RESISTing the Need to Quantify: Putting Qualitative FDG-PET/CT Tumor Response Assessment Criteria into Daily Practice.

Tumor response assessments are essential to evaluate cancer treatment efficacy and prognosticate survival in patients with cancer. Response criteria have evolved over multiple decades, including many imaging modalities and measurement schema. Advances in FDG-PET/CT have led to tumor response criteria that harness the power of metabolic imaging. Qualitative PET/CT assessment schema are easy to apply clinically, are reproducible, and yield good prognostic results. We present 3 such criteria, namely, the Lugano classification for lymphoma, the Hopkins criteria, and the Neck Imaging Reporting and Data Systems criteria for head and neck cancers. When comparing baseline PET/CTs with interim or end-of-treatment PET/CTs, radiologists can classify the tumor response as complete metabolic response, partial metabolic response, no metabolic response, or progressive disease, which has important implications in directing further cancer management and long-term patient prognosis. The purpose of this article is to review the progression of tumor response assessments from CT- and PET/CT-based quantitative and semi-quantitative systems to PET/CT-based qualitative systems; introduce the classification schema for these systems; and describe how to use these rapid, powerful, and qualitative PET/CT-based systems in daily practice through illustrative cases.

Staging and response assessment in lymphomas: the new Lugano classification.

Staging and response criteria were initially developed for Hodgkin lymphoma (HL) over 60 years ago, but not until 1999 were response criteria published for non-HL (NHL). Revisions to these criteria for both NHL and HL were published in 2007 by an international working group, incorporating PET for response assessment, and were widely adopted. After years of experience with these criteria, a workshop including representatives of most major international lymphoma cooperative groups and cancer centers was held at the 11(th) International Conference on Malignant Lymphoma (ICML) in June, 2011 to determine what changes were needed. An Imaging Task Force was created to update the relevance of existing imaging for staging, reassess the role of interim PET-CT, standardize PET-CT reporting, and to evaluate the potential prognostic value of quantitative analyses using PET and CT. A clinical task force was charged with assessing the potential of PET-CT to modify initial staging. A subsequent workshop was help at ICML-12, June 2013. Conclusions included: PET-CT should now be used to stage FDG-avid lymphomas; for others, CT will define stage. Whereas Ann Arbor classification will still be used for disease localization, patients should be treated as limited disease [I (E), II (E)], or extensive disease [III-IV (E)], directed by prognostic and risk factors. Since symptom designation A and B are frequently neither recorded nor accurate, and are not prognostic in most widely used prognostic indices for HL or the various types of NHL, these designations need only be applied to the limited clinical situations where they impact treatment decisions (e.g., stage II HL). PET-CT can replace the bone marrow biopsy (BMBx) for HL. A positive PET of bone or bone marrow is adequate to designate advanced stage in DLBCL. However, BMBx can be considered in DLBCL with no PET evidence of BM involvement, if identification of discordant histology is relevant for patient management, or if the results would alter treatment. BMBx remains recommended for staging of other histologies, primarily if it will impact therapy. PET-CT will be used to assess response in FDG-avid histologies using the 5-point scale, and included in new PET-based response criteria, but CT should be used in non-avid histologies. The definition of PD can be based on a single node, but must consider the potential for flare reactions seen early in treatment with newer targeted agents which can mimic disease progression. Routine surveillance scans are strongly discouraged, and the number of scans should be minimized in practice and in clinical trials, when not a direct study question. Hopefully, these recommendations will improve the conduct of clinical trials and patient management.

Quality assessment program for EuroFlow protocols: summary results of four-year (2010-2013) quality assurance rounds.

