Table 2 Comparative summary of characteristics of clinical studies relating to second, expert opinion: excluded studies Study ID Study characteristics Country Population Prior test Intervention Comparator Outcomes Azam 2002 Prospective multi-institutional study of cases sent for personal (expert) consultation in 1999. Study concluded when 20 cases were documented or 4 months had passed, whichever came first. Participants included 180 institutions enrolled in the College of American Pathologists (CAP) voluntary Q-Probes quality improvement program. Cases excluded if no diagnostic impression was rendered in the primary laboratory. Cases resulting from a patient’s referral to a different institution were excluded. United States (95.6%), Canada and Australia Surgical pathology (any organ system) and haematopathology (lymph node and bone marrow) cases N=2746 cases Initial diagnosis. Most participating institutions (59.9%) did not have an expert in a branch of surgical pathology in their pathology group EEO, requested by the pathologist, clinician or patient. Additional special histopathologic studies conducted as required. Initial diagnosis Diagnostic accuracy Characteristics of participating laboratories Extra-departmental consultation rate Turnaround time Satisfaction rate Reason for selecting the consultant pathologist Nature of the specimen Type of specimen provided Communication characteristics Institutional protocol characteristics Factors contributing to delays Fajardo 2011 Prospective study of consecutive cases of prostatic needle core biopsies in which the EEO was Gleason pattern 5. The final diagnosis was then compared to the Gleason score assigned by the initiating pathologist. United States Prostatic needle core biopsies N=59 (138 biopsy parts) Initial diagnosis EEO provided by an expert pathologist at The John Hopkins Medical Institution. EEO was sought by clinicians or patients and not because the initial pathologist was seeking a second opinion. Initial diagnosis Diagnostic accuracy (correlation of initial and expert Gleason score) Morphologic pattern of Gleason pattern 5 and its relationship to its under-diagnosis
Hamady 2004 Retrospective review of all patients referred to endocrine multidisciplinary meetings at a teaching hospital for further management of thyroid malignancy or for expert thyroid surgical pathology opinion from Jan 2001 to March 2003. United Kingdom All patients with an initial diagnosis of thyroid cancer N=66 cases (n=49 for routine review of referred cases, n=17 sent for EEO) Initial diagnosis EEO provided by an expert pathologist at the Institute of Pathology at Leeds Teaching Hospitals, and was confirmed by a second expert pathologist if diagnosis was discrepant from initial diagnosis. EEO requested by general pathologists from district hospitals. Initial diagnosis Reason for referral Nature of disagreement Effect on therapy and prognosis Herawi 2005 Prospective study of all prostate needle biopsies sent for expert consultation over a period in 2004. Only included cases referred for suspected malignancy, where a review of the entire case diagnosed the case to be benign. United States All prostate needle biopsy cases where diagnosis was changed from malignant to benign. N=345 cases (567 lesions of concern) Initial diagnosis of suspected malignancy EEO provided by an expert pathologist at Johns Hopkins School of Medicine. EEO requested by pathologists from 183 centres in 35 states in the US. Initial diagnosis of suspected malignancy Incidence of benign lesions causing diagnostic difficulty IHC results Kronz 2003 Prospective study of all prostate needle biopsy cases referred to a urological pathology consult service over a 10-month period in United States Prostate needle biopsy N=3251 cases Initial diagnosis EEO at John Hopkins Hospital. All cases were previewed by uropathology fellows or anatomic pathology residents and then reviewed for final diagnosis by the faculty expert in urological pathology. Initial diagnosis Outside preliminary diagnosis Expert review diagnosis Number of missed lesions (including details of cases with missed lesions such as age and type of outside institution) Type of missed lesion Whether the missed lesion(s) were on the slide(s) of concern month
