Incidence and Mortality Rates for Childhood Acute Lymphoblastic Leukemia in Puerto Rican Hispanics, 2012-2016.

BACKGROUND: Acute lymphoblastic leukemia (ALL) accounts for 80% of all leukemias diagnosed in children. Although ALL age patterns are consistent across racial/ethnic groups, their incidence and mortality rates are highly variable. We assessed the age-standardized ALL incidence and mortality rates of Puerto Rican Hispanic (PRH) children and compared them with those of US mainland Hispanics (USH), non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), and Non-Hispanic Asian or Pacific Islanders (NHAPI). METHODS: Differences between racial/ethnic groups were assessed by estimating the standardized rate ratio (SRR) for 2010 to 2014. Secondary data analyses of the Puerto Rico Central Cancer Registry and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) databases were performed for the 2001 to 2016 period. RESULTS: PRH children had 31% lower incidence rates than USH, but 86% higher incidence rates than NHB. In addition, the incidence trends of ALL increased significantly from 2001 to 2016 among PRH and USH, with 5% and 0.9% per year, respectively. Moreover, PRH have a lower 5-year overall survival (81.7%) when compared with other racial/ethnic groups. CONCLUSIONS: PRH children were found to have disparities in ALL incidence and mortality rates compared with other racial/ethnic groups in the US. Additional research is warranted to identify the genetic and environmental risk factors that may be associated with the disparities observed. IMPACT: This is the first study reporting the incidence and mortality rates of childhood ALL for PRH and making comparisons with other racial/ethnic groups in the US. See related commentary by Mejía-Aranguré and Núñez-Enríquez, p. 999.

Molecular and Sociodemographic Colorectal Cancer Disparities in Latinos Living in Puerto Rico.

BACKGROUND: The incidence of sporadic colorectal cancer (CRC) among individuals <50 years (early-onset CRC) has been increasing in the United States (U.S.) and Puerto Rico. CRC is currently the leading cause of cancer death among Hispanic men and women living in Puerto Rico (PRH). The objective of this study was to characterize the molecular markers and clinicopathologic features of colorectal tumors from PRH to better understand the molecular pathways leading to CRC in this Hispanic subpopulation. METHODS: Microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutation status were analyzed. Sociodemographic and clinicopathological characteristics were evaluated using Chi-squared and Fisher's exact tests. RESULTS: Of the 718 tumors analyzed, 34.2% (n = 245) were early-onset CRC, and 51.7% were males. Among the tumors with molecular data available (n = 192), 3.2% had MSI, 9.7% had BRAF, and 31.9% had KRAS mutations. The most common KRAS mutations observed were G12D (26.6%) and G13D (20.0%); G12C was present in 4.4% of tumors. A higher percentage of Amerindian admixture was significantly associated with early-onset CRC. CONCLUSIONS: The differences observed in the prevalence of the molecular markers among PRH tumors compared to other racial/ethnic groups suggest a distinct molecular carcinogenic pathway among Hispanics. Additional studies are warranted.

Molecular profiling of colorectal cancer in a genetically admixed Hispanic population.

BACKGORUND: Colorectal cancer (CRC) is among the leading causes of cancer-related deaths among Hispanics living in the United States (USH). Understanding the most common carcinogenic molecular pathways that affect Hispanics with CRC is crucial to guide research efforts in developing new therapeutic modalities incorporating genomically diverse populations. Tumor profiling techniques help identify actionable alternatives to recommend treatment and improve survival in cancer patients. METHODS: We conducted a secondary data analysis to evaluate the mutational profile of 218 CRC tumors in Hispanics living in Puerto Rico (PRH) who underwent next-generation sequencing (NGS) testing from 2015 to 2020. We compared the prevalence of CRC tumor somatic mutations in PRHs with the mutational profiles reported for CRC from The Cancer Genome Atlas (TCGA) Pan-Cancer Clinical Data, the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE)-Non-Hispanic, and GENIE-Hispanic datasets. RESULTS: Among the top mutated genes in CRC tumors in PRHs were APC, TP53, and KRAS, which had significantly higher mutational frequencies in PRH compared to the examined datasets, including GENIE-Hispanics. The most frequent gene amplifications for PRH were CDX2, CDKN1B, and HNRNPA2B1. Targetable biomarkers for CRC, such as microsatellite instability-high (MSI), wild-type KRAS, wild-type NRAS, V600E BRAF, and ERBB2 gene amplifications were found in 2.0%, 43.8%, 97.8%, 3.9%, and 2.3%, respectively, of PRH patients. CONCLUSION: This is the first study to report the mutational profile of CRC tumors in PRHs and make comparisons to other non-Hispanic and USH populations.

