Histopathologic Diagnosis of Pediatric Neoplasms A Review of International Consultations Teresa C. Santiago, MD; Jesse J. Jenkins, MD
Context.—Correct histopathologic diagnosis is fundamental to defining proper treatment and improving outcomes in children with malignancies. The Department of Pathology at St. Jude Children’s Research Hospital (SJCRH) has collaborated with SJCRH International Outreach Program partner sites to improve the accuracy of histopathologic diagnoses in countries with limited resources. Pathologists at SJCRH provide review and evaluation of cases that are considered difficult or complex. Objectives.—To determine the quality of pathology diagnosis and to identify areas for improvement in our international partner sites, we retrospectively analyzed all the international cases that were submitted for review. A comparison of our data with selected reports of surgical pathology error rates published in the medical literature was performed. Design.—From January 2009 through December 2011, SJCRH received 763 cases submitted by international pathologists from 37 countries for histopathologic review
and evaluation. Of 763 cases reviewed, 705 (92.4%) met the criteria for inclusion in this study. Rates of concordance between the submitted diagnoses and SJCRH reviewed diagnoses were analyzed. Results.—Overall concordance, minor disagreement, and major disagreement rates between submitted diagnoses and SJCRH reviewed diagnoses were 430 (61.0%), 98 (13.9%), and 177 (25.1%) of the cases, respectively. Major disagreement rates ranged from 13.7% to 37.1% among studied countries. Conclusions.—The major disagreement rate between referring international sites and SJCRH was substantially higher than the major disagreement rate among US institutions. Lack of the availability of immunohistochemistry and the training of pathologists in the diagnosis of pediatric neoplasms may have contributed to the discrepancies. (Arch Pathol Lab Med. 2013;137:1648–1653; doi: 10.5858/arpa.2012-0571-OA)
T
children with malignancies has been one of the priorities of the SJCRH International Outreach Program. Local pathologists are identified and trained at SJCRH for periods of weeks or months. In addition, support for improvement of the local laboratory infrastructure and ongoing maintenance is provided. Moreover, given the rarity and diagnostic difficulties presented by many pediatric neoplasms, SJCRH pathologists provide ongoing histopathologic review of complex cases, which benefits the patient and provides education for international pathologists. To identify areas for potential improvement in histologic diagnoses internationally in our partner sites, we retrospectively analyzed cases submitted to the SJCRH Department of Pathology for histopathologic review. We sought to determine the rates of, and reasons for, histologic-diagnostic discrepancy between international and SJCRH pathologists. Selected factors potentially associated with discrepancies were investigated and recommendations were made to improve the accuracy of the histopathologic diagnosis of pediatric neoplasms.
he survival rate of children with malignancies has increased dramatically in recent years. Data from the United States and Western Europe show estimated cure rates around 80%.1,2 Critical to this progress are accurate diagnoses and adequate treatment. However, most of the world’s children live in areas with limited resources, where training in diagnoses and access to treatment is limited; hence, not surprisingly, the estimates of survival are lower than those in developed countries, ranging from 5% to 40%.3 To improve the survival rates of children with cancer in selected low- and middle-income countries, St Jude Children’s Research Hospital (SJCRH) has developed a comprehensive program to increase access to care, including expanding the diagnostic capabilities of pathologists and the treatment opportunities of children with neoplasms.4–13 Creating the local capacity to provide correct diagnoses of Accepted for publication January 7, 2012. From the Department of Pathology, University of Tennessee Health Science Center, Memphis (Dr Santiago); and the Department of Pathology, St. Jude Children’s Research Hospital, Memphis (Dr Jenkins). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Jesse J. Jenkins, MD, Department of Pathology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678 (e-mail: [email protected]).
From January 1, 2009, through December 31, 2011, 763 pediatric cases referred from outside of the United States were received for histopathologic review at the SJCRH Department of Pathology. The cases were submitted by community and pediatric hospitals and academic medical centers from 37 countries (Table 1).
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MATERIALS AND METHODS
Table 1.
a
St. Jude Children’s Research Hospital’s Histopathologic Review of International Cases From January 1, 2009, to December 31, 2011
Countries, n ¼ 37
Cases, No. (%), n ¼ 763
Brazil Chile Costa Rica Ecuador El Salvador Guatemala Honduras Lebanon Nicaragua Othersa
40 73 14 85 48 76 169 108 61 89
Referring Pathologists, No. (%), n ¼ 184
(5.2) (9.6) (1.8) (11.1) (6.3) (10.0) (22.1) (14.2) (8.0) (11.7)
12 12 6 27 2 1 31 28 7 58
Excluded Cases, No. (%), n ¼ 58
(6.5) (6.5) (3.3) (14.7) (1.1) (0.5) (16.8) (15.2) (3.8) (31.5)
2 3 1 4 2 4 21 13 2 6
(3.4) (5.2) (1.7) (6.9) (3.4) (6.9) (36.2) (22.4) (3.4) (10.3)
Male, No. (%), n ¼ 431
Female, No. (%), n ¼ 274
Benign, No. (%), n ¼ 154
Malignant, No. (%), n ¼ 517
23 45 9 51 30 43 91 51 42 46
15 25 4 30 16 29 57 44 17 37
12 11 0 24 17 17 28 21 8 16
24 54 10 56 27 50 116 67 50 63
(5.3) (10.4) (2.1) (11.8) (7.0) (10.0) (21.1) (11.8) (9.7) (10.7)
(5.5) (9.1) (1.5) (10.9) (5.8) (10.6) (20.8) (16.1) (6.2) (13.5)
(7.8) (7.1) (0.0) (15.6) (11.0) (11.0) (18.2) (13.6) (5.2) (10.4)
(4.6) (10.4) (1.9) (10.8) (5.2) (9.7) (22.4) (13.0) (9.7) (12.2)
Uncertain Malignant Potential, No. (%), n ¼ 34 2 5 3 1 2 5 4 7 1 4
(5.9) (14.7) (8.8) (2.9) (5.9) (14.7) (11.8) (20.6) (2.9) (11.8)
Argentina, Bolivia, China, Colombia, Dominican Republic, Egypt, France, India, Israel, Jamaica, Japan, Jordan, Mexico, Morocco, Panama, Paraguay, Peru, Philippines, Puerto Rico, Russia, Singapore, Slovakia, Spain, Syria, Turkey, United Kingdom, Venezuela, Zimbabwe.
