Diagnostic Pitfalls Research Articles

Early T-cell precursor acute lymphoblastic leukemia: diagnostic pitfalls, genomic alteration, novel therapeutics, and minimal residual disease monitoring

Early precursor T-cell acute lymphoblastic leukemia (ETP-ALL) is a rare type of T-cell ALL (T-ALL) that was initially described in 2009. Since its initial description, it has been formally recognized as a distinct entity, according to the 2016 World Health Organization classification. ETP-ALL is characterized by unique immunophenotypic and genomic profiles. The diagnosis and management of ETP-ALL remain challenging. Poorer outcomes, high incidence of induction failure and relapsed/refractory disease demand novel therapies. This review emphasizes the challenges of initial diagnosis, the molecular mechanisms underlying leukemogenesis, and the available therapeutic options. Additionally, it discusses the importance of induction failure, the prognostic value of detecting minimal residual disease, and the implications of hematopoietic stem cell transplantation, along with emerging novel therapies.

Identification of diagnostic challenges in RP1 Alu insertion and strategies for overcoming them

Recently, a founder Alu insertion in exon 4 of RP1 was detected in Japanese and Korean patients with inherited retinal diseases (IRDs). However, carrier frequency and diagnostic challenges for detecting AluY insertion are not established. We aim to investigate the frequency of AluY in individuals with or without IRDs and to overcome common diagnostic pitfalls associated with AluY insertion. A total of 1,072 subjects comprising 411 patients with IRD (IRD group) and 661 patients with other suspected Mendelian genetic disease (non-IRD group) was screened for AluY insertion. Targeted panel sequencing and whole-genome sequencing were used for detection of AluY insertion, and an optimized allele-specific PCR (AS-PCR) was used for validation. The AluY insertion was detected in 1.5% in IRD group (6/411). The AluY insertion was not observed in non-IRD group (0/661). All patients with AluY were confirmed to have RP1 pathogenic variants on the paired allele. We identified AluY allele dropout leading to false homozygosity for c.4196del pathogenic variant in Sanger sequencing. The allelic relationship between variants of RP1 was accurately determined by AluY AS-PCR. Delineating diagnostic challenges of AluY insertion and strategies to avoid potential pitfalls could aid clinicians in an accurate molecular diagnosis for patients with IRD.

A Comprehensive Review of TRPS1 as a Diagnostic Immunohistochemical Marker for Primary Breast Carcinoma: Latest Insights and Diagnostic Pitfalls

Background/Objectives: Immunohistochemical expression of TRPS1 (trichorhinophalangeal syndrome type 1) protein is usually used by pathologists to confirm breast origin for triple-negative breast cancers (TNBC) or metastatic carcinomas of unknown primary. However, recent studies have reported TRPS1 expression in a variety of non-breast lesions. This review aims to provide a comprehensive evaluation of TRPS1 expression across various tumor types, highlighting both its diagnostic utility and potential pitfalls that may arise in clinical practice. Methods: A thorough search of the PubMed database on TRPS1 immunoexpression in tumor pathology was conducted. While the gene itself has been known for several decades, most studies regarding its use in immunohistochemistry emerged in the late 2010s. Particular emphasis was placed on case reports and cohort studies that examined the implications of TRPS1 expression in non-breast tissues, as well as variations in the results between commercially available TRPS1 clones, which may influence the staining intensity and specificity. Results: TRPS1 demonstrated a strong diagnostic utility in identifying primary breast lesions, particularly in TNBC cases. However, its expression in a growing number of non-breast cancers, such as lung adenocarcinoma, prostate adenocarcinoma, urothelial carcinoma, ovarian high-grade serous carcinoma, and endometrial adenocarcinoma, as well as up to 96% of synovial sarcomas with SS18-SSX fusion, emphasizes the need for caution when interpreting TRPS1 positivity and suggests a multi-marker approach in order to increase the diagnostic accuracy. Conclusions: While TRPS1 remains a highly sensible immunohistochemical marker for confirming breast primary lesions, pathologists should be aware of its low specificity and incorporate complementary diagnostic methods in order to ensure accurate clinical management. Further research should focus on elucidating the molecular pathways regulating TRPS1 expression in various tumor types, which may better define its clinical utility.

Diagnostic incidence and pitfalls of rete testis hyperplasia and hyaline globules in a multi-institutional study of 348 testicular germ cell tumors.

