My worst mistakes and what I have learned from them

Transcription

1 My worst mistakes and what I have learned from them Dina G. Tiniakos Dept of Pathology, Aretaieion Hospital, National & Kapodistrian University of Athens, Greece Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, UK

2 Enterprise Interest None

3 Institute of Medicine (USA) 2015 Diagnostic error is a major problem It is likely that most of us will experience at least one diagnostic error in our lifetime, sometimes with devastating consequences DIAGNOSTIC ERROR Failure to establish an accurate and timely explanation of the patient s health problem(s) or Failure to communicate that explanation to the patient

4 Pathologist s knowledge and experience Clinical correlation Accurate histological diagnosis Possible ancillary studies Standardised diagnostic language Case reviews Nakhleh RE, Arch Pathol Lab Med 2016

5 Laennec Liver Pathology Society Survey 2016 Which are the most important skills/attributes that helped you become a good pathologist? visual memory: the more you see the more you know good in dealing with uncertainty knowing limitations

6 Laennec Liver Pathology Society Survey 2016 Which are the most important skills/attributes that helped you become a good pathologist? visual memory: the more you see the more you know good in dealing with uncertainty knowing limitations admitting mistakes The diagnosis is not an extension of the Ego

7 ECP 2011 Helsinki

8 ECP 2011 Helsinki

9 ECP 2011 Helsinki

10 ECP 2011 Helsinki

11 Play it safe? Make huge mistakes public? Admit small mistakes?

12 Mistake No 1 of?

13 Clinical details 37-year-old female with a ten-year history of - recurrent febrile episodes - non-tender subcutaneous nodules in the lower extremities - symmetric peripheral sensory neuropathy - arthralgia Initial diagnosis: Weber-Christian disease Initial treatment: methylprednizolone

14 Clinical details On admission: fever - 39 o C widespread papular erythema of upper eyelids, face, neck, chest and periumbilical area loss of eyelashes and partial loss of eyebrows erythematous plaques on distal lower extremities and deep ulcerations of the elbows and soles obesity (BMI 31)

15 Laboratory and other studies Laboratory findings: haematocrit 31.7% white cell count 12,200/mm 3 (82% neutrophils, 15% lymphocytes, 3% monocytes) CRP mildly AST, ALT, γgt Negative: viral markers, autoantibodies, test for syphilis blood and urine cultures U/S: hepatosplenomegaly Clinical D.D.: Weber-Christian disease Lupus erythematosus panniculitis Percutaneous liver biopsy

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23 Masson trichrome

24 PAS dpas

25 Ziehl-Neelsen

26 Liver in Weber-Christian disease

27 My initial diagnosis: Fatty liver disease with numerous lipogranulomas in a patient with Weber Christian disease and obesity

28 The case was discussed at the Liver CPC A skin biopsy had been sent to the Hospital of Cutaneous & Venereal Diseases Massone, Clin Dermatol, 2015

29 The case was discussed at the Liver CPC A skin biopsy had been sent to the Hospital of Cutaneous & Venereal Diseases Wade-Fite stain (modified Z-N) Massone, Clin Dermatol, 2015 Skin involvement by lepromatous leprosy

30 The case was discussed at the Liver CPC A skin biopsy had been sent to the Hospital of Cutaneous & Venereal Diseases Massone, Clin Dermatol, 2015 Wade-Fite stain (modified Z-N) Skin biopsy from an active site is the gold standard for the diagnosis of leprosy

31 Wade-Fite stain (modified Z-N) Mycobacterial cell walls contain a waxy substance composed of mycolic acids Acid fastness is related to the carbon chain length of the mycolic acid M. leprae is much less acid and alcohol fast compared to M. tuberculosis Wade-Fite stain: - No alcohol - 10% sulphuric acid to decolour - sections deparaffinised with peanut oil/xylene mixture to protect the waxy coat of M. leprae

32 Wade-Fite

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34 Wade-Fite x600

35 Reticulin

36 Lepromatous leprosy. Biopsy showing a cluster of foamy macrophages. On Wade Fite stain, these contained degenerate acid-fast bacilli.