The histopathologic review at SJCRH was conducted by a boardcertified anatomic pathologist, a hematopathologist, and/or a neuropathologist. In some cases, more than one pathologist at the SJCRH pathology department has reviewed the case and contributed to the final diagnosis (intradepartmental review). The material submitted to SJCRH included a copy of the original pathology report and histopathologic specimens. Hematoxylineosin–stained slides, unstained slides, and/or formalin-fixed paraffin-embedded tissue block(s) that the referring pathologist considered representative of the lesion were received. A brief clinical history, which included patient age, gender, and location of the lesion, were also provided by the referring pathologist in most cases. Patient’s age and sex, the anatomic site of the lesion, the ancillary techniques used to support the diagnosis (eg, immunohistochemistry [IHC]), and the country of origin were reviewed and entered into a database for further classification and analysis. The availability of IHC varied among the referring centers, and in some locations, access to reagents was limited or nonexistent. Of 763 cases, 455 (59.6%) had not been studied with any IHC stains at the international sites; hence, the primary diagnosis was based exclusively on morphologic features (examination of hematoxylineosin–stained slides only). At the discretion of the SJCRH pathologists, IHC, fluorescence in situ hybridization, Epstein-Barr virus encoded RNA in situ hybridization, or molecular diagnostic studies (usually reverse transcription-polymerase chain reaction) were performed at SJCRH laboratories using formalin-fixed, paraffin-embedded tissue sections or unstained slides. The final diagnosis of the SJCRH pathologist was compared with that of the referring pathologists, and the frequencies of concordance and disagreement were recorded. Disagreement was considered minor when it would not change treatment or outcome and was considered major when it would result in significant treatment modifications or when there was remarkable difference in the final histomorphologic and/or immunophenotypic diagnosis. Patients older than 21 years at the time of diagnosis were excluded from retrospective analysis. Cases were also excluded when a diagnosis was not possible because of insufficient tissue
quantity or quality or when the original primary diagnostic report was not available for review. The SJCRH institutional review board approved this study.
Results A total of 763 cases were reviewed and 705 cases (92.4%) were found eligible for inclusion. Ten patients (1.3%) who were older than 21 years at the time of diagnosis or whose age was unavailable were excluded from analysis. In 48 cases (6.3%), a comparison between the SJCRH final diagnosis and referring diagnosis was not recorded for the following reasons: unsatisfactory tissue preservation or insufficient tissue for diagnosis (11 cases, 1.4%), the original primary diagnostic report was not available for review (19 cases, 2.5%), or the final SJCRH diagnosis was not definitively conclusive (18 cases, 2.4%). Among the 705 eligible cases, the median age of 431 boys (61.1%) and 274 girls (38.9%) was 7.75 years (range, 3 days to 21 years). All patients had originally been diagnosed by the referring international pathologists (184 different pathologists). Of the 705 cases, 154 (21.8%) were benign processes and 517 (73.3%) malignant neoplasms. The remaining 34 cases (4.8%) could not be definitively classified as benign or malignant and included lesions with uncertain malignant potential. Of the 705 eligible cases, 542 (76.9%) were subjected to IHC at SJCRH. The panel of antibodies was based on the differential diagnoses considered for each case. The number of antibodies used per case at SJCRH ranged from 1 to 33 (average, 7.7). At the referring sites, IHC use was limited to 317 cases (45.0%), but, when IHC was used, the number of antibodies per case at the international sites was similar to SJCRH, ranging from 1 to 28 (average 7.1).
Table 2. Number of Casesa per Concordance per Year Agreement Year 2009, n ¼ 236 2010, n ¼ 242 2011, n ¼ 227 Overall, n ¼ 705 a
Per Year No. (%) 168 130 132 430
Minor Disagreement
Per Concordance %
(71.2) (53.8) (58.2) (61.0)
39.1 30.2 30.7 100
Per Year No. (%) 24 41 33 98
(10.2) (16.9) (14.5) (13.9)
Per Concordance % 24.5 41.8 33.7 100
Major Disagreement Per Year No. (%) 44 71 62 177
(18.6) (29.3) (27.3) (25.1)
Per Concordance % 24.9 40.1 35.0 100
Total after exclusions.
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Table 3. Rates of Agreement and Discrepancy Between Submitted Diagnoses and Diagnoses by St. Jude Children’s Research Hospital by Anatomic Site or Organ, N ¼ 705a Anatomical Site/ Organ Abdominal cavity Adrenal gland Bone marrow Bone CNS and spinal cord Eye Gastrointestinal Kidney Liver Lung Lymph node Mediastinal Naso/oropharynx Pelvic/peritoneal Retroperitoneal Skin Soft tissue Others, n ¼14 Total
Cases,a No. (%) 23 24 21 73 119 17 18 30 15 9 109 18 12 8 24 22 123 40 705
(3.3) (3.4) (3.0) (10.4) (16.9) (2.4) (2.6) (4.3) (2.1) (1.3) (15.5) (2.6) (1.7) (1.1) (3.4) (3.1) (17.4) (5.7) (100)
Agreement, No. (%) 12 20 16 50 59 9 11 16 8 4 68 10 10 5 16 14 80 22 430
(52.2) (83.4) (76.2) (68.5) (49.6) (52.9) (61.1) (53.3) (53.4) (44.4) (62.4) (55.5) (83.3) (62.5) (66.7) (63.6) (65.0) (55.0) (61.0)
Minor Disagreement, No. (%) 4 2 2 7 21 3 6 6 2 1 14 3 0 0 3 1 13 10 98
(17.4) (8.3) (9.5) (9.6) (17.6) (17.7) (33.3) (20.0) (13.3) (11.2) (12.8) (16.7) (0.0) (0.0) (12.5) (4.5) (10.6) (25.0) (13.9)
Major Disagreement, No. (%) 7 2 3 16 39 5 1 8 5 4 27 5 2 3 5 7 30 8 177
(30.4) (8.3) (14.3) (21.9) (32.8) (29.4) (5.6) (26.7) (33.3) (44.4) (24.8) (27.8) (16.7) (37.5) (20.8) (31.9) (24.4) (20.0) (25.1)
Abbreviation: CNS, central nervous system. a Total after exclusions.