Flow cytometric immunophenotyping has become essential for accurate diagnosis, classification, and disease monitoring in hemato-oncology. The EuroFlow Consortium has established a fully standardized "all-in-one" pipeline consisting of standardized instrument settings, reagent panels, and sample preparation protocols and software for data analysis and disease classification. For its reproducible implementation, parallel development of a quality assurance (QA) program was required. Here, we report on the results of four consecutive annual rounds of the novel external QA EuroFlow program. The novel QA scheme aimed at monitoring the whole flow cytometric analysis process (cytometer setting, sample preparation, acquisition and analysis) by reading the median fluorescence intensities (MedFI) of defined lymphocytes' subsets. Each QA participant applied the predefined reagents' panel on blood cells of local healthy donors. A uniform gating strategy was applied to define lymphocyte subsets and to read MedFI values per marker. The MedFI values were compared with reference data and deviations from reference values were quantified using performance score metrics. In four annual QA rounds, we analyzed 123 blood samples from local healthy donors on 14 different instruments in 11 laboratories from nine European countries. The immunophenotype of defined cellular subsets appeared sufficiently standardized to permit unified (software) data analysis. The coefficient of variation of MedFI for 7 of 11 markers performed repeatedly below 30%, average MedFI in each QA round ranged from 86 to 125% from overall median. Calculation of performance scores was instrumental to pinpoint standardization failures and their causes. Overall, the new EuroFlow QA system for the first time allowed to quantify the technical variation that is introduced in the measurement of fluorescence intensities in a multicentric setting over an extended period of time. EuroFlow QA is a proficiency test specific for laboratories that use standardized EuroFlow protocols. It may be used to complement, but not replace, established proficiency tests. © 2014 International Society for Advancement of Cytometry.

[Second expert review on lymphoma: assessment of a one year activity in a general hospital]. / Expertise systématique des lymphomes diagnostiqués au cours d'une année d'activité d'un centre hospitalier : évaluation.

A standardized second histological review for lymphomas was established by the French National Cancer Institute in 2010. The objective of our study was to assess the clinical impact of this process between a general hospital (reader 1) and an expert (reader 2). This prospective study was conducted between April 1st 2010 and April 1st 2011. Fifty-four cases of lymphoma were subjected to an expert review following the "LYMPHOPATH" recommendations and diagnoses of readers 1 and 2 were compared according to the WHO 2008 classification of lymphomas. We distinguished serious discrepancies (lymphoma versus other malignancy) from subtyping disagreement with or without impact on therapeutic strategy. We also determined the delays between the initial reception of the sample and reader 1's (period A) and reader 2's (period B) reports, respectively. Any additional analysis performed by second reader was also reported. Our study revealed one case of subtyping discordance (1.85%). The mean delays were 7 days for period A and 20 days for period B, respectively. Additional immunohistochemical techniques were requested by reader 2 in 11 cases (20.4%). These data provide evidence to suggest that in our department, a second review targeted on difficult diagnoses, rare lymphomas or when further analyses are required would be more relevant than a standardized second review.

[State of medical care of patients with hematological malignancies in Kyïv].

In the article data are presented about morbidity by oncogematologic pathology - one of the most meaningful of social-economic problems. In Ukraine annually diagnose the to 8 thousand new cases of haemoblastosis. Indexes of morbidity on a 100 thousand population are 5,2; at illness of Hodgkin's lymphoma - 2,5, at plural myeloma - 1,6; at leukemia - 8,1. Morbidity by haematological pathology in Kyiv long time remains high: annually 250 expose patients with malignant lymphnoma, 57 - with myeloma, 190 - with leukemia, from them at 55 % is a sharp form and at 40 % - chronic. The anxiety of doctors causes circumstance that the special treatment is overcome 58,1 % patients by leukemia, 68,6 % - plural myeloma and 77,8 % patients with malignant lymphoma. World experience shows that application of complex methods of therapy allows to prolong life-span 80-90 % patients with Hodgkin's malignant lymphoma on 10, and at 95 % patients by a lymphogranulomatosis - to attain nonrecurrence survival to 5 years.

IHC and the WHO classification of lymphomas: cost effective immunohistochemistry using a deductive reasoning "decision tree" approach.