The dual pathogenesis of penile neoplasia: The heterogeneous morphology of human papillomavirus-related tumors.

Objective: Penile neoplasia, usually of squamous histogenesis, is currently classified into human papillomavirus (HPV)-related or -dependent and non-HPV-related or -independent. There are distinct morphological differences among the two groups. New research studies on penile cancer from Northern countries showed that the presence of HPV is correlated with a better prognosis than virus negative people, while studies in Southern countries had not confirmed, perhaps due to differences in staging or treatment. Methods: We focused on the description of the HPV-related carcinomas of the penis. The approach was to describe common clinical features followed by the pathological features of each entity or subtype stressing the characteristics for differential diagnosis, HPV genotypes, and prognostic features of the invasive carcinomas. Similar structure was followed for penile intraepithelial neoplasia, except for prognosis because of the scant evidence available. Results: Most of HPV-related lesions can be straightforwardly recognized by routine hematoxylin and eosin stains, but in some cases surrogate p16 immunohistochemical staining or molecular methods such as in situ hybridization or polymerase chain reaction can be utilized. Currently, there are eight tumor invasive variants associated with HPV, as follows: basaloid, warty, warty-basaloid, papillary basaloid, clear cell, medullary, lymphoepithelioma-like, and giant condylomas with malignant transformation. Conclusion: This review presents and describes the heterogeneous clinical, morphological, and genotypic features of the HPV-related subtypes of invasive and non-invasive penile neoplasia.

Bioinformatic Characterization and Molecular Evolution of the Lucina pectinata Hemoglobins.

(1) Introduction: Lucina pectinata is a clam found in sulfide-rich mud environments that has three hemoglobins believed to be responsible for the transport of hydrogen sulfide (HbILp) and oxygen (HbIILp and HbIIILp) to chemoautotrophic endosymbionts. The physiological roles and evolution of these globins in sulfide-rich environments are not well understood. (2) Methods: We performed bioinformatic and phylogenetic analyses with 32 homologous mollusk globin sequences. Phylogenetics suggests a first gene duplication resulting in sulfide binding and oxygen binding genes. A more recent gene duplication gave rise to the two oxygen-binding hemoglobins. Multidimensional scaling analysis of the sequence space shows evolutionary drift of HbIILp and HbIIILp, while HbILp was closer to the Calyptogena hemoglobins. Further corroboration is seen by conservation in the coding region of hemoglobins from L. pectinata compared to those from Calyptogena. (3) Conclusions: Presence of glutamine in position E7 in organisms living in sulfide-rich environments can be considered an adaptation to prevent loss of protein function. In HbILp a substitution of phenylalanine in position B10 is accountable for its unique reactivity towards H2S. It appears that HbILp has been changing over time, apparently not subject to functional constraints of binding oxygen, and acquired a unique function for a specialized environment.

Characterization of Histone Genes from the Bivalve Lucina Pectinata.