After exclusions, the overall agreement, minor disagreement, and major disagreement rates between the referring and SJCRH diagnoses were calculated as 430 (61.0%), 98 (13.9%), and 177 (25.1%), respectively (Table 2). The major disagreement rate among the countries that referred most of the cases ranged from 13.7% to 37.1%. Of the 177 major disagreements, 50 cases (28.2%) had a final benign diagnosis, and 119 cases (67.2%) were malignant. In 8 cases (4.5%), the exact histopathologic nature of the lesion could not be established by the SJCRH reviewer, but the difference between original diagnosis and the final SJCRH diagnosis was sufficient to classify the cases as a major disagreement (eg, a soft tissue lesion of the distal third of left thigh: original diagnosis, high-grade sarcoma; SJCRH final diagnosis, negative for definitive neoplastic process). Lesions were located in all sites of the body. As shown in Table 3, the anatomic sites that resulted in most of the major disagreements were the central nervous system, lymph nodes, and soft tissues. Sorting for anatomic location, the major disagreement rate ranged from 5.6% (1 of 18) for the gastrointestinal tract to 44.4% (4 of 9) for the lung (Table 3). As shown in Table 4, most (57.6%) major disagreements (102 of 177) were equally diagnosed as malignant by the international pathologist and SJCRH pathologist, but the difference in the final diagnosis was significant enough for
the case to be considered major disagreements (eg, a cerebellar tumor originally diagnosed as anaplastic ependymoma, a World Health Organization grade III tumor, but with a reviewed diagnosis of atypical teratoid-rhabdoid tumor, a World Health Organization grade IV tumor; IHC was performed in this case at the referring site and at SJCRH). Our analysis revealed that the change from malignant diagnosis by the international pathologist to a final benign diagnosis by the SJCRH pathologist (n ¼ 46) was three times more frequent than the change from benign to malignant (n ¼ 15; Table 4). Among the 177 major disagreements, 85 cases (48.0%) had IHC done at an international site. In 78 of 85 cases (91.8%), the number of antibodies used ranged from 1 to 17. In 7 other cases (8.2%), IHC was performed, but the number of antibodies used is unknown. With the exception of 2 cases (2.4%), all of the other 83 cases (97.6%) had IHC done at SJCRH. The 2 cases in which SJCRH pathologist deemed IHC unnecessary in discordance with the international pathologist were (1) an original diagnosis of embryonal rhabdomyosarcoma with an SJCRH final diagnosis of fibroosseous lesion and possible fracture with secondary aneurysmal bone cyst and no evidence of rhabdomyosarcoma in the reviewed material; and (2) an original diagnosis that included the following differential diagnosis: possible
Table 4. Cases of Major Disagreement and Correlation With Use of Immunohistochemistry (IHC) by International Pathologists and Changes to the Diagnosis by St. Jude Children’s Research Hospital, N ¼ 177a IHC Used by Referring Pathologists Change in the Diagnosis From malignant to benign From benign to malignant Malignant to malignant Benign to benign Not determined Total a
Yes, No. (%) 20 (11.3) 5 (2.8) 55 (31.1) 0 (0.0) 5 (2.8) 85 (48.0)
No, No. (%) 22 (12.4) 7 (4.0) 36 (20.3) 2 (1.1) 7 (4.0) 74 (41.8)
No Information Available, No. (%) 4 (2.3) 3 (1.7) 11 (6.2) 0 (0.0) 0 (0.0) 18 (10.2)
Total,a No. (%) 46 15 102 2 12 177
(26.0) (8.5) (57.6) (1.1) (6.8) (100)
Total after exclusions.
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Table 5. Cases of Major Disagreement in Which Immunohistochemistry Was Not Used by Either St. Jude Children’s Research Hospital (SJCRH) Reviewers or Referring Pathologists, N ¼ 18 Anatomic Site/Organ Soft tissue, neck mass Eye, right Bone, right distal femur Skin, face, biopsy Bone, left humerus Bone, mandible Brain, septal lesion Soft tissue, left arm Brain, posterior cranial fossa Thyroid gland Brain, right temporal lobe Bone, posterior cranial fossa Lymph node, retroperitoneal Eye, right Bone and dura, right parietal region Bone, third thoracic vertebra Soft tissue, left arm Bone, maxilla
SJCRH-Reviewed Diagnosis Ganglioneuroblastoma, Schwannian stroma-rich, intermixed Coats disease; negative for neoplastic process Favor chondrosarcoma, grade I, arising in an osteochondroma Favor nevus sebaceous of Jadassohn Favor aneurysmal bone cyst Chondroblastic osteosarcoma Brain parenchyma negative for definitive neoplastic process Fibrous hamartoma of infancy Pilocytic astrocytoma, WHO grade I Favor follicular adenoma Glioblastoma, WHO grade IV Favor aneurysmal bone cyst Neuroblastoma, Schwannian stroma-poor, poorly differentiated, low MKI, Shimada unfavorable Infiltrative process in uveal tract and choroid (toxocariasis?) Favor malignant melanoma; melanocytoma should also be included in differential diagnosis. Telangiectatic osteosarcoma, high grade Nodular fasciitis Conventional high-grade osteosarcoma, fibroblastic type
Submitted Diagnosis Ganglioneuroma Melanoma? versus retinoblastoma? Osteochondroma with no definitive evidence of malignancy Sebaceous carcinoma Osteosarcoma, well differentiated Low-grade chondromyxoid tumor Recurrent medulloblastoma Neurilemmoma (schwannoma) Oligodendroglioma Follicular carcinoma? Medullary carcinoma? Pleomorphic xanthoastrocytoma (WHO II) Giant cell tumor PNET/Ewing sarcoma Malignant melanoma Melanotic neuroectodermal tumor of infancy Langerhans cell histiocytosis? Aggressive infantile myofibromatosis Fibro-osseous tumor of uncertain malignant potential
Abbreviations: MKI, mitosis-karyorrhexis index; PNET, primitive neuroectodermal tumor; WHO, World Health Organization.