The 2008 World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues defines current standards of practice for the diagnosis and classification of malignant lymphomas and related entities. More than 50 different types of lymphomas are described, combining fine morphologic criteria with immunohistochemical (IHC), and sometimes molecular, findings. Faced with such a broad range of different lymphomas, some encountered only rarely, and a rapidly growing, ever changing, armamentarium of approximately 80 pertinent IHC "stains", the challenge to the pathologist is to employ IHC in an efficient manner, to arrive at an assured diagnosis as rapidly as possible. This review uses deductive reasoning, after a decision tree or dendrogram model that relies upon recognition of basic morphologic patterns for efficient selection, use and interpretation of IHC markers to classify node-based malignancies by the World Health Organization schema. The review is divided into 2 parts, the first addressing those lymphomas that produce a follicular or nodular pattern of lymph nodal involvement; the second addressing diffuse proliferations in lymph nodes. It is accepted that only specialized centers are able to apply all of the technical resources and experience necessary for definitive diagnosis of unusual cases. Emphasis therefore is given to the more common lymphomas and the more commonly available IHC "stains", for a pragmatic and practical approach that is both broadly feasible and cost effective. By this method an assured diagnosis may be reached in the majority of nodal lymphomas, at the same time developing a sufficiency of data to recognize those rare or atypical cases that require referral to a specialized center.

A practical approach to the understanding and diagnosis of lymphoma: an assessment of the WHO classification based on immunoarchitecture and immuno-ontogenic principles.

This review aims to interrelate the major lymphoma types in the current World Health Organization (WHO) classification to construct a framework for understanding and diagnostic application. Multiple morphological, phenotypical and molecular genotypical data are assessed in order to categorise lymphomas into germinal centre (GC) and extracentric (EC) subgroups. GC entities [lymphocyte-predominant Hodgkin, follicular, Burkitt's, angioimmunoblastic T-cell and diffuse large B-cell lymphoma (DLBCL) with GC profile] express bcl-6, CD10 and/or the GC-homing chemokine CXCL13, and harbour ongoing somatic hypermutations (SHM), but not Epstein-Barr virus (EBV) in its higher latency states. Post-GC entities [classical Hodgkin, marginal zone and lymphoplasmacytic lymphomas, half of chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL), DLBCL with 'activated' or post-GC profile, primary effusion lymphoma, plasmacytoma and myeloma] express, instead, MUM.1 and/or CD138, harbour static rather than ongoing SHM, and may harbour EBV in higher latency states. The remainder of CLL/SLL and the majority of mantle cell lymphoma without SHM constitute the pre-GC ('naive') category, with coexpression of IgD and CD5. Lymphomas can be categorised across lineage (B- or T-cell) and relationship against host immune response (Hodgkin or non-Hodgkin) into GC and EC groups, affording leverage in their differential diagnosis.

Cutaneous lymphomas.

This paper is a written presentation of a workshop held at the American Academy of Insurance Medicine 115th Annual Meeting held in October 2006 in San Antonio, Texas. Cutaneous lymphomas, though not common, are encountered several times per year in insurance medicine. Significant advances have been made in the diagnosis and classification of lymphomas. This paper serves as a general primer to help classify and assess mortality risk of various cutaneous lymphomas.

Investigation of leukaemia and lymphoma AR-DRGs at a Sydney teaching hospital.

Using non-blinded methodology, this study checked the coding of acute leukaemia, non-acute leukaemia and lymphoma episodes assigned to the AR-DRGs R60 A, B, C and R61 A, B during the fiscal year 2000-2001 at a Sydney teaching hospital. The purpose was to investigate whether the assignment of fewer episodes of these diseases to the highest complexity AR-DRGs during that year compared to 1999-2000 was due to miscoding, or due to a true decrease in episodes. A check of all 242 episodes revealed a degree of miscoding (mainly under-coding) of complications and comorbidities that had caused a 15% DRG error rate; nevertheless, there was a true decrease in the highest complexity episodes. The error in DRG assignment may have caused some financial disadvantage to the hospital.

Prognostic value of cell-cycle markers in ocular adnexal lymphoma: an assessment of 230 cases.