Lucina pectinata is a clam that lives in sulfide-rich environments and houses intracellular sulfide-oxidizing endosymbionts. To identify new Lucina pectinata proteins, we produced libraries for genome and transcriptome sequencing and assembled them de novo. We searched for histone-like sequences using the Lucina pectinata histone H3 partial nucleotide sequence against our previously described genome assembly to obtain the complete coding region and identify H3 coding sequences from mollusk sequences in Genbank. Solen marginatus histone nucleotide sequences were used as query sequences using the genome and transcriptome assemblies to identify the Lucina pectinata H1, H2A, H2B and H4 genes and mRNAs and obtained the complete coding regions of the five histone genes by RT-PCR combined with automated Sanger DNA sequencing. The amino acid sequence conservation between the Lucina pectinata and Solen marginatus histones was: 77%, 93%, 83%, 96% and 97% for H1, H2A, H2B, H3 and H4, respectively. As expected, the H3 and H4 proteins were the most conserved and the H1 proteins were most similar to H1's from aquatic organisms like Crassostrea gigas, Aplysia californica, Mytilus trossulus and Biomphalaria glabrata. The Lucina pectinata draft genome and transcriptome assemblies, obtained by semiconductor sequencing, were adequate for identification of conserved proteins as evidenced by our results for the histone genes.

Novel Histologic Finding: Adipose Tissue Is Prevalent Within Penile Tunica Albuginea and Corpora Cavernosa: An Anatomic Study of 63 Specimens and Considerations for Cancer Invasion.

Adipose tissue, along with arteries, veins, and peripheral nerves, is a normal constituent of mesenchymal tissues encasing the corpora cavernosa at the level of the penile shaft, variously designated as penile fascia or Bucks fascia. To our knowledge, the presence of fat has not been previously reported within the corpora cavernosa. One or 2 transversal histologic sections at the level of the surgical margin at the shaft of 63 consecutive partial penectomy specimens for squamous cell carcinoma were evaluated. From outer to inner tissues, 3 anatomic levels were identified: (1) outer fascia composed of a loose fibrovascular mesenchyme containing some nerve branches. Adipose tissue was present in the majority of the cases. (2) The tunica albuginea, a thick and dense fibroelastic band of tissue separating the outer fascia from the erectile tissues of the corpora cavernosa. Adipose tissue within the albuginea was present in 21 specimens (19%). (3) Erectile tissues of corpora cavernosa. Besides the typical erectile tissues, adipose tissue was present in 33 cases (52%). The fatty tissue was focal or multifocal and scant and peripherally located at the junction of the tunica albuginea with the corpora. In some cases, it was associated with small amounts of fibrous tissue, small vessels, and nerves. We are reporting the presence of adipose tissue in the tunica albuginea and the corpora cavernosa. It is possible that adipose tissue, along with small nutritional vessels and nerves perforates from the fascia, in which fat is usually present, through the tunica albuginea to reach the corpora. In a previous examination of the local routes of cancer spread, we found this pathway to be one of the mechanisms of cancer invading the penile corpora from the penile fascia.

Medullary Carcinoma of the Penis: A Distinctive HPV-related Neoplasm: A Report of 12 Cases.

A third to half of penile invasive squamous cell carcinomas are human papillomavirus (HPV) related. Warty (condylomatous), warty-basaloid, and basaloid carcinomas are the most common subtypes associated with HPV. Less frequent are clear cell and lymphoepithelioma-like carcinomas. Here we report a novel penile tumor associated with HPV. Twelve cases were selected from 1010 penile carcinomas, part of an international HPV detection study conducted at the Institut Català d'Oncologia, Barcelona, Spain. Immunostaining with p16 was performed on all cases, and HPV-mRNA detection was also performed. En bloc full tumor staining was the utilized criteria for positivity of p16. For HPV-DNA detection, whole-tissue section polymerase chain reaction analysis was performed by SPF10-DEIA-LiPA25 (version 1). The patients' ages ranged from 42 to 92 years (average, 71 y). The tumor was most commonly located in the glans. A characteristic microscopic finding was the presence of a moderate to dense tumor-associated inflammatory cell infiltrate composed of neutrophils, lymphocytes, plasma cells, or eosinophils. Tumors grew in large solid sheets, nests, or had a trabecular pattern. Cells were large and poorly differentiated or anaplastic. Keratinization was minimal or absent. Nuclei were large with prominent nucleoli. Mitoses were numerous. Tumor necrosis was common. Deep invasion of the corpora cavernosa was frequent. p16 and HPV-DNA were positive in all cases, whereas mRNA detection was positive in 9 cases only. The prevalent genotype was HPV16 (9 cases, 75%). Other genotypes were HPVs 58, 33, and 66. Medullary carcinomas of the penis are morphologically distinctive HPV-related high-grade neoplasms affecting older individuals. More studies are necessary to delineate the epidemiological, clinical, and molecular features of this unusual penile neoplasm.