extranodal histiocytic sarcoma, synovial sarcoma, or rhabdomyosarcoma; whereas the SJCRH final diagnosis favored osteosarcoma. Immunohistochemistry was not performed by international pathologists in 74 of 177 major disagreements (41.8%). In 18 of 74 cases (24.3%), the SJCRH pathologist made a final diagnosis based on histomorphology alone (Table 5). In the remaining cases (56 of 74; 75.7%), IHC was performed at SJCRH and deemed necessary for diagnosis. COMMENT Review of the histopathologic diagnosis of challenging and difficult cases increases diagnostic accuracy and precision of pediatric neoplasms. Referring cases for second opinion would not only help to elucidate the diagnosis but also can and should be used as part of a quality control program in pathology practices. Sending a case for review and evaluation by an expert pathologist is a healthy practice for identifying errors in anatomic pathology laboratories and has been recommended by accrediting agencies in the United States.14 Some institutions in the United States require that every new diagnosis of malignancy be reviewed by a second inhouse pathologist before case verification (prospective peer review), which may decrease the final disagreement rate.15 In many countries with limited resources, however, the pathology service is run by a lone pathologist, who may not have formal training in the diagnosis of pediatric neoplasms and may have only limited on-the-job training. Some pediatric international oncology services in developing countries have dedicated pathologists who demonstrate familiarity with the common pediatric neoplasms and are willing to participate as members of a multidisciplinary team with the pediatric oncologists, radiologists, and surgeons. Referring sites with a dedicated pathologist Arch Pathol Lab Med—Vol 137, November 2013
working closely with a pediatric oncology team or with a pathologist with specialized training in the diagnosis of pediatric neoplasms demonstrate a lower rate of major disagreements compared with international sites that do not have such a pathologist. Focused training of a general pathologist in the diagnosis of pediatric neoplasms, implementation of a basic IHC panel in a pathology laboratory in a developing country, and inclusion of the pathologist in a multidisciplinary team can dramatically improve the diagnostic accuracy of pediatric neoplasms.16 Immunohistochemistry is an important and sometimes essential tool for the definitive diagnosis of pediatric neoplasms. In a limited resource area, use of a comprehensive panel of available antibodies is probably unrealistic. The cost-effective aspect of having at least a basic panel of antibodies available at pediatric pathology laboratories seems to be a reasonable approach to improving diagnostic accuracy. In our experience, a reasonable basic panel of antibodies to aid in the diagnosis of most common childhood neoplasm should include pancytokeratin (cytokeratin AE1–AE3), epithelial membrane antigen, vimentin, synaptophysin, CD99, terminal deoxynucleotidyl transferase, CD43, myogenin, CD1a, placental alkaline phosphatase, a-fetoprotein, CD30, CD15, CD20, and CD3, although the use and interpretation of IHC should always be performed within the context of the lesion histomorphology, pattern of expression and intensity of the IHC stain, and proper evaluation of positive and negative controls. In our analysis, when IHC was available, its use by the international pathologists seemed appropriate. In 97.6% of major disagreement cases in which IHC was performed at the international sites (83 out of 85 cases), the use of IHC was considered necessary by SJCRH pathologists to establish a final diagnosis. Our current data preclude definite conclusions, but the nonavailability of an essential IHC antibody, selection of an inappropriate antibody panel, misinterpre-
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tation of the performed IHC, or technical problems with the IHC reaction may be contributory factors in the misdiagnosis in these cases. In 18 of 177 cases classified as major disagreements (10.2%; Table 5), IHC was not used by the referring pathologists or the pathologist at SJCRH, and the diagnosis was based on histomorphology only. This emphasizes the importance of in-depth training of the international pathologists in the diagnosis of pediatric tumors and in the appropriate use of IHC. However, we believe training goals and objectives should be tailored to the international pathologist’s individual needs and level of expertise. A rootcause analysis of each individual international pathology service is also likely necessary to correct and eliminate fault events. Although not directly focused on pathology laboratories that diagnose pediatric neoplasms, the work of Pathologists Overseas (Del Mar, California) has helped to improve the conditions of many general pathology services in developing countries.17 The activities of Pathologists Overseas are done through the efforts of many volunteer pathologists and technologists, are tailored to local needs, and have included installation of new equipment, establishment of a basic quality control program, training of local physicians in anatomic pathology, and participation in teaching in international medical and medical technology schools. Some of the international pathologists had the opportunity for sabbatical training in United States, and the volunteer pathologists helped to cover the local service in the absence of the trainee. An annual visit to international sites to monitor the activities and progress was also performed. Problems with tissue fixation and processing, which can lead to suboptimal preservation of tissue antigens, must be appropriately addressed before implementation and use of diagnostic IHC. Many international histopathologic specimens received at SJCRH for review demonstrate problems with tissue fixation, and in some cases, those problems precluded a final diagnosis. The use of an adequate fixative (10% neutral-buffered formalin, pH ranging from 6.8 to 7.1), fixation time (including processing time up to 24 hours and 3–4 mm thickness of the tissue sample) are simple and implementable actions that can be accomplished in any pathology laboratory worldwide, which are key determinants for the quality of the tissue morphology as well as the preservation of tissue antigenicity for future IHC reactions, if applicable. Lones et al18 evaluated the effect of poor technical quality of histology and its adverse effects on the diagnosis of mature B-cell non-Hodgkin lymphoma in children and adolescents. Their analysis of 187 such cases demonstrated that the rate of agreement was significantly higher with good or medium histology technical quality than with low histology technical quality. Targeted therapy and genomics have greatly changed the way we understand and treat cancer, and a discussion of proper tissue fixation and availability of IHC may seem passe, ´ but, unfortunately, those are still real problems among many pediatric oncology centers around the world. Although outstanding pediatric diagnostic centers with state-of-the-art facilities and highly qualified diagnosticians exist in many developing countries, they are in the minority and are largely limited to larger centers. Many countries in South and Central America, Africa, and East Asia still lack dedicated pediatric-oncology units, and pathology services and pathologists are nonexistent in some places. An analysis
of a local pathology service in one hospital in Uganda has demonstrated serious problems with tissue handling, proper fixation, and the availability of IHC. Based on morphology alone, the Uganda local pathologist was able to diagnose 82% of the Burkitt lymphoma cases (37 out of 45 cases).19 Similar conditions for pathology practices are seen in Nigeria.20 The rate of major disagreement between the referring international sites and SJCRH is far beyond what is seen in US institutions. Roy and Hunt21 have showed in their review article that diagnostic discrepancy when reviewing outside material from general sign-out range from 1.4% to 11.3%. The error rate can vary by anatomic site, and specialized and focused review of cases can lead to a higher major disagreement as noted by Thway and Fisher.22 In their retrospective review of 349 soft tissue tumors, a 15.7% (n ¼ 55) rate of major disagreement was identified. In our review, soft tissue, central nervous system, and hematolymphoid lesions encompass most of the cases sent for review and represent most of the cases of major disagreement (Table 3). Nevertheless, when we evaluate the discrepancy rate according to anatomic location, a wide range of variation in major disagreements by site is noted (5.6% to 44.4%). The nature of the lesions and pathologists who lack familiarity with rare and specific entities might explain the high rate of major disagreement in some anatomic locations. In an overall assessment, the type, selective difficulty, and complexity of cases submitted from the international sites for review at SJCRH may have significantly affected our rate of disagreement and contributed to a higher discordance rate in our analysis. A random and unbiased review of cases from the same international pathology centers could possibly provide a lower disagreement rate, but corrective actions should be encouraged, and our overall major disagreement rate of 25.1% (range, 13.7% to 37.1%) is worrisome. In summary, we hope our experience, reviewed in this article, will increase awareness of the challenge to correctly diagnose pediatric neoplasms, especially in low- and middle-income countries where the pathology services may be suboptimal. We also hope to promote the establishment of a basic IHC panel that would aid in the diagnosis of the most common pediatric malignancies, especially the group of small blue cell neoplasms. We strongly believe these initiatives would improve the overall quality and accuracy of the diagnoses of pediatric solid tumors and lymphomas in more disadvantaged areas of the world and decrease the rates of disagreement and discrepancies.
