Assessment of Interobserver Agreement Among Gynecologic Pathologists Between Three-Tier Versus Binary Pattern-based Classification Systems for HPV-associated Endocervical Adenocarcinoma.

The three-tier (A vs. B vs. C) pattern-based (Silva) classification system is a strong and fairly reproducible predictor of the risk of lymph node involvement and recurrence of human papillomavirus (HPV)-associated endocervical adenocarcinoma (EA). Recently, a binary pattern-based classification system has been proposed which incorporates the Silva pattern and lymphovascular invasion (LVI) to assign tumors as "low risk" or "high risk" and this may have superior prognostic significance compared with the three-tier system as well as current International Federation of Gynecology and Obstetrics (FIGO) staging of cervix-confined disease. The interobserver reproducibility of this binary system, however, is unknown. Representative slides from 59 HPV-associated EAs (1-3 slides/case) were independently reviewed by 5 gynecologic pathologists who participated in an online training module before the study. In the first review, a pattern was assigned using the three-tier system. On the second review, a "low risk" or "high risk" designation was assigned and the presence or absence of LVI was specifically documented. Interobserver agreement was assessed using Fleiss' kappa. The binary system showed improved interobserver agreement (kappa=0.634) compared with the three-tier system (kappa=0.564), with a higher proportion of cases having agreement between at least 4/5 reviewers (86% vs. 73%). Nineteen and 8 cases showed improved and worse interobserver agreement using the binary system, respectively; the remainder showed no change. 3/5 reviewers showed no intraobserver discrepancy while the remaining 2 did in a small subset of cases (n=2 and 4, respectively). In this study, a binary pattern-based classification system showed improved interobserver agreement compared with the traditional three-tier system.

Mesonephric-type adenocarcinomas of the ovary: prevalence, diagnostic reproducibility, outcome, and value of PAX2.

Mesonephric-type (or -like) adenocarcinomas (MAs) of the ovary are an uncommon and aggressive histotype. They appear to arise through transdifferentiation from Müllerian lesions creating diagnostic challenges. Thus, we aimed to develop a histologic and immunohistochemical (IHC) approach to optimize the identification of MA over its histologic mimics, such as ovarian endometrioid carcinoma (EC). First, we screened 1,537 ovarian epithelial neoplasms with a four-marker IHC panel of GATA3, TTF1, ER, and PR followed by a morphological review of EC to identify MA in retrospective cohorts. Interobserver reproducibility for the distinction of MA versus EC was assessed in 66 cases initially without and subsequently with IHC information (four-marker panel). Expression of PAX2, CD10, and calretinin was evaluated separately, and survival analyses were performed. We identified 23 MAs from which 22 were among 385 cases initially reported as EC (5.7%) and 1 as clear cell carcinoma. The interobserver reproducibility increased from fair to substantial (κ = 0.376-0.727) with the integration of the four-marker IHC panel. PAX2 was the single most sensitive and specific marker to distinguish MA from EC and could be used as a first-line marker together with ER/PR and GATA3/TTF1. Patients with MA had significantly increased risk of earlier death from disease (hazard ratio = 3.08; 95% CI, 1.62-5.85; p < 0.0001) compared with patients with EC, when adjusted for age, stage, and p53 status. A diagnosis of MA has prognostic implications for stage I disease, and due to the subtlety of morphological features in some tumors, a low threshold for ancillary testing is recommended.

Does Double Mean Trouble? Coexistence of Myeloproliferative and Lymphoproliferative Neoplasms.

