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Support vector machine classification of 18F-FDG PET scans across subtypes of amyotrophic lateral sclerosis.

PURPOSE: While 18F-FDG PET imaging has demonstrated diagnostic value in people with Amyotrophic Lateral Sclerosis (PwALS) and group-level differences were identified between different disease subtypes (e.g., genetic and clinical variants), refining and validating a machine-learning-based subject-level diagnostic algorithm may improve the general applicability and reliability of 18F-FDG PET as a diagnostic tool in ALS. In this study, we employed support vector machines (SVM) to further explore the diagnostic potential of 18F-FDG PET in ALS, alongside its ability to classify between different genetic subtypes or clinical phenotypes. METHODS: 18F-FDG PET data of 36 healthy volunteers (HV), 25 people with ALS-mimicking diseases (Mimics), and 167 PwALS, grouped by genetic status (e.g., sporadic (sALS) or carrying a C9orf72 hexanucleotide repeat expansion (ALSC9orf72RE) and onset (bulbar or spinal) type, acquired with Biograph 'TruePoint' PET/CT scanner, were included in the study (Dataset 1). A second dataset of 183 PwALS and 31 Mimics acquired with Biograph 'HiRez' scanner was included as an independent cross-validation set (Dataset 2). PET images were spatially normalised to MNI space to fit linear SVMs with cross-validation. Only age-matched groups were considered to eliminate age-related effects. RESULTS: For Dataset 1, the linear SVM resulted in an average accuracy of 0.86 for the classification of ALS vs. HV, 0.53 for ALS vs. Mimics, 0.83 for ALSC9orf72RE vs. sALS, and 0.58 for bulbar vs. spinal onset. These findings were corroborated with Dataset2, with an accuracy of up to 0.76 for ALSC9orf72RE vs. sALS, and 0.59 for bulbar vs. spinal. CONCLUSION: 18F-FDG brain PET imaging, combined with SVM and age-matching, can distinguish between ALSC9orf72RE and sALS with good accuracy, but lacks sufficient discriminative power to differentiate between ALS and Mimics and between different sites of onset.

Humans

The classification of acute leukaemia (AL) and its clinical significance.

The combination of morphological, cytochemical and immunological methods has resulted in a reproducible and more objective classification of AL. Several of the AML-FAB subtypes (M2, M3 and M5) correlate with specific chromosome abnormalities and are associated with distinct clinical and laboratory features. The classification of ALL based on morphology (FAB types L1, L2 and L3) has been shown to have prognostic value. The heterogeneity of ALL is better recognised by membrane marker analysis, now improved by the use of monoclonal antibodies. The enzyme terminal transferase is the best marker for lymphoblasts and helps in the differential diagnosis between ALL and AML. Cases of undifferentiated AL and rare types of AML can be identified by ultrastructural cytochemistry. The clinical significance of the classification of AL is briefly discussed.

Acute Disease

Thymoma. Histologic subclassification is an independent prognostic factor.

