Histopathologic Diagnosis of Pediatric

A Review of International Consultations

Teresa C. Santiago, MD; Jesse J. Jenkins, MD

Context.—Correct histopathologic diagnosis is funda- and evaluation. Of 763 cases reviewed, 705 (92.4%) met mental to defining proper treatment and improving the criteria for inclusion in this study. Rates of concor- outcomes in children with malignancies. The Department dance between the submitted diagnoses and SJCRH of Pathology at St. Jude Children’s Research Hospital reviewed diagnoses were analyzed. (SJCRH) has collaborated with SJCRH International Out- Results.—Overall concordance, minor disagreement, reach Program partner sites to improve the accuracy of and major disagreement rates between submitted diagno- histopathologic diagnoses in countries with limited re- ses and SJCRH reviewed diagnoses were 430 (61.0%), 98 sources. Pathologists at SJCRH provide review and (13.9%), and 177 (25.1%) of the cases, respectively. Major evaluation of cases that are considered difficult or disagreement rates ranged from 13.7% to 37.1% among complex. studied countries. Objectives.—To determine the quality of pathology diagnosis and to identify areas for improvement in our Conclusions.—The major disagreement rate between international partner sites, we retrospectively analyzed all referring international sites and SJCRH was substantially the international cases that were submitted for review. A higher than the major disagreement rate among US comparison of our data with selected reports of surgical institutions. Lack of the availability of immunohistochem- pathology error rates published in the medical literature istry and the training of pathologists in the diagnosis of was performed. pediatric neoplasms may have contributed to the discrep- Design.—From January 2009 through December 2011, ancies. SJCRH received 763 cases submitted by international (Arch Pathol Lab Med. 2013;137:1648–1653; doi: pathologists from 37 countries for histopathologic review 10.5858/arpa.2012-0571-OA)

he survival rate of children with malignancies has children with malignancies has been one of the priorities of T increased dramatically in recent years. Data from the the SJCRH International Outreach Program. Local pathol- United States and Western Europe show estimated cure ogists are identified and trained at SJCRH for periods of rates around 80%.1,2 Critical to this progress are accurate weeks or months. In addition, support for improvement of diagnoses and adequate treatment. However, most of the the local laboratory infrastructure and ongoing maintenance world’s children live in areas with limited resources, where is provided. Moreover, given the rarity and diagnostic training in diagnoses and access to treatment is limited; difficulties presented by many pediatric neoplasms, SJCRH hence, not surprisingly, the estimates of survival are lower pathologists provide ongoing histopathologic review of than those in developed countries, ranging from 5% to complex cases, which benefits the patient and provides 3 40%. To improve the survival rates of children with cancer education for international pathologists. To identify areas for in selected low- and middle-income countries, St Jude potential improvement in histologic diagnoses internation- Children’s Research Hospital (SJCRH) has developed a ally in our partner sites, we retrospectively analyzed cases comprehensive program to increase access to care, including submitted to the SJCRH Department of Pathology for expanding the diagnostic capabilities of pathologists and the histopathologic review. We sought to determine the rates of, 4–13 treatment opportunities of children with neoplasms. and reasons for, histologic-diagnostic discrepancy between Creating the local capacity to provide correct diagnoses of international and SJCRH pathologists. Selected factors potentially associated with discrepancies were investigated and recommendations were made to improve the accuracy Accepted for publication January 7, 2012. From the Department of Pathology, University of Tennessee Health of the histopathologic diagnosis of pediatric neoplasms. Science Center, Memphis (Dr Santiago); and the Department of Pathology, St. Jude Children’s Research Hospital, Memphis (Dr MATERIALS AND METHODS Jenkins). The authors have no relevant financial interest in the products or From January 1, 2009, through December 31, 2011, 763 pediatric companies described in this article. cases referred from outside of the United States were received for Reprints: Jesse J. Jenkins, MD, Department of Pathology, St. Jude histopathologic review at the SJCRH Department of Pathology. The Children’s Research Hospital, 262 Danny Thomas Place, Memphis, cases were submitted by community and pediatric hospitals and TN 38105-3678 (e-mail: [email protected]). academic medical centers from 37 countries (Table 1). 