Squamous Morules Research Articles

Morules and β-catenin predict POLE mutation status in endometrial cancer: A pathway to more cost-effective diagnostic procedures.

The characterization of DNA polymerase epsilon (POLE) mutations has transformed the classification of endometrial endometrioid carcinomas (EECs), highlighting the need for efficient identification methods. This study aims to examine the relationship between distinct morphologic features-namely, squamous morules and squamous differentiation (SD), as well as β-catenin expression-and the POLE mutation status in endometrial cancer (EC). Our study included 35 POLE-mutated (POLEmut) EC cases and 395 non-POLEmut EEC cases. Notably, we observed no presence of morules in POLEmut cases, while SD was identified in 20% of instances. Conversely, morules and SD were identified in 12.7% and 26.1% of non-POLEmut EC cases, respectively, with morules consistently linked to a POLE wild-type status. The nuclear β-catenin expression is typically absent in tumors with wild-type POLE (wt-POLE) status. Our findings suggest that the presence of either morules or nuclear β-catenin expression in EEC could practically rule out the presence of POLE mutations. These morphologic and immunohistochemical features can be used as preliminary screening tools for POLE mutations, offering significant savings in time and resources and potentially enhancing clinical decision-making and patient management strategies. However, further validation in larger, multi-institutional studies is required to fully understand the implications of these findings on clinical practice.

Intracholecystic Tubular Non-Mucinous Neoplasm: A Distinct Entity

Abstract Introduction/Objective Intracholecystic tubular non-mucinous neoplasm (ICTN) of the gallbladder is a pre-invasive high-grade tumor of non-mucinous tubules which is a rare entity. Histologic morphology distinguishes this tumor from other more common gallbladder neoplasms like intracholecystic papillary neoplasm (ICPN) or gallbladder pyloric adenoma. Methods/Case Report A 62-year-old female with no significant past medical history was found to have elevated transaminase in routine lab work. Ultrasound incidentally revealed a pedunculated 1.7 cm polyp in the gallbladder, along with numerous smaller and unmeasured polyps. Six months later, a repeat ultrasound revealed multiple echogenic polyps with the largest polyp measuring 2 cm. She had a laparoscopic cholecystectomy. During surgery, the contents of the polyp were iatrogenically expulsed were submitted as a seperate specimen. Grossly, the gallbladder contents consisted of multiple irregular red soft tissue fragments measuring up to 2 cm, and the gallbladder had an attached cystic lymph node and diffuse small yellow polyps along the wall. The gallbladder and node were entirely evaluated microscopically and revealed diffuse cholesterolosis with cholesterol polyps without dysplasia. The gallbladder content revealed a polypoid neoloplasm with cauliflower-like surfaces, back-to-back tubules, and squamous morules. The lining epithelial cells are cuboidal in shape with vesicular pale nuclei with prominent nucleoli and scant cytoplasm. No papillary structures with fibrovascular core were identified. These findings confirmed the diagnosis of ICTN. Results (if a Case Study enter NA) NA Conclusion ICTN commonly presents as detached sludge mimicking granular material within the gallbladder lumen and can be a “disappearing” polyp. There is a clear distinction between ICTN and ICPN based on histological features. ICTN is characterized exclusively by high-grade features, while ICPN can be either low-grade or high-grade with high risk of invasion. ICTN is characterized by pedunculated polyps with a thin stalk and multilobulated growth, typically in the background of a relatively unremarkable gallbladder with a crowded proliferation of small tubular units without a fibrovascular core. Pyloric gland adenomas usually don’t show dysplasia and are less than 1 cm. It is important to submit any identified content of the gallbladder. Keeping this rare entity in mind as a differential diagnosis is essential for gallbladder neoplasms.