BACKGROUND: Several histologic classifications of thymomas have been proposed, and attempts have been made to correlate the different histologic subtypes to clinical behavior and prognosis. Recently, Marino and Müller-Hermelink and Kirchner et al. proposed a new morphologic classification of thymomas based on the resemblance of the neoplastic cells to subtypes of the normal thymic epithelial cells. In this classification, six categories of thymic epithelial tumors are recognized. They define four categories of thymoma: medullary, mixed, organoid (predominantly cortical), and cortical, and two subgroups of thymic carcinomas: well differentiated thymic carcinoma and high grade carcinomas. METHODS: The authors studied 116 patients with thymic epithelial tumors classified according to the proposals of Marino and Müller-Hermelink and Kirchner et al. to assess the effect of histologic classification and other factors (stage, size of tumor, lymphoid hyperplasia, myasthenia gravis, age, sex, and treatment) on survival, and freedom from relapse. RESULTS: Eight cases (7%) were medullary, 32 cases (28%) mixed, 20 cases (17%) organoid (predominantly cortical), 21 cases (18%) cortical, 29 cases (25%) well differentiated carcinoma (WDTC), two cases (2%) high grade carcinoma, and four cases (3%) unclassifiable. Fifty-two patients were in stage I, 32 stage II (16 IIA, 16 IIB), 28 stage III, and four Stage IVA. Only stage (P = 0.0001; hazard ratio = 5.36) and histology (P = 0.0019; hazard ratio = 8.010) were significant in predicting recurrence. Histology was highly correlated with stage, but by multivariate analysis was an independent factor in predicting relapse (P = 0.0281; hazard ratio = 5.92). None of the medullary or mixed thymomas recurred, even though 30% were invasive. Patients with WDTC recurred more often and earlier than patients with organoid and cortical thymoma (log rank, P = 0.0001). The actuarial freedom from relapse for patients with WDTC was 58% at 5 years and 46% at 10 years compared with 100% for other subtypes. Both advanced stage (III and IV) and the WDTC histologic subtype significantly increased the risk of death from thymoma (log rank, P = 0.0001). The actuarial survival of patients with WDTC was 80% at 5 years and 54% at 10 years, whereas that of patients with the other subtypes was 100% at 5 and 10 years. Five of seven relapses and six of seven deaths from thymoma occurred in patients with WDTC. In Stage II patients, one of 16 minimally invasive (Stage IIA) tumors recurred, compared with 3 of 16 grossly invasive (Stage IIB) tumors, indicating that microscopic assessment of invasion is important in staging. CONCLUSIONS: The histologic classification of Marino and Müller-Hermelink has prognostic significance, independent of tumor stage. Medullary and mixed thymomas were benign tumors with no risk of recurrence, even when capsular invasion was present. Organoid and cortical thymoma showed intermediate invasiveness and a low, but significant, risk of late relapse, even with minimal invasion. WDTC were always invasive and had a significantly increased risk of relapse and death, even for Stage II patients. Adjuvant therapy appears unnecessary for medullary and mixed thymomas, even when invasive.

Adolescent

Classifying acute leukemia by immunophenotyping: a combined FAB-immunologic classification of AML.

A panel of commercially available monoclonal antibodies and five heteroantisera were used to distinguish and subtype 138 cases of acute leukemia (AL). The immunophenotype was compared with the French-American-British (FAB) classification obtained on the cases. The immunophenotype discriminated acute myelogenous leukemia (AML) from acute lymphoblastic leukemia (ALL) and recognized cases not distinguished by cytochemistry (22% of cases), mixed lineage phenotypes (13% of cases), and cases with separate populations of lymphoblasts and myeloblasts (one case). Using the immunologic panel and derived criteria to subtype AML, correspondence of the immunophenotype to the FAB subtypes M1, M2, M4, and M5 was possible in greater than 80% of cases. A combined classification of the immunophenotype and FAB morphology/cytochemistry was devised for AML subtyping. It is recommended that immunophenotyping should be done at least in all cases with negative or inconclusive cytochemistry. At present, we suggest that until a "gold standard" for identifying leukemic subtypes is developed, the best method for typing acute leukemia is by using a combination of morphology, cytochemistry and immunophenotyping.

Antibodies, Monoclonal

Pathology of Hodgkin's disease: anything new?

This presentation deals with the gross and microscopic pathology of HD. Recent advances in immunohistochemistry, gene rearrangement studies and cell culture are not discussed, except where they shed light on the pathology. Clinical and pathological experience, over the past 2 decades, suggests that HD should be divided into six subtypes, as originally proposed by Lukes et al. (1966b), rather than the four subtypes included in the Rye classification. Nodular lymphocyte/histiocyte predominant HD forms a clinicopathological entity separate from the other subtypes. It most frequently presents at a single nodal site and, even without therapy, progresses only slowly over a period of many years. A proportion of the patients (in the region of 10%) develop large cell NHL and a smaller number develop other types of Hodgkin's disease. This progression is not due to therapy since it most frequently occurs in untreated patients. Characteristic polylobated RS cell variants are seen in NLPHD. These differ from classic RS cells in that they have a B-cell phenotype, they do not show light chain restriction and, therefore, they do not appear to be a clonal proliferation. Although current dogma states that classic RS cells must be identified before a diagnosis of HD, including NLPHD, is made, it is the author's contention, supported by immunohistochemistry, that this type of RS cell does not occur in NLPHD. Polylobated RS cell variants in the appropriate cellular setting are, in themselves, diagnostic of NLPHD. They also serve to differentiate NLPHD from progressive transformation of germinal centres, an unusual proliferative expansion that may occur in association with HD but which, in itself, appears to be an entirely benign, reactive process. Diffuse lymphocyte/histiocyte predominant HD (DLPHD) differs from NLPHD in its diffuse growth pattern and the frequent presence of larger numbers of histiocytes. Polylobated RS cells are characteristic of both diseases. In some biopsies nodular and diffuse areas are seen in the same lymph node. Despite these similarities, the two diseases differ clinically (NLPHD is usually stage 1, DLPHD is frequently of a higher stage) and in their immunohistochemistry (fewer RS cell variants in DLPHD contain J-chain than in NLPHD). The reasons for these differences are not apparent and require further investigation. It may be due, at least in part, to the inclusion of cases of MCHD and NHL in the DLPHD category. Nodular sclerosis is the commonest category of HD in most reported series.(ABSTRACT TRUNCATED AT 400 WORDS)