1648 Arch Pathol Lab Med—Vol 137, November 2013 International Consultations of Pediatric Neoplasms––Santiago & Jenkins Table 1. St. Jude Children’s Research Hospital’s Histopathologic Review of International Cases From January 1, 2009, to December 31, 2011 Referring Uncertain Cases, Pathologists, Excluded Cases, Male, Female, Benign, Malignant, Malignant Potential, Countries, No. (%), No. (%), No. (%), No. (%), No. (%), No. (%), No. (%), No. (%), n ¼ 37 n ¼ 763 n ¼ 184 n ¼ 58 n ¼ 431 n ¼ 274 n ¼ 154 n ¼ 517 n ¼ 34 Brazil 40 (5.2) 12 (6.5) 2 (3.4) 23 (5.3) 15 (5.5) 12 (7.8) 24 (4.6) 2 (5.9) Chile 73 (9.6) 12 (6.5) 3 (5.2) 45 (10.4) 25 (9.1) 11 (7.1) 54 (10.4) 5 (14.7) Costa Rica 14 (1.8) 6 (3.3) 1 (1.7) 9 (2.1) 4 (1.5) 0 (0.0) 10 (1.9) 3 (8.8) Ecuador 85 (11.1) 27 (14.7) 4 (6.9) 51 (11.8) 30 (10.9) 24 (15.6) 56 (10.8) 1 (2.9) El Salvador 48 (6.3) 2 (1.1) 2 (3.4) 30 (7.0) 16 (5.8) 17 (11.0) 27 (5.2) 2 (5.9) Guatemala 76 (10.0) 1 (0.5) 4 (6.9) 43 (10.0) 29 (10.6) 17 (11.0) 50 (9.7) 5 (14.7) Honduras 169 (22.1) 31 (16.8) 21 (36.2) 91 (21.1) 57 (20.8) 28 (18.2) 116 (22.4) 4 (11.8) Lebanon 108 (14.2) 28 (15.2) 13 (22.4) 51 (11.8) 44 (16.1) 21 (13.6) 67 (13.0) 7 (20.6) Nicaragua 61 (8.0) 7 (3.8) 2 (3.4) 42 (9.7) 17 (6.2) 8 (5.2) 50 (9.7) 1 (2.9) Othersa 89 (11.7) 58 (31.5) 6 (10.3) 46 (10.7) 37 (13.5) 16 (10.4) 63 (12.2) 4 (11.8) a 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 board- quantity or quality or when the original primary diagnostic report certified anatomic pathologist, a hematopathologist, and/or a was not available for review. The SJCRH institutional review board neuropathologist. In some cases, more than one pathologist at approved this study. the SJCRH pathology department has reviewed the case and contributed to the final diagnosis (intradepartmental review). The Results material submitted to SJCRH included a copy of the original pathology report and histopathologic specimens. Hematoxylin- A total of 763 cases were reviewed and 705 cases (92.4%) eosin–stained slides, unstained slides, and/or formalin-fixed were found eligible for inclusion. Ten patients (1.3%) who paraffin-embedded tissue block(s) that the referring pathologist were older than 21 years at the time of diagnosis or whose considered representative of the lesion were received. A brief age was unavailable were excluded from analysis. In 48 clinical history, which included patient age, gender, and location of cases (6.3%), a comparison between the SJCRH final the lesion, were also provided by the referring pathologist in most diagnosis and referring diagnosis was not recorded for the cases. Patient’s age and sex, the anatomic site of the lesion, the following reasons: unsatisfactory tissue preservation or ancillary techniques used to support the diagnosis (eg, immuno- insufficient tissue for diagnosis (11 cases, 1.4%), the original histochemistry [IHC]), and the country of origin were reviewed and entered into a database for further classification and analysis. primary diagnostic report was not available for review (19 The availability of IHC varied among the referring centers, and in cases, 2.5%), or the final SJCRH diagnosis was not some locations, access to reagents was limited or nonexistent. Of definitively conclusive (18 cases, 2.4%). 763 cases, 455 (59.6%) had not been studied with any IHC stains at Among the 705 eligible cases, the median age of 431 boys the international sites; hence, the primary diagnosis was based (61.1%) and 274 girls (38.9%) was 7.75 years (range, 3 days exclusively on morphologic features (examination of hematoxylin- to 21 years). All patients had originally been diagnosed by eosin–stained slides only). At the discretion of the SJCRH the referring international pathologists (184 different pathologists, IHC, fluorescence in situ hybridization, Epstein-Barr virus encoded RNA in situ hybridization, or molecular diagnostic pathologists). Of the 705 cases, 154 (21.8%) were benign studies (usually reverse transcription-polymerase chain reaction) processes and 517 (73.3%) malignant neoplasms. The were performed at SJCRH laboratories using formalin-fixed, remaining 34 cases (4.8%) could not be definitively classified paraffin-embedded tissue sections or unstained slides. as benign or malignant and included lesions with uncertain The final diagnosis of the SJCRH pathologist was compared with malignant potential. that of the referring pathologists, and the frequencies of Of the 705 eligible cases, 542 (76.9%) were subjected to concordance and disagreement were recorded. Disagreement was IHC at SJCRH. The panel of antibodies was based on the considered minor when it would not change treatment or outcome differential diagnoses considered for each case. The number and was considered major when it would result in significant treatment modifications or when there was remarkable difference of antibodies used per case at SJCRH ranged from 1 to 33 in the final histomorphologic and/or immunophenotypic diagnosis. (average, 7.7). At the referring sites, IHC use was limited to Patients older than 21 years at the time of diagnosis were 317 cases (45.0%), but, when IHC was used, the number of excluded from retrospective analysis. Cases were also excluded antibodies per case at the international sites was similar to when a diagnosis was not possible because of insufficient tissue SJCRH, ranging from 1 to 28 (average 7.1).