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Context.—Correct histopathologic diagnosis is fundamental to defining proper treatment and improving outcomes in children with malignancies. The Department of Pathology at St. Jude Children’s Research Hospital (SJCRH) has collaborated with SJCRH International Outreach Program partner sites to improve the accuracy of histopathologic diagnoses in countries with limited resources. Pathologists at SJCRH provide review and evaluation of cases that are considered difficult or complex. Objectives.—To determine the quality of pathology diagnosis and to identify areas for improvement in our international partner sites, we retrospectively analyzed all the international cases that were submitted for review. A comparison of our data with selected reports of surgical pathology error rates published in the medical literature was performed. Design.—From January 2009 through December 2011, SJCRH received 763 cases submitted by international pathologists from 37 countries for histopathologic review
and evaluation. Of 763 cases reviewed, 705 (92.4%) met the criteria for inclusion in this study. Rates of concordance between the submitted diagnoses and SJCRH reviewed diagnoses were analyzed. Results.—Overall concordance, minor disagreement, and major disagreement rates between submitted diagnoses and SJCRH reviewed diagnoses were 430 (61.0%), 98 (13.9%), and 177 (25.1%) of the cases, respectively. Major disagreement rates ranged from 13.7% to 37.1% among studied countries. Conclusions.—The major disagreement rate between referring international sites and SJCRH was substantially higher than the major disagreement rate among US institutions. Lack of the availability of immunohistochemistry and the training of pathologists in the diagnosis of pediatric neoplasms may have contributed to the discrepancies. (Arch Pathol Lab Med. 2013;137:1648–1653; doi: 10.5858/arpa.2012-0571-OA)
T
children with malignancies has been one of the priorities of the SJCRH International Outreach Program. Local pathologists are identified and trained at SJCRH for periods of weeks or months. In addition, support for improvement of the local laboratory infrastructure and ongoing maintenance is provided. Moreover, given the rarity and diagnostic difficulties presented by many pediatric neoplasms, SJCRH pathologists provide ongoing histopathologic review of complex cases, which benefits the patient and provides education for international pathologists. To identify areas for potential improvement in histologic diagnoses internationally in our partner sites, we retrospectively analyzed cases submitted to the SJCRH Department of Pathology for histopathologic review. We sought to determine the rates of, and reasons for, histologic-diagnostic discrepancy between international and SJCRH pathologists. Selected factors potentially associated with discrepancies were investigated and recommendations were made to improve the accuracy of the histopathologic diagnosis of pediatric neoplasms.
he survival rate of children with malignancies has increased dramatically in recent years. Data from the United States and Western Europe show estimated cure rates around 80%.1,2 Critical to this progress are accurate diagnoses and adequate treatment. However, most of the world’s children live in areas with limited resources, where training in diagnoses and access to treatment is limited; hence, not surprisingly, the estimates of survival are lower than those in developed countries, ranging from 5% to 40%.3 To improve the survival rates of children with cancer in selected low- and middle-income countries, St Jude Children’s Research Hospital (SJCRH) has developed a comprehensive program to increase access to care, including expanding the diagnostic capabilities of pathologists and the treatment opportunities of children with neoplasms.4–13 Creating the local capacity to provide correct diagnoses of Accepted for publication January 7, 2012. From the Department of Pathology, University of Tennessee Health Science Center, Memphis (Dr Santiago); and the Department of Pathology, St. Jude Children’s Research Hospital, Memphis (Dr Jenkins). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Jesse J. Jenkins, MD, Department of Pathology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678 (e-mail: [email protected]).
From January 1, 2009, through December 31, 2011, 763 pediatric cases referred from outside of the United States were received for histopathologic review at the SJCRH Department of Pathology. The cases were submitted by community and pediatric hospitals and academic medical centers from 37 countries (Table 1).
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MATERIALS AND METHODS
Table 1.
a
St. Jude Children’s Research Hospital’s Histopathologic Review of International Cases From January 1, 2009, to December 31, 2011
Countries, n ¼ 37
Cases, No. (%), n ¼ 763
Brazil Chile Costa Rica Ecuador El Salvador Guatemala Honduras Lebanon Nicaragua Othersa
40 73 14 85 48 76 169 108 61 89
Referring Pathologists, No. (%), n ¼ 184
(5.2) (9.6) (1.8) (11.1) (6.3) (10.0) (22.1) (14.2) (8.0) (11.7)
12 12 6 27 2 1 31 28 7 58
Excluded Cases, No. (%), n ¼ 58
(6.5) (6.5) (3.3) (14.7) (1.1) (0.5) (16.8) (15.2) (3.8) (31.5)
2 3 1 4 2 4 21 13 2 6
(3.4) (5.2) (1.7) (6.9) (3.4) (6.9) (36.2) (22.4) (3.4) (10.3)
Male, No. (%), n ¼ 431
Female, No. (%), n ¼ 274
Benign, No. (%), n ¼ 154
Malignant, No. (%), n ¼ 517
23 45 9 51 30 43 91 51 42 46
15 25 4 30 16 29 57 44 17 37
12 11 0 24 17 17 28 21 8 16
24 54 10 56 27 50 116 67 50 63
(5.3) (10.4) (2.1) (11.8) (7.0) (10.0) (21.1) (11.8) (9.7) (10.7)
(5.5) (9.1) (1.5) (10.9) (5.8) (10.6) (20.8) (16.1) (6.2) (13.5)
(7.8) (7.1) (0.0) (15.6) (11.0) (11.0) (18.2) (13.6) (5.2) (10.4)
(4.6) (10.4) (1.9) (10.8) (5.2) (9.7) (22.4) (13.0) (9.7) (12.2)
Uncertain Malignant Potential, No. (%), n ¼ 34 2 5 3 1 2 5 4 7 1 4
(5.9) (14.7) (8.8) (2.9) (5.9) (14.7) (11.8) (20.6) (2.9) (11.8)
Argentina, Bolivia, China, Colombia, Dominican Republic, Egypt, France, India, Israel, Jamaica, Japan, Jordan, Mexico, Morocco, Panama, Paraguay, Peru, Philippines, Puerto Rico, Russia, Singapore, Slovakia, Spain, Syria, Turkey, United Kingdom, Venezuela, Zimbabwe.
The histopathologic review at SJCRH was conducted by a boardcertified anatomic pathologist, a hematopathologist, and/or a neuropathologist. In some cases, more than one pathologist at the SJCRH pathology department has reviewed the case and contributed to the final diagnosis (intradepartmental review). The material submitted to SJCRH included a copy of the original pathology report and histopathologic specimens. Hematoxylineosin–stained slides, unstained slides, and/or formalin-fixed paraffin-embedded tissue block(s) that the referring pathologist considered representative of the lesion were received. A brief clinical history, which included patient age, gender, and location of the lesion, were also provided by the referring pathologist in most cases. Patient’s age and sex, the anatomic site of the lesion, the ancillary techniques used to support the diagnosis (eg, immunohistochemistry [IHC]), and the country of origin were reviewed and entered into a database for further classification and analysis. The availability of IHC varied among the referring centers, and in some locations, access to reagents was limited or nonexistent. Of 763 cases, 455 (59.6%) had not been studied with any IHC stains at the international sites; hence, the primary diagnosis was based exclusively on morphologic features (examination of hematoxylineosin–stained slides only). At the discretion of the SJCRH pathologists, IHC, fluorescence in situ hybridization, Epstein-Barr virus encoded RNA in situ hybridization, or molecular diagnostic studies (usually reverse transcription-polymerase chain reaction) were performed at SJCRH laboratories using formalin-fixed, paraffin-embedded tissue sections or unstained slides. The final diagnosis of the SJCRH pathologist was compared with that of the referring pathologists, and the frequencies of concordance and disagreement were recorded. Disagreement was considered minor when it would not change treatment or outcome and was considered major when it would result in significant treatment modifications or when there was remarkable difference in the final histomorphologic and/or immunophenotypic diagnosis. Patients older than 21 years at the time of diagnosis were excluded from retrospective analysis. Cases were also excluded when a diagnosis was not possible because of insufficient tissue
quantity or quality or when the original primary diagnostic report was not available for review. The SJCRH institutional review board approved this study.