Hodgkin Disease

Correlations between histopathological and biological findings in nasopharyngeal carcinoma and its prognostic significance.

Forty-five consecutive cases of nasopharyngeal carcinoma were morphologically and immunocytochemically studied using monoclonal (anti-B and anti-T cell) and polyclonal (anti-S100 protein and antilysozyme) antibodies with the peroxidase-anti-peroxidase method to identify infiltrating lymphocytes (T and B cell) and histiocytes (monocytic/macrophagic and dendritic cells) in nasopharyngeal carcinoma. A variable density of dendritic cells was found within the tumor nests in 22 (49%) of 45 nasopharyngeal carcinomas examined; infiltrating macrophages were demonstrated in 15 (33%) specimens and around the tumor in almost all cases. Cases with moderate or marked density of dendritic cells (S100+) survived longer than those without such infiltration (mean 5-year survival rates of 31%, 55%, or 64% in patients with absent, moderate, or marked densities, respectively; P less than 0.05). A significant relationship between monocytic/macrophagic cells (lysozyme+) within the tumor and survival was also found (mean 5-year survival rate of 27% or 61% in patients with absent, moderate, or marked densities, respectively). However, lymphocytic infiltration was not statistically related to a better survival. Analyzing lymphocytic infiltration, we found a large prevalence of T cells in the neoplastic tissue without any prognostic significance. These data were correlated to different histological subtypes according to the principal histological classifications of nasopharyngeal carcinomas (Micheau, et al.; World Health Organization; Cologne University) to individualize the scheme which correlates best with prognosis and biological features of nasopharyngeal carcinomas. Our data suggest that, considering dendritic cells and macrophages within cancer nests, nasopharyngeal carcinoma histiotypes can be correlated to patient prognosis.

Adult

Alpha 1-antitrypsin: the PiMM subtypes. Do they play a role in development of chronic obstructive pulmonary diseases?

In a comparative study, we examined 324 sera of the PiMM phenotype by isoelectric focusing. Sera were obtained from 254 healthy individuals, and from 70 patients suffering from chronic obstructive pulmonary disease (COPD). All individuals were examined, a detailed history and chest x-ray films were taken, and lung function tests were performed. The classification into PiMM subtypes according to a modified method, originally described by Genz et al, showed a significantly higher number of subtypes, containing more slowly migrating protein fractions (M2) in the group of patients. Since the prevalence of bronchitic symptoms is unusually common in industry, in workers who are exposed to dust and smoke tobacco, these findings are important, especially in regard to prophylactic measures in industry.

Bronchitis

Follow-up studies with sequential bone marrow biopsies in chronic myeloid leukaemia and so-called primary (idiopathic) osteo-myelofibrosis. Evolution of histopathological lesions and clinical course in 40 patients.

