Correlation of Cytomorphology, Immunophenotyping, and Interphase Fluorescence in Situ Hybridization (FISH) in 381 Patients with MGUS and 310 Patients with Multiple Myeloma.
Bibliographic record
Abstract
Abstract Abstract 2812 Poster Board II-788 From cytomorphological aspects, monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) are overlapping disorders. According to the WHO classification, a threshold of 10% of plasma cells (PCs) in bone marrow (BM) aspirates separates both categories. To clarify whether this separation is justified from cytogenetic aspects, we performed comparison of interphase fluorescence in situ hybridization (FISH) patterns in 691 patients with MGUS (n=381) or MM (n=310). Also, the results of cytomorphology and immunophenotyping using multiparameter flow cytometry (MFC) were correlated. 278 females and 413 males (22.8-92.8 yrs) at first presentation of MM/MGUS were analyzed between 2005-2009 in our laboratory with a combination of cytomorphology, MFC, and FISH following magnetic activated cell sorting (MACS) of CD138+ PCs (Robosep, STEMCELL Technologies, Vancouver). According to cytomorphological WHO criteria, 381 patients were categorized as MGUS (median BM PCs, 5%), 310 as MM (median PCs, 18.5%). The number of FISH probes being applicable to samples was depending on the amount of plasma cells yielded from MACS procedure. In the MM pts, a median of 12 probes was applied (range, 0-22) which was slightly higher than in the MGUS patients (median: 11; 0-18) (p=0.00002). FISH procedure was hampered by insufficient PC numbers more frequently in MGUS (79/381, 20.7%) than in MM pts (29/310; 9.3%) (p=0.0004). In MM pts, FISH revealed a median of 2 and a maximum of 7 cytogenetic alterations per patient in contrast to a median of 0 and a maximum of 5 in MGUS (p<0.0001). In more detail, in MM the maximum number of gains of genetic material per patient was 7 (MGUS: 5), of losses 7 (MGUS: 3), and of reciprocal rearrangements 2 (MGUS: 1). Subsequently, cytogenetic alterations were compared in those 527 pts (260 MM and 267 MGUS pts; 76.3% of all pts), in whom PC numbers allowed performance of at least 5 FISH probes (t(11;14), t(4;14), t(14;16), 13q14, TP53). Abnormal FISH results were detected in 145/260 MM (55.8%) and 106/267 MGUS pts (39.7%) (p=0.0002). In MM, 31/260 (11.8%) had a t(4;14)/IGH-FGFR3 in contrast to 5/268 (1.9%) in MGUS (p<0.0001). The t(11;14)/IGH-CCND1 (MM: n=41; 15.6%; MGUS: n=50; 18.7%; n.s.) and t(14;16)/IGH-MAF were similarly frequent in both cohorts (MM: n=8; 3.1%; MGUS: n=3; 1.1%; n.s.). Monosomy13/del(13)(q14) was more frequent in MM (n=103; 39.3%) when compared to MGUS (n=59; 22.1%, p=0.0001). Deletions of TP53/17p13 were seen in 16 MM (6.1%) and in 6 MGUS pts (2.2%) (p=0.029). Notably, in 7 MGUS cases with <1% PCs in cytomorphology, FISH revealed genetic alterations in 3 cases. PCs as quantified by cytomorphology vs. MFC ranged from 0-96% vs. 0-84% (median 8.5 vs. 2.0), respectively, with a highly significant correlation between both methods (Pearson, r=0.712, p<0.0001). However, as previously reported, MFC detected lower numbers in general: the median ratio of PCs by cytomorphology:MFC amounted to 4.25 (range 0.00-178.00). In 12 MGUS cases (1.7%) as defined with cytomorphology, MFC did not detect any PCs. Conversely, in 5 MGUS cases, MFC detected PCs while cytomorphology did not. In conclusion, cytogenetic patterns showed higher genetic complexity in MM cases when compared to MGUS, and both the t(4;14) as -13/del(13)(q14) were significantly more frequent in MM when compared to MGUS. However, the cytogenetic alterations showed no specific pattern for MM or MGUS categories. Therefore, the overlaps being seen from morphological aspects do also exist on the genetic level. This suggests that a cytogenetically based categorization of these cases might correlate better with the clinical profiles than the cytomorphological separation of MM/MGUS. Finally, this study supports the performance of FISH in MGUS cases. The demonstrated detection of malignant/monoclonal PCs by MFC also in cases in which cytomorphology fails to diagnose MM/MGUS emphasizes the inclusion of MFC in a standard diagnostic procedure. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Weiss:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".