Two Rare Cases of Paratubal Leydig Cell Nodules: Clinical Relevance and Debated Terminology of a Noteworthy Incidentaloma.

Cells with cytologic and immunohistochemical features of Leydig cells are normally present in the ovary and the ovarian hilum, are testosterone-producing, and have been referred to as ovarian hilus cells. Rarely these cells form nests or nodules in extraovarian sites such as the mesovarium or mesosalpinx. Because they are so rare, these nodules can present a diagnostic challenge when first encountered. This report describes 2 such incidental nodules in the mesosalpinx associated with a small paratubal cyst and suggests that the term Leydig cell nodule be preferred over the nonspecific and confusing historical term ovarian hilus cell nest.

Histologic effects of medroxyprogesterone acetate on endometrioid endometrial adenocarcinoma: a Gynecologic Oncology Group study.

Progestins have been used in the treatment of recurrent endometrial adenocarcinoma for almost 50 yr. Some endometrial carcinomas respond to hormonal therapy, but the mechanism of action remains incompletely known. We wished to determine the efficacy of progestins to induce a histologic response in endometrioid carcinomas and explore its effects on histologic and immunohistochemical measures of growth and cell death. The Gynecologic Oncology Group initiated a study of 75 women with endometrioid endometrial adenocarcinoma, 59 of whom received the progestin, medroxyprogesterone acetate for 21 to 24 d immediately before hysterectomy and had available slides. Initial biopsies and hysterectomies were hematoxylin and eosin-stained and immunostained for estrogen receptor (ER) and progesterone receptor (PR), progesterone receptor-ß (PRB), Bcl-2, Ki-67, and cleaved caspase-3 (Casp3). A histologic response was defined subjectively, following which specific histologic measurements and semiquantitative scores of immunohistologic variables of initial biopsies were compared with posttreatment slides. Only 1 complete histologic response was seen, but 37 tumors (63%) had a partial histologic response. Specific histologic changes included the following: a decrease in the nuclear grade, the number of mitotic figures, nucleoli, and mean gland cellularity, and acquisition of more abundant eosinophilic cytoplasm, squamous metaplasia, and secretion. The tumors that displayed a subjectively defined histologic response following treatment differed initially from those that did not only with respect to initial nuclear grade and the mitotic index. Statistically significant differences in the specific histologic features in carcinomas of responders versus nonresponders following treatment were found only with respect to acquisition of pale eosinophilic cytoplasm and luminal secretion. More than 90% of tumors were initially ER positive and 76% were PR positive. The initial presence of ER or PR was not related to subjective histologic response. PR and PRB were significantly downregulated following progestin therapy, as were Ki-67 and Bcl-2. However, ER and Casp3 did not change significantly. Tumors that displayed a histologic response had significantly lower pretreatment levels of Ki-67. Mean Ki-67 and Bcl-2 decreases following medroxyprogesterone acetate were greater in histologic responders than nonresponders, but not decreases in ER, PR, PRB, and Casp3. The histologic response in the tumors and their stroma differed quantitatively and qualitatively from that of the adjacent benign endometrium, where decidual change accompanied luminal secretion and secretory exhaustion of glands. Three weeks of medroxyprogesterone acetate therapy induces partial histologic responses in most endometrioid adenocarcinomas. Previously suggested features of histologic response do not capture the entire spectrum of changes seen. Downregulation of ER, PR, PRB, Ki-67, and Bcl-2 occurs without a significant change in Casp3. These alterations suggest that progestins act by differentiation of neoplastic cells with diminished proliferation rather than tumor cell death. As stromal decidualization was confined to areas surrounding benign glands, a paracrine effect may be involved in complete response to progestins.

Malakoplakia of the Endometrium: A Rare Unexpected Disease Raising Clinical Concern for Malignancy.

Malakoplakia is a rare disease that manifests as a histiocytic inflammatory process and most often occurs in the urinary bladder. It is caused by an impaired capacity of histiocytes to kill and digest bacteria. The typical histopathologic findings are sheets of histiocytes with granular eosinophilic cytoplasm and characteristic Michaelis-Gutmann bodies, spherical bodies with a targetoid appearance. Malakoplakia is even rarer in the gynecologic tract, and our literature search found only 21 published patients of malakoplakia involving the endometrium. Here we report a 60-year-old female patient who presented with recurrent pelvic infections and postmenopausal bleeding, which raised concern for an endometrial malignancy. Hysterectomy with salpingo-oophorectomy revealed malakoplakia involving the endometrium and also the right ovary. Michaelis-Gutmann bodies were visible on the intraoperative frozen section that was performed to rule out an endometrial malignancy. We summarize the clinicopathologic findings of the published patients of endometrial malakoplakia.