A clinicopathological follow-up study was performed on 17 patients with chronic myeloid leukaemia (CML) and 23 cases with so-called primary (idiopathic) osteo-/myelofibrosis (OMF) concentrating on a comparison between clinical data and multiple sequential biopsies of the bone marrow. Histological classification of bone marrow lesions was done according to the subtypes proposed by Georgii et al. At clinical diagnosis initial trephine biopsies in CML showed in only 6/17 cases a pronounced granulocytic proliferation or CGL. In 9/23 patients with OMF a so-called hyperplastic or early hypercellular stage was encountered with a mixed megakaryocytic-granulocytic pattern without or with minimal reticulin fibres (CMGM/EMS). The histopathology of this early stage OMF as well as the later evolving advanced fibrosclerotic lesions (AMS/OMS) were by morphological aspects alone not distinguishable from cases with CML showing prominent fibrosclerotic alterations. At presentation 5/17 patients with CML displayed already some degree of reticulin fibre formation (EMS). Following serial trephine biopsies in CML with an increased megakaryocyte proliferation (CMGM), a remarkable tendency for myelofibrosis was present. The dynamics of this fibrosclerotic transformation seem to be variable in CML and OMF likewise. However, they are related to abnormal megakaryopoiesis as well as to duration respectively progress of disease, paralleled by corresponding haematological parameters. This longitudinal case control study emphasizes that histopathology of the bone marrow taken at clinical diagnosis may reflect different stages of chronic myeloproliferative diseases and therefore should be always accompanied by relevant clinical and cytogenetic findings to enable a correct diagnosis.

Adult

Prognostic factors of peripheral T-cell lymphoma (PTL): statistical analysis on 30 patients.

Peripheral T-cell lymphoma (PTL) is a distinctive clinical entity, albeit it comprises several diseases with histologically heterogeneous diagnoses. We studied prognostic factors on 30 patients diagnosed and treated at Shikoku Cancer Center Hospital. Clinical findings and laboratory data were evaluated by statistical analysis to investigate the important factors influencing survival duration. Variables influencing survival were stage, leukemic change, bone marrow infiltration (BMI), anti-human T-lymphocyte virus-type I antibody, white blood cell count, and lactate dehydrogenase (LDH). Multivariate analysis revealed high level of LDH and positive BMI as the important factors for short survival. Histological classifications of the Working Formulation and the T-lymphoma classification by Suchi et al. were also evaluated whether these were related with prognosis. Our data revealed that there was no significant relationship between histological subtype and survival duration. The study of prognostic factors provides valuable aids for us to understand the clinical characteristics of PTL patients with various backgrounds.

Adult

Validity of the Hamilton Endogenous Subscale: an independent replication.

We calculated scores on the Hamilton Endogenous Subscale (HES) (Thase et al., 1983) for 252 depressed inpatients. The HES scores were bimodally distributed, and HES classification was significantly associated with endogenous (Research Diagnostic Criteria) and melancholic (DSM-III) subtyping. Based on a cutoff score of 8, HES classification was not associated with either family history of specific psychiatric illness or abnormal dexamethasone suppression test (DST) results. When the cutoff was raised to 10, DST nonsuppression was more frequent in HES endogenous depressives, although we again failed to find an association with a family history of psychiatric disorders.

Adult

Some problems on the histopathological diagnosis of non-Hodgkin's malignant lymphoma -- a proposal of a new type.

A new classification for non-Hodgkin's malignant lymphoma is proposed as the one suited for the Lymphomas in Japan, which is to provide a new subtype "pleomorphic" for those more or less rapid-growing lymphomas of peripheral T-cell nature, along with another subtype lymphoblastic, after Nathwani et al. for those of central T-cell nature. The proposal is based on the result of the investigation by the Study Group for Histopathological Diagnosis on Malignant Lymphoma that (1) the presence of a significant number of T-cell lymphomas with peculiar "pleomorphism" is responsible for the very low reproducibility rate of histopathological diagnosis on the diffuse, mixed L&H type of Rappaport classification, and (2) the relative incidence of lymphoms as peripheral T-cell nature including the so-called adult T-cell leukemia is much higher in Japan than in the Western countries.

B-Lymphocytes

Recommendations for modification of terminology of neuroblastic tumors and prognostic significance of Shimada classification. A clinicopathologic study of 213 cases from the Pediatric Oncology Group.