The variable morphological spectrum of penile basaloid carcinomas: differential diagnosis, prognostic factors and outcome report in 27 cases classified as classic and mixed variants

Background: Basaloid carcinomas of the penis, HPV-related tumors, are morphologically less homogenous than originally thought. The study objective was to evaluate the prognostic influence of the basaloid pattern in mixed tumors. Methods: We studied 154 Mexican patients from the Hospital de Oncología, CMN, Mexico City (2000­2013) and found 27 with basaloid features in at least 20% of the sections classified as classic basaloid (8 cases), warty-basaloid (7), papillary-basaloid (5) and usual-basaloid squamous cell carcinomas (7). We evaluated patients' age, site and size of tumor, histological classification, grade, thickness, anatomical level, vascular and perineural invasion, prognostic index score and node involvement. Penile intraepithelial neoplasia in adjacent epithelia was documented. Follow up ranged from 12­78 months. Statistical methods were Fisher's exact test and Kruskal-Wallis test. Kaplan-Meier method and log-rank test were used for survival analysis. The cutoff for statistical significance was p <0.05. Results: There were not clinical differences. Microscopically types were distinctive and easy to separate. Usual-basaloid squamous cell carcinomas were smaller, thinner and rarely invaded corpora cavernosa, with a low prognostic index score. Classic basaloid, warty-basaloid and papillary-basaloid carcinomas had higher rates of vascular and perineural invasion and higher prognostic index scores. These findings correlated with the rate of nodal metastasis. The majority of patients with classic and papillary-basaloid neoplasms died from systemic metastasis (87.5 and 80%) whereas only 1 patient with usual-basaloid carcinoma died of the disease (14%). Conclusions: Basaloid carcinomas are not a single entity but a spectrum of variable histological architectures mixed with those of classic basaloid tumors. Identification of mature squamous cells in a basaloid carcinoma may be important to recognize and report because patients with these tumors may carry a better prognosis (AU)

Clear Cell Carcinoma of the Penis: An HPV-related Variant of Squamous Cell Carcinoma: A Report of 3 Cases.

Penile clear cell carcinoma originating in skin adnexal glands has been previously reported. Here, we present 3 morphologically distinctive penile tumors with prominent clear cell features originating not in the penile skin but in the mucosal tissues of the glans surface squamous epithelium. Clinical and pathologic features were evaluated. Immunohistochemical stains were GATA3 and p16. Human papilloma virus (HPV) detection by in situ hybridization was performed in 3 cases, and whole-tissue section-polymerase chain reaction was performed in 1 case. Patients' ages were 52, 88, and 95 years. Tumors were large and involved the glans and coronal sulcus in all cases. Microscopically, nonkeratinizing clear cells predominated. Growth was in solid nests with comedo-like or geographic necrosis. Focal areas of invasive warty or basaloid carcinomas showing in addition warty or basaloid penile intraepithelial neoplasia were present in 2 cases. There was invasion of corpora cavernosa, lymphatic vessels, veins, and perineural spaces in all cases. p16 was positive, and GATA3 stain was negative in the 3 cases. HPV was detected in 3 cases by in situ hybridization and in 1 case by polymerase chain reaction. Differential diagnoses included other HPV-related penile carcinomas, skin adnexal tumors, and metastatic renal cell carcinoma. Features that support primary penile carcinoma were tumor location, concomitant warty and/or basaloid penile intraepithelial neoplasia, and HPV positivity. Clinical groin metastases were present in all cases, pathologically confirmed in 1. Two patients died from tumor dissemination at 9 and 12 months after penectomy. Clear cell carcinoma, another morphologic variant related to HPV, originates in the penile mucosal surface and is probably related to warty carcinomas.

