. What is the cause of the bladder injury?

Part 3

1. What changes occurred in the lab data over the four days?

Part 4

1. What is your diagnosis and explanation of the cause of death?

2. Why do you think she was having respiratory distress?

Part 5

Using all of the information you have gathered from the chart, prepare a presentation about this
case as you would for attending rounds with a concise summary of the history, physical findings,
labs and x-rays. Your presentation should be about 5 minutes long. A copy of your presentation
needs to be handed in to your facilitator by the end of the lab on 11/22/04.

Incorporate the following into your report:

1. What is osteoporosis?

2. Who is at risk for developing osteoporosis?

3. What is the effect of estrogen on osteoporosis?

4. How is the diagnosis of osteoporosis made?

5. How can osteoporosis be prevented?

6. What are the complications of osteoporosis?

7. What is the treatment for osteoporosis?

8. What are the different types of fractures?

9. What happens to the bone when it fractures and how is it repaired?

10. What factors can impede healing of a fracture?

11. What is fat embolization and why is it associated with fractures?

Case 9

Part 1

1. What is dwarfism?

Part 2

1. What is the differential diagnosis for this infant?

2. What does the shape of the bones tell you?

Part 3

1. Review the sections of bone from this infant and compare them to normal fetal bone. What is
the pathophysiology of this abnormality?

Part 4

Using all of the information you have gathered from the chart, prepare a presentation about this
case as you would for attending rounds with a concise summary of the history, physical findings,
labs and x-rays. Your presentation should be about 5 minutes long. A copy of your presentation
needs to be handed in to your facilitator by the end of the lab on 11/22/04.

Incorporate the following into your report:

1. What are the findings in Thanatophoric dwarfism?

2. What is the differential diagnosis of dwarfism with non-shortening of the trunk and no
evidence of fractures?

3. What is achondroplasia?

4. What is Thanatophoric dysplasia?

5. What is Matatrophic dysplasia?

6. What is Opsismodysplasia?

7. How do you make the diagnosis of Thanatophoric dysplasia?

8. What is the underlying genetic defect in achondroplasia and Thanatophoric dysplasia?

9. How should the family be counseled for future pregnancies?

10. What abnormalities are seen on microscopic sections of bone in Thanatophoric dysplasia?

Case 10

Part 1

1. What is your differential for lower back pain in this woman?

2. Why might pain the pain have become worse after injection?

Part 2

1. What is your diagnosis?

Part 3

1. What was found on the MRI?

Part 4

1. What is the cause of death and how is this related to the rheumatoid arthritis?

2. Describe the changes of the bone.

3. Describe the rheumatoid nodule.

Part 5

Using all of the information you have gathered from the chart, prepare a presentation about this
case as you would for attending rounds with a concise summary of the history, physical findings,
labs and x-rays. Your presentation should be about 5 minutes long. A copy of your presentation
needs to be handed in to your facilitator by the end of the lab on 11/22/04.

Incorporate the following into your report:

1. What is the underlying cause of rheumatoid arthritis?

2. What is the difference between rheumatoid arthritis and degenerative joint disease?

3. What is the treatment for rheumatoid arthritis?

4. What is the treatment for degenerative joint disease?

5. What are the side effects of high dose steroid treatments?

6. What is the cause of death in this case?