37 Correct diagnosis: Hepatic involvement by lepromatous leprosy

38 Leprosy (Hansen s disease) chronic infectious disease with acute episodes (reactional states) caused by Mycobacterium leprae (M. leprae) tropical subtropical regions - endemic countries: Nepal, Madagascar, Indonesia - >80% of patients live in India and North Brazil 2003 Aftab, BMC Research Notes 2016 Truman, NEJM 2011 Scollard, Clin Microbiol Rev 2006

39 Leprosy (Hansen s disease) chronic infectious disease with acute episodes (reactional states) caused by Mycobacterium leprae (M. leprae) tropical subtropical regions - endemic countries: Nepal, Madagascar, Indonesia - >80% of patients live in India and North Brazil people affected transmitted mainly via respiratory droplets 2003 In 2013, 180,618 new cases registered Aftab, BMC Research Notes 2016 Truman, NEJM 2011 Scollard, Clin Microbiol Rev 2006

40 Leprosy (Hansen s disease) multisystemic disease - mainly affects the skin and peripheral nervous system - internal organs may be affected WHO classification: - pausibacillary (tuberculoid disease) - multibacillary (lepromatous disease) Leprosy: A model for human immune response to infection Montoya, Adv Immunol 2010 CD4+ T cells CD8+ T cells

41 The liver in leprosy significant involvement is uncommon 20% in paucibacillary and 60% in multibacillary disease good correlation between patterns of skin and liver lesions Paucibacillary leprosy Tuberuloid granulomas very few or no AFB Multibacillary (lepromatous) leprosy (up to 10 5 bacilli/ml blood) Foamy macrophage aggregates acinar or in portal tracts many AFB: - in foamy macrophages - in Kupffer cells neutrophil infiltrates in erythema nodosum leprosum (reaction state type II) Karat, BMJ 1971 Chen, Arch Pathol Lab Med 1976 Patnaik, Int J Lep Other Mycobact Dis 1989 Liver as a source of bacilli in cases of relapse

42 Foamy macrophages in lepromatous leprosy First described by Rudolph Virchow in 1863 Virchow cells

43 Foamy macrophages in lepromatous leprosy Divergent macrophage programs in leprosy: - Tuberculoid leprosy antimicrobial pathway (type 1 cytokines i.e. IL 15) - Lepromatous leprocy phagocytic pathway (type 2 cytokines i.e. IL10) Macrophages phagocytose mycobacteria and host oxidized LDL FOAM CELLS Modlin, Curr Opin Immunol 2010

44 Differential diagnosis of hepatic foamy macrophage aggregates mycobacterial infections (M. leprae, M. tuberculosis, M. avium intracellulare) Whipple disease (Tropheryma whippeli) xanthoma cells in cholestasis (LDBO, PBC, PSC) total parenteral nutrition Erdheim-Chester disease xanthoma disseminatum (systemic xanthogranuloma) hyperlipidemia disorders of lipoprotein and lipid metabolism toxic Brachiaria brizantha hay (cattle)

45 What I learned from Mistake No 1 Not to get misguided by the presumed clinical diagnosis Not to misinterpret histological findings Not to rush Always exclude all other entities in the differential diagnosis before issuing the final report

46 What I learned from Mistake No 1 Not to get misguided by the presumed clinical diagnosis Not to misinterpret histological findings Not to rush Always exclude all other entities in the differential diagnosis before issuing the final report When confronted with granulomas and Z-N is negative ask for a Wade-Fite stain!

47 Mistake No 2 of?

48 Clinical details 49-year-old man - HIV-positive - no known HIV-defining diseases - i.v. drug user fever of unknown origin (3 weeks, 38.0 o o C) hepatosplenomegaly

49 Laboratory studies CD4 T lymphocyte count 110/μl mildly AST, ALT, γgt hepatotropic viral markers negative autoantibodies negative blood and urine cultures negative stool negative for microspora and cryptospora

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52 Reticulin

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57 Prussian blue x10

58 My preliminary diagnosis: Liver biopsy: Non-specific inflammation and mild siderosis Clinico-pathological correlation advised

59 The case was discussed at the Liver CPC A young hepatology consultant mentioned that the most common causes of FUO in HIV patients were tuberculosis and visceral leishmaniasis Tuberculosis had been ruled out Serology for leishmania was negative

60 Prussian blue x20

61 Prussian blue x40

62 Giemsa

63 CD68

64 CD34

65 Reticulin

66 My final diagnosis: Hepatic involvement by visceral leishmaniasis in HIV-infected patient

67 Visceral leishmaniasis (kala azar) protozoan parasite Leishmania is highly prevalent in many areas of the world Kubar, Lancet Infect Dis 2005 Endemic areas of VL 12 million people infected worldwide, at risk new VL cases/year, deaths/year (WHO 2009) >90% of VL cases in India, Bangladesh, Sudan, Brazil

