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  1. Journal Reading2004-10-15 (1)myoepithelial tumor of soft tissue (2)neonatal intrahepatic cholestasis R3陳志榮

  2. Part I: myoepithelial tumors of soft tissue Myoepithelial tumors of soft tissue a clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters Jason L. Hornick MD,PhD and Christopher D. M. Fletcher MD,FRCPath Am J Surg Pathol.2003;27:1183-1196

  3. Myoepithelial tumors of Soft Tissue • Myoepitholiomas and mixed tumors of soft tissue were recently recognized • Few case numbers: (1)Kilpatrick SE,Hitchcock MG,Kraus MD et al. Am.J Surg Pathol. 1997;21:13-22=>19 cases (2)Michal M,Miettinen M,Virchows Arch.1999;434:393-400.=>12 cases

  4. Myoepithelial tumors of Soft Tissue • Myoepithelioma and mixed tumor(61 cases) =>tumor with benign cytomorphology or mild cytologic atypia(low grade) • Myoepithelial carcinoma and malignant mixed tumor(40 cases) =>moderate to severe atypia(high-grade)

  5. Clinical Findings • Male : female≒ 1:1(♂:53 cases;♀:48 cases ) • Age:3 ~83 years with a peak in 3rd to 5th decades (mean age:38 years) • Symptoms:painless or painful mass • Location:most common in limbs and limb girdle. • Subcuits and deep soft tissue

  6. Figure 1

  7. Table 2

  8. Macroscopic Features • Size: 0.7 to 20 cm (mean 4.7cm) • Well circumscribed mostly ,nodular or lobulated • Firm or hard • Yellow/white to tan • Glistening ,myxoid or gelatinous cut surface • Few with necrosis (2 cases)

  9. Microscopic Features • Well circumscribed or focal infiltration(43 cases) • Lobulated or mutinodular • Most frequently reticular growth pattern with intersecting cords of in variable amount of chondromyxoid(52 cases) or hyalinzed(14 cases) stroma. • Hypercellular and lacked significant stromal component(19 cases)

  10. Microscopic Features • Parachordoma :large epitheloid cells with eosinophilic to clear,variably vacuolated cytoblasm and abundant hyalined or chondromyxoid stroma.

  11. Microscopic Features • Tumor cells: epithelioid, spindled , plasmacytoid, parachordoma,clear cells or pleomorphic cells • Ductual differentiation(20%) • Metaplastic components: cartilaginous, osseous, squamous(six cases) or adipocytic(one case)

  12. Microscopic Features • Spindle cell myoepithelioma • Pure plasmacytoid cell: plasmastoid monomorphic adenoma or hyaline cell-rich chondroid syringoma • Pure epithelioid cells

  13. Myoepithelioma • Initailly,composed of spindled or plasmacytoid cells demonstrating a solid growth pattern • Variable matrix:myxoid or hyalinized stroma • Different architectural patterns:reticular, trabecular. • Epithelioid or clear cells • Ductal differentiation=>mixed tumor category • Ps 5~10% ductal differentiation in myoepithelioma

  14. Immunohistochemical Finding • Keratins and S-100 protein:nearly all are positivehalf • Calponin:nearly 86% (most sensitive myogenic marker) • GFAP:46% • SMA:36% • Desmin:14% • CK14:32%

  15. Myoepithelial tumors of Soft Tissue

  16. Treatment and Follow-up • Treatment:excision ; chemotherapy and postoperative radiotherapy • 64 patients were followed (1)Benign or low-grade cytology:33 cases =>Local recurrence(18%):6 cases =>Metastasis:none (2)Cytological malignant:31 cases =>Local recurrence(42%):13 cases =>Metastases(32%):10 cases =>Died of metastatic tumor:4 cases

  17. Criteria for myoepithelial carcinoma of soft tissue • Not yet to be well established. • Moderate or severe cytologic atypia which proved to be prognostically relevant. • Invasive growth pattern is insufficient unlike the salivary counterpart. =>microscopically infiltrative margins with no local recurrence or metastasis.

  18. Criteria for myoepithelial carcinoma of soft tissue • Benign or morphologically low grade soft tissue myoepitheliomas with 18% recurrence and none metastases • Conclusion: at least moderate cytologic atypia(prominent nucleoli,vesicular or coarse chromatin, pleomorphism) should warrant classification as myoepithelial carcinoma with significant risk for aggressive behavior and propensity for metastasis.