Characterization and Expression of the Lucina pectinata Oxygen and Sulfide Binding Hemoglobin Genes.

The clam Lucina pectinata lives in sulfide-rich muds and houses intracellular symbiotic bacteria that need to be supplied with hydrogen sulfide and oxygen. This clam possesses three hemoglobins: hemoglobin I (HbI), a sulfide-reactive protein, and hemoglobin II (HbII) and III (HbIII), which are oxygen-reactive. We characterized the complete gene sequence and promoter regions for the oxygen reactive hemoglobins and the partial structure and promoters of the HbI gene from Lucina pectinata. We show that HbI has two mRNA variants, where the 5'end had either a sequence of 96 bp (long variant) or 37 bp (short variant). The gene structure of the oxygen reactive Hbs is defined by having 4-exons/3-introns with conservation of intron location at B12.2 and G7.0 and the presence of pre-coding introns, while the partial gene structure of HbI has the same intron conservation but appears to have a 5-exon/ 4-intron structure. A search for putative transcription factor binding sites (TFBSs) was done with the promoters for HbII, HbIII, HbI short and HbI long. The HbII, HbIII and HbI long promoters showed similar predicted TFBSs. We also characterized MITE-like elements in the HbI and HbII gene promoters and intronic regions that are similar to sequences found in other mollusk genomes. The gene expression levels of the clam Hbs, from sulfide-rich and sulfide-poor environments showed a significant decrease of expression in the symbiont-containing tissue for those clams in a sulfide-poor environment, suggesting that the sulfide concentration may be involved in the regulation of these proteins. Gene expression evaluation of the two HbI mRNA variants indicated that the longer variant is expressed at higher levels than the shorter variant in both environments.

Pathological factors, behavior, and histological prognostic risk groups in subtypes of penile squamous cell carcinomas (SCC).

Pathologists' contribution in the determination of prognosis in invasive penile squamous cell carcinoma is crucial. The TNM staging system is based on the identification of pathological data. There are multiple pathologically based factors believed to be important in relation to the rates of regional inguinal lymph node and specific cancer death. Among them are tumor site, size, histological subtypes, thickness or anatomical level of invasion, tumor front, and vascular or perineural invasion. The identification of these factors determines the prognostic profile of patients with penile cancer. These factors are used for the construction of pathological risk groups, prognostic index, or nomograms and are helpful in the prediction of nodal metastasis or patients' outcome. This review will describe in detail the influential pathological prognostic factors present in each tumor category emphasizing the impact of especial histological subtypes in tumor spread and final outcome. There are few studies comprehensibly addressing the relation of tumor morphology and prognosis according to histological types. We are summarizing findings of prognostic factors in 3 different series for the most common types and individual series in more recently described tumor entities. We had found a broad correlation of special subtypes of penile squamous cell carcinomas that made regional nodal status and final outcome predictable according to histological features of the tumor. These findings permitted grouping special subtypes of squamous cell carcinomas into prognosis risk groups of low, intermediate, and high. In the first category of excellent prognoses are the usual grade I, verrucous, papillary NOS, pseudohyperplastic and cuniculatum carcinomas. In the second group, there are the grade II usual, mixed and warty carcinomas. The third category of tumors, with the worst prognosis is composed of high grade usual, basaloid, warty-basaloid, papillary basaloid, and sarcomatoid carcinomas. We found that subtyping of penile squamous cell carcinoma is important to determine risk for nodal metastasis and patients' survival.

Epidemiologic profile, sexual history, pathologic features, and human papillomavirus status of 103 patients with penile carcinoma.