Table 2. Number of Casesa per Concordance per Year Agreement Minor Disagreement Major Disagreement Per Year Per Concordance Per Year Per Concordance Per Year Per Concordance Year No. (%) % No. (%) % No. (%) % 2009, n ¼ 236 168 (71.2) 39.1 24 (10.2) 24.5 44 (18.6) 24.9 2010, n ¼ 242 130 (53.8) 30.2 41 (16.9) 41.8 71 (29.3) 40.1 2011, n ¼ 227 132 (58.2) 30.7 33 (14.5) 33.7 62 (27.3) 35.0 Overall, n ¼ 705 430 (61.0) 100 98 (13.9) 100 177 (25.1) 100 a Total after exclusions. Arch Pathol Lab Med—Vol 137, November 2013 International Consultations of Pediatric Neoplasms––Santiago & Jenkins 1649 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/ Cases,a Agreement, Minor Disagreement, Major Disagreement, Organ No. (%) No. (%) No. (%) No. (%) Abdominal cavity 23 (3.3) 12 (52.2) 4 (17.4) 7 (30.4) Adrenal gland 24 (3.4) 20 (83.4) 2 (8.3) 2 (8.3) Bone marrow 21 (3.0) 16 (76.2) 2 (9.5) 3 (14.3) Bone 73 (10.4) 50 (68.5) 7 (9.6) 16 (21.9) CNS and spinal cord 119 (16.9) 59 (49.6) 21 (17.6) 39 (32.8) Eye 17 (2.4) 9 (52.9) 3 (17.7) 5 (29.4) Gastrointestinal 18 (2.6) 11 (61.1) 6 (33.3) 1 (5.6) Kidney 30 (4.3) 16 (53.3) 6 (20.0) 8 (26.7) Liver 15 (2.1) 8 (53.4) 2 (13.3) 5 (33.3) Lung 9 (1.3) 4 (44.4) 1 (11.2) 4 (44.4) Lymph node 109 (15.5) 68 (62.4) 14 (12.8) 27 (24.8) Mediastinal 18 (2.6) 10 (55.5) 3 (16.7) 5 (27.8) Naso/oropharynx 12 (1.7) 10 (83.3) 0 (0.0) 2 (16.7) Pelvic/peritoneal 8 (1.1) 5 (62.5) 0 (0.0) 3 (37.5) Retroperitoneal 24 (3.4) 16 (66.7) 3 (12.5) 5 (20.8) Skin 22 (3.1) 14 (63.6) 1 (4.5) 7 (31.9) 123 (17.4) 80 (65.0) 13 (10.6) 30 (24.4) Others, n ¼14 40 (5.7) 22 (55.0) 10 (25.0) 8 (20.0) Total 705 (100) 430 (61.0) 98 (13.9) 177 (25.1) Abbreviation: CNS, central nervous system. a Total after exclusions.

