Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from ...3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.
BACKGROUND
Fourteen cases of testicular sarcoma have been reported in the contemporary era. These included 7 cases of rhabdomyosarcoma, 2 spindle cell sarcoma, 2 osteosarcoma, 1 leiomyosarcoma, 1 ...fibrosarcoma, and 1 chondrosarcoma.
METHODS
In this report, immunohistochemical stains, electron microscopy, and DNA flow cytometric analysis were performed on primary testicular sarcomas from three patients.
RESULTS
The patients were age 47, 40, and 33 years. Each presented initially with a testicular mass. The tumors measured 4.8, 4.0, and 4.0 cm in greatest dimension. There were no associated germ cell elements nor elevated alpha‐fetoprotein or beta‐human chorionic gonadotropin. Case 1 was positive for actin, vimentin, and alpha‐1‐chymotrypsin. Case 2 was positive for vimentin but not desmin. Case 3 was positive for desmin and S‐100. Smooth muscle differentiation was identified by electron microscopy. Flow cytometric analysis revealed DNA aneuploidy in all cases: 1.27, 1.29, and 1.71. The 3 patients were alive and well without recurrent disease at 7, 6, and 4 years after diagnosis. Inguinal orchiectomy was the initial treatment in all 17 patients, there was 1 death from metastatic disease and 2 patients with distant metastases.
CONCLUSIONS
Primary testicular sarcoma is a rare indolent tumor with potential for distant metastases. Two cases of primary testicular leiomyosarcoma and one of unclassified sarcoma of the testis are reported. Cancer 1996; 77:1524‐8.
Abstract
Background
Racial and ethnic variations in attribution of cervical precancer and cancer to human papillomavirus (HPV) types may result in different HPV vaccine protection, screening test ...coverage, and clinical management.
Methods
Pooling data from 7 US studies, we calculated the proportional attribution of precancers and cancers to HPV types using HPV DNA typing from diagnosis. All statistical tests were 2-sided.
Results
For all racial and ethnic groups, most cases of cervical intraepithelial neoplasia grade 3 (CIN3) (84.2%-90.8% of 5526) and squamous cell carcinoma (SCC) (90.4%-93.8% of 1138) were attributed to types targeted by the 9-valent vaccine. A higher proportion of CIN3s were attributed to nonvaccine HPV types among non-Hispanic Black women (15.8%) compared with non-Hispanic Asian or Pacific Islander (9.7%; P = .002), non-Hispanic White (9.2%; P < .001), and Hispanic (11.3%; P = .004) women. The proportion of SCCs attributed to 9-valent types was similar by race and ethnicity (P = .80). A higher proportion of CIN3s were attributed to nonvaccine HPV35 among non-Hispanic Black (9.0%) compared with non-Hispanic Asian or Pacific Islander (2.2%), non-Hispanic White (2.5%), and Hispanic (3.0%; all P < .001) women. Compared with CIN3, the proportion of SCCs attributed to HPV35 among non-Hispanic Black women (3.2%) was lower and closer to other groups (0.3%-2.1%; P = .70).
Conclusion
The 9-valent HPV vaccine will prevent nearly all cervical precancers and invasive cancers among major racial and ethnic groups in the United States. Adding HPV35 to vaccines could prevent a small percentage of CIN3s and SCCs, with greater potential impact for CIN3s among Black women. HPV screening tests target high-risk HPV types, including HPV35. Future genotyping triage strategies could consider the importance of HPV35- and other HPV16-related types.
Because most low-grade squamous intraepithelial lesions (LSIL) regress spontaneously, the appropriate follow-up of women with a cytologic diagnosis of LSIL has engendered discussion. This ...retrospective study was undertaken to assess the feasibility of limiting colposcopy to women with cytologic interpretations of high-grade squamous intraepithelial lesions (HSIL) in a high-risk population.
The pathology computer files (including files from January to December 1997) of The University Hospital, University of Oklahoma Health Sciences Center, revealed 197 women whose histologic samples were coded as severe dysplasia. Of these, 138 had a cervical smear interpreted in our laboratory before the colposcopic visit. On review, the tissue samples of 119 women met consensus criteria for severe dysplasia.
Original cytologic diagnoses for 119 cytologic smears included 80 (62.7%) that were interpreted as HSIL. After retrospective review, 28 cases with LSIL or less were reclassified as HSIL and were considered to be discrepant for the purpose of this study. Major confounding factors in the original categorization include lack of consistency among the pathologists for the interpretation of metaplastic patterns and specimen adequacy, particularly air-drying artifact. Eleven cases (10.2%) did not have cells identifiable as HSIL because of sampling error and/or severe air-drying artifact.
These results indicate that a substantial number of histologically verified cases of severe dysplasia can have a smear interpretation of LSIL or less. The factors that hampered recognition of the true severity of the lesion in this series were identified and tabulated.