PURPOSE: The incidence of penile cancer is four times higher in Paraguay than in the United States or Europe. There are no adequate scientific explanations for this geographical variation. The goal of this study was to evaluate the interplay among risk factors, morphology of the primary tumor, and HPV status. METHODS: Information on socioeconomic status, education level, habits, and sexual history was obtained in 103 Paraguayan patients with penile cancer. All patients were then treated by surgery, and specimens were evaluated histopathologically. RESULTS: Patients usually dwelled in rural/suburban areas (82%), lived in poverty (75%), had a low education level (91%), and were heavy smokers (76%). Phimosis (57%), moderate/poor hygienic habits (90%), and history of sexually transmitted diseases (74%) were frequently found. Patients with >10 lifetime female partners had an odds ratio of 3.8 (95% CI 1.1, 12.6; P-trend = .03) for presenting HPV-positive tumors when compared to patients with <6 partners. However, this trend was not significant when the number of sexual partners was adjusted for age of first coitus and antecedents of sexually transmitted diseases. HPV-related tumors (found in 36% of the samples) were characterized by a warty and/or basaloid morphology and high histological grade in most cases. CONCLUSIONS: In our series, patients with penile cancer presented a distinctive epidemiologic and pathologic profile. These data might help explaining the geographical differences in incidence and aid in the design of strategies for cancer control in Paraguay.

Distribution and characterization of subtypes of penile intraepithelial neoplasia and their association with invasive carcinomas: a pathological study of 139 lesions in 121 patients.

We are presenting the morphological features of 121 cases of atypical penile intraepithelial lesions. The term penile intraepithelial neoplasia (PeIN) was used to encompass all of them, and lesions were classified into 2 major groups, differentiated and undifferentiated. The latter was further divided in warty, basaloid, and warty-basaloid subtypes. Ninety-five cases were associated with invasive squamous cell carcinomas. Differentiated lesions predominated (68%), followed by warty-basaloid (14%), basaloid (11%), and warty (7%) subtypes. Multifocality was found in 15% of the cases. Differentiated lesions were preferentially located in foreskin, whereas warty and/or basaloid subtypes were more prevalent in the glans. The former lesions were preferentially seen in association with keratinizing variants of squamous carcinoma, whereas the latter subtypes were found mostly in conjunction with invasive warty, basaloid, and warty-basaloid carcinomas. Lichen sclerosus was present in 51% of cases of differentiated lesions and absent in warty and/or basaloid subtypes. In summary, PeIN can be classified into 4 distinctive morphological subtypes. The proper pathological characterization of these lesions may provide important clues to the understanding of the pathogenesis and natural history of penile cancer.

Distinctive immunohistochemical profile of penile intraepithelial lesions: a study of 74 cases.

Several classification schemes for penile precancerous lesions have been proposed, but none of them seems to correlate with the current understanding of penile cancer pathogenesis. Recently, a system, which takes into account morphologic features and purported etiopathogenesis, was proposed, separating penile intraepithelial neoplasia (PeIN) in differentiated and warty/basaloid subtypes. This study was designed to seek an immunohistochemical profile that can be helpful in the classification and differential diagnosis of penile epithelial abnormalities and precancerous lesions using the aforementioned system. The immunohistochemical panel included stains for p16, p53, and Ki-67. For p16 immunostaining, only full-thickness positivity in all epithelial cells was considered as positive; for p53 and Ki-67 immunostaining, patchy or diffuse nuclear positivity above the basal layer was considered as positive. Seventy-four lesions in 59 patients were selected and classified as follows: differentiated PeIN, 34 cases; squamous hyperplasia (SH), 21 cases; basaloid PeIN, 15 cases; and warty PeIN, 4 cases. The mean age of patients was 64 years. Forty-two lesions (56.8%) were located in the glans and 32 (43.2%) in the foreskin. Overexpression of p16 was useful for distinguishing SH from warty/basaloid PeINs (0% vs. 94.7%, P<0.0001) but not SH from differentiated PeINs (0% vs. 5.9%, P=0.519). In addition, p16 allowed the distinction of differentiated and warty/basaloid PeINs (5.9% vs. 94.7%, P<0.0001). Immunohistochemistry results for p53 allowed the separation of SH and differentiated PeIN (9.5% vs. 44.1%, P=0.0078) and SH and warty/basaloid PeIN (9.5% vs. 55.6%, P=0.0042). Ki-67 immunostain was useful for distinguishing SH from differentiated PeIN (52.6% vs. 89.7%, P=0.0062) and SH from PeIN with warty and/or basaloid features (52.6% vs. 100%, P=0.0011). There seems to be a distinctive immunohistochemical profile for associated and precursor epithelial lesions of the penis. SH was p16 and p53 negative, with variable Ki-67 positivity. Differentiated PeIN was p16 negative and Ki-67 positive, with variable p53 positivity. Basaloid and warty PeINs were consistently p16 and Ki-67 positive, with variable p53 positivity. The use of a triple p16/p53/Ki-67 immunohistochemical panel was found to be helpful in the classification, differential diagnosis, and morphologic standardization of penile intraepithelial lesions.