  19. Differential Diagnosis • Mixed tumor • Extraskeletal myxoid chondrosarcoma. • Ossifying fibromyxoid tumor. • Leiomyoma • Schwannoma • Metastatic carcinoma • Metastatic melanoma • Proximal-type epithelioid sarcoma

  20. Differential Diagnosis • Extraskeletal myxoid chondrosarcoma.: (1)Multinodular growth pattern with interlacing cords of spindled cells in myxoid or chondromyxoid stroma. (2)Lack intratumoral heterogeneity ,lack mixture of epitheloid and spindle cells (3)S-100 protein in minority (4)Epithelial and myogenic markers are rarely positive

  21. Differential Diagnosis • Ossifying fibromyxoid tumor (1)Lobulated proliferation of pale-staining ovoid to round cells in cords or nests in myxoid or hyalinized stroma with peripherical rim of metaplastic bone. (2)S-100 protein(+):70% (3)Desmin(+):50%=>myoepithlioma generally negative (4)GFAP:rare=>myoepithelioma nearly half positive

  22. Differential Diagnosis • Leiomyoma: (1)Broader cigar-shapped nuclei (2)Desmin:majority are positive =>myoepithelioma rarely positive (3)S-100 protein:less 5% positive (4)GFAP:negative (5)keratin:positive(40%)

  23. Differential Diagnosis • Schawannoma: (1)Alternating cellular zones with nuclear palisading and hypocellular myxoid zone with hyaline vessels. (2)S-100 protein and GFAP: positive (3)Lack epithelial and myogenic makers.

  24. Differential Diagnosis • Metastatic carcinoma: (1)Lack myxoid stroma and mutinodular architecture (2)Immunoreactivity of S-100 protein,GFAP and myogenic markers supports a diagnosis of myoepithlial carcinoma • Metastatic melanoma: (1)Myxoid storma is unusual (2)GFAP,keratin and myogenic markers exceptionally rare

  25. Differential Diagnosis • Proximal-type epithelioid sarcoma: (1)Morphologic uniformity and rhabdoid cytomorphology is common. (2)Positivity for EMA and keratins. (3)Negativity for S-100 protein, GFAP, myogenic markers.

  26. PartII:Neonatal Intrahepatic Cholestasis Neonatal intrahepatic cholestasis caused by citrin deficiency:severe hepatic dysfunction in an infant requiring liver transplanation ~Eur J Pediatr (2002) 161:609-613~

  27. NICCD • Neonatal intrahepatic cholestasis caused by citrin deficiency(NICCD) • Citrullinaemia: (1)classical (CTLN1):neonatal/infantile onset autosominal recessive (chromosome9q34) argininosuccinate synthetase deficiency (2)adult-onset type 2 (CTLN2) :late onset(11~79y/o) SLC25A13gene mutation (chromosome7q21.3) (3)NICCD: SLC25A13gene mutation

  28. NICCD (1) SLC25A13 gene: Calcium-binding mitochondrial protein,designated citrin (2)Citrin :aspartate glutamate carrier (3)malate-aspartate NADH shuttle,urea synthesis and gluconeogenesis


  30. Hepatomegaly ALT 

  31. Pathology study:normal =>mild fat accumulation, interface hepatitis,mild periportal fibrosis

  32. NICCD • 5 cases: (1)One case received liver transplantation at 10 months of age (2)Four cases:spontaneous improved by the ages of 5-7 months

  33. NICCD • About half of NICCD patients are detected on newborn mass screening ( galactose , phenylalanine, methionine) • Newborn neonatal screening for homozygote with SLC25A13 mutation: 1/10000~1/38000 in East Asia ~Effects of cirtirin deficiency in the perinatal period:fesibility of newborn mass screening for citrin deficiency Pediatr Res 56:608-614,2004

  34. NICCDCharacteristic clinical featrues (1)White colored or yellow-white colored stools (2)poor body weight gain until 1 month after birth (3)direct bilirubin,total bile acid,ALP,r-glutamyl transpepidase, (4)citrulline, tyrosine,methionine,threonine/serine ration, (5)branched-chain amino acid/aromatic amino acid ratio,

  35. NICCDCharacteristic clinical featrues (6) vitamin K-dependent coagulation factor (7)mild hyperammonemia (8) alpha-fetoprotein(not seen in CTLN2) (9)hypoglycameia

  36. NICCDhistological feature • Very rare report • Variable pathological features: =>minimal histological change,fatty change to cirrhosis and chronic hepatitis =>case 1(accept liver transplantation) diffuse fatty changes of hepatocytes, cholestasis in lobules with proliferation of bile ducts,portal to portal bridging fibrosis and pseudolobules.

  37. NICCDconclusion • SLC25A13 gene mutationcitrin deficiency hypercitrullinameia intrahepatic cholestasis in infancy • Often self-limiting and spontaneous disappear:maturation of hepatocytes and/or compensations of other mitochondrial carriers • Compensatory failure is likely to occurred with resultant relapse of the disease in adulthood(after 10 or more years)

  38. NICCDconclusion • Severe phenotype of NICCD may not be that rare ,therefore patients with NICCD should be followed up carefully,even during infancy.