BACKGROUND: To determine the prognostic value of cell-cycle associated markers in ocular adnexal lymphoma (OAL). METHODS: Two hundred sixty-one consecutive cases of ocular adnexal lymphoproliferative lesions were subdivided into reactive lymphoid hyperplasia (RLH), atypical lymphoid hyperplasia (ALH) and OAL. The latter were sub-typed according to the new WHO Lymphoma Classification. All lesions were investigated applying standard immunohistochemical methods with antibodies specific for pRB, p53, p16, p21, BCL-6 and for multiple myeloma oncogene-1-protein (MUM1, also known as IRF4). The main endpoints included the development of a local recurrence, of systemic disease and of lymphoma-related death. The association of prognostic variables with endpoints was assessed by multiple logistic and Cox regression models, respectively. RESULTS: The ocular adnexal lymphoproliferative lesions were categorised as OAL ( n=230; 88%), RLH ( n=29; 11%), and ALH ( n=2; 1%). The major lymphoma subtypes included 136 extranodal marginal zone B-cell lymphoma (EMZL), 31 diffuse large cell B-cell lymphomas, 27 follicular lymphomas, 9 plasmacytomas, 9 lymphoplasmocytic lymphoma/immunocytomas and 8 mantle cell lymphomas. The median follow-up time was 44.5 months. Most OAL patients had Stage IE disease and were treated with radiotherapy. Thirty-seven (25%) Stage IE patients had tumour relapses: these were significantly associated with an increased BCL6 blast percentage. Sixty-two (42%) Stage IE patients developed systemic disease: they had "non-EMZL" with large growth fractions and increased blast percentages for BCL6. Fifty-seven (25%) OAL patients died because of their lymphoma; lymphoma-related death was significantly associated on multivariable analysis with advanced clinical stage, an age >60 years and large tumour growth fractions. CONCLUSION: Subtyping of OAL according to the new WHO Lymphoma Classification, the stage of disease and tumour cell growth fraction aided the prediction of (1) tumour relapse, (2) the development of systemic disease and (3) lymphoma-related death in OAL.

The lymphomas.

Hodgkin's disease and the malignant lymphomas are, by all available evidence, eminently curable neoplasms. The debates, therefore, on how best the largest numbers of individuals in any community can receive appropriate treatment and this implies their ready access to an experienced multi disciplinary combined clinic. It is important that proper perspective be retained in the African context so that preventive medicine can be employed where appropriate but, based on current understanding, those with lymphoreticular malignancy become immediate beneficiaries of whatever diagnostic and therapeutic resources need to be expended in ensuring optimal outcome. The last word is far from written on how we, as inhabitants of the African continent, will achieve this goal and so measure up to our obligation. However, as resources continue to contract, three observations justify reiteration. Firstly, diagnostic skills need to be honed by experienced pathologists together reviewing all biopsy material and, wherever possible, participating in national or international study groups. Secondly, the silly distinction propagated by some self serving individuals who fantasize that state hospitals and private clinics somehow differ, must be replaced by a more responsible attitude in which resources are pooled in the common quest for maintaining academic standards. Thirdly, given acceptance of the above common sense proposals, a mechanism will exist for the establishment and constant upgrading of national guidelines for management on agreed and achievable protocols. Whilst the theme remains that of tested conventional treatment, flexibility must exist, where appropriate, for palliative care on the one hand with scientific growth and exploration of innovative options on the other. One might conclude by observing that Africa is most certainly unique and this extends to the frequency with which some of these tumours occur; a classical example would be Burkitt's Lymphoma. This places an obligation on all of us to gather and record such experiences and, from this basis, sustain our intellectual drive by forging international bonds with colleagues in the First World. Such collaboration will provide the natural bridge between clinical studies in Africa and the more sophisticated cellular and molecular biology that is being provided by basic scientists in other parts of the world. Such a marriage is practical and both parties stand to gain significantly in the research, development and evaluation of new drugs and protocols that, ultimately, serve the best interests of patients and do so on a world-wide basis.

[Diagnosis and treatment of lymphomas. Retrospective quality assessment of a 10-year material]. / Lymfomdiagnostikk og behandling. Retrospektiv kvalitetsvurdering av et tiårsmateriale.