Early growth response 1 and fatty acid synthase expression is altered in tumor adjacent prostate tissue and indicates field cancerization.

BACKGROUND: Field cancerization denotes the occurrence of molecular alterations in histologically normal tissues adjacent to tumors. In prostate cancer, identification of field cancerization has several potential clinical applications. However, prostate field cancerization remains ill defined. Our previous work has shown up-regulated mRNA of the transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS) in tissues adjacent to prostate cancer. METHODS: Immunofluorescence data were analyzed quantitatively by spectral imaging and linear unmixing to determine the protein expression levels of EGR-1 and FAS in human cancerous, histologically normal adjacent, and disease-free prostate tissues. RESULTS: EGR-1 expression was elevated in both structurally intact tumor adjacent (1.6× on average) and in tumor (3.0× on average) tissues compared to disease-free tissues. In addition, the ratio of cytoplasmic versus nuclear EGR-1 expression was elevated in both tumor adjacent and tumor tissues. Similarly, FAS expression was elevated in both tumor adjacent (2.7× on average) and in tumor (2.5× on average) compared to disease-free tissues. CONCLUSIONS: EGR-1 and FAS expression is similarly deregulated in tumor and structurally intact adjacent prostate tissues and defines field cancerization. In cases with high suspicion of prostate cancer but negative biopsy, identification of field cancerization could help clinicians target areas for repeat biopsy. Field cancerization at surgical margins on prostatectomy specimen should also be looked at as a predictor of cancer recurrence. EGR-1 and FAS could also serve as molecular targets for chemoprevention.

A phase II evaluation of lapatinib in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a gynecologic oncology group study.

OBJECTIVE: Activation and dimerization of the ERBB family play a role in the pathogenesis and progression of ovarian cancer. We conducted a phase II trial to evaluate the activity and tolerability of lapatinib in patients with recurrent or persistent epithelial ovarian cancer (EOC) and to explore the clinical value of expression levels of epidermal growth factor receptors (EGFR), phosphorylated EGFR, HER-2/neu, and Ki-67, and the presence of EGFR mutations. METHODS: Eligible patients had recurrent or persistent EOC or primary peritoneal carcinoma, measurable disease, and up to 2 prior chemotherapy regimens for recurrent disease. Patients were treated with lapatinib 1500 mg/day. The primary endpoint of efficacy was 6-month progression free survival (PFS). RESULTS: Twenty-five of 28 patients were eligible and evaluable for analysis of efficacy and toxicity. Two (8.0%) were alive and progression-free at 6 months. No objective responses were observed. There were 1 grade 4 toxicity (fatigue) and few grade 3 toxicities. Associations between Ki-67 with prior platinum-free interval, PFS, and a polymorphism in EGFR were suggested. CONCLUSIONS: Lapatinib has minimal activity in recurrent ovarian cancer. Ki-67 expression may be associated with prior PFS and a polymorphism in EGFR exon 20 (2361G>A, Q787Q).

Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer.

OBJECTIVE: A phase II trial was performed to evaluate the efficacy and safety of the tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, lapatinib, and to explore EGFR, HER2 (EGFR2), phosphorylated ERK MAP kinase (pERK), and Ki67 expression, as well as EGFR mutations in persistent/recurrent endometrial cancer (EC). METHODS: Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 1500 mg oral lapatinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with 6 month PFS as the primary endpoint. The trial had a 10% type I error rate with 90% power. EGFR, HER2, pERK, and Ki67 were evaluated by immunohistochemistry (IHC) from hysterectomy specimens, pre-treatment biopsies, and post-treatment biopsies (when available). Exons 18-21 of EGFR were sequenced. RESULTS: Three patients of 30 evaluable had PFS ≥6 months, one had a partial response, seven had stable disease, 21 had progressive disease and one was indeterminate. Three mutations in EGFR were identified. Two of these, L688F and K754E, were not associated with response or PFS. However, a newly identified mutation in exon 18, E690K, occurred in the patient with a partial response and progression-free survival extending past six months. CONCLUSION: While lapatinib has limited activity in unselected cases, the identification of a previously unreported mutation in EGFR (E690K) with a response suggests that lapatinib may be beneficial in some cases of EC.