INTRAOPERATIVE FROZEN SECTION ANALYSIS OF ENDOMETRIOID OVARIAN BORDERLINE TUMOR: A DIFFICULT DIAGNOSIS

Abstract Introduction/Objective Borderline ovarian tumors (BOT) comprise approximately 15% of all primary ovarian neoplasms; of these endometroid borderline ovarian tumors (EBOT) are much rarer (2-3%). BOT is often potentially misdiagnosed as a malignant tumor based on its challenging histomorphological features and thus, treated aggressively. Herein, we present an unusual case of EBOT with adenofibromatous pattern in a 50-year-old gravida 3, para 2 female diagnosed on intraoperative frozen sections (IOFS). Methods/Case Report Patient with history of endometriosis presented with left lower quadrant abdominal pain. MRI revealed complex bilateral ovarian masses with solid and cystic components measuring 5 cm and 6.7 cm in right and left ovary, respectively. An ovarian malignancy was suspected. Patient underwent exploratory laparotomy, total abdominal hysterectomy with bilateral salpingo-opherectomy, and omentectomy. Grossly, bilateral ovaries (BO) showed intact capsule with solid and cystic components. On IOFS, the solid areas demonstrated endometrioid glands arranged in a lobular fashion with squamous morules. The cystic component demonstrated papillary projections with squamous differentiation. Cytology is mildly atypical at best. Based on these findings, a diagnosis of EBOT was made, necessitating staging. Differential diagnoses include atypical endometriosis, endometrioid adenofibroma (EAF) and endometrioid adenocarcinoma (EA). Lack of endometrial stroma surrounding the glands ruled out endometriosis. Presence of CC with papillary architecture ruled out EAF and lack of destructive stromal invasion with desmoplasia, confluence of glands and significant cytologic atypia ruled out EA. Final histopathological diagnosis of formalin-fixed paraffin-embedded specimen revealed EBOT, pT1bN0M0. Uterus and cervix revealed endometrial hyperplasia with atypia, adenomyosis, leiomyomas, and endocervical polyp. Results (if a Case Study enter NA) NA Conclusion The accurate diagnosis of BOT during IOFS is critical as it directs surgeons towards staging studies and in choosing conservative surgical treatment over aggressive treatment especially in cases of young women who desire future childbearing. As this is a rare entity, it serves the pathologist well to keep all relevant differential diagnoses in mind.

Endometrioid Squamous Proliferations of the Endometrium Express Alpha-Methylacyl-CoA Racemase (P504s).

Squamous morular metaplasia is closely associated with endometrioid proliferative lesions such as endometrial intraepithelial neoplasia, whereas endometrioid adenocarcinoma may also demonstrate squamous differentiation (morular or nonmorular). Alpha-methylacyl-CoA racemase (AMACR; P504s) is an immunohistochemistry marker expressed in many tumors, including prostate adenocarcinoma, renal cell carcinoma, and in a subset of gynecologic carcinomas, predominantly of clear cell histology. In small biopsy samples, the distinction between cervical high-grade squamous intraepithelial lesions (HSILs) involving endocervical glands from endometrioid squamous proliferations can be challenging, given their anatomic vicinity and some degree of morphologic overlap. Following the observation of AMACR positivity by immunohistochemistry within squamous morules in an index case, 35 endometrial samples containing squamous morular metaplasia (25) and nonmorular squamous metaplasia (10), and 32 cases of cervical HSIL involving endocervical glands were stained with AMACR. The endometrial cohort consisted of 2 benign anovulatory endometrium, 7 endometrial polyps, 7 endometrial intraepithelial neoplasia, 4 atypical polypoid adenomyomas, and 15 endometrioid adenocarcinomas. Positive cases were scored as diffuse (≥50%) or focal (<50%). AMACR staining was present in 96.7% of endometrial squamous lesions, including 14 (93.3%) of endometrioid carcinomas, and in all cases of endometrial intraepithelial neoplasia, endometrial polyps, atypical polypoid adenomyomas, and anovulatory endometrium with squamous morular metaplasia or nonmorular squamous metaplasia. In comparison, only 2 cases (5.8%) of cervical HSIL demonstrated positivity for AMACR. In conclusion, AMACR can reliably differentiate the cervical versus endometrial origin of squamous lesions in small biopsy specimens.

Squamous Morules in a Fundic Gland Polyp: A Rare Benign Mimic of Well-Differentiated Neuroendocrine Tumor