We have performed a quality assessment of staging and treatment of 64 patients with non-Hodgkin's lymphoma treated at the Department of Internal Medicine, Nordland Central Hospital from 1982 to 1991. The assessment was based on defined quality criteria. Journal records of patient history, physical examination and stage were unsatisfactory. Histological examinations, use of laboratory tests and X-ray examinations were appropriate. The choice of chemotherapy for high grade malignancy was adequate, average relative dose-intensity was low. Low utilization of radiotherapy could be explained in most cases by individual patient factors. 5-years disease-specific survival was 54% for all patients and 70% for those presenting with localized disease.

Use of hair coloring products and the risk of lymphoma, multiple myeloma, and chronic lymphocytic leukemia.

OBJECTIVES: Hair coloring products are widely used and contain components that are mutagenic and carcinogenic. An association between occupational exposure to hair coloring products and hematopoietic cancers has been reported, but the risk for these cancers among users has not been carefully evaluated. METHODS: We conducted a population-based, case-control study with telephone interviews from 385 with telephone interviews from 385 non-Hodgkin's lymphoma cases, 70 Hodgkin's disease cases, 72 multiple myeloma cases, 56 chronic lymphocytic leukemia cases, and 1432 controls. RESULTS: Among women, use was associated with odds ratios of 1.5 for non-Hodgkin's lymphoma, 1.7 for Hodgkin's disease, 1.8 for multiple myeloma, and 1.0 for chronic lymphocytic leukemia. Risk was higher for permanent hair coloring products than for semi- or nonpermanent products, particularly for dark colors. Long duration and early age of first use tended to increase risk, but the patterns were inconsistent. Use was much less common in men and did not significantly increase risk. CONCLUSIONS: The use of hair coloring products appears to increase the risk of non-Hodgkin's lymphoma. Multiple myeloma and Hodgkin's disease were also associated, although based on far fewer subjects. If these results represent a causal association, use of hair coloring products would account for 35% of non-Hodgkin's lymphoma cases in exposed women and 20% in all women.

Assessment of new macroscopical classification of gastric malignant lymphoma.

We macroscopically classified gastric malignant lymphoma into ST type (submucosal tumor type), non-ST type (non-submucosal tumor type) and Combined type (combination of ST and non-ST type) and assessed this new classification by examining 60 surgically resected cases. Of these, 18 cases (21 lesions) were classified into ST type, 38 cases (54 lesions) into non-ST type and 4 cases (4 lesions) into Combined type. All the large cell, immunoblastic type cases were of ST type and most of the diffuse, small cleaved cell type cases and all the plasmacytoma cases were of non-ST type. Diffuse, large cell type and diffuse, mixed type cases did not seem to be biased toward any of these three macroscopical types. The non-ST type cases frequently showed an infiltrative growth pattern and reactive lymphoid cell hyperplasia adjoining the lesions, while the ST type cases frequently showed an expansive growth pattern without reactive lymphoid cell hyperplasia. The Combined type cases showed both infiltrative and expansive growth patterns in the same lesion. The macroscopical classification defined in this study can be considered useful in determining a range for surgical resection of gastric malignant lymphoma.

Linfomas en el Perú y el mundo: un estudio multinacional de las neoplasias del sistema linfático / Lymphomas in Perú and at the world: a multinational study of lymphatic system neoplasies