The concept of rete hyperplasia with hyaline globules simulating testicular yolk sac tumor was first reported in a mostly retrospective review over 30 years ago. Nonetheless, we continue to encounter examples where this scenario resulted in misdiagnosis. Herein, we sought to investigate the incidence of rete hyperplasia/hyaline globules in germ cell tumors and their associated subtypes and hypothesize an etiology. A consecutive series of 348 germ cell tumor orchiectomies was evaluated for the presence of rete hyperplasia and hyaline globules, with clinicopathologic features recorded. The incidence of rete hyperplasia and/or hyaline globules in our cohort was 30%, with 56% of specimens with rete hyperplasia containing concomitant hyaline globules. Hyaline globules were more often identified in specimens with nonfocal rete hyperplasia (78%) vs focal rete hyperplasia (22%). Absence of a yolk sac tumor component was seen in over half (61%) of orchiectomies with concurrent rete hyperplasia/hyaline globules (n = 105), inclusive of tumors with "pure" subtypes (ie, pure seminoma, pure teratoma, or pure embryonal carcinoma). Of these 105 specimens, rete invasion was seen in only 48%; notably, Paneth cell-like metaplasia was identified in efferent ductules/epididymis in 13%. Rete hyperplasia and hyaline globules are not uncommon findings in the setting of germ cell tumors (including occurrences in various pure/mixed germ cell tumors) and can show striking overlap with yolk sac tumor. We hypothesize that these histologic pitfalls evolve secondary to testicular obstruction by the tumor mass. Recognition of and distinguishing this morphologic mimicry is fundamental to guide appropriate clinical management.

Diagnostic and treatment pitfalls in glossopharyngeal neuralgia: evidence from a case series.

Glossopharyngeal neuralgia (GN) is a rare pain syndrome often underdiagnosed. This study aimed to assess the challenges in diagnosing GN and identify patients at risk of misdiagnosis. Between 2010 and 2019, nine patients underwent microvascular decompression (MVD) of the glossopharyngeal nerve at two tertiary care hospitals. A retrospective analysis examined symptom characteristics, time to correct diagnosis, operative technique, and clinical outcomes. Barrow Neurological Institute (BNI) pain scores were assessed before surgery and on follow-up. Six women and three men, aged 55 ± 14.3years, with unilateral GN were included. Pain was predominantly in the ear (otalgic type) in four patients (44.4%), the pharynx or base of the tongue (pharyngeal type) in four (44.4%), and mixed in one (11.1%). Five patients reported pain radiating to the mandible, all initially misdiagnosed with trigeminal neuralgia (TN) and treated for 2.4(± 3.1) years before presenting to our institution. One case resulted in MVD of the trigeminal nerve and subsequent thermocoagulation of the Gasserian ganglion due to persistent pain. The correct diagnosis of GN was established later in patients with otalgic or mixed pain (3.8 ± 3.4years) compared to those with pharyngeal pain (0.5 ± 1.0years), showing a trend (U = 17.0, p = 0.07). There was a significant association between pain radiation to the mandible and misdiagnosis (x2 = 9.00, p = 0.003). Endoscopically assisted MVD via the median suboccipital subtonsillary approach was performed, resolving neurovascular conflicts with the PICA (9/9) and vertebral artery (3/9). Follow-up after 15.7(± 18.2) months showed significant pain reduction according to the BNI (preoperative BNI = 5.0 ± 0.0, postoperative BNI = 1.7 ± 1.0,t (8) = 10,CI [1.6-5.1], p < 0.001). No permanent surgery-related deficits occurred. Patients with GN, especially those with predominant otalgic pain and pain radiating to the mandible, are at higher risk of misdiagnosis due to similarities with TN. Despite the rarity of GN, increased awareness of its various pain manifestations may lead to earlier correct diagnoses, which is crucial for surgical treatment.

Thoracoscopic Repair for Kluth Type Ⅲb3 Esophageal Atresia and Distal TracheoesophagealFistula

IntroductionThis report aims to present our initial miniseries of successful thoracoscopic repair for esophageal atresia (EA) and distal tracheoesophageal fistula (TEF) of Kluth type Ⅲb3 in accordance with Kluth's classification. MethodsFrom January 2012 to January 2024, ten patients with Kluth type Ⅲb3 EA-TEF were treated by thoracoscopic surgery. The therapeutic methods and surgical outcomes were retrospectively reviewed. ResultsAll procedures were completed thoracoscopically without conversions. A preoperative bronchoscopy assessment was conducted in four of the cases, revealing that the fistula from the distal segment was located high on the trachea at the level of T2 vertebral. The mean age of the patients at the time of operation was 2.0 ± 0.7 d (range, 1-3 d), and the mean weight at operation was 2.6 ± 0.4 kg (range, 1.8-3.0 kg). The mean operative time (skin to skin) for the entire series was 137.0 ± 8.9 min (range, 120-150 min). Oral feeding was initiated on the postoperative day 8.0 ± 1.9 (range, 6-12 d), and the mean duration for patients after surgery was 14.0 ± 2.4 d (range, 12-20 d). The postoperative period has been uneventful with no occurrences of mortality or morbidity to date. Three cases of formatted anastomotic stricture required at least one esophageal dilation after surgery. ConclusionsPediatric surgeons should be aware of the rare variants of EA-TEF to avoid the diagnostic and management pitfalls. Patients with Kluth type Ⅲb3 EA-TEF were amenable to repair by thoracoscopic surgery.