Abstract Introduction/Objective Fundic gland polyp is a benign polypoid lesion consisting of cystically dilated oxyntic glands; it can be either sporadic or associated with familial adenomatous polyposis or MUTYH-associated polyposis. Squamous morules are well-described in association with numerous epithelial lesions including tubular adenomas, cribriform- morular variant of papillary thyroid carcinoma, and endometrial neoplasia. However, to date only 2 cases have been reported in the stomach. Methods/Case Report We describe a third case, in a 53-year-old female who presented to endoscopy for hematemesis. Thirty-five sessile polyps ranging from 10-18 mm were identified and resected. On histologic sections, all were fundic gland polyps. Of these, one showed scattered small nests of epithelial cells with monomorphic round nuclei, inconspicuous nucleoli, and moderate eosinophilic cytoplasm, situated just below the luminal surface in continuity with adjacent glands. The nests showed focal expression of synaptophysin and cytokeratin 5/6, striking nuclear expression of β-catenin, and no expression of p63. Ki67 proliferative index was &amp;lt;1%. Interestingly, all 3 cases of gastric squamous morules have arisen in adults with symptoms of reflux, including our patient who was on a proton pump inhibitor. All were identified in a gastric polyp (either hyperplastic or fundic gland) within a background of numerous large fundic gland polyps (up to 2 cm), and none were associated with lower gastrointestinal polyposis. Nuclear accumulation of β-catenin, a common feature of squamous morules, was demonstrated in the one prior case that was tested. Results (if a Case Study enter NA) NA. Conclusion Gastric squamous morules are a rare finding. Given the nested arrangement of cells and bland cytology, well-differentiated neuroendocrine tumor may enter the differential diagnosis. Features that can help distinguish squamous morules from neuroendocrine tumor are: (1) focal expression of synaptophysin, (2) superficial location and continuity with adjacent glandular epithelium, and (3) nuclear accumulation of β-catenin.

Robotic hysterectomy for the treatment of refractory menometrorrhagia and squamous endometrial morules: A case report

Introduction: Abnormal uterine bleeding (AUB) is a common presentation in the field of gynecology. Proper diagnosis and management of this condition can be difficult and permanent treatment options, including robotic hysterectomy, may be necessary. In patients with a history of previous abdominal surgery, pelvic adhesions may present obstacles to this surgical approach. Case Report: In this case report, a 41-year-old woman desired permanent treatment for AUB. The patient underwent endometrial biopsy which revealed inexplicit squamous morules. She opted for permanent treatment via robotic hysterectomy. Her operation was complicated by the presence of dense pelvic adhesions caused by previous surgeries. Conclusion: This report aims to detail the potential difficulties in the clinical management of inconclusive biopsy results and in using a robotic approach to hysterectomy in the setting of pelvic adhesions. Authors encourage ongoing clinical investigation to determine the optimal methods for diagnosing and treating AUB.

Robotic-Hysterectomy for the treatment of Refractory Menometrorrhagia and Squamous Endometrial Morules: A case report

Robotic-Hysterectomy for the treatment of Refractory Menometrorrhagia and Squamous Endometrial Morules: A case report

Morules But Not Squamous Differentiation are a Reliable Indicator of CTNNB1 (β-catenin) Mutations in Endometrial Carcinoma and Precancers.

Although collectively regarded as "squamous differentiation (SD)" in endometrial endometrioid carcinoma (EEC) and atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN), morules (often referred to as "squamous morules") and true SD may represent two distinct phenomena. Here, we explored the distinction between morules versus SD and investigated the association of morules and SD with CTNNB1 mutations. A total of 270 cases of EEC and AH/EIN were studied, including EEC with (n=36) or without (n=36) morules and AH/EIN with (n=80) or without (n=118) morules. Cases were analyzed by immunohistochemistry and selected cases (n=20) by targeted next-generation sequencing panel. Near-perfect agreement was found between morules and glandular β-catenin nuclear staining in AH/EIN and EEC. A strong positive association was found between morules and glandular β-catenin nuclear staining ( P &lt;0.0001, Φ=0.59 in AH/EIN; P &lt;0.0001, Φ=0.85 in EEC). There was no association between (1) morules and glandular PAX2 or PTEN aberrant expression or (2) SD and aberrant expression of β-catenin, PAX2 or PTEN (Φ=0.09, β-catenin; Φ=0.16, PAX2; Φ=0.13, PTEN). CTNNB1 mutations were identified in all 20 selected morule-containing cases (100%). Next-generation sequencing was performed on 2 (preprogestin and postprogestin treatment) biopsies from 1 patient, revealing identical mutational profile in morules and glands. In conclusion, (1) SD and morules are distinct biological phenomena; (2) the presence of morules, but not SD, is a reliable indicator of CTNNB1 mutations in EEC and AH/EIN. Our findings demonstrate that SD and morules are distinct biological phenomena. Since morules but not SD are associated with β-catenin mutations, the distinction is clinically relevant and should be included in diagnostic reports.