68 The liver in visceral leishmaniasis Histological patterns of acute hepatic VL A. typical or classical - Kupffer cell hypertrophy and hyperplasia - portal inflammation - diffuse sinusoidal chronic inflammatory infiltrate rich in plasma cells Parasites present in Kupffer cells or portal macrophages

69 The liver in visceral leishmaniasis Histological patterns of acute hepatic VL B. nodular - Groups of macrophages within the acinus with scanty parasites Duarte, J Infect 2008

70 The liver in visceral leishmaniasis C. Chronic adult VL-fibrogenic pattern diffuse panacinar fibrosis scanty amastigotes Alves, Practical Hepatic Pathology 2011 Rogers cirrhosis - portal tracts intact of - septa dividing small groups hepatocytes Fibrosis regression with successful treatment CE Corbett, Rev Inst Med Trop Sao Paulo 1987 MacSween s Pathology of the Liver, 2012

71 Diagnosis of visceral leishmaniasis Giemsa-stained smears of spleen, bone marrow or lymph node aspirates serologic assays direct agglutination, ELISA immunochromatography, immunofluorescence culture in specialized medium PCR analysis of bone marrow or blood specimens liver biopsy is not the most sensitive diagnostic technique: parasites in liver aspirate in 75% of cases Kedzerski, Hum Vaccin 2011 Murray, Am J Trop Med Hyg 2012 MacSween s Pathology of the Liver, 2012

72 VL in HIV-infected patients leishmaniasis is a well known opportunistic infection in HIV-infected patients L. parasites latent for years may reactivate as immune competence HIV-1 increases risk of VL x100-2,300 in endemic areas Europe: i.v. drug users Highest prevalence in Spain and SW Europe L. infantum

73 Global distribution of reported cases of leishmaniasis and Leishmania/HIV co-infection, human i/v infection i/v infection human presence of both pathogens in the same cell (macrophage) Vicious circle: Leishmania induces more robust HIV-1 production and HIV-1 mediates parasitic replication

74 VL in HIV-infected patients leishmaniasis is a well known opportunistic infection in HIV-infected patients clinical course and prognosis of VL-HIV patients differs relapse risk, therapy-related toxicity and mortality therapy success 25% die within one month of presentation Ezra, J Glob Infect Dis 2010

75 Diagnosis of VL in HIV-infected patients sensitivity of serology is low (40% negative ab titres) Gold standard for diagnosis: microscopy of bone marrow aspirates/trephines or biopsies from other tissues i.e. liver PCR analysis: high sensitivity but reserved for monitoring clinical course Liver histology is similar to that of symptomatic non-hiv infected patients or, occasionally, with inflammatory infiltrates

76 Liver biopsy (LB) in HIV-infected patients with fever of unknown origin (FUO) establishes diagnosis in the majority of cases most common causes of FUO: - tuberculosis (50%) - v. leishmaniasis (20.7%) LB: - diagnostic 43% - helpful 22% - normal/non-specific findings 35% Garcia-Ordonez, J Infect 1999

77 What I learned from near-mistake No 2 Not to rush when making a diagnosis Always look at least one section of a liver biopsy at x40

78 What I learned from near-mistake No 2 Not to rush when making a diagnosis Always look at least one section of a liver biopsy at x40 Reticulin is a great stain to highlight leishmania amastigotes within macrophages

79 What I learned from near-mistake No 2 Not to rush when making a diagnosis Always look at least one section of a liver biopsy at x40 Reticulin is a great stain to highlight leishmania amastigotes within macrophages Liver biopsies from special populations require extra attention and clinico-pathological correlation Working with a multidisciplinary team reduces diagnostic error

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81 Mistakes are the stepping stones to learning

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84 VL in HIV-infected patients co-infection with HIV alters the immune response to VL Typically, immune response to L. infection is cell mediated Th1 response (CD4+ T lymphocytes: IFNγ, IL2,-12,-15) results to resolving infection Th2 response (IL-4, -5, -10) results to disease progression, disseminated disease mortality Ezra, J Glob Infect Dis 2010

85 VL in HIV-infected patients co-infection with HIV alters the immune response to VL Typically, immune response to L infection is cell mediated Th1 response (CD4+ T lymphocytes), producing IFNγ, IL2,-12,-15, results to resolving infection Th2 response (IL-4, -5, -10) results to disease progression, disseminated disease and mortality HIV induces a Th2-like state and CD4+ T cell depletion Inhibition of Th1-type cytokine secretion susceptibility to infection Ezra, J Glob Infect Dis 2010