Renshaw 2005 Review of inter-departmental consultations (incoming from outside institutions, outgoing, or clinician-generated outgoing) during a 2-year period from 2003 to 2005. United States Pathology cases; any organ system Incoming: N=328 Outgoing: N=928 pathologist-generated, N=227 patient- or clinician-generated Initial diagnosis Incoming: SO provided by outside institutions. SO requested by pathologists from Department of Pathology Baptist Hospital of Miami. Outgoing: SO provided by Department of Pathology, Baptist Hospital of Miami. SO requested from outside the department (but may include requests from within the institution). Initial diagnosis Diagnostic accuracy (disagreement rate) Nature of consultations with follow-up (additional consultation, additional biopsy, additional testing) Renshaw 2009 A retrospective review of SOs requested by patients or clinicians from 2004 to 2009. The aim of the study was to compare disagreement rates based on whether the initial pathologist sent all or only selected slides. United States All routine slides (excluding frozen section slides and IHC slides, unless the IHC stains were necessary to make a diagnosis) N=596 Initial diagnosis Original material rather than recuts were sent for review, unless there were known legal reasons for retaining the originals, which occurred in less than 1% of cases. Initial diagnosis Diagnostic accuracy (disagreement rate, error rates at first and second laboratories) Disagreement rate according to whether all or selected slides were reviewed Whether outside institution attempted to contact original institution regarding discrepant cases Renshaw 2013 A review of consultations (incoming and outgoing) handled by the Baptist Hospital of Miami from 2006 to 2012. United States All anatomic pathology (including surgical pathology and cytology) Incoming: N=1966 Outgoing: N=1532 Initial diagnosis EEO requested or provided by the Baptist Hospital of Miami. All discrepant cases were reviewed by one of the authors. Initial diagnosis Diagnostic accuracy (disagreement rate) Change in disagreement rate over time Use of IHC generated
Santiago 2013 Retrospective review of international paediatric cases from low- to middle-income countries submitted to an International Outreach Program for histopathologic EEO during a 3-year period from 2009 to 2011. Excluded cases when EEO was not definitively conclusive, insufficient tissue quality or quantity for diagnosis, or when original primary diagnostic report not available. Low- to middle-income countries obtaining EEO from United States Paediatric malignancy histopathology cases N=705 Initial diagnosis EEO provided by one or more pathologists (a board-certified anatomic pathologist, a haematopathologist, and/or a neuropathologist) from the Department of Pathology at St. Jude Children’s Research Hospital. EEO requested by 184 pathologists from 37 countries (International Outreach Program partner sites). Initial diagnosis Diagnostic accuracy (agreement, minor disagreement, major disagreement) Diagnostic accuracy by anatomic site Characteristics of cases sent for review Nature of IHC used by initial pathologist and EEO pathologist Correlation between major disagreements and use of IHC Zembowicz 2011 Review of dermatopathology cases received for SO consultation from within the United States during a 6-month period from February to August, 2009. United States Dermatopathology cases N=1229 cases (average case consisted of 3.4 ± 3 slides) Initial diagnosis or no diagnosis rendered EEO provided by a consultant pathologist at a free-standing clinical laboratory with no formal affiliations with large medical institutions. EEO requested by pathologists or clinicians due to diagnostic challenges or specific policies at outside institutions requiring external second opinion. Initial diagnosis Turnaround time Diagnostic categories of specimens submitted for review Abbreviations: EEO, external expert opinion; IHC, immunohistochemistry; SO, second opinion.
Table Comparative summary of characteristics of clinical studies relating to external expert opinion: Scenario 1 studies Study ID Study characteristics Country Population Prior test Intervention Comparator Outcomes ALL SURGICAL PATHOLOGY - - - - - - Cook 2001 Retrospective review of all cases sent for SO during 1998, compared to 1990, from two large district general hospitals histopathology laboratories. United Kingdom All histopathology cases; any organ system N=128 casesa Initial diagnosis or no diagnosis rendered SO provided by “external experts” from other pathology laboratories in the UK. SO was mainly requested by pathologistsb at Portsmouth Hospitals National Health Service (NHS) Trust. Initial diagnosis SO consultation rate Specimen anatomical site Nature of initial pathology opinion (no/differential/provisional diagnosis) Reason for referral Diagnostic accuracy (concordance/discordance; major discrepancies) Turnaround time Nature of expert diagnosis (no diagnosis/confident diagnosis) Hsu 2010 Retrospective review of consecutive cases sent for extra-departmental anatomic pathology consultation by Taiwan Society of Pathology (TSP) members from 2003 to 2006. TSP received research funding for EEO provided. Study does not include cases sent directly to Taiwan-based or overseas consultants. Taiwan Anatomic pathology; any organ system N=2686 cases Initial diagnosis or no diagnosis rendered EEO provided by 65 pathologists with subspecialty expertise from teaching hospitals across Taiwan. Additional specialised testing performed as required. EEO requested by 224 pathologists from 79 institutes across Taiwan. Reasons for consultation not provided. Initial diagnosis Annual SO consultation rate Tissue origin of specimens Nature of initial pathology opinion (no diagnosis, tentative diagnosis) Diagnostic accuracy (concordance, discordance; major and minor discrepancies) Turnaround time Use of special stains Characteristics of referring pathologists Characteristics of EEO pathologists