Squamous Metaplasia in Colonic Tubulovillous Adenoma: A Three Case Series and review of literature

Abstract Introduction/Objective Although squamous metaplasia of colonic tubulovillous adenoma is a rare phenomenon, colorectal polyps can show focal squamous metaplasia. While the exact cause in unknown, it has been suggested that mechanical irritation, torsion and chronic inflammation may predispose to squamous metaplasia within large colonic polyps. Methods/Case Report We observed this finding in two men and one woman with colorectal polyps who underwent endoscopic mucosal resection in a three-week timeframe. In two cases the polyps were rectal, while in the third case, it was located in the descending colon. Polyp size ranged from 1-5 cm and were semi-pedunculated. Histologically, all three lesions were tubulovillous adenomas with focal high-grade dysplasia and multiple foci of squamous metaplasia characterized by cells with benign-appearing nuclei, eosinophilic cytoplasm, and solid growth pattern. Some metaplastic foci approached the muscularis mucosae, mimicking adenocarcinoma at low power magnification. Interestingly, these metaplastic foci were reactive against p16 immunohistochemical stain. Results (if a Case Study enter NA) NA Conclusion We present these three cases to add to the few previously reported. Pathologists should be aware of this finding to avoid the overdiagnosis of invasive carcinoma in the setting of nested and pseudo invasive squamous morules, especially in polyps with high grade dysplasia. In addition, squamous metaplasia could be a precursor lesion for colorectal squamous cell carcinoma.

Atypical polypoid adenomyoma

Atypical polypoid adenomyoma is an uncommon polypoid lesion, located in the lower uterine segment or endometrial cavity, often diagnosed on biopsy or curettage.[1][1] It is characterized by endometrial glands, often...

Evidence for a Novel Endometrioid Carcinogenic Sequence in the Fallopian Tube With Unique Beta-Catenin Expression.

Epithelial proliferations in the fallopian tube have been characterized by some as stem cell outgrowths (SCOUTs) and divided into type I and type II. Type II SCOUTs exhibit diffuse cellular beta-catenin nuclear staining (β-catenin), implying a CTNNB1 mutation. SCOUTs are more common in perimenopausal and postmenopausal women and are associated with ovarian cancer but have not been linked directly to malignancy. We analyzed type II SCOUTs in various gynecologic conditions, and searched for endometrioid atypical hyperplasias (tubal endometrioid intraepithelial neoplasia) or adenocarcinomas in the tube. β-catenin SCOUT frequency in cases of neoplasia was 66.7% per case and 30.7% per nonfimbrial cross-section for uterine endometrioid carcinomas versus 25% and 13.3% for controls, respectively (P=0.02 and 0.09). Multiple (3 or more) β-catenin SCOUTs in a single section were uncommon; 6 of 9 were associated with a carcinoma or proliferative lesion in the endometrium. Tubal endometrioid intraepithelial neoplasia/atypical hyperplasia displayed complex growth, including focal cribriform growth patterns and squamous morules. Two cases of type II SCOUTs associated with tubal endometrioid intraepithelial neoplasia/atypical hyperplasia and/or adenocarcinomas in the fallopian tube were identified, both of which coexisted with a separate endometrioid adenocarcinoma, one with bilateral ovarian endometrioid adenocarcinomas. Both benign and neoplastic tubal lesions were β-catenin. This report is the first to link components of a unique β-catenin endometrioid carcinogenic sequence in the fallopian tube. It further emphasizes the multifocal nature of endometrioid neoplasia in the female genital tract and poses questions regarding the frequency and biologic underpinnings of β-catenin proliferations in the oviduct.

SATB2 is Consistently Expressed in Squamous Morules Associated With Endometrioid Proliferative Lesions and in the Stroma of Atypical Polypoid Adenomyoma.