HPV-associated carcinosarcoma of the anal canal: A rare case provides insight into the pathogenesis of these biphasic neoplasms.

Carcinosarcomas are biphasic malignant neoplasms and are rare outside the corpus uteri. Here we report a carcinosarcoma arising in the anal canal in a 60 year-old female. This is only the fourth reported case of a carcinosarcoma arising at this site, the second reported case with molecular evidence of high risk HPV association, and the first case with reported cytogenetics analysis. The finding of high risk HPV in both the epithelial and mesenchymal components of the tumor provides important insight into the pathogenesis of the tumor, and strongly suggests that both components of this carcinosarcoma are derived from a common immature epithelial progenitor cell during tumorigenesis.

A Deep Learning Convolutional Neural Network Can Differentiate Between Helicobacter Pylori Gastritis and Autoimmune Gastritis With Results Comparable to Gastrointestinal Pathologists.

CONTEXT.­: Pathology studies using convolutional neural networks (CNNs) have focused on neoplasms, while studies in inflammatory pathology are rare. We previously demonstrated a CNN that differentiates reactive gastropathy, Helicobacter pylori gastritis (HPG), and normal gastric mucosa. OBJECTIVE.­: To determine whether a CNN can differentiate the following 2 gastric inflammatory patterns: autoimmune gastritis (AG) and HPG. DESIGN.­: Gold standard diagnoses were blindly established by 2 gastrointestinal (GI) pathologists. One hundred eighty-seven cases were scanned for analysis by HALO-AI. All levels and tissue fragments per slide were included for analysis. The cases were randomized, 112 (60%; 60 HPG, 52 AG) in the training set and 75 (40%; 40 HPG, 35 AG) in the test set. A HALO-AI correct area distribution (AD) cutoff of 50% or more was required to credit the CNN with the correct diagnosis. The test set was blindly reviewed by pathologists with different levels of GI pathology expertise as follows: 2 GI pathologists, 2 general surgical pathologists, and 2 residents. Each pathologist rendered their preferred diagnosis, HPG or AG. RESULTS.­: At the HALO-AI AD percentage cutoff of 50% or more, the CNN results were 100% concordant with the gold standard diagnoses. On average, autoimmune gastritis cases had 84.7% HALO-AI autoimmune gastritis AD and HP cases had 87.3% HALO-AI HP AD. The GI pathologists, general anatomic pathologists, and residents were on average, 100%, 86%, and 57% concordant with the gold standard diagnoses, respectively. CONCLUSIONS.­: A CNN can distinguish between cases of HPG and autoimmune gastritis with accuracy equal to GI pathologists.

Florid Mesothelial Hyperplasia Associated with Abdominal Wall Endometriosis Mimicking Invasive Carcinoma.

Florid mesothelial hyperplasia typically occurs in the pelvis, abdomen, or chest associated with an underlying neoplastic or inflammatory process. These lesions are of clinical significance because they can mimic a neoplasm. Early reports were published in the 1970s, but only a few case series of such lesions have been published in the gynecologic pathology literature. Here, we report a case of florid mesothelial hyperplasia with an infiltrative growth pattern, mimicking an invasive carcinoma. The lesion was associated with endometriosis forming a mass lesion in the abdominal wall. Histologically, tubular arrangements and nests of mesothelial cells, some with artifactual slit-like spaces, formed a stellate lesion adjacent to endometrial glands and stroma. Cytologic atypia was mild and reactive, and positive immunostaining for calretinin, WT-1, and cytokeratin 5 identified the lesion as mesothelial and benign. We describe in detail the histologic findings in this case and review the pertinent literature. We discuss the clinically importance of this diagnostic pitfall and the path to arriving at the correct diagnosis.

Organ-wide telomeric status in diseased and disease-free prostatic tissues.