Endocervical-like mucinous borderline tumors of the ovary: a clinicopathologic analysis of 31 cases.

Ovarian mucinous borderline tumors are divided into two morphologic groups: endocervical-like and intestinal type, the latter comprising the majority of cases. Thirty-one endocervical-like ovarian mucinous borderline tumors (ELMBTs) were reviewed and evaluated for the presence of intraepithelial carcinoma and microinvasion. Intraepithelial carcinoma was identified in 13% and stromal microinvasion in 23% of cases. All but 1 patient were stage I. Follow-up information was available for 21 patients; all were alive with no evidence of disease at a mean follow-up interval of 5.7 years. Six of 8 patients with ELMBT containing foci of microinvasion and/or intraepithelial carcinoma and for whom follow-up was available were alive with no evidence of disease at a mean follow-up interval of 6.6 years. These results indicate that ELMBTs, specifically those exhibiting intraepithelial carcinoma and microinvasion, are tumors associated with an excellent prognosis. The frequency of occurrence and criteria for the diagnosis of intraepithelial carcinoma and microinvasion in ELMBT are discussed.

Malignant mesonephric tumors of the female genital tract: a clinicopathologic study of 9 cases.

Nine malignant mesonephric tumors were obtained from the consultation files of one of the authors (J.P.) over a 13-year period (1988-2001). There were 4 adenocarcinomas (ACs) and 5 malignant mixed mesonephric tumors (MMMTs). The ACs were found in the cervix (3) and vagina (1). The MMMTs involved the uterus (1), cervix (3), and vagina (1). Most patients presented with abnormal vaginal bleeding. The 4 patients with mesonephric AC ranged in age from 24 to 54 years (mean, 41 years). The tumors measured 2 to 6 cm (mean, 3.7 cm). Two ACs were stage I and two were stage II. Two of the three patients with follow-up information were alive without clinical evidence of disease at 3 and 11.5 years, and the other was alive with recurrent tumor 8.5 years postoperatively. The 5 patients with MMMTs ranged in age from 37 to 62 years (mean, 49 years). The mean size of four tumors was 5.2 cm (range, 3.5-8 cm). The uterine MMMT infiltrated the entire myometrial wall extending to the endometrial cavity where it resembled an endometrial polyp. Although the most common histologic pattern in the current series was the glandular (ductal) pattern, retiform, tubular, and solid growth patterns were also encountered. Among the MMMT subgroup, the sarcomatous component was homologous in 3 cases (endometrial stromal or spindle cell) and heterologous in the other 2 cases (skeletal muscle and cartilage). Of the 4 patients with follow-up information available, 1 (stage II) died of disease 7 months after surgery, another (stage IV) was alive with bone metastases at 3.3 years, and the other 2 patients (stages IB and IC) had no clinical evidence of disease at 1 and 3.7 years, respectively. Evidence of mesonephric hyperplasia was found in 5 (42%) cases. The MMMT that arose in the corpus presented as an endometrial polyp. In this case, histologic differential diagnosis includes serous carcinoma, endometrial stromal sarcoma, and uterine tumor resembling ovarian sex cord-stromal tumor. Immunostainings are not helpful. Mesonephric ACs often present in early stage and have better prognosis than their müllerian counterparts. Surgery alone appears to be the treatment of choice. In contrast, MMMTs may present in advanced stage and are aggressive tumors, similar to malignant mixed müllerian tumors.