So-called squamous morules are closely associated with endometrioid proliferative lesions, in the endometrium and the ovary. Morules have an unusual immunophenoptype, typically exhibiting nuclear staining with β-catenin, positivity with CDX2, CD10, and p16 and are negative with hormone receptors and p63. We report the previously undescribed occurrence of consistent SATB2 nuclear positivity within morules. Nuclear positivity was present in 38/43 (88%) cases of morules (24 focal; 14 diffuse) while all cases of nonmorular squamous metaplasia in endometrioid proliferative lesions (n=13) were SATB2 negative, except for occasional positive nuclei in 1 case. We also observed that the stromal cells of atypical polypoid adenomyoma typically exhibited diffuse nuclear immunoreactivity with SATB2 while the stromal cells of other endometrial polypoid lesions (endometrial polyp, adenomyoma, adenosarcoma) were usually negative, although there was focal weak staining in occasional cases. Pathologists should be aware of this previously undescribed phenomenon which represents a further example of the unusual immunophenotype of so-called squamous morules. The reasons underlying SATB2 nuclear positivity in squamous morules and the stroma of atypical polypoid adenomyoma are unknown.

Immunophenotype of Atypical Polypoid Adenomyoma of the Uterus: Diagnostic Value and Insight on Pathogenesis.

Atypical polypoid adenomyoma (APA) is a rare uterine lesion constituted by atypical endometrioid glands, squamous morules, and myofibromatous stroma. We aimed to assess the immunophenotype of the 3 components of APA, with regard to its pathogenesis and its differential diagnosis. A systematic review was performed by searching electronic databases from their inception to January 2019 for immunohistochemical studies of APA. Thirteen studies with 145 APA cases were included. APA glands appeared analogous to atypical endometrial hyperplasia (endometrioid cytokeratins pattern, Ki67≤50%, common PTEN loss, and occasional mismatch repair deficiency); the prominent expression of hormone receptors and nuclear β-catenin suggest that APA may be a precursor of "copy number-low," CTNNB1-mutant endometrial cancers. Morules appeared as a peculiar type of hyperdifferentiation (low KI67, nuclear β-catenin+, CD10+, CDX2+, SATB2+, p63-, and p40-), analogous to morular metaplasia in other lesions and distinguishable immunohistochemically from both conventional squamous metaplasia and solid cancer growth. Stroma immunphenotype (low Ki67, α-smooth-muscle-actin+, h-caldesmon-, CD10-, or weak and patchy) suggested a derivation from a metaplasia of normal endometrial stroma. It was similar to that of nonatypical adenomyoma, and different from adenosarcoma (Ki67 increase and CD10+ in periglandular stroma) and myoinvasive endometrioid carcinoma (h-caldesmon+ in myometrium and periglandular fringe-like CD10 pattern).

Beta-Catenin Expression in Squamous Morules of Sinonasal Nonintestinal-Type Adenocarcinoma: A Curious Finding Confirmed by Molecular Analysis

Beta-Catenin Expression in Squamous Morules of Sinonasal Nonintestinal-Type Adenocarcinoma: A Curious Finding Confirmed by Molecular Analysis

Histopathologic Features of Colorectal Adenoma and Adenocarcinoma Developing Within Inflammatory Polyps in Miniature Dachshunds.

Biopsy samples of colorectal polyps were collected and examined from 67 Miniature Dachshund dogs (including 35 cases with an additional biopsy). Histopathologic diagnoses of the initial biopsy samples were "inflammatory polyp" in 52 cases (78%), "adenoma" in 10 cases (15%), and "adenocarcinoma" in 5 cases (8%). Eight of 10 cases (80%) diagnosed as adenoma also had inflammatory polyp lesions in the same specimen. A second biopsy was performed in 25 cases (48%) initially diagnosed with inflammatory polyp. Pathologic diagnoses for the second biopsy were inflammatory polyp in 11 cases (44%), adenoma in 9 cases (36%), and adenocarcinoma in 5 cases (20%). The number of beta-catenin-positive nuclei in epithelial cells was significantly higher in adenoma (46%) and adenocarcinoma (75%) as compared with inflammatory polyp (6%). Normal epithelial cells and hyperplastic goblet cells in inflammatory polyps showed homogeneous positive cytoplasmic immunoreactivity for adenomatous polyposis coli (APC) antigen. However, APC expression was decreased in areas of intense nuclear beta-catenin expression in adenoma and adenocarcinoma lesions. Foci of cytokeratin 5/6-positive squamous cell-like neoplastic cells showed intense beta-catenin nuclear expression that was similar to squamous morules described in human colorectal tumors. The results of the present study suggest that the inflammatory polyp in Miniature Dachshunds is a progressive disease that may develop into adenoma and/or adenocarcinoma. In addition, immunohistochemical findings suggest that aberrations of APC and beta-catenin expression may be involved in tumor development within the inflammatory polyp lesions.