SOFT TISSUE/ SARCOMA - - - - - - Arbiser 2001 Retrospective review of 500 consecutive cases referred to a soft tissue consultation practice for EEO in a period in 1998. United States Soft tissue lesions. Sample obtained by biopsy or definitive excisions (92.4%), or needle or punch biopsy (7.6%) N=500 cases Initial diagnosis or no diagnosis rendered EEO provided by a Soft Tissue Consultation Service, “which serves as an excellent resource to evaluate situations in which pathologists themselves recognise their limitations and/or seek guidance”. EEO was ‘self-referred’ from across the US. Additional IHC conducted as required. Initial diagnosis Nature of initial pathology opinion (no diagnosis, provisional diagnosis) Diagnostic accuracy (concordance; major and minor disagreements) Specimen diagnostic category Ray-Coquard 2012 Prospective review of 1463 cases of soft tissue or visceral sarcoma reviewed by expert pathologists between 2005 and 2008. The study included cases referred for expert SO at the request of the initial pathologist and also cases in which the initial ‘non-expert’ pathologist did not request confirmation of diagnosis and whose findings were reviewed in the context of the study. France Soft tissue or visceral sarcoma N=1463 casesc Initial diagnosis EEO provided by an expert pathologist. In rare cases, the reviewing expert requested that the diagnosis was re-examined by another expert or discussed at panel meetings and a final consensus was reached. All pathologist from the three regions involved in this ‘central review’ attended training sessions in order to homogenise the review process. Initial diagnosis Patient characteristics Type of referring laboratory (public/private) Characteristics of submitted tumours (tumour site, histological subtype, grade, type of sample) Diagnostic accuracy (full/partial concordance, complete discordance) Nature of discordance (grade, histological type, subtype) month
DERMATOLOGY - - - - - - Gaudi 2013 Retrospective review of all outside cases referred to a dermatopathology unit for expert consultation or mandatory second review during one calendar year. United States Dermatopathology N=405 casesd Initial diagnosis or no diagnosis rendered Expert review provided by either of two dermatopathologists, from the University of Pittsburgh Dermatopathology Unit. Expert review requested by 85 pathologists – 18.8% were dermatopathology trained. Initial diagnosis Number of cases with no initial diagnosis Diagnostic accuracy (major and minor discrepancies) Diagnostic category of major discrepancies Use of IHC Training of referring pathologist van Dijk 2008 Retrospective review of 1887 lesions sent to the pathology panel of the Dutch Melanoma Working Group for voluntary expert review between 1991 and 2004. Fifty lesions were not diagnosed as cutaneous melanocytic lesions and were subsequently excluded from the study. The Netherlands Cutaneous melanocytic lesions N=1837 cases Initial diagnosis or no diagnosis rendered EEO provided by the Dutch Melanoma Working Group when a primary pathologist encountered difficulties diagnosing or classifying potential cutaneous melanocytic lesion. Approximately 75% of submitted lesions were reviewed by an individual panel member and discussed at a regular pathology panel meetinge; 25% were reviewed by the individual panel member only and were not discussed with other panel members. Initial diagnosis Nature of initial pathology opinion (no/differential/provisional diagnosis) Characteristics of submitted lesions (Spitz naevus, melanoma, etc) Diagnostic accuracy (concordance, discordance; over- and Use of IHC Features of problematic lesions Changes over time regarding the features of submitted lesions