After exclusions, the overall agreement, minor disagree- the case to be considered major disagreements (eg, a ment, and major disagreement rates between the referring cerebellar tumor originally diagnosed as anaplastic ependy- and SJCRH diagnoses were calculated as 430 (61.0%), 98 moma, a World Health Organization grade III tumor, but (13.9%), and 177 (25.1%), respectively (Table 2). The major with a reviewed diagnosis of atypical teratoid-rhabdoid disagreement rate among the countries that referred most of tumor, a World Health Organization grade IV tumor; IHC the cases ranged from 13.7% to 37.1%. was performed in this case at the referring site and at Of the 177 major disagreements, 50 cases (28.2%) had a SJCRH).

final benign diagnosis, and 119 cases (67.2%) were Our analysis revealed that the change from malignant malignant. In 8 cases (4.5%), the exact histopathologic diagnosis by the international pathologist to a final benign nature of the lesion could not be established by the SJCRH diagnosis by the SJCRH pathologist (n ¼ 46) was three times reviewer, but the difference between original diagnosis and more frequent than the change from benign to malignant (n the final SJCRH diagnosis was sufficient to classify the cases ¼ 15; Table 4). as a major disagreement (eg, a soft tissue lesion of the distal Among the 177 major disagreements, 85 cases (48.0%) third of left thigh: original diagnosis, high-grade ; had IHC done at an international site. In 78 of 85 cases SJCRH final diagnosis, negative for definitive neoplastic (91.8%), the number of antibodies used ranged from 1 to 17. process). In 7 other cases (8.2%), IHC was performed, but the number Lesions were located in all sites of the body. As shown in of antibodies used is unknown. With the exception of 2 Table 3, the anatomic sites that resulted in most of the major cases (2.4%), all of the other 83 cases (97.6%) had IHC done disagreements were the central nervous system, lymph at SJCRH. The 2 cases in which SJCRH pathologist deemed nodes, and soft tissues. Sorting for anatomic location, the IHC unnecessary in discordance with the international major disagreement rate ranged from 5.6% (1 of 18) for the pathologist were (1) an original diagnosis of embryonal gastrointestinal tract to 44.4% (4 of 9) for the lung (Table 3). with an SJCRH final diagnosis of fibro- As shown in Table 4, most (57.6%) major disagreements osseous lesion and possible fracture with secondary (102 of 177) were equally diagnosed as malignant by the aneurysmal bone cyst and no evidence of rhabdomyosar- international pathologist and SJCRH pathologist, but the coma in the reviewed material; and (2) an original diagnosis difference in the final diagnosis was significant enough for 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 Yes, No. (%) No, No. (%) No Information Available, No. (%) Total,a No. (%) From malignant to benign 20 (11.3) 22 (12.4) 4 (2.3) 46 (26.0) From benign to malignant 5 (2.8) 7 (4.0) 3 (1.7) 15 (8.5) Malignant to malignant 55 (31.1) 36 (20.3) 11 (6.2) 102 (57.6) Benign to benign 0 (0.0) 2 (1.1) 0 (0.0) 2 (1.1) Not determined 5 (2.8) 7 (4.0) 0 (0.0) 12 (6.8) Total 85 (48.0) 74 (41.8) 18 (10.2) 177 (100) a Total after exclusions. 1650 Arch Pathol Lab Med—Vol 137, November 2013 International Consultations of Pediatric Neoplasms––Santiago & Jenkins 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 SJCRH-Reviewed Diagnosis Submitted Diagnosis Soft tissue, neck mass Ganglioneuroblastoma, Schwannian stroma-rich, Ganglioneuroma intermixed Eye, right Coats disease; negative for neoplastic process Melanoma? versus retinoblastoma? Bone, right distal femur Favor chondrosarcoma, grade I, arising in an Osteochondroma with no definitive evidence osteochondroma of malignancy Skin, face, biopsy Favor nevus sebaceous of Jadassohn Sebaceous carcinoma Bone, left humerus Favor aneurysmal bone cyst Osteosarcoma, well differentiated Bone, mandible Chondroblastic osteosarcoma Low-grade chondromyxoid tumor Brain, septal lesion Brain parenchyma negative for definitive Recurrent medulloblastoma neoplastic process Soft tissue, left arm Fibrous hamartoma of infancy Neurilemmoma (schwannoma) Brain, posterior cranial fossa Pilocytic astrocytoma, WHO grade I Oligodendroglioma Thyroid gland Favor follicular adenoma Follicular carcinoma? Medullary carcinoma? Brain, right temporal lobe Glioblastoma, WHO grade IV Pleomorphic xanthoastrocytoma (WHO II) Bone, posterior cranial fossa Favor aneurysmal bone cyst Giant cell tumor Lymph node, retroperitoneal Neuroblastoma, Schwannian stroma-poor, poorly PNET/Ewing sarcoma differentiated, low MKI, Shimada unfavorable Eye, right Infiltrative process in uveal tract and choroid Malignant melanoma (toxocariasis?) Bone and dura, right parietal Favor malignant melanoma; melanocytoma Melanotic neuroectodermal tumor of infancy region should also be included in differential diagnosis. Bone, third