Abstract Research on the pathogenicity of human papillomaviruses (HPVs) during cervical carcinogenesis often relies on the study of homogenized tissue or cultured cells. This approach does not detect ...molecular heterogeneities within the infected tissue. It is desirable to understand molecular properties in specific histological contexts. We asked whether laser capture microdissection (LCM) of archival cervical tumors in combination with real-time polymerase chain reaction and bisulfite sequencing permits (i) sensitive DNA diagnosis of small clusters of formalin-fixed cells, (ii) quantification of HPV DNA in neoplastic and normal cells, and (iii) analysis of HPV DNA methylation, a marker of tumor progression. We analyzed 26 tumors containing HPV-16 or 18. We prepared DNA from LCM dissected thin sections of 100 to 2000 cells, and analyzed aliquots corresponding to between nine and 70 cells. We detected nine to 630 HPV-16 genome copies and one to 111 HPV-18 genome copies per tumor cell, respectively. In 17 of the 26 samples, HPV DNA existed in histologically normal cells distant from the margins of the tumors, but at much lower concentrations than in the tumor, suggesting that HPVs can infect at low levels without pathogenic changes. Methylation of HPV DNA, a biomarker of integration of the virus into cellular DNA, could be measured only in few samples due to limited sensitivity, and indicated heterogeneous methylation patterns in small clusters of cancerous and normal cells. LCM is powerful to study molecular parameters of cervical HPV infections like copy number, latency and epigenetics.
Malignant struma ovarii is a rare form of ovarian carcinoma; only 3 cases of its pure papillary type have been reported in the literature. A new case of malignant papillary struma ovarii arising in ...an asymptomatic 32-year-old woman is presented. Due to its rarity, there has been confusion in the diagnosis and management of malignant struma ovarii. Criteria for the diagnosis of malignant papillary struma ovarii are proposed. Conservative treatment after a complete staging procedure is possible due to the usually benign course and low incidence of metastases of this tumor.
Factors associated with progression from cervical intraepithelial neoplasia (CIN) grades 2 and 3 to invasive cancer are not well understood; most CIN2 and CIN3 do not progress to cancer. Among ...carcinogenic human papillomavirus (HPV) types, infections with HPV16 have the highest risk of progressing to cancer. We evaluated the heterogeneity of risk factors, lesion size, colposcopic impression and colposcopic biopsy results in relation to HPV16 status among 627 women with CIN2 or CIN3 in women referred to colposcopy at the University of Oklahoma. Loop excision specimens were evaluated in 12 radial segments to estimate lesion size. The mean age at CIN3 was 27.7 years for HPV16‐positive women (n = 225) and 33.6 years for HPV16‐negative women (n = 104). The average lesion size did not differ by HPV16 status (p = 0.83). Among HPV16‐positive women with CIN3, lesions were significantly larger in women 30 years and older (p = 0.03). Colposcopic impression was worse in women with HPV16 infections (p = 0.009), but the detection of CIN3 at the preceding biopsy was not improved in HPV16‐positive women. CIN3 is detected at the same lesion size, but at much younger age in women with HPV16 infections, suggesting faster growth. CIN2 lesion size in women without HPV16 peaks below 30 years and then decreases, suggesting frequent regression, whereas HPV16‐related CIN2 is more likely to persist. Lesion size seems to be an important determinant of colposcopy and biopsy performance. Genotyping for HPV16 in cervical cancer screening can improve risk stratification but may pose challenges to finding small lesions in colposcopy.
Background
New cervical cancers continue to be diagnosed despite the success of Papanicolaou (Pap) tests. In an effort to identify pitfalls that limit the diagnosis of adenocarcinoma, the authors ...reviewed the cytologic characteristics of endocervical adenocarcinomas in their patient population.
Methods
Liquid‐based cytology slides from 45 women who had concurrent, histologically confirmed cervical adenocarcinomas were reviewed retrospectively and semiquantitatively for 25 key cytologic traits. The original sign‐out diagnosis, available clinical findings, and high‐risk human papillomavirus (HR HPV) results also were noted.
Results
Abundant tumor cellularity, nuclear size from 3 to 6 times normal, abundant 3‐dimensional tumor cell groups, round cell shape, and cytoplasmic neutrophils characterized the 23 cases that were identified correctly as adenocarcinomas. Key reasons for undercalls included low tumor cellularity and low‐grade columnar morphology; these also tended to correlate with low‐grade or unusual adenocarcinoma variants on histology. Overall, 73% of adenocarcinomas had a concurrent positive HR HPV test.
Conclusions
Most endocervical adenocarcinomas can be diagnosed accurately in cases with classical features, but some cases continue to be problematic when evaluated based on cytologic features alone. Reflex HPV testing may help increase Pap test sensitivity for challenging cases that have atypical glandular cells of undetermined significance. Occasional cases with negative HR HPV test results remain of concern.
This retrospective review of 45 Papanicolaou tests from histologically confirmed endocervical adenocarcinomas reveals that most cases can be recognized based on classical cytologic criteria, whereas underdiagnosed cases tend to have low cellularity and columnar‐shaped nuclei. Reflex human papillomavirus testing may be useful in increasing sensitivity for endocervical adenocarcinoma on Papanicolaou tests.
Chromosomal rearrangements of the human MLL gene are a hallmark for aggressive (high-risk) pediatric, adult and therapy-associated acute leukemias. These patients need to be identified in order to ...subject these patients to appropriate therapy regimen. A recently developed long-distance inverse PCR method was applied to genomic DNA isolated from individual acute leukemia patients in order to identify chromosomal rearrangements of the human MLL gene. We present data of the molecular characterization of 414 samples obtained from 272 pediatric and 142 adult leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) was determined and several new TPGs were identified. The combined data of our study and published data revealed a total of 87 different MLL rearrangements of which 51 TPGs are now characterized at the molecular level. Interestingly, the four most frequently found TPGs (AF4, AF9, ENL and AF10) encode nuclear proteins that are part of a protein network involved in histone H3K79 methylation. Thus, translocations of the MLL gene, by itself coding for a histone H3K4 methyltransferase, are presumably not randomly chosen, rather functionally selected.
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