Veenhuizen 1997 Retrospective review of 1069 consecutive lesions sent to the pathology panel of the Dutch Melanoma Working Group for expert review between 1992 and 1994. Cases were referred from hospitals and institutes throughout The Netherlands and from some pathologists abroad. The Netherlands Skin lesions N=1069 cases Initial diagnosis or no diagnosis rendered EEO provided by the pathology panel of the Dutch Melanoma Working Group when a primary pathologist encountered difficulties in making an unequivocal diagnosis of a potential cutaneous melanocytic lesion. One of the three members of the pathology panel provided the EEO. Where doubt remained, the case was sent to other panel members and/or reviewed at panel meetings. If panel discussion led to a clinically relevant change in the original expert diagnosis, an additional report was promptly issued. Initial diagnosis SO consultation rate (number of cases referred per institution; size of requesting institutions) Nature of initial pathology opinion (no/differential/provisional diagnosis) Patient characteristics of submitted cases (age, gender) Diagnostic accuracy (concordance; over- and under-diagnosis) Number of cases in which expert panel made an unequivocal diagnosis LUNG - - - - - - Hutton Klein 2010 Prospective study of 100 consecutive lung biopsies referred to a pulmonary pathology consultation service by a pathologist or clinician over a 7-week period in 2008. United States Granulomatous or giant cell reactions in the lung N=80 casesf Initial diagnosis or no diagnosis rendered EEO provided by one or more of three pulmonary pathologists at the Mayo Clinic Scottsdale Pulmonary Pathology Consult Service, using an algorithmic approach to diagnosis. Initial diagnosis Nature of initial pathology opinion (no diagnosis/provisional diagnosis) Diagnostic accuracy (agreement/disagreement) Nature of specimens (not reported separately for requests initiated by pathologist) Clinical follow-up (not reported separately for requests initiated by pathologist) ORAL AND MAXILLOFACIAL - - - - - - Jones 2010 Retrospective review of Oral and Initial diagnosis EEO provided by an OMP Initial Nature of initial pathology opinion monthly
Table 2 Comparative summary of characteristics of clinical studies relating to second, expert opinion: Scenario 2 studies Study ID Study characteristics Country Population Prior test Index test Comparator Outcomes ALL SURGICAL PATHOLOGY - - - - - - Ahmed 2004 Retrospective study of all consecutive cases referred to a major referral centre for EEO in a period 2001 to 2002. Cases excluded if no initial diagnosis provided. Pakistan Surgical pathology; any organ system N=381 cases Initial diagnosis EEO provided by Section of Histopathology at the Aga Khan University Hospital. EEO requested by clinicians and in some cases the primary pathologist, across Pakistan. Additional IHC conducted as required. Initial diagnosis Nature of initial pathology opinion (no diagnosis/ provisional diagnosis) Diagnostic accuracy (agreement, disagreement) Use of IHC Specimen anatomical site Number of cases in which expert could not provide diagnosis BRAIN AND SPINAL CORD - - - - - - Bruner 1997 Retrospective review of 500 consecutive brain and spinal cord biopsies referred to a neuropathology consultation service for review (referred patient cases) or EEO in 1995. United States Brain and spinal cord biopsies or resections of tumours or suspected tumours N=500 casesa Initial diagnosis or no diagnosis rendered EEO provided by 3 faculty neuropathologists after conference review at a multihead microscope, from the Section of Neuropathology, Department of Pathology at the University of Texas M.D. Anderson Cancer Center. EEO requested by “pathologists or other attending physicians, such as surgeons, internists, or radiotherapists” (70.1%) or as part of protocol studies for second opinions with regard to therapy (29.9%). Additional special histopathologic studies conducted as required. Initial diagnosis Nature of initial pathology opinion (no diagnosis/ provisional diagnosis) Diagnostic accuracy (no discrepancy, minor discrepancy, total discrepancy) Nature of major diagnostic discrepancies Initiation of therapy before expert opinion in cases that turned out to be major discrepancies PROSTATE - - - - - - Chan 2005 Retrospective review of all prostate needle biopsies Prostate needle Initial diagnosis EEO provided by an expert pathologist at John Hopkins Initial Type of referral (patient or urologist-initiated)