Composite intestinal adenoma-microcarcinoid in the colon and rectum: a case series and historical review

BackgroundComposite intestinal adenoma-microcarcinoid (CIAM) is a rare colorectal lesion that mostly comprises a conventional adenomatous component with a minute proportion of neuroendocrine (NE) component. Although microcarcinoids are well-recognized in the setting of chronic inflammatory disorders of the gastrointestinal tract, large intestinal microcarcinoids associated with intestinal adenoma are exceedingly rare and their clinicopathologic characteristics are yet to be elucidated. This study was performed to clarify their clinicopathologic characteristics and to review the relevant literature.MethodsIn total, 24 cases of CIAM in which tumors were excised endoscopically (n = 22) or surgically (n = 2) were retrieved from the Department of Pathology, Daehang Hospital. We analyzed their clinicopathologic characteristics and performed immunohistochemical staining for NE markers to determine their endocrine nature.ResultsCIAM usually developed in middle-aged and elderly patients, with a mean age of 62.0 years (range, 44–81 years). Thirteen patients were men and 11 were women, indicating a nearly equal sex ratio. Unlike classic carcinoid tumors, CIAMs occurred mostly in the colon (83.3% of cases), particularly in the proximal colon. Histologically, the microcarcinoid component consisted of low-grade NE cells arranged in small nests, glands or cords interspersed with glandular elements or less frequently resembled squamous morules. There was no expansile nodular or organoid growth pattern, which is typical of carcinoid tumors. The microcarcinoids were 1–20 mm in size (mean size, 4.7 mm) and were mostly situated in the basal lamina propria with no submucosal layer involvement; none showed desmoplastic reaction or increased proliferative activity. Follow-up data (mean, 23.1 months) were available for 18 patients; all patients are alive and well.ConclusionsTo the best of our knowledge, ours is the largest series of patients with CIAM in the English-language literature. Microcarcinoids found in CIAMs appear to show favorable clinical outcomes regardless of their size, likely due to the absence of submucosal extension and/or increased proliferative activity. We recommend avoiding additional radical surgeries in patients who have endoscopically undergone complete CIAM excision unless they exhibit ominous histologic features such as submucosal extension or increased proliferative activity.

Squamous Morules (Microcarcinoids) in Gastroesophageal Polyps; a Mimicker of Invasive Carcinoma

Colorectal lesions termed squamous morules or microcarcinoids display predominantly squamous and variable endocrine differentiation and are often found in colorectal adenomas with high grade dysplasia thus mimicking invasion. Herein, we describe histopathologic, immunohistochemical classification and clinical correlation of analogous lesions in the esophagus and stomach. We identified five cases (3 men, 2 women) from November 2004-March 2013 of gastric and gastroesophageal polyps with squamous morules. Four of the patients were white. The median age was 70 years (range 59-85 years). Two patients presented with gastrointestinal bleeding, one was undergoing routine screening, and two were followed up for Barrett esophagus (BE) and a history of gastric polyps respectively. Three lesions were gastric, one gastroesophageal (GE), and one patient had both GE and proximal gastric lesions. Four patients had multiple polyps; one had a 2.5 cm polypoid GE lesion. The median size of the polyps was 1.5 cm. All of the gastric squamous morules arose in hyperplastic polyps (HP) (one patient had separate fundic gland polyps). Two HPs showed high grade dysplasia, 1 low grade dysplasia, and 1 erosions and reactive changes. One of the GE lesions was associated with polypoid papillary high grade dysplasia arising in BE, this patient had follow up biopsy 1 month later showing BE with features indefinite for dysplasia. He died in 2009 (5 years) of unknown cause. The remaining patients are alive. The areas of squamous morule formation ranged in size from 1-3 mm. They were multifocal showing a lobular growth pattern connecting directly to the epithelium. Four of the lesions demonstrated pseudolumina. Immunohistochemical analysis was done on all cases. Sixty percent showed nuclear beta catenin, and all demonstrated a low KI67 index (< 2%). Endocrine markers (synaptophysin, chromogranin) were expressed in all of the lesions, and P63 showed focal labeling in two lesions. In summary, the histopathological features and immunohistochemical labeling of GE squamous morules/ microcarcinoids are similar to those previously described in the colorectum. GE lesions can be associated with reactive processes and more frequently in a background of dysplasia. Underrecognition of upper gastrointestinal squamous morules provides potential for over diagnosis of invasive carcinoma. Familiarity with the histopathologic pattern and immunoprofile can aid in avoiding this pitfall.