Gastrointestinal Stromal Tumor (GIST) masquerading as undifferentiated gastric carcinoma; a potential diagnostic pitfall

Abstract Introduction/Objective Epithelioid variant of the GIST can mimic carcinoma and misdiagnosis has grave implications in patient management. The purpose of this report is to describe such a case and to remind pathologists to keep epithelioid GIST in the differential. Methods/Case Report A 66-year-old male presented with melena for 2 weeks. Endoscopy showed a large, infiltrative, and ulcerated mass in the gastric fundus. CT imaging showed a 16 x 12 cm mass-like gastric wall thickening, most compatible with gastric carcinoma. The mass was biopsied, which showed sheets and clusters of anaplastic, large to medium sized polygonal epithelioid cells with areas of rhabdoid phenotype characteristic of an undifferentiated gastric carcinoma. Initial immunohistochemical stains including pancytokeratin and p40 showed negativity, prompting additional stains including Cam5.2, SOX10, CD45, synaptophysin, INSM1, EMA, CK7 and CK20- all of which were also negative. At this point the main diagnostic consideration was undifferentiated gastric carcinoma. However, for completion purposes, DOG1 stain was added that came back positive. Since rhabdoid morphology is a bit unusual, even for epithelioid GISTs, and literature review suggested that DOG1 positivity can be seen in up to 11% of carcinomas, confirmatory NGS testing was performed. This demonstrated a KIT W557R gene mutation, confirming the diagnosis of GIST. The patient was treated with imatinib and subsequent imaging showed decreased size and hypermetabolism of the gastric mass. Patient is alive with disease 6 months after the diagnosis. Results (if a Case Study enter NA) NA Conclusion Using a panel of appropriate immunohistochemical stains and keeping epithelioid GIST in the differential can help avoid this diagnostic pitfall.

An Anaplastic Lymphoma Kinase (ALK) Immunohistochemical Pitfall: ALK-positive Histiocytosis versus Angiomatoid Fibrous Histiocytoma

Abstract Introduction/Objective The 5th Edition WHO classification expanded the histiocytic/dendritic cell neoplasms to include ALK-positive histiocytosis, which can present as multisystem or single-site disease, affecting various age groups. These tumors lack high-grade cytologic features but express ALK by immunohistochemistry, typically indicating ALK locus rearrangements. In this case study, a cutaneous mass initially suspected as ALK-positive histiocytosis was found to be angiomatoid fibrous histiocytoma (AFH) with ALK expression, highlighting the potential diagnostic pitfall due to overlapping histomorphology and ALK expression. Methods/Case Report A previously healthy twelve-year-old boy sought evaluation for a growing and ulcerating mass on his left arm, which developed gradually over a year post-injury. Laboratory tests showed elevated inflammatory markers and mild anemia. A biopsy of the ulcer revealed Staphylococcus aureus infection. Initial histological examination revealed mixed inflammatory infiltrates with focal necrosis, prominent histiocytes, and giant cells. Despite favoring an infectious cause, immunostains were performed. AE1/AE3, ERG, CD34, CD30, S100, SOX10, SMA, and MyoD1 were negative, while INI1 was retained. However, ALK was strongly positive in some histiocytoid cells, suggesting ALK-positive histiocytosis. Surgical resection was subsequently performed to manage the abscess and characterize the lesion. Histologic examination revealed a solid nodule containing spindled and epithelioid cells with a bland histiocytoid appearance, arranged in a compact syncytial growth pattern within the dermis and subcutis. Surrounding the tumor, there was a distinct cuffing of fibrosis with organized lymphoplasmacytic cells. Break apart fluorescence in situ hybridization studies showed rearrangement of EWSR1 but not ALK. The diagnosis of angiomatoid fibrous histiocytoma was rendered. Results (if a Case Study enter NA) NA Conclusion This case highlights the importance of understanding immunohistochemical features, especially those that are unusual and unexpected in rare diseases. With the growing use of minimally invasive sampling techniques, this case study underscores the significance of integrating molecular diagnostics with clinical, histological, and immunophenotypic evaluations to achieve an accurate diagnosis in surgical pathology.

Pitfalls in Diagnosis of Myoepithelial Carcinoma of Salivary Glands: A Study of 3 Cases with Cytologic-histologic Correlation and Molecular Analysis.