van Dijk 2008 Cutaneous melanocytic lesions N=1837 Cases with no initial diagnosis Cases with a differential diagnosis Cases with a provisional diagnosis 160/1837 (8.7%) 435/1837 (23.7%) 1217/1837 (66.2%) Expert pathology panel unable to provide specific diagnosis Expert pathology panel unable to provide specific diagnosis but able to provide a presumed working diagnosis Expert pathology panel unable to provide specific diagnosis but able to provide a presumed working diagnosis + advice for further diagnostic and/or therapeutic procedures 67/1837 (3.6%) 42/1837 (2.3%) 25/1837 (1.4%) Veenhuizen 1997 Skin lesions N=1069 Cases with no initial diagnosis Cases with a differential diagnosis Cases with a provisional diagnosis 90/1069 (8.4%) 131/1069 (12.3%) 798/1069 (74.6%) Expert or expert pathology panel unable to provide a diagnosis Expert or expert pathology panel able to provide differential diagnosis Expert pathology panel provided unequivocal diagnosis in cases with no initial diagnosis Expert pathology panel provided unequivocal diagnosis in cases with initial differential diagnosis 7/1069 (0.7%) 23/1069 (2.2%) 81/90 (90.0%) 122/131 (93.1%) ORAL AND MAXILLOFACIAL - - - - - Jones 2010 Oral and maxillofacial pathology N=142 cases Cases with no initial diagnosis Cases with a provisional diagnosis 7/142 (4.9%) 135/142 (95.1%) NR NR UROTHELIAL - - - - - Tavora 2009 Urothelial lesions of the renal pelvis and mid-upper ureter N=76 Cases with no initial diagnosis Cases with a provisional diagnosis 0/76 (0%) 76/76 (100%) NR NR LUNG - - - - - Hutton Klein 2010 Granulomatous or giant cell reactions in the lung Cases with no initial diagnosis Cases with a provisional diagnosis 25/80 (31.3%) 55/80 (68.8%) Expert pathologist provided a confident diagnosis Expert pathologist provided a probable (strongly favoured) diagnosis 27/100 (27.0%)g 34/100 (34.0%)g
Table A4.1 Minor discrepancy rates – as reported in Scenario 1 studies Study ID Population (N) Outcome Results n/N (%) SOFT TISSUE/ SARCOMA - - - Arbiser 2001 Cases of soft tissue lesions N=500 cases Number of cases with a provisional diagnosis Minor discrepancy 266/500 (53.2%) 20/266 (7.5%) Ray-Coquard 2012 Soft tissue or visceral sarcoma N=1463 casesa Number of cases with a provisional diagnosis Partial concordance with initial diagnosisb (i.e. minor discrepancies) Nature of major and minor discrepanciesc: Subtype alone Grade alone Histological type alone Grade and subtype Grade and histological type 564/564 (100%) 263/564 (46.6%) 11/334 (3.3%) 104/334 (31.1%) 89/334 (26.6%) 114/334 (34.1%) 16/334 (4.8%) DERMATOLOGY - - - Gaudi 2013 Dermatopathology N=405 casesd Number of cases with a provisional diagnosis Minor discrepancy Nature of minor discrepancies (as a proportion of cases with a provisional diagnosis): Minimal disagreements (e.g. errors in spelling) Minor disagreementse Defects in diagnosis with minimal effect on patient caref Nature of minor discrepancies (as a proportion of total minor discrepancies): Minimal disagreements (e.g. errors in spelling) Minor disagreementse Defects in diagnosis with minimal effect on patient caref 354/405 (87.4%) 121/354 (34.2%) 10/354 (2.8%) 56/354 (15.8%) 55/354 (15.5%) 10/121 (8.3%) 56/121 (46.3%) 55/121 (45.5%) van Dijk 2008 Cutaneous melanocytic lesions N=1837 Number of cases with a provisional diagnosis Minor discrepancyg 1217/1837 (66.2%) 350/1217 (28.8%)
Additional economic information Table A6.1 Summary of economic studies identified in the literature search Author (year) Population Setting/Country Intervention Diagnostic accuracy and change in management Economic evaluation Results of economic evaluation Bajaj (2012) N=922 thyroid FNAC cases referred to institution over a period. Long Island Jewish Medical Center in the United States Second opinion on outside FNAC specimens for all cases referred to the institution. 122/922 (13%) discordant, 44 major and 78 minor. 75/122 (62%) resulted in change in management: 33 surgical to medical 29 medical to surgical 13 changed surgery type 39/44 (90%) major discrepancies resulted in a change in management, with 28 undergoing surgery. Of those, the second opinion was supported in 25 patients and the original opinion was supported in 3 patients. CBA in USD. Considers savings due to unnecessary surgery avoided. Excludes potential savings due to: lost wages surgical complications life-long thyroid replacement therapy, with accompanying morbidity litigation Total cost of 922 FNAC consultations (assuming Medicare reimbursement $97/consult): $89,434. Potential cost saving for 33 patients that avoided surgery (at an average cost of $31,200/case): $940,166. Bejarano (2001) N=124 patients (125 cases) who had undergone a liver biopsy and were referred for treatment over a 2-year period. University medical centre in the United States Second opinion on outside specimens by a hepatopathologist with a hepatologist who shared clinical information. All discordant diagnoses were reviewed by another hepatopathologist. 35/125 (28%) discordant, classified as major (defined as a description or diagnosis that may have resulted in inappropriate management decisions if left unmodified. Total cost of second opinion in USD. Direct pathology cost at original institutions: $18,422.45. Second opinion on 125 cases: $8,490.56, including: $7,332.50 as professional charge by consult pathologists $1,158.06 for charges relating to generation of additional slides and special stains