Background: The occurrence of myeloproliferative neoplasms (MPNs) that evolve into each other is well-described, as is this occurrence of lymphoproliferative neoplasms (LPNs). However, less is known about rare MPN/LPN coexistence, and the aim of our study was to analyze charachteristics of these patients after long term follow-up. Methods: Fourteen patients with MPN/LPN coexistence were diagnosed and treated according to guidelines at a single university center across two decades. Results: The overall median age was 53 years (22-69). MPNs patients with subsequent LPNs had a shorter period of second malignancy development and a more aggressive course of LPN, which can cause fatal outcomes. Polycythemia vera and chronic lymphocytic leukemia were most commonly associated (36%). The JAK2V617F mutation had 2/3 and cytogenetic abnormalities occurred in 1/3 of patients. MPN/LPN coexistence cases had significantly higher thrombotic potential (42.8%) and a higher third malignancy accruement frequency (21.4%) versus those without such malignancies. Conclusions: Considering the younger ages at MPN diagnosis, it is recommended to check regularly for blood lymphocytosis or lymphadenopathy occurrences and organomegaly progression faster than expected for MPN, with the aim of timely LPN diagnoses. The presence of molecular-cytogenetic abnormalities in a majority of patients indicate possible genetic instability and increased risk of development of multiple neoplasms, thus elevating thrombotic risk.

TP53 as a Diagnostic Aid in the Distinction of Ovarian Mucinous Borderline Tumors From Mucinous Carcinoma.

Ovarian mucinous borderline tumors (MBTs) are clinically managed as benign neoplasms while the management of ovarian mucinous carcinomas (MC) is dependent on tumor stage. Despite the standardization of sampling of ovarian mucinous neoplasms, limited interobserver reproducibility between MBT and MC persists. Based on our recent finding that abnormal TP53 expression is associated with unfavorable outcome in MBT, we hypothesized that TP53 status might improve the reproducible distinction of MBT from MC. A virtual slide set of 85 consecutive ovarian mucinous neoplasms received at a single institution, with each case represented by 3 full sections, were reviewed by 3 pathologists in 2 iterations. The initial assessment was based solely on morphologic review, while the second iteration was performed with knowledge of TP53 status. The reproducibility of a trinary categorization (MBT, MBT with intraepithelial carcinoma [IEC], MC) significantly improved from a κ of 0.60 based on the initial morphologic assessment to a κ of 0.76 (t-test, P =0.0042) after consideration of TP53 immunohistochemistry (IHC) results. Six out of 85 patients died of disease, and in 2 of them, at least 1 pathologist assessed MBT with IEC and not MC even after integration of TP53 IHC. With the integration of TP53 IHC, substantial interobserver agreement for MBT and MC can be reached, particularly in cases with an uncertain degree of confluent growth. TP53 IHC can also be used to highlight and support the presence of IEC in MBT, however, discordances remained in 2 cases with adverse outcome.

Infiltrative pattern of invasion is independently associated with shorter survival and desmoplastic stroma markers FAP and THBS2 in mucinous ovarian carcinoma.

AIMS: Mucinous ovarian carcinoma (MOC) is a rare ovarian cancer histotype with generally good prognosis when diagnosed at an early stage. However, MOC with the infiltrative pattern of invasion has a worse prognosis, although to date studies have not been large enough to control for covariables. Data on reproducibility of classifying the invasion pattern are limited, as are molecular correlates for infiltrative invasion. We hypothesized that the invasion pattern would be associated with an aberrant tumour microenvironment. METHODS AND RESULTS: Four subspecialty pathologists assessed interobserver reproducibility of the pattern of invasion in 134 MOC. Immunohistochemistry on fibroblast activation protein (FAP) and THBS2 was performed on 98 cases. Association with survival was tested using Cox regression. The average interobserver agreement for the infiltrative pattern was moderate (kappa 0.60, agreement 86.3%). After reproducibility review, 24/134 MOC (18%) were determined to have the infiltrative pattern and this was associated with a higher risk of death, independent of FIGO stage, grade, and patient age in a time-dependent manner (hazard ratio [HR] = 10.2, 95% confidence interval [CI] 3.0-34.5). High stromal expression of FAP and THBS2 was more common in infiltrative MOC (FAP: 60%, THBS2: 58%, both P < 0.001) and associated with survival (multivariate HR for FAP: 1.5 [95% CI 1.1-2.1] and THBS2: 1.91 [95% CI 1.1-3.2]). CONCLUSIONS: The pattern of invasion should be included in reporting for MOC due to the strong prognostic implications. We highlight the histological features that should be considered to improve reproducibility. FAP and THBS2 are associated with infiltrative invasion in MOC.