BACKGROUND: Telomere attrition occurs early in the development of prostatic adenocarcinoma. However, little is known about either telomere status in benign prostatic hyperplasia (BPH), or the spatial and organ-wide distribution of potential telomere aberrations throughout all areas of prostatic glands affected by cancer or BPH. METHODS: Slot blot titration assay was used to determine telomere DNA content (TC), a proxy for telomere length, in macrodissected tissue consisting of 54 normal samples from 5 disease-free prostates, 128 BPH samples from 4 non-cancerous prostates, and 45 tumor, 73 BPH, and 4 prostatic intraepithelial neoplasia (PIN) samples from 5 cancerous prostates. RESULTS: Compared to TC in normal prostate samples (n = 54; TC mean = 0.98), tumor samples displayed telomere attrition (n = 45; TC mean = 0.67). TC in PIN samples was similar to tumors. TC in BPH samples from cancerous prostates was similar to TC in tumors and also displayed telomere shortening (n = 73; TC mean = 0.76), whereas BPH samples from non-cancerous prostates displayed longer telomeres (n = 128; TC mean = 1.06). In prostates affected by adenocarcinoma, areas of potential telomere attrition occurred in histologically normal tissues through the entire gland. However, three-dimensional zoning revealed a pattern of increasing TC as a function of distance from the primary (index) tumor. CONCLUSIONS: Spatial distributions of TC in prostate specimens indicate a complex "field effect" with varying contributions from both cancer and BPH. The observation that telomere length variations occur in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it may have implications for the diagnosis and focal therapy of prostate cancer.

Localized Breast Amyloidosis Associated with Sjörgren Syndrome.

Sjörgren syndrome is a systemic autoimmune disease that is rarely associated with amyloid deposits, and in most reported cases, these deposits are localized to a single organ. Amyloidosis of the breast is a rare and unexpected finding, and only 5 case series with 63 patients have been published in the past 40 years. To date, only 6 cases have been reported in which Sjörgren syndrome is associated with amyloid deposits in the breast. A 61-year-old female diagnosed with Sjörgren syndrome underwent a breast needle core biopsy for calcifications. Microscopic examination revealed amyloid deposits in the periductular basement membranes, in the walls of arteries and veins, and in the surrounding connective tissue. No malignancy was found. Clinical workup revealed the amyloid deposits to be localized to the breast and did not reveal an underlying hematolymphoid neoplasm. The association between Sjörgren syndrome and breast amyloidosis is rare, but few reports have appeared in recent years, and it may be an emerging disease association. The finding of localized amyloid in the breast and other organs should lead to a clinical workup not only for hematopoietic neoplasms but also for autoimmune diseases such as Sjörgren syndrome.

Nuclear Morphology and the Biology of Cancer Cells.

BACKGROUND: For more than a century, diagnostic pathologists have used morphologic abnormalities of the nucleus as essential diagnostic features to distinguish benign from malignant cells. These features include nuclear enlargement and increased nuclear-to-cytoplasmic ratio, nuclear membrane irregularities, hyperchromasia, and abnormal chromatin distribution. As our knowledge about the genetic and epigenetic abnormalities of cancer cells has increased in recent decades, the pathophysiologic mechanisms that underlie these morphologic abnormalities remain incompletely understood. SUMMARY: This review attempts to summarize biologic abnormalities in malignant cells related to these morphologic changes. The molecular anatomy of the nuclear envelope in normal and malignant cells is discussed as well as regulation of nuclear size and shape, regulation of signal transduction pathways by molecules of the nuclear envelope, chromatin distribution, and the effects of HPV infection on dysplastic cells in the uterine cervix. Key Message: Causes of morphologic nuclear abnormalities in malignant cells are likely multifactorial. They probably include mutations, dysregulation of signal transduction pathways, abnormal gene expression patterns, alterations of nuclear envelope proteins and chromatin, and aneuploidy.

Assessment of the frequency of allelic imbalance in human tissue using a multiplex polymerase chain reaction system.

Genomic instability can generate chromosome breakage and fusion randomly throughout the genome, frequently resulting in allelic imbalance, a deviation from the normal 1:1 ratio of maternal and paternal alleles. Allelic imbalance reflects the karyotypic complexity of the cancer genome. Therefore, it is reasonable to speculate that tissues with more sites of allelic imbalance have a greater likelihood of having disruption of any of the numerous critical genes that cause a cancerous phenotype and thus may have diagnostic or prognostic significance. For this reason, it is desirable to develop a robust method to assess the frequency of allelic imbalance in any tissue. To address this need, we designed an economical and high-throughput method, based on the Applied Biosystems AmpFlSTR Identifiler multiplex polymerase chain reaction system, to evaluate allelic imbalance at 16 unlinked, microsatellite loci located throughout the genome. This method provides a quantitative comparison of the extent of allelic imbalance between samples that can be applied to a variety of frozen and archival tissues. The method does not require matched normal tissue, requires little DNA (the equivalent of approximately 150 cells) and uses commercially available reagents, instrumentation, and analysis software. Greater than 99% of tissue specimens with >or=2 unbalanced loci were cancerous.