Results A total of 763 cases were reviewed and 705 cases (92.4%) were found eligible for inclusion. Ten patients (1.3%) who were older than 21 years at the time of diagnosis or whose age was unavailable were excluded from analysis. In 48 cases (6.3%), a comparison between the SJCRH final diagnosis and referring diagnosis was not recorded for the following reasons: unsatisfactory tissue preservation or insufficient tissue for diagnosis (11 cases, 1.4%), the original primary diagnostic report was not available for review (19 cases, 2.5%), or the final SJCRH diagnosis was not definitively conclusive (18 cases, 2.4%). Among the 705 eligible cases, the median age of 431 boys (61.1%) and 274 girls (38.9%) was 7.75 years (range, 3 days to 21 years). All patients had originally been diagnosed by the referring international pathologists (184 different pathologists). Of the 705 cases, 154 (21.8%) were benign processes and 517 (73.3%) malignant neoplasms. The remaining 34 cases (4.8%) could not be definitively classified as benign or malignant and included lesions with uncertain malignant potential. Of the 705 eligible cases, 542 (76.9%) were subjected to IHC at SJCRH. The panel of antibodies was based on the differential diagnoses considered for each case. The number of antibodies used per case at SJCRH ranged from 1 to 33 (average, 7.7). At the referring sites, IHC use was limited to 317 cases (45.0%), but, when IHC was used, the number of antibodies per case at the international sites was similar to SJCRH, ranging from 1 to 28 (average 7.1).
Table 2. Number of Casesa per Concordance per Year Agreement Year 2009, n ¼ 236 2010, n ¼ 242 2011, n ¼ 227 Overall, n ¼ 705 a
Per Year No. (%) 168 130 132 430
Minor Disagreement
Per Concordance %
(71.2) (53.8) (58.2) (61.0)
39.1 30.2 30.7 100
Per Year No. (%) 24 41 33 98
(10.2) (16.9) (14.5) (13.9)
Per Concordance % 24.5 41.8 33.7 100
Major Disagreement Per Year No. (%) 44 71 62 177
(18.6) (29.3) (27.3) (25.1)
Per Concordance % 24.9 40.1 35.0 100
Total after exclusions.
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Table 3. Rates of Agreement and Discrepancy Between Submitted Diagnoses and Diagnoses by St. Jude Children’s Research Hospital by Anatomic Site or Organ, N ¼ 705a Anatomical Site/ Organ Abdominal cavity Adrenal gland Bone marrow Bone CNS and spinal cord Eye Gastrointestinal Kidney Liver Lung Lymph node Mediastinal Naso/oropharynx Pelvic/peritoneal Retroperitoneal Skin Soft tissue Others, n ¼14 Total
Cases,a No. (%) 23 24 21 73 119 17 18 30 15 9 109 18 12 8 24 22 123 40 705
(3.3) (3.4) (3.0) (10.4) (16.9) (2.4) (2.6) (4.3) (2.1) (1.3) (15.5) (2.6) (1.7) (1.1) (3.4) (3.1) (17.4) (5.7) (100)
Agreement, No. (%) 12 20 16 50 59 9 11 16 8 4 68 10 10 5 16 14 80 22 430
(52.2) (83.4) (76.2) (68.5) (49.6) (52.9) (61.1) (53.3) (53.4) (44.4) (62.4) (55.5) (83.3) (62.5) (66.7) (63.6) (65.0) (55.0) (61.0)
Minor Disagreement, No. (%) 4 2 2 7 21 3 6 6 2 1 14 3 0 0 3 1 13 10 98
(17.4) (8.3) (9.5) (9.6) (17.6) (17.7) (33.3) (20.0) (13.3) (11.2) (12.8) (16.7) (0.0) (0.0) (12.5) (4.5) (10.6) (25.0) (13.9)
Major Disagreement, No. (%) 7 2 3 16 39 5 1 8 5 4 27 5 2 3 5 7 30 8 177
(30.4) (8.3) (14.3) (21.9) (32.8) (29.4) (5.6) (26.7) (33.3) (44.4) (24.8) (27.8) (16.7) (37.5) (20.8) (31.9) (24.4) (20.0) (25.1)
Abbreviation: CNS, central nervous system. a Total after exclusions.
After exclusions, the overall agreement, minor disagreement, and major disagreement rates between the referring and SJCRH diagnoses were calculated as 430 (61.0%), 98 (13.9%), and 177 (25.1%), respectively (Table 2). The major disagreement rate among the countries that referred most of the cases ranged from 13.7% to 37.1%. Of the 177 major disagreements, 50 cases (28.2%) had a final benign diagnosis, and 119 cases (67.2%) were malignant. In 8 cases (4.5%), the exact histopathologic nature of the lesion could not be established by the SJCRH reviewer, but the difference between original diagnosis and the final SJCRH diagnosis was sufficient to classify the cases as a major disagreement (eg, a soft tissue lesion of the distal third of left thigh: original diagnosis, high-grade sarcoma; SJCRH final diagnosis, negative for definitive neoplastic process). Lesions were located in all sites of the body. As shown in Table 3, the anatomic sites that resulted in most of the major disagreements were the central nervous system, lymph nodes, and soft tissues. Sorting for anatomic location, the major disagreement rate ranged from 5.6% (1 of 18) for the gastrointestinal tract to 44.4% (4 of 9) for the lung (Table 3). As shown in Table 4, most (57.6%) major disagreements (102 of 177) were equally diagnosed as malignant by the international pathologist and SJCRH pathologist, but the difference in the final diagnosis was significant enough for
the case to be considered major disagreements (eg, a cerebellar tumor originally diagnosed as anaplastic ependymoma, a World Health Organization grade III tumor, but with a reviewed diagnosis of atypical teratoid-rhabdoid tumor, a World Health Organization grade IV tumor; IHC was performed in this case at the referring site and at SJCRH). Our analysis revealed that the change from malignant diagnosis by the international pathologist to a final benign diagnosis by the SJCRH pathologist (n ¼ 46) was three times more frequent than the change from benign to malignant (n ¼ 15; Table 4). Among the 177 major disagreements, 85 cases (48.0%) had IHC done at an international site. In 78 of 85 cases (91.8%), the number of antibodies used ranged from 1 to 17. In 7 other cases (8.2%), IHC was performed, but the number of antibodies used is unknown. With the exception of 2 cases (2.4%), all of the other 83 cases (97.6%) had IHC done at SJCRH. The 2 cases in which SJCRH pathologist deemed IHC unnecessary in discordance with the international pathologist were (1) an original diagnosis of embryonal rhabdomyosarcoma with an SJCRH final diagnosis of fibroosseous lesion and possible fracture with secondary aneurysmal bone cyst and no evidence of rhabdomyosarcoma in the reviewed material; and (2) an original diagnosis that included the following differential diagnosis: possible
Table 4. Cases of Major Disagreement and Correlation With Use of Immunohistochemistry (IHC) by International Pathologists and Changes to the Diagnosis by St. Jude Children’s Research Hospital, N ¼ 177a IHC Used by Referring Pathologists Change in the Diagnosis From malignant to benign From benign to malignant Malignant to malignant Benign to benign Not determined Total a
Yes, No. (%) 20 (11.3) 5 (2.8) 55 (31.1) 0 (0.0) 5 (2.8) 85 (48.0)
No, No. (%) 22 (12.4) 7 (4.0) 36 (20.3) 2 (1.1) 7 (4.0) 74 (41.8)
No Information Available, No. (%) 4 (2.3) 3 (1.7) 11 (6.2) 0 (0.0) 0 (0.0) 18 (10.2)
Total,a No. (%) 46 15 102 2 12 177
(26.0) (8.5) (57.6) (1.1) (6.8) (100)
Total after exclusions.