Laparoscopic approach in the treatment of splenic angiolipomatous hamartoma: the first report of a case.

Angiolipomatous hamartoma is a benign mesenchymal proliferation of unknown aetiology. Only a few cases have been documented in the published literature. This current case report describes a 57-year-old female patient who was hospitalized for an assessment of a previously radiologically-verified splenic lesion and further treatment. The patient had been surgically treated 10 years previously; a lobectomy of the superior left pulmonary lobe had been performed in order to remove a verified tumour lesion. A complete radiological examination was undertaken, which verified a spleen of a size that was within the physiological range, with a centrally-located lobular tumour lesion. Given the risk of splenic rupture, as well as the fact that the lesion's aetiology was still undetermined, and finally the fact that differential diagnostics indicated the possibility of a metastasis, the patient was treated surgically. Laparoscopic splenectomy, in the treatment of splenic diseases, even rare ones such as this, is not a novelty. Indeed, it needs to be applied as the standard approach, with the well-known benefits that the minimalized approach offers.

Utility of CK8, CK10, CK13, and CK17 in Differential Diagnostics of Benign Lesions, Laryngeal Dysplasia, and Laryngeal Squamous Cell Carcinoma.

There are no reliable immunohistochemical markers for diagnosing laryngeal squamous cell carcinoma (SCC) or diagnosing and grading laryngeal dysplasia. We aimed to evaluate the diagnostic utility of CK8, CK10, CK13, and CK17 in benign laryngeal lesions, laryngeal dysplasia, and laryngeal SCC. This retrospective study included 151 patients diagnosed with laryngeal papilloma, laryngeal polyps, laryngeal dysplasia, and laryngeal SCC who underwent surgical treatment between 2010 and 2020. Immunohistochemistry (IHC) was carried out using specific monoclonal antibodies against CK8, CK10, CK13, and CK17. Two experienced pathologists performed semi-quantitative scoring of IHC positivity. The diagnostic significance of the markers was analyzed. CK13 showed a sensitivity of 100% and a specificity of 82.5% for distinguishing between laryngeal SCC and laryngeal dysplasia and benign lesions. CK17 showed a sensitivity of 78.3% and specificity of 57.1% for the detection of laryngeal SCC vs. laryngeal dysplasia. CK10 showed a sensitivity of 80.0% for discriminating between low-grade and high-grade dysplasia, and a specificity of 61.1%. Loss of CK13 expression is a reliable diagnostic tool for diagnosing laryngeal lesions with malignant potential and determining resection lines. In lesions with diminished CK13 expression, CK17 could be used as an auxiliary immunohistochemical marker in diagnosing laryngeal SCC. In CK13-negative and CK17-positive lesions, CK10 positivity could be used to determine low-grade dysplasia. CK8 is not a useful IHC marker in differentiating between benign laryngeal lesions, laryngeal dysplasia, and laryngeal SCC.

Accurate Distinction of Ovarian Clear Cell From Endometrioid Carcinoma Requires Integration of Phenotype, Immunohistochemical Predictions, and Genotype: Implications for Lynch Syndrome Screening.

Ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC) are both associated with endometriosis but differ in histologic phenotype, biomarker profile, and survival. Our objectives were to refine immunohistochemical (IHC) panels that help distinguish the histotypes and reassess the prevalence of mismatch repair deficiency (MMRd) in immunohistochemically confirmed OCCC. We selected 8 candidate IHC markers to develop first-line and second-line panels in a training set of 344 OCCC/OEC cases. Interobserver reproducibility of histotype diagnosis was assessed in an independent testing cohort of 100 OCC/OEC initially without and subsequently with IHC. The prevalence of MMRd was evaluated using the testing cohort and an expansion set of 844 ovarian carcinomas. The 2 prototypical combinations (OCCC: Napsin A+/HNF1B diffusely+/PR-; OEC: Napsin A-/HNF1B nondiffuse/PR+) occurred in 75% of cases and were 100% specific. A second-line panel (ELAPOR1, AMACR, CDX2) predicted the remaining cases with 83% accuracy. Integration of IHC improved interobserver reproducibility (κ=0.778 vs. 0.882, P<0.0001). The prevalence of MMRd was highest in OEC (11.5%, 44/383), lower in OCCC (1.7%, 5/297), and high-grade serous carcinomas (0.7%, 5/699), and absent in mucinous (0/126) and low-grade serous carcinomas (0/50). All 5 MMRd OCCC were probable Lynch syndrome cases with prototypical IHC profile but ambiguous morphologic features: 3/5 with microcystic architecture and 2/5 with intratumoral stromal inflammation. Integration of first-line and second-line IHC panels increases diagnostic precision and enhances prognostication and triaging for predisposing/predictive molecular biomarker testing. Our data support universal Lynch syndrome screening in all patients with OEC when the diagnosis of other histotypes has been vigorously excluded.

Expression of kisspeptin and KISS1 receptor in pituitary neuroendocrine tumours - an immunohistochemical study.

INTRODUCTION: Pituitary neuroendocrine tumours (PitNETs), traditionally designated as pituitary adenomas, show elatively frequent invasive growth with exceptional metastatic potential, the causes of which are not entirely elucidated. Kisspeptins, which perform their activity through KISS1 receptor (KISS1R), are recognised as metastatic suppressors in many malignant tumours. This study aimed to investigate the immunohistochemical expression of kisspeptin and KISS1R in different types of PitNETs and to compare it with the expression in the normal anterior pituitary, using tissue microarray. MATERIAL AND METHODS: The experimental group consisted of 101 patients with PitNETs, with 45 (37.3%) being of gonadotroph, 40 (33.9%) somatotroph, 4 (3.4%) corticotroph, 4 (3.4%) thyrotroph, 3 (2.5%) lactotroph, and 6 (5.1%) null-cell type. The control group consisted of anterior pituitary tissue accidentally removed during the surgery for PitNETs in 17 patients. RESULTS: Kisspeptin expression was observed in both experimental and control groups, without statistically significant differences in the staining intensity. Negative kisspeptin staining was detected in 10 (9.9%), weak in 79 (78.2%), and moderate in 12 tumours (11.9%); none of the tumours had strong staining intensity. The weak staining intensity was predominant in all PitNET types except thyrotroph tumours. Significant statistical difference in terms of kisspeptin expression between types of PitNET and the control group was not observed. Immunohistochemical expression of KISS1R was not observed in the control group or in the experimental group. CONCLUSIONS: We conclude that immunohistochemistry, as a method, cannot confirm the involvement of kisspeptin in tumourigenesis and aggressiveness of PitNETs, but potentially supports its antimetastatic role. The absence of KISS1R immunohistochemical expression in all anterior pituitaries and PitNETs in our cohort needs verification through the use of different procedures designed for the detection of the presence and localisation of proteins in the cell.

Bridging the Gap with Clinicians: The Issue of Underrecognition of Pathologists and Radiologists as Scientific Authors in Contemporary Medical Literature.

The purpose of this study was to evaluate recognition of pathologists and radiologists as coauthors in case reports in the field of surgical oncology. The MEDLINE database was searched for all full free text case reports involving human material published from April 1, 2011 until March 31, 2016, using search terms: "case report" + "tumors" + "surgery" + "malignant". The search strategy identified a total of 1427 case reports of which 907 were included in this analysis. Of 807 articles with histopathological images and/or descriptions, 352 (43.6%) did not acknowledge or include the pathologist as a coauthor. Of 662 case reports with radiographic images and/or their description, 537 (81.1%) did not list the radiologist as coauthor nor acknowledge them. In case reports containing histopathological images, significantly more pathologists were either listed as coauthors or acknowledged compared to those who were not (Z = 5.128; p = 0.001). However, among case reports containing radiographic images, there were significantly less articles either listing radiologists as coauthors or acknowledging them compared to a larger proportion of articles in which radiologists were omitted (Z = - 22.646; p = 0.001). In conclusion, pathologists and radiologists are underrecognized as coauthors in surgical oncology case reports in spite of obvious proof of their contribution to manuscript preparation. When involved in research and publishing, all physicians should be aware of fair and honest collaboration with specialists in other clinical and non-clinical disciplines to better serve the scientific community.