thoracic vertebra Telangiectatic osteosarcoma, high grade Langerhans cell ? Soft tissue, left arm Aggressive infantile myofibromatosis Bone, maxilla Conventional high-grade osteosarcoma, Fibro-osseous tumor of uncertain malignant fibroblastic type potential Abbreviations: MKI, mitosis-karyorrhexis index; PNET, primitive neuroectodermal tumor; WHO, World Health Organization. extranodal histiocytic sarcoma, , or rhab- working closely with a pediatric team or with a domyosarcoma; whereas the SJCRH final diagnosis favored pathologist with specialized training in the diagnosis of osteosarcoma. pediatric neoplasms demonstrate a lower rate of major Immunohistochemistry was not performed by interna- disagreements compared with international sites that do not tional pathologists in 74 of 177 major disagreements have such a pathologist. Focused training of a general (41.8%). In 18 of 74 cases (24.3%), the SJCRH pathologist pathologist in the diagnosis of pediatric neoplasms, made a final diagnosis based on histomorphology alone implementation of a basic IHC panel in a pathology (Table 5). In the remaining cases (56 of 74; 75.7%), IHC was laboratory in a developing country, and inclusion of the performed at SJCRH and deemed necessary for diagnosis. pathologist in a multidisciplinary team can dramatically improve the diagnostic accuracy of pediatric neoplasms.16 COMMENT Immunohistochemistry is an important and sometimes essential tool for the definitive diagnosis of pediatric Review of the histopathologic diagnosis of challenging neoplasms. In a limited resource area, use of a comprehen- and difficult cases increases diagnostic accuracy and sive panel of available antibodies is probably unrealistic. The precision of pediatric neoplasms. Referring cases for second cost-effective aspect of having at least a basic panel of opinion would not only help to elucidate the diagnosis but antibodies available at pediatric pathology laboratories also can and should be used as part of a quality control seems to be a reasonable approach to improving diagnostic program in pathology practices. Sending a case for review accuracy. In our experience, a reasonable basic panel of and evaluation by an expert pathologist is a healthy practice antibodies to aid in the diagnosis of most common for identifying errors in anatomic pathology laboratories and childhood should include pancytokeratin (cyto- has been recommended by accrediting agencies in the 14 keratin AE1–AE3), epithelial membrane antigen, vimentin, United States. synaptophysin, CD99, terminal deoxynucleotidyl transfer- Some institutions in the United States require that every ase, CD43, myogenin, CD1a, placental alkaline phospha- new diagnosis of malignancy be reviewed by a second in- tase, a-fetoprotein, CD30, CD15, CD20, and CD3, although house pathologist before case verification (prospective peer the use and interpretation of IHC should always be 15 review), which may decrease the final disagreement rate. performed within the context of the lesion histomorphology, In many countries with limited resources, however, the pattern of expression and intensity of the IHC stain, and pathology service is run by a lone pathologist, who may not proper evaluation of positive and negative controls. In our have formal training in the diagnosis of pediatric neoplasms analysis, when IHC was available, its use by the interna- and may have only limited on-the-job training. tional pathologists seemed appropriate. In 97.6% of major Some pediatric international oncology services in devel- disagreement cases in which IHC was performed at the oping countries have dedicated pathologists who demon- international sites (83 out of 85 cases), the use of IHC was strate familiarity with the common pediatric neoplasms and considered necessary by SJCRH pathologists to establish a are willing to participate as members of a multidisciplinary final diagnosis. Our current data preclude definite conclu- team with the pediatric oncologists, radiologists, and sions, but the nonavailability of an essential IHC antibody, surgeons. Referring sites with a dedicated pathologist selection of an inappropriate antibody panel, misinterpre- Arch Pathol Lab Med—Vol 137, November 2013 International Consultations of Pediatric Neoplasms––Santiago & Jenkins 1651 tation of the performed IHC, or technical problems with the of a local pathology service in one hospital in Uganda has IHC reaction may be contributory factors in the misdiag- demonstrated serious problems with tissue handling, proper nosis in these cases. fixation, and the availability of IHC. Based on morphology In 18 of 177 cases classified as major disagreements alone, the Uganda local pathologist was able to diagnose (10.2%; Table 5), IHC was not used by the referring 82% of the Burkitt lymphoma cases (37 out of 45 cases).19 pathologists or the pathologist at SJCRH, and the diagnosis Similar