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Table 5. Cases of Major Disagreement in Which Immunohistochemistry Was Not Used by Either St. Jude Children’s Research Hospital (SJCRH) Reviewers or Referring Pathologists, N ¼ 18 Anatomic Site/Organ Soft tissue, neck mass Eye, right Bone, right distal femur Skin, face, biopsy Bone, left humerus Bone, mandible Brain, septal lesion Soft tissue, left arm Brain, posterior cranial fossa Thyroid gland Brain, right temporal lobe Bone, posterior cranial fossa Lymph node, retroperitoneal Eye, right Bone and dura, right parietal region Bone, third thoracic vertebra Soft tissue, left arm Bone, maxilla
SJCRH-Reviewed Diagnosis Ganglioneuroblastoma, Schwannian stroma-rich, intermixed Coats disease; negative for neoplastic process Favor chondrosarcoma, grade I, arising in an osteochondroma Favor nevus sebaceous of Jadassohn Favor aneurysmal bone cyst Chondroblastic osteosarcoma Brain parenchyma negative for definitive neoplastic process Fibrous hamartoma of infancy Pilocytic astrocytoma, WHO grade I Favor follicular adenoma Glioblastoma, WHO grade IV Favor aneurysmal bone cyst Neuroblastoma, Schwannian stroma-poor, poorly differentiated, low MKI, Shimada unfavorable Infiltrative process in uveal tract and choroid (toxocariasis?) Favor malignant melanoma; melanocytoma should also be included in differential diagnosis. Telangiectatic osteosarcoma, high grade Nodular fasciitis Conventional high-grade osteosarcoma, fibroblastic type
Submitted Diagnosis Ganglioneuroma Melanoma? versus retinoblastoma? Osteochondroma with no definitive evidence of malignancy Sebaceous carcinoma Osteosarcoma, well differentiated Low-grade chondromyxoid tumor Recurrent medulloblastoma Neurilemmoma (schwannoma) Oligodendroglioma Follicular carcinoma? Medullary carcinoma? Pleomorphic xanthoastrocytoma (WHO II) Giant cell tumor PNET/Ewing sarcoma Malignant melanoma Melanotic neuroectodermal tumor of infancy Langerhans cell histiocytosis? Aggressive infantile myofibromatosis Fibro-osseous tumor of uncertain malignant potential
Abbreviations: MKI, mitosis-karyorrhexis index; PNET, primitive neuroectodermal tumor; WHO, World Health Organization.
extranodal histiocytic sarcoma, synovial sarcoma, or rhabdomyosarcoma; whereas the SJCRH final diagnosis favored osteosarcoma. Immunohistochemistry was not performed by international pathologists in 74 of 177 major disagreements (41.8%). In 18 of 74 cases (24.3%), the SJCRH pathologist made a final diagnosis based on histomorphology alone (Table 5). In the remaining cases (56 of 74; 75.7%), IHC was performed at SJCRH and deemed necessary for diagnosis. COMMENT Review of the histopathologic diagnosis of challenging and difficult cases increases diagnostic accuracy and precision of pediatric neoplasms. Referring cases for second opinion would not only help to elucidate the diagnosis but also can and should be used as part of a quality control program in pathology practices. Sending a case for review and evaluation by an expert pathologist is a healthy practice for identifying errors in anatomic pathology laboratories and has been recommended by accrediting agencies in the United States.14 Some institutions in the United States require that every new diagnosis of malignancy be reviewed by a second inhouse pathologist before case verification (prospective peer review), which may decrease the final disagreement rate.15 In many countries with limited resources, however, the pathology service is run by a lone pathologist, who may not have formal training in the diagnosis of pediatric neoplasms and may have only limited on-the-job training. Some pediatric international oncology services in developing countries have dedicated pathologists who demonstrate familiarity with the common pediatric neoplasms and are willing to participate as members of a multidisciplinary team with the pediatric oncologists, radiologists, and surgeons. Referring sites with a dedicated pathologist Arch Pathol Lab Med—Vol 137, November 2013
working closely with a pediatric oncology team or with a pathologist with specialized training in the diagnosis of pediatric neoplasms demonstrate a lower rate of major disagreements compared with international sites that do not have such a pathologist. Focused training of a general pathologist in the diagnosis of pediatric neoplasms, implementation of a basic IHC panel in a pathology laboratory in a developing country, and inclusion of the pathologist in a multidisciplinary team can dramatically improve the diagnostic accuracy of pediatric neoplasms.16 Immunohistochemistry is an important and sometimes essential tool for the definitive diagnosis of pediatric neoplasms. In a limited resource area, use of a comprehensive panel of available antibodies is probably unrealistic. The cost-effective aspect of having at least a basic panel of antibodies available at pediatric pathology laboratories seems to be a reasonable approach to improving diagnostic accuracy. In our experience, a reasonable basic panel of antibodies to aid in the diagnosis of most common childhood neoplasm should include pancytokeratin (cytokeratin AE1–AE3), epithelial membrane antigen, vimentin, synaptophysin, CD99, terminal deoxynucleotidyl transferase, CD43, myogenin, CD1a, placental alkaline phosphatase, a-fetoprotein, CD30, CD15, CD20, and CD3, although the use and interpretation of IHC should always be performed within the context of the lesion histomorphology, pattern of expression and intensity of the IHC stain, and proper evaluation of positive and negative controls. In our analysis, when IHC was available, its use by the international pathologists seemed appropriate. In 97.6% of major disagreement cases in which IHC was performed at the international sites (83 out of 85 cases), the use of IHC was considered necessary by SJCRH pathologists to establish a final diagnosis. Our current data preclude definite conclusions, but the nonavailability of an essential IHC antibody, selection of an inappropriate antibody panel, misinterpre-