GATA3 Expression in Common Gynecologic Carcinomas: A Potential Pitfall.

GATA binding protein 3 (GATA3) immunohistochemistry is primarily used as a marker of breast and urothelial differentiation, particularly in metastatic settings. In the gynecologic tract it also serves a robust marker for mesonephric and trophoblastic tumors. However, expression has also been described in more common malignancies of gynecologic tract including ovarian, endometrial, and cervical carcinomas. Data on the distribution of GATA3 expression in gynecologic malignancies is somewhat limited, particularly across different histologic subtypes of ovarian, endometrial, and cervical carcinomas. To assess the rates of GATA3 expression among common gynecologic cancers of various histologic types, 100 ovarian carcinomas, 64 endometrial carcinomas/atypical hyperplasias, 16 cervical squamous cell carcinomas (SCCs), and 14 endocervical adenocarcinomas were evaluated by immunohistochemistry for GATA3 positivity. Eight percent of endometrial carcinomas expressed GATA3, including 2 serous carcinomas, 1 carcinosarcoma, and 1 case of atypical hyperplasia. Six percent of ovarian carcinomas were GATA3-positive including 2 clear cell carcinomas, 2 mucinous adenocarcinomas, and 2 high-grade serous carcinomas. Thirty-eight percent of cervical SCCs showed weak to moderate staining in up to 50% of tumor cells. All endocervical adenocarcinomas were entirely negative for GATA3. In summary, GATA3 shows focal weak to moderate expression in a subset of endometrial and ovarian carcinomas. In contrast, usual-type endocervical adenocarcinomas are typically negative for GATA3, which can be helpful in differentiating them from mesonephric proliferations or carcinomas. A larger proportion of cervical SCCs express GATA3, therefore caution should be exercised when using this stain in the setting of a lower genitourinary carcinomas.

The predictive value of morphological findings in early diagnosis of acute myeloid leukemia with recurrent cytogenetic abnormalities.

This study explores cytomorphologic features and their predictive role for early identification of acute myeloid leukemia (AML) with morphological distinctive recurrent cytogenetic abnormalities (RCA): t(15;17), t(8;21) and inv(16)/t(16;16). We retrospectively evaluated 396 de novo AML cases, diagnosed and treated at single institution, between 2013-2017. Specific cytomorphologic features suggesting distinctive AML-RCA were revealed at diagnosis in 62 (15.65%) patients, including AML with t(15;17) in 41 (66.13%), t(8;21) in 13 (20.97%) and inv(16)/t(16;16) in 8 (12.90%). Final diagnoses of AML-RCA according to WHO integrated diagnostic criteria were established in 66 (16.66%) cases, including AML with t(15;17) 40 (60.60%), t(8;21) 17 (25.76%), and inv(16)/t(16;16) 9 (13.64%). Discordance between cytomorphological and other integrated criteria was detected as missed/wrong-call in 0/1 for t(15;17), 6/2 for t(8;21) and 2/1 for inv(16)/t(16;16). The cytomorphological accuracy was 97.56% (40/41) for t(15;17), 57.89% (11/19) for t(8;21) and 70% (7/10) for inv (16)/t(16;16). Positive/negative predictive values of cytomorphological evaluation were: 97.56%/100% for t(15;17); 84.62%/88.68% for t(8;21); 87.50%/96.65% for inv(16)/t(16;16). Sensitivity/specificity were: 100%/96.15% for t(15;17); 64.10%/95.92% for t(8;21); 77.78%/98.25% for inv(16)/t(16;16). We confirmed that morphology is still a highly relevant evaluation method in diagnosing several common AML-RCAs before completing cytogenetic and molecular studies, enabling early detection, particularly of AML with t(15;17).