Atypical Polypoid Adenomyoma of the Uterus: An Immunohistochemical and Molecular Study of 21 Cases.

Atypical polypoid adenomyoma (APA) is an uncommon uterine lesion that commonly recurs after local excision and is occasionally associated with or precedes the development of atypical hyperplasia or endometrioid adenocarcinoma. Despite the fact that about 230 cases have been reported in the literature, only 2 studies of 6 and of 7 cases have investigated the molecular aspects; as such, molecular alterations that occur in APA remain largely unknown. We undertook a comprehensive immunohistochemical and molecular analysis of 21 cases of APA in 17 patients (including 4 recurrent/persistent lesions). The analyzed genes were PTEN and TP53 (by fluorescence in situ hybridization) and KRAS, BRAF, EGFR, and NRAS (all by polymerase chain reaction). Immunohistochemical staining was performed for PTEN, p53, mTOR, β-catenin, HNF-1β, and GLUT1 and for the mismatch-repair proteins MLH-1, MSH-2, MSH-6, and PMS-2. In most cases, there was nuclear expression of β-catenin in squamous morules and expression of HNF-1β, mTOR, and GLUT1 in the glandular component. All cases exhibited "wild-type" expression of p53. A common finding was loss of PTEN expression (6/19 cases). In 1 of these cases, loss of PTEN expression was accompanied by PTEN deletion. Mutation of the KRAS gene was found in 5/19 cases. Intact mismatch-repair protein expression was present in all cases, and TP53 abnormalities or mutations of EGFR, NRAS, or BRAF genes were not found. Given the association with atypical hyperplasia and endometrioid adenocarcinoma and the shared immunohistochemical and molecular features, we feel that, conceptually, APA is best regarded as analogous to a localized form of atypical hyperplasia.

Mesonephric adenocarcinoma (endometrioid type) of endocervix with diffuse mesonephric hyperplasia involving cervical wall and myometrium: An unusual case report

Malignant mesonephric tumors are rare variants of cervical adenocarcinoma, derived from remnants of mesonephric ducts and are associated with mesonephric remnants and/or mesonephric hyperplasia. Few cases have been described in literature. We report an unusual case of cervical mesonephric adenocarcinoma of endometrioid type with squamous morules in association with diffuse mesonephric hyperplasia involving the cervical walls and extending into the myometrium.

Squamous morules are functionally inert elements of premalignant endometrial neoplasia

Squamous morules are a common component of premalignant glandular lesions that are followed by glandular, rather than squamous, carcinomas. We tested the hypothesis that the appearance of glands associated with morules predicts cancer risk, and undertook molecular testing to determine the clonal and hormonal response properties of admixed squamous and glandular elements. A total of 66 patients with squamous morules in an index endometrial biopsy had follow-up clinical data (average follow-up: interval 31 months, 2.5 biopsies) showing development of carcinoma in 11% (7/66) of cases. The histological appearance of morule-associated glands in the index biopsy was significantly associated with this clinical outcome, with the majority (71%, 5/7) of cancer occurrences following an overtly premalignant lesion (endometrial intraepithelial neoplasia) with squamous morules. Eight endometrial intraepithelial neoplasias with squamous morules were examined by immunohistochemistry for estrogen and progesterone receptors and mitotic activity (Ki-67 antigen percent stained). Glandular components had abundant estrogen and progesterone receptors, and high levels of mitotic activity in all cases. In sharp contrast, all squamous morules were devoid of sex hormone receptors and had undetectable or extremely low-proliferation rates. When mutated, the same specific PTEN mutation was detected in squamous and glandular elements, indicating that both are of common lineage. The clinical and laboratory data are consistent with a model of morule biology in which squamous morules are a hormonally incompetent subpopulation of endometrial glandular lesions. Isolated morules might result from artifactual displacement from their native glandular context, or selective hormonally induced regression of the glandular but not squamous components over time. Subsequent cancer risk, as promoted by estrogens, is greatest when the glandular component has the appearance of endometrial intraepithelial neoplasia. Even isolated morules should be carefully followed, however, to exclude a coexisting undersampled, or occult, glandular lesion.