To develop consistency in terminology and pathologic criteria, the authors reviewed the literature and 213 cases of neuroblastic tumors (NT) registered with Pediatric Oncology Group (POG) protocols 8104 and 8441. The patients were given standardized therapy stratified according to POG stage and patient age, and four or more histologic sections of primary tumor resected before therapy were available in each of these 213 cases. All stages were represented. The recommended nomenclature combines conventional terms and criteria with those used by Bove and McAdams and Shimada et al. The main features of the recommended nomenclature are as follows: (1) the terms neuroblastoma (NB) and ganglioneuroblastoma (GNB) are retained instead of stroma-poor NB and stroma-rich NB, recommended by Shimada et al.; (2) undifferentiated NB is considered a subtype separate from poorly differentiated NB; and (3) the term GNB is used only when there is a predominant ganglioneuromatous component admixed with the minor neuroblastomatous component. With the use of these criteria and terms, the Shimada classification was determined in the 213 cases. The results showed that, even after stratification for age, POG stage, and primary site, there is a statistically significant difference in survival rate between favorable histologic and unfavorable histologic prognostic subgroups. The authors recommend that definitive prognostic categorization of an NT according to Shimada classification should be done only when adequate histologic material is available from a primary tumor resected before any other therapy. Categorization done on histologic material from small biopsy specimens, previously treated primary tumors, or metastatic sites should be considered tentative.

Child, Preschool

[NHL-BFM 90 therapy study in treatment of malignant non-Hodgkin's lymphomas in children and adolescents. Part 1: Classification and allocation to strategic therapy groups. BIF study group].

One of the goals of the study NHL-BFM 90 was to investigate the distribution and prognosis of the different subtypes of Non-Hodgkin's Lymphoma (NHL) in children and adolescents according to histological, cytomorphological and immunological characteristics. From 4/1990 to 12/1992, 346 patients (pts) (84 females, 262 males) were enrolled (median age: 9.1 years; range: 0.8-17.9 years). Histology was available from 290 pts (84%), cytomorphology from 155 (44%), and immunophenotyping from 245 (70%). Cases with L1 oder L2 cytomorphology according to the French-American-British Classification were classified as lymphoblastic lymphoma and those with L3 cytomorphology as Burkitt-Type lymphoma or acute B-cell leukemia (B-ALL) if a histological classification was not available. By means of the combined analysis of all three diagnostic criterias the classification of the NHL according to the updated Kiel-classification was possible in 312 cases: 49% were classified as Burkitt-type-lymphoma (incl. B-ALL), 22% als lymphoblastic lymphoma, 10% as large cell anaplastic lymphoma (LCAL), 6% as centroblastic lymphoma, only few cases were classified as NHL of other subtypes, 3 pts (1%) suffered from low grade malignant lymphomas, and in 34 pts (10%) the NHL was not further classified. Patients were stratified according to NHL-subentities in 3 branches (Non-B-NHL, B-NHL, LCAL) of different treatment modalities. The estimated probability of a 3-year event free survival (pEFS) was 88 +/- 2% for the whole group (follow up 7 to 40 months, median 23 months) while pEFS of different subtypes was: lymphoblastic lymphoma: 91 +/- 4%; Burkitt-type-lymphoma/B-ALL: 90 +/- 2%; centroblastic lymphoma: 94 +/- 6%, LCAL: 88 +/- 6%. We conclude that the stratification of treatment modalities in study NHL-BFM 90 according to biological entities provided patients of different NHL-subtypes an equal chance to survive event free. The efficacy of the treatment strategy for rare subtypes, however, is not evaluable yet.

Adolescent

[Analysis of liposarcoma].

Liposarcoma is one of the most common soft tissue sarcomas, ranking with rhabdomyosarcoma and malignant fibrous histiocytoma. We have treated 47 cases of liposarcoma, comprising 35 males and 12 females ranging in age from 22 to 86 years, with a median age of 56 years. The most common site of primary tumor was the thigh, the most common primary tumor stage by the UICC classification was T2, and the most common histological subtype by the WHO classification was myxoid type. Xerography, CT and angiography are useful forms of examination for diagnosis before surgery. Naked eye findings of the tumor often show a lobular or nodular growth pattern. Surgical therapy for the primary tumor, especially curative wide resection (by the method of Kawaguchi, et al.) is most effective for preventing local recurrence. Radiotherapy is not as effective as for rhabdomyosarcoma and chemotherapy should be applied for occult micro-metastases. Ten of the 47 cases died due to distant metastases and the 5 year survival rate was 76.2%.