Expression of Disialoganglioside (GD2) in Neuroblastic Tumors: A Prognostic Value for Patients Treated With Anti-GD2 Immunotherapy.

Neuroblastoma, a malignant neoplasm of the sympathetic nervous system, is one of the most aggressive pediatric cancers. Patients with stage IV high-risk neuroblastoma receive an intensive multimodal therapy ending with an immunotherapy based on a chimeric monoclonal antibody ch14.18. Although the use of ch14.18 monoclonal antibody has significantly increased the survival rate of high-risk neuroblastoma patients, about 33% of these patients still relapse and die from their disease. Ch14.18 targets the disialoganglioside, GD2, expressed on neuroblastic tumor (NT) cells. To better understand the causes of tumor relapse following ch14.18 immunotherapy, we have analyzed the expression of GD2 in 152 tumor samples from patients with NTs using immunohistochemical stainings. We observed GD2 expression in 146 of 152 samples (96%); however, the proportion of GD2-positive cells varied among samples. Interestingly, low percentage of GD2-positive cells before immunotherapy was associated with relapse in patients receiving ch14.18 immunotherapy. In addition, we demonstrated in vitro that the sensitivity of neuroblastoma cell lines to natural killer-mediated lysis was dependent on the proportion of GD2-positive cells, in the presence of ch14.18 antibody. In conclusion, our results indicate that the proportion of tumor cells expressing GD2 in NTs should be taken in consideration, as a prognostic marker, for high-risk neuroblastoma patients receiving anti-GD2 immunotherapy.

DICER1 Mutations Are Consistently Present in Moderately and Poorly Differentiated Sertoli-Leydig Cell Tumors.

Ovarian Sertoli-Leydig cell tumors (SLCTs) are uncommon sex cord-stromal tumors associated with both germ-line and somatic DICER1 mutations, the frequency of which has varied widely in different studies (0% to 62.5%). The current World Health Organization Classification includes 3 histologic types of SLCTs (well-differentiated, moderately differentiated, and poorly differentiated); heterologous elements and/or retiform patterns may be present in moderately and poorly differentiated neoplasms. We investigated the frequency of DICER1 mutations in a series of 38 ovarian tumors initially diagnosed as SLCTs, and explored whether identified mutations were associated with specific morphologic features. Specialist pathology review performed blinded to molecular results confirmed 34 tumors to be SLCTs (22 moderately differentiated, 8 poorly differentiated; 4 well-differentiated), while the remaining 4 neoplasms were considered not to represent SLCTs. Of the 34 cases diagnosed as SLCTs, 30 (88%) harbored ≥1 DICER1 mutation. All 30 moderately differentiated/poorly differentiated SLCTs contained mutations, but we did not find deleterious DICER1 mutations in the 4 well-differentiated SLCTs. Our study reports the highest DICER1 mutation frequency to date in SLCTs, with 100% of moderately differentiated and poorly differentiated tumors being DICER1-mutated. This suggests that DICER1 mutation may be a defining feature of these neoplasms. Although the number of cases is limited, well-differentiated SLCTs appear to be DICER1-independent. Moderately differentiated and poorly differentiated SLCT components often coexist with each other and form part of a spectrum, while well-differentiated SLCTs usually occur in pure form, suggesting that fundamentally, these represent 2 separate and independent tumor types with a different pathogenesis. We suggest that all patients with ovarian SLCTs undergo germ-line DICER1 mutation testing.

Bilateral ocular panadnexal mass as initial presentation of systemic blastoid variant of mantle-cell lymphoma.