Sarcoma-like mural nodules in mucinous cystic tumors of the ovary revisited: a clinicopathologic analysis of 10 additional cases.

Ten mucinous cystic ovarian tumors that contained sarcoma-like mural nodules are described. The nodules were studied by conventional and immunohistochemical methods. The sarcoma-like mural nodules occurred predominantly in middle-aged women, were multiple and sharply demarcated from the adjacent mucinous tumor, had small size, and exhibited a heterogeneous cell population. Distinction of these lesions from true sarcomatous nodules and foci of anaplastic carcinoma is important because of the worse prognosis of the two latter tumors compared with the favorable behavior of the sarcoma-like mural nodules. Six of the eight patients with follow-up information were alive and clinically free of recurrence at a mean follow-up interval of 12 years. Two patients died of other causes (thyroid and breast carcinomas). The nature of the nodules is not clear. Sarcoma-like mural nodules probably represent a reactive and self-limited phenomenon within a neoplasia. Their coexpression of vimentin and cytokeratins is consistent with an origin from submesothelial mesenchymal cells, which undergo partial transformation into epithelial cells.

Mucinous tumors of the ovary: a clinicopathologic analysis of 75 borderline tumors (of intestinal type) and carcinomas.

With the exception of benign cystadenomas, mucinous ovarian tumors are rare and heterogeneous neoplasms. They have been classified as either borderline tumors or carcinomas for almost 30 years. Subsequently, the borderline tumors have been subclassified into endocervical-like and intestinal types. The diagnostic criteria for distinguishing borderline tumors of the intestinal type from mucinous carcinomas have varied, making difficult the interpretation of prognostic information. More recently, a further subdivision of the former tumors into forms with only epithelial atypia and variants with focal intraepithelial carcinoma has been proposed. Consequently, in this study of 41 mucinous borderline tumors of intestinal type and 34 mucinous carcinomas, the former were also subdivided into 30 cases with mild to moderate atypia only and 11 with areas of intraepithelial carcinoma. All 30 purely borderline tumors were stage I tumors, and all 15 with follow-up information (including one case with microinvasion) were clinically benign. All 11 mucinous borderline tumors that had foci of intraepithelial carcinoma were also stage I neoplasms, and none of the eight patients with follow-up data (including one with microinvasive carcinoma) recurred. Thirty-four invasive carcinomas were subclassified into 15 expansile and 19 infiltrative subtypes. All 15 carcinomas with only expansile invasion were stage I; none of the 11 with follow-up data recurred. Three of nine patients with stage I infiltrative carcinomas with follow-up information had a fatal recurrence. Eight of the remaining 10 infiltrative carcinomas had extended beyond the ovary at the time of diagnosis (stages II and III); of the six patients with follow-up data, four died of tumor and two were alive with disease. In stage I carcinomas nuclear grade and tumor rupture correlated with unfavorable prognosis, but less than infiltrative invasion. However, all three fatal tumors were infiltrative carcinomas that had ruptured, and two contained grade 3 malignant nuclei. Combination of infiltrative invasion, high nuclear grade, and tumor rupture is a strong predictor of recurrence for stage I mucinous ovarian tumors. Among the 19 infiltrative tumors, 13 contained foci of anaplastic carcinoma. Of the seven patients with stage I tumors and follow-up data, only one patient whose tumor had ruptured intraoperatively had a fatal recurrence. The presence of anaplastic components in stage Ia (intact) carcinomas did not have an adverse effect in their outcome, even when the undifferentiated carcinomatous elements appeared in the form of mural nodules.