Management of abnormal uterine bleeding and the pathology of endometrial hyperplasia.

There are no screening tests for endometrial carcinoma, and patients typically present with abnormal uterine bleeding. This article discusses the pathophysiology and clinical work-up of abnormal uterine bleeding, and risk factors for endometrial carcinoma. Atypical complex hyperplasia and the more recently defined endometrial intraepithelial neoplasia are well recognized as precancers. Evolving knowledge of their genetic alterations provides the opportunity to develop molecular markers, so that endometrial diseases may be diagnosed at the precancerous or early invasive stage. Emerging molecular markers also provide the opportunity to develop clinically useful screening tests for the most common malignancy of the female genital tract.

Altered protein levels in the isolated extracellular matrix of failing human hearts with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is associated with extensive pathological cardiac remodeling and involves numerous changes in the protein expression profile of the extracellular matrix of the heart. We obtained seven human, end-stage, failing hearts with DCM (DCM-failing) and nine human, nonfailing donor hearts and compared their extracellular matrix protein profiles. We first showed that the DCM-failing hearts had indeed undergone extensive remodeling of the left ventricle myocardium relative to nonfailing hearts. We then isolated the extracellular matrix from a subset of these hearts and performed a proteomic analysis on the isolated matrices. We found that the levels of 26 structural proteins were altered in the DCM-failing isolated cardiac extracellular matrix compared to nonfailing isolated cardiac extracellular matrix. Overall, most of the extracellular matrix proteins showed reduced levels in the DCM-failing hearts, while all of the contractile proteins showed increased levels. There was a mixture of increased and decreased levels of cytoskeletal and nuclear transport proteins. Using immunoprobing, we verified that collagen IV (α2 and α6 isoforms), zyxin, and myomesin protein levels were reduced in the DCM-failing hearts. We expect that these data will add to the understanding of the pathology associated with heart failure with DCM.

Anti-glomerular basement membrane glomerulonephritis: a morphologic study of 80 cases.

Anti-glomerular basement membrane (anti-GBM) glomerulonephritis is a rare disease caused by IgG autoantibodies against the glomerular basement membrane. We describe clinical and pathologic findings in a series of renal biopsy specimens from 80 patients. The patients ranged in age from 16 to 87 years. The age distribution was bimodal, with one peak at a young age predominated by males and a second peak in the sixth to eighth decades with females predominating. Most patients (70 [88%]) had severe necrotizing glomerulonephritis with crescents in more that 50% of glomeruli. The fraction of crescentic glomeruli in biopsy specimens correlated well with serum creatinine levels but not with serologic titers for anti-GBM antibodies. Interstitial fibrosis was uncommon and, when present, minimal to mild. Linear IgG deposition defines this entity, but immunofluorescent costaining for other immunoglobulins and complement is found frequently. To our knowledge, this is the largest series of renal biopsy specimens with anti-GBM glomerulonephritis studied to date.

Perinuclear dot-like cytokeratin 20 staining in small cell neuroendocrine carcinoma of the ovary (pulmonary-type).

Primary ovarian small cell carcinomas are rare tumors that are subclassified into the hypercalcemic (HT) and the pulmonary type (PT), and each tumor type has different clinicopathologic characteristics. However, overlapping morphologic features can make the distinction between these lesions difficult. The PT small cell carcinoma is very rare, with only one series and a few case reports published. The authors report two additional cases of this entity and also report for the first time the immunohistochemical finding of perinuclear dot-like staining with cytokeratin 20. This staining pattern has been reported only for Merkel cell carcinoma and salivary gland small cell carcinoma. The authors suggest that the punctate CK20 staining is a useful tool in the diagnostic distinction of PT small cell carcinoma from HT small cell carcinoma, from other primary ovarian tumors such as granulosa cell tumors, and from metastatic neuroendocrine tumors originating at primary sites such as the lung. Since the authors' conclusions are based on two cases of this rare entity, additional cases will need to be studied in the future.