A 66-year-old man developed a slowly enlarging, bilateral, painless, periorbital, and orbital swelling with ptosis, nonaxial proptosis, chemosis, exposure keratopathy, and decreased vision in both eyes. He had fever, night sweats, and weight loss (B-symptoms), along with lymphadenopathy and elevated serum lactate dehydrogenase, with no prior history of lymphoma. A transpalpebral incisional biopsy revealed a rare case of mantle-cell lymphoma of blastoid variant, stage IVB. The main immunophenotype characteristics were cyclin D1+, CD5+, CD10-, CD23-, Bcl-6-/+, and a high (up to 80%) Ki-67 proliferation index. Following an excellent response to the immune-chemotherapy treatment plan, all ocular adnexal lymphoma manifestations disappeared completely; however, 13 months after the initial presentation, there was a recurrence of the disease with rapid worsening and death. The blastoid variant of mantle cell lymphoma, a rare subtype of mantle-cell lymphoma, is a highly aggressive neoplasm, ultimately having a fatal outcome. As the initial manifestation of the disease, ocular adnexal region blastoid variant of mantle-cell lymphoma is an exceptional event, with only one previous case reported.

CK7 Immunohistochemistry as a Predictor of CIN1 Progression: A Retrospective Study of Patients From the Quadrivalent HPV Vaccine Trials.

Cervical high-grade squamous intraepithelial lesion (CIN2-3) is thought to arise from a distinct population of cells at the squamocolumnar junction (SCJ). Immunohistochemical (IHC) biomarkers that characterize the SCJ phenotype, including CK7, have been proposed as tools to separate the subset of low-grade squamous intraepithelial lesions (LSILs) (CIN1) that will progress to high-grade squamous intraepithelial lesion from the majority of cases, which will resolve without further intervention. We conducted a retrospective study of CK7 IHC on adjudicated CIN1 tissue from women in the placebo arm of the quadrivalent human papillomavirus (HPV) vaccine trials. Tissue sections were stained with CK7 IHC and scored as negative, patchy, gradation (ie, top-down), or full-thickness pattern. Results were assessed for the prediction of future diagnosis of CIN2-3/AIS (eg, CIN2+ progression) along with p16 IHC, antecedent high-grade cytology, and HPV16 status. A total of 517 patients with CIN1 biopsies and complete data were identified, 12% of whom showed CIN2+ progression on follow-up. Full-thickness CK7 staining showed the highest correlation with CIN2+ progression (odds ratio [OR] 2.8, P=0.021) relative to the other risk factors (HPV16: OR 2.0, P=0.035; antecedent high-grade cytology: OR 2.2, P=0.028; p16 IHC: OR 1.5, P=0.16). Inclusion of the gradation/"top-down" CK7 pattern resulted in a less robust association with progression (CIN2+: OR 2.0, P=0.028; CIN3+: OR 1.3, P=0.74). Interobserver variability ranged from slight to substantial and was not contingent on gynecologic pathology training experience (κ=0.7078 for negative/patchy vs. gradation/full thickness; κ=0.5672 for negative/patchy/gradation vs. full thickness). These data support the theory that SCJ-derived LSILs are precursors to a potentially aggressive subset of cervical SILs and that CK7 staining may inform risk stratification for LSIL (CIN1). However, clinical utility is significantly tempered by the relatively low amplitude of the risk increase, interpretative variability, and limitations of colposcopic sampling.

Orbital lymphoma with isolated occult bilateral adrenal involvement: report of an extremely rare case.

Orbital lymphoma is very rare malignant neoplasm, usually diagnosed in early stage of disease as primary lymphoma, but dissemination occurs in approximately 33% of cases. Isolated bilateral adrenal lymphomatous involvement is extremely rare, described in 0.83% of cases. We present autopsy case of a 63-year-old man with bilateral orbital diffuse large cell lymphoma, clinical stage IEA, successfully treated by one cycle of chemo- and radiotherapy, but after administration of the second cycle, the patient developed signs of gastrointestinal hemorrhage and died two months after the diagnosis. Autopsy findings exclude lymphoma involvement of any organ except histopathological infiltration of both adrenal glands without evidence of a mass lesion.