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tation of the performed IHC, or technical problems with the IHC reaction may be contributory factors in the misdiagnosis in these cases. In 18 of 177 cases classified as major disagreements (10.2%; Table 5), IHC was not used by the referring pathologists or the pathologist at SJCRH, and the diagnosis was based on histomorphology only. This emphasizes the importance of in-depth training of the international pathologists in the diagnosis of pediatric tumors and in the appropriate use of IHC. However, we believe training goals and objectives should be tailored to the international pathologist’s individual needs and level of expertise. A rootcause analysis of each individual international pathology service is also likely necessary to correct and eliminate fault events. Although not directly focused on pathology laboratories that diagnose pediatric neoplasms, the work of Pathologists Overseas (Del Mar, California) has helped to improve the conditions of many general pathology services in developing countries.17 The activities of Pathologists Overseas are done through the efforts of many volunteer pathologists and technologists, are tailored to local needs, and have included installation of new equipment, establishment of a basic quality control program, training of local physicians in anatomic pathology, and participation in teaching in international medical and medical technology schools. Some of the international pathologists had the opportunity for sabbatical training in United States, and the volunteer pathologists helped to cover the local service in the absence of the trainee. An annual visit to international sites to monitor the activities and progress was also performed. Problems with tissue fixation and processing, which can lead to suboptimal preservation of tissue antigens, must be appropriately addressed before implementation and use of diagnostic IHC. Many international histopathologic specimens received at SJCRH for review demonstrate problems with tissue fixation, and in some cases, those problems precluded a final diagnosis. The use of an adequate fixative (10% neutral-buffered formalin, pH ranging from 6.8 to 7.1), fixation time (including processing time up to 24 hours and 3–4 mm thickness of the tissue sample) are simple and implementable actions that can be accomplished in any pathology laboratory worldwide, which are key determinants for the quality of the tissue morphology as well as the preservation of tissue antigenicity for future IHC reactions, if applicable. Lones et al18 evaluated the effect of poor technical quality of histology and its adverse effects on the diagnosis of mature B-cell non-Hodgkin lymphoma in children and adolescents. Their analysis of 187 such cases demonstrated that the rate of agreement was significantly higher with good or medium histology technical quality than with low histology technical quality. Targeted therapy and genomics have greatly changed the way we understand and treat cancer, and a discussion of proper tissue fixation and availability of IHC may seem passe, ´ but, unfortunately, those are still real problems among many pediatric oncology centers around the world. Although outstanding pediatric diagnostic centers with state-of-the-art facilities and highly qualified diagnosticians exist in many developing countries, they are in the minority and are largely limited to larger centers. Many countries in South and Central America, Africa, and East Asia still lack dedicated pediatric-oncology units, and pathology services and pathologists are nonexistent in some places. An analysis
of a local pathology service in one hospital in Uganda has demonstrated serious problems with tissue handling, proper fixation, and the availability of IHC. Based on morphology alone, the Uganda local pathologist was able to diagnose 82% of the Burkitt lymphoma cases (37 out of 45 cases).19 Similar conditions for pathology practices are seen in Nigeria.20 The rate of major disagreement between the referring international sites and SJCRH is far beyond what is seen in US institutions. Roy and Hunt21 have showed in their review article that diagnostic discrepancy when reviewing outside material from general sign-out range from 1.4% to 11.3%. The error rate can vary by anatomic site, and specialized and focused review of cases can lead to a higher major disagreement as noted by Thway and Fisher.22 In their retrospective review of 349 soft tissue tumors, a 15.7% (n ¼ 55) rate of major disagreement was identified. In our review, soft tissue, central nervous system, and hematolymphoid lesions encompass most of the cases sent for review and represent most of the cases of major disagreement (Table 3). Nevertheless, when we evaluate the discrepancy rate according to anatomic location, a wide range of variation in major disagreements by site is noted (5.6% to 44.4%). The nature of the lesions and pathologists who lack familiarity with rare and specific entities might explain the high rate of major disagreement in some anatomic locations. In an overall assessment, the type, selective difficulty, and complexity of cases submitted from the international sites for review at SJCRH may have significantly affected our rate of disagreement and contributed to a higher discordance rate in our analysis. A random and unbiased review of cases from the same international pathology centers could possibly provide a lower disagreement rate, but corrective actions should be encouraged, and our overall major disagreement rate of 25.1% (range, 13.7% to 37.1%) is worrisome. In summary, we hope our experience, reviewed in this article, will increase awareness of the challenge to correctly diagnose pediatric neoplasms, especially in low- and middle-income countries where the pathology services may be suboptimal. We also hope to promote the establishment of a basic IHC panel that would aid in the diagnosis of the most common pediatric malignancies, especially the group of small blue cell neoplasms. We strongly believe these initiatives would improve the overall quality and accuracy of the diagnoses of pediatric solid tumors and lymphomas in more disadvantaged areas of the world and decrease the rates of disagreement and discrepancies.
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15. Renshaw AA, Gould EW. Measuring the value of review of pathology material by a second pathologist. Am J Clin Pathol. 2006;125(5):737–739. 16. Santiago TC, Jenkins JJ, Pedrosa F, et al. Improving the histopathologic diagnosis of pediatric malignancies in a low-resource setting by combining focused training and telepathology strategies. Pediatr Blood Cancer. 2012;59(2): 221–225. 17. Hoenecke H, Lee V, Roy I. Pathologists overseas: coordinating volunteer pathology services for 19 years. Arch Pathol Lab Med. 2011;135(2):173–178. 18. Lones MA, Raphael M, Perkins SL, et al. Mature B-cell lymphoma in children and adolescents: international group pathologist consensus correlates with histology technical quality. J Pediatr Hematol Oncol. 2006;28(9):568–574. 19. Ogwang MD, Zhao W, Ayers LW, Mbulaiteye SM. Accuracy of Burkitt lymphoma diagnosis in constrained pathology settings: importance to epidemiology. Arch Pathol Lab Med. 2011;135(4):445–450. 20. Adeyi OA. Pathology services in developing countries: the West African experience. Arch Pathol Lab Med. 2011;135(2):183–186. 21. Roy JE, Hunt JL. Detection and classification of diagnostic discrepancies (errors) in surgical pathology. Adv Anat Pathol. 2010;17(5):359–365. 22. Thway K, Fisher C. Histopathological diagnostic discrepancies in soft tissue tumours referred to a specialist centre. Sarcoma. 2009;2009:741975. doi: 10. 1155/2009/741975.
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