conditions for pathology practices are seen in was based on histomorphology only. This emphasizes the Nigeria.20 importance of in-depth training of the international The rate of major disagreement between the referring pathologists in the diagnosis of pediatric tumors and in international sites and SJCRH is far beyond what is seen in the appropriate use of IHC. However, we believe training US institutions. Roy and Hunt21 have showed in their review goals and objectives should be tailored to the international article that diagnostic discrepancy when reviewing outside pathologist’s individual needs and level of expertise. A root- material from general sign-out range from 1.4% to 11.3%. cause analysis of each individual international pathology The error rate can vary by anatomic site, and specialized and service is also likely necessary to correct and eliminate fault focused review of cases can lead to a higher major events. disagreement as noted by Thway and Fisher.22 In their Although not directly focused on pathology laboratories retrospective review of 349 soft tissue tumors, a 15.7% (n ¼ that diagnose pediatric neoplasms, the work of Pathologists 55) rate of major disagreement was identified. Overseas (Del Mar, California) has helped to improve the In our review, soft tissue, central nervous system, and conditions of many general pathology services in developing hematolymphoid lesions encompass most of the cases sent countries.17 The activities of Pathologists Overseas are done for review and represent most of the cases of major through the efforts of many volunteer pathologists and disagreement (Table 3). Nevertheless, when we evaluate technologists, are tailored to local needs, and have included the discrepancy rate according to anatomic location, a wide installation of new equipment, establishment of a basic range of variation in major disagreements by site is noted quality control program, training of local physicians in (5.6% to 44.4%). The nature of the lesions and pathologists anatomic pathology, and participation in teaching in who lack familiarity with rare and specific entities might international medical and medical technology schools. explain the high rate of major disagreement in some Some of the international pathologists had the opportunity anatomic locations. In an overall assessment, the type, for sabbatical training in United States, and the volunteer selective difficulty, and complexity of cases submitted from pathologists helped to cover the local service in the absence the international sites for review at SJCRH may have of the trainee. An annual visit to international sites to significantly affected our rate of disagreement and contrib- monitor the activities and progress was also performed. uted to a higher discordance rate in our analysis. A random Problems with tissue fixation and processing, which can and unbiased review of cases from the same international lead to suboptimal preservation of tissue antigens, must be pathology centers could possibly provide a lower disagree- appropriately addressed before implementation and use of ment rate, but corrective actions should be encouraged, and diagnostic IHC. Many international histopathologic speci- our overall major disagreement rate of 25.1% (range, 13.7% mens received at SJCRH for review demonstrate problems to 37.1%) is worrisome. with tissue fixation, and in some cases, those problems In summary, we hope our experience, reviewed in this precluded a final diagnosis. The use of an adequate fixative article, will increase awareness of the challenge to correctly (10% neutral-buffered formalin, pH ranging from 6.8 to 7.1), diagnose pediatric neoplasms, especially in low- and fixation time (including processing time up to 24 hours and middle-income countries where the pathology services 3–4 mm thickness of the tissue sample) are simple and may be suboptimal. We also hope to promote the implementable actions that can be accomplished in any establishment of a basic IHC panel that would aid in the pathology laboratory worldwide, which are key determi- diagnosis of the most common pediatric malignancies, nants for the quality of the tissue morphology as well as the especially the group of small blue cell neoplasms. preservation of tissue antigenicity for future IHC reactions, if We strongly believe these initiatives would improve the applicable. overall quality and accuracy of the diagnoses of pediatric Lones et al18 evaluated the effect of poor technical quality solid tumors and lymphomas in more disadvantaged areas of histology and its adverse effects on the diagnosis of of the world and decrease the rates of disagreement and mature B-cell non-Hodgkin lymphoma in children and discrepancies. adolescents. Their analysis of 187 such cases demonstrated References that the rate of agreement was significantly higher with 1. 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