Early post-transplant lymphoproliferative disorder ­ Case of fatal lymphoma after kidney transplantation.

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a common malignancy following organ transplantation. Risk for PTLD is associated with the use of anti-thymocyte globulin in the prevention and treatment of acute rejection following kidney transplantation. Case Outline: We report a case of fatal PTLD presented with sudden onset of fever. A 33-year-old male patient with primary diagnosis of left kidney agenesia underwent kidney transplantation six years following hemodialysis treatment initiation. Deceased donor was a 66-year-old female whose cause of death was cerebrovascular accident. Immunosuppressive regimen consisted of basiliximab, corticosteroids, tacrolimus, and mycophenolate mofetil. Six months upon transplantation the patient was hospitalized due to fever of unknown origin. All microbiological samples were negative, but abdominal ultrasound revealed round solid mass in the right native kidney. Right nephrectomy was performed showing tumor 35 × 35 × 20 mm in size within the 70 × 40 × 35 mm kidney. Pathohistological analysis confirmed very rare monomorphic B-cell PTLD ­ B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. Conclusion: We consider this case of PTLD following kidney transplantation particular because of the tumor mass in native kidney after basiliximab induction and rare pathohistology. In a transplanted patient with fever, PTLD must always be considered, irrespective of immunosuppressive regimen.

BCL2 positive and BCL6 negative diffuse large B cell lymphoma patients benefit from R-CHOP therapy irrespective of germinal and non germinal center B cell like subtypes.

PURPOSE: Despite major advances in the treatment of diffuse large B cell lymphoma (DLBCL), approximately one third of the patients progress or die, suggesting the existence of additional oncogenic events. The purpose of this study was to evaluate the prognostic value of the "Hans classifier", and BCL2 and MYC protein expression and gene alterations in DLBCL patients treated with CHOP or R-CHOP chemotherapy over a 5-year period. Furthermore, we tried to correlate these parameters with the International Prognostic Index (IPI). METHODS: The immunohistochemical (IHC) expression of CD10, BCL6, MUM1 and BCL2 on paraffin-embedded formalin-fixed tumor samples from 103 centroblastic DLBCLs was analyzed. IHC expression of MYC and fluorescence in situ hybridization (FISH) for MYC and BCL2 gene alterations was performed on 67 samples using the tissue microarray (TMA) method. RESULTS: The Hans algorithm was not predictive of survival in both therapy groups. No significant difference in BCL2 and MYC alterations or MYC protein expression in relation to complete response (CR), event-free survival (EFS) and overall survival (OS) was observed in our study. High IPI correlated significantly with poor outcome and it was identified as independent prognostic factor for OS and EFS (both p=0.000). The 5-year OS was 61% in the R-CHOP compared to 38% in the CHOP group (p=0.007). Rituximab significantly improved the OS in the BCL2 positive (60 vs 29%, p=0.008), and the BCL6 negative (73 vs 25%, p=0.001) cases. CONCLUSION: IPI is an independent prognosticator for DL-BCL patients and the addition of rituximab significantly improved survival. Furthermore, patients with BCL2+ and BCL6-DLBCL benefited from R-CHOP.

Management of myelofibrosis during pregnancy: a case report.

INTRODUCTION: Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm that occurs most commonly in the decade six of life and it is very rare in the young persons. CASE REPORT: We reported a 28-year-old female patient with primary myelofibrosis who had a normal pregnancy and delivery in the week 40 of pregnancy without any complications. Two years before the diagnosis of PMF she had normal pregnancy. The patient was treated with interferon-alpha and low dose aspirin during the whole pregnancy and with low-molecular-weight heparin a week before delivery and 6 weeks after. The patient had no complications during pregnancy. She delivered in term with healthy, normal baby weight. CONCLUSION: Decision about treatment strategy of pregnancy associated hematologic malignancies should be made for each patient individually.