En este estudio se pone en evidencia algunas semejanzas y varias diferencias en la frecuencia relativa de Linfomas en el Perú, en comparación con otros países del Mundo, y se discute la posibilidad que factores ambientales y genéticos influyan en su patogénesis. El año 1966 reportamos el incremento relativo de la frecuencia de la Enfermedad de Hodgkin infantil en el Perú en contraste con el predominio de la enfermedad en los adultos jóvenes en otros países. Esta misma distribución atárea fue posteriormente encontrada en otros países en desarrollo, y corresponde históricamente a la distribución etárea que presentaba la enfermedad de Hodgkin en las primeras décadas de este siglo en los países que, ahora desarrollados, tienen predominio por la E. de Hodgkin en adultos. Aparentemente la aparición de esta enfermedad en la primera década de la vida guarda relación con el desarrollo económico a través del estado sanitario de otros países. Un fenómeno similar ocurre en el linfoma de Burkitt de los niños africanos. Esta condición, endémica en Africa, ha sido descrita esporádicamente en los países desarrollados En cambio en el Perú por el Dr. Pedro Weiss en 1954, llamando la atención su carácter necrotizante. Ahora se sabe que es una neoplasia angiocéntrica y angiodestructiva, con marcadores de superficie que lo tipifican como Linfoma de Células T. Esta rara neoplasia es inusitadamente frecuente en nuestro medio, y estando la mucosa nasal tan expuesta a la persistente estimulación antigénica, es lógico inferir que factores extrínsecos ambientales tienen un rol en su patogenia. El linfoma del intestino delgado, en su condición de "Linfoma difuso del intestino con malbsorción" fue también descrito originalmente por investigadores peruanos el a 1963; esta misma condición fue reportada en 1965 ocurriendo en la población de árabes y judíos de pobres condición económica, en una área geográfica quedio lugar a la denominación de Linfoma Mediterráneo. Esta variedad de Linfoma Intestinal constituye aproximadamente el 50% de los Linfomas intestinales de nuestra serie, nuevamente asemejando nuestra realidad a la de los países del norte de Africa y Medio Este. Y marcando una diferencia más con la realidad del mundo desarrollado en que esta es una condición raramente descrita.Finalmente, un estudio multinacional prospectivo, llevando a cabo entre los años 1985 y 1986, ha permitido precisar semejanza y diferencias entre los linfomas de la población peruana y los de otros países.

Correlación clínico-pronostica en el linforma no-hodgkin: valoración de la nueva clasificación propuesta en un estudio retrospectivo / Clinico prognostic correlation in non-Hodgkin lymphoma: value of the new classification proposed in a retrospective study

Se revisaron en forma retrospectiva los datos clínicos e histológicos de 282 pacientes con linfoma No-Hodgkin, estudiados en el Hospital General de México de la S.S.A. Se establecieron los diagnósticos y correlaciones pronósticas de acuerdo a la nueva formulación internacional. Los resultados muestran que la nueva clasificación ofrece buena precisión pronóstica y adecuada reproducibilidad al patólogo. Los linfomas más frecuentes fueron los de grado intermedio de malignidad (60.9%), seguidos de los de alto grado (30.1%) y los menos frecuentes fueron los de bajo grado (8.8%). La mayor parte de los pacientes estaban en estadio clínico IV, sin diferencias significativas entre los tres grupos. El porcentaje de defunciones correlacionó adecuadamente en los tres grupos (bajo grado 24%, grado intermedio 32.5% y alto grado 47%). Los linfomas foliculares constituyeron un bajo porcentaje, en contraste con lo informado por autores extranjeros. Se mencionan algunos aspectos comparativos con las clasificaciones de Rappaport y de Lukes y Collins

Myeloma with immunohistochemically different cell populations: implication for the validity of immunohistochemical assessment of lymphoma cell monoclonality.

A case of myeloma showed histologically a monotonous pattern of relatively mature myeloma cells and an IgG-kappa paraproteinemia. In contrast to ordinary stains, the immunoperoxidase reactions for kappa and gamma gave inhomogeneous results. Light and heavy chains were formed by clusters of different subpopulations of myeloma cells. Serial sections showed that kappa-positive clusters were gamma-negative and vice versa. Thus, this morphologically homogeneous myeloma turned out to be immunohistochemically heterogeneous. We assume that two subpopulations have developed that produced separately kappa- and gamma-chains. Therefore, these chains might have been circulating separately and not as complete IgG-kappa molecules. Guided by our findings, the results of other investigators are discussed. Some considerations on the validity of immunohistochemical demonstration of tumor cell monoclonality are given implicating the diagnostic equivocation of immunohistochemistry for non-Hodgkin's lymphomas, especially for so-called "immunocytomas".