Adult

[Pseudohypoparathyroidism].

Pseudohypoparathyroidism (PsH) is a disease (or syndrome) characterized by biochemical abnormalities of hypoparathyroidism, increased serum PTH levels and the resistance to exogenous PTH. Since the first description of this disease by Albright et al, there has been substantial progress in understanding the pathogenesis of PTH resistance and the genetic basis for this disease. The differential diagnosis includes other forms of hypoparathyroidism, especially idiopathic hypoparathyroidism. Normocalcemic PsH, a rare and atypical subtype, has to be differentiated from pseudo-PsH (Albright's hereditary osteodystrophy without hypoparathyroidism). This review discusses current concepts and classification of PsH (types I a, I b, I c and II) and the recent demonstration of genetic defects in patients with type I a or I b of PsH. The pathophysiology and treatment of PsH will also be discussed.

Calcitriol

Karyotypically unrelated clones in acute leukemias and myelodysplastic syndromes.

Karyotypically unrelated clones were observed in nine of 399 newly diagnosed acute leukemia or myelodysplastic syndrome (MDS) patients: two (3.0%) of 66 French-American-British classification (FAB)-M2 patients, five (12.5%) of 40 M5 patients, one (20%) of five chronic myelomonocytic leukemia (CMMoL), patients, one (12.5%) of eight refractory anemia with excess blasts in transformation (RAEBT) patients, and none (0%) of 177 acute lymphoblastic leukemia patients had such clones. Cytogenetically unrelated clones occurred more frequently in FAB-M5 than in the other subtypes of AL or MDS (p less than 0.01). Five (55%) of the nine patients had trisomy 8, two (22%) had partial deletion of the long arm of chromosome 5 and two had (22%) trisomy 11. Patients had short survival times (median 2 months, range 1-26 months) after detection of unrelated clones; eight of the nine failed to respond to chemotherapy. None of our patients had two phenotypically different leukemic cell populations or underwent phenotypic conversion of leukemic cells during the course of the disease. These findings suggest that the unrelated clones may have been derived from the common leukemic clone without microscopic chromosome changes, and that the different chromosome abnormalities of the unrelated clones may represent additional genetic changes in leukemogenesis.

Adolescent

Immunophenotyping of childhood acute lymphoblastic leukemia in Saudi Arabia: second look.

Geographical variations in the incidence of disease are of considerable theoretical and practical importance. It has been claimed that the distribution of acute lymphoblastic leukemia (ALL) phenotypes in Saudi Arabia is different from that recorded in the Western literature. One hundred and twelve (112) patients under 15 years of age, diagnosed as ALL between January 1992 and May 1994 had immunophenotypes performed on their blast cells. Common ALL (cALL) together with pre-B-ALL, formed 86.5% of the total; B-cell 3%, T-cell 6% and null cell 4.5%. These figures are not significantly different from the Western literature. A previous claim from this institution in 1990, that both null and B-cell ALL were significantly increased compared with elsewhere, is not supported by the present figures. Age and sex distribution, and FAB classification, L1 77%, L2 20% and L3 3%, were also of the same order as described elsewhere and, in particular, there was no increase in the frequency of L3 subtype.

Adolescent

Infantile acute leukemia with 11q23 chromosome abnormality and lineage infidelity.

An infant case of acute leukemia (AL) showed lineage infidelity and a chromosome rearrangement involving 11q23. This case was morphologically diagnosed as ALL-L2 according to the FAB classification. However, the blast cells were highly positive for monoclonal antimyeloid antigens (Mol and TG-8) and lymphoid markers (B1, J5 and TdT). These immunologic findings indicated that the blast cells had characteristics of lymphoid B-cell and myeloid lines. In the literature, so-called "11q23 chromosome abnormalities," commonly observed in acute nonlymphoblastic leukemia (ANLL) and in a subtype of acute lymphoblastic leukemia (ALL) with t(4;11) were observed in both lymphoid and myeloid acute leukemias, with some of them recently reported to have lineage infidelity. These unique characteristics may indicate the possibility that the latter is a variation of the former, and support the hypothesis that the chromosomal rearrangement at 11q23 occurs at a multipotent stem-cell level.

Acute Disease