Myoepithelial carcinoma (MECA) represents < 1% percent of salivary gland (SG) tumors with a mean age of 55 years. These tumors can arise de novo or in association with pre-existing pleomorphic Adenoma (PA). The cytologic features of MECA overlap with other SG neoplasms including the more common benign entities like PA and myoepithelioma and can pose a diagnostic challenge. A database search for MECA was performed spanning 10 years. 3 cases qualified with available cyto-histologic correlation. All were morphologically MECA with one case diagnosed as MECA ex-PA. The cases were subjected to a comprehensive immunohistochemical and molecular evaluation (Case#1 has been previously reported and published in head and neck pathology in 2021). A comparative analysis of these cases is presented in Table1. All three cases were initially diagnosed as PA on cytology. On review of cytology slides, presence of metachromatic stromal fragments and bland myoepithelial cells was found to be the most common diagnostic pitfall. S100 was positive in all cases while myosin, p63, and GFAP were variably positive. Molecular analysis revealed novel, previously undescribed mutations in the three cases. Additionally, two of three cases expressed PD-L1, suggesting a role for immunotherapy in treatment. Cytomorphology of MECA is poorly described in literature and can pose a diagnostic challenge due to overlapping features with salivary gland benign neoplasms. A conclusive diagnosis on cytology is often not possible. However, a high cellularity, predominant oncocytoid/ myoepithelial cell population on smears and cell block, along with a strong clinical and radiologic suspicion for malignant salivary gland tumor, should alert the cytopathologist and help avoid an erroneous benign diagnosis on cytology.

All that is squamoid is not squamous: A rare case of Squamoid Eccrine Ductal Carcinoma presenting as an intranasal mass

Abstract Introduction/Objective Squamoid eccrine ductal carcinoma (SEDC) is a rare adnexal tumor that poses diagnostic challenges because of the rarity, variable clinical presentation, and misdiagnosis on superficial biopsy sampling. Methods/Case Report We report a 52-year-old immunosuppressed male, status-post kidney and heart transplants who presented with an anterior nasal mass, the biopsy of which was interpreted as squamous cell carcinoma (SCC). Resection revealed a 2.5cm intranasal mass eroding through the hard palate. Histology showed a biphasic tumor arising from nasal vestibular skin with a superficial squamoid component (p40 positive) and a deeply invasive component demonstrating ductal differentiation (CEA positive) consistent with SEDC. SEDC has a predilection towards skin of head and neck region but SEDC presenting as an intranasal mass has not been reported. In our case, the tumor arose from nasal vestibular skin with destructive bony invasion within the nasal cavity. The patient’s long- term immunosuppression likely played a role in the etiopathogenesis and aggressive progression of this tumor. Interestingly, he also had history of multiple sebaceous carcinomas and cutaneous T-cell lymphoma with no known genetic predisposition, further implicating immunosuppression as the key risk factor for development of his cutaneous malignances. Results (if a Case Study enter NA) N/A Conclusion This case exemplifies the potential diagnostic pitfalls in squamoid lesions of the head and neck. Given the overwhelming prevalence of conventional SCC, rarer tumors with squamous differentiation often are not considered in the differential diagnosis, especially of an intranasal mass. A superficial biopsy often is misdiagnosed as SCC due to the lack of representation of deep-seated ductal components. A high index of suspicion and adequate examination of deeper aspects of the lesion are imperative for accurate diagnosis.

HPV-Independent Cervical Adenocarcinoma Discovered by Cytology-Based Screening: A case report of gastric type adenocarcinoma of the uterine cervix from cytopathology to histopathology

Abstract Introduction/Objective In recent years, the relative prevalence of adenocarcinoma has increased, comprising 20–25% of all cervical carcinomas in developed countries. Approximately 15% of cervical adenocarcinomas are unrelated to human papilloma virus (HPV) infection. With the shift toward HPV primary testing, an increased understanding of HPV-independent cervical adenocarcinomas becomes more important. Methods/Case Report This case report demonstrates a rare case of gastric-type adenocarcinoma (GAS) of the cervix discovered during a routine well-woman exam. Patient-reported episodes of vaginal spotting were noted prior to screening. HPV testing by PCR on the initial pap smear was negative. Cytology findings raised concerns about endocervical glandular cell abnormalities. Subsequent cervical biopsy revealed GAS, a finding supported by positive CK7, MUC5AC, CDX2, and aberrant (mutant) p53 expression by immunohistochemistry. HPV independence was further confirmed by negative results on mRNA ISH for high-risk HPV and HPV16/18. Results (if a Case Study enter NA) NA Conclusion Here we discuss the impact of cytology-based screening on HPV-independent cervical cancers, with focus on adenocarcinoma. While the move to primary HPV screening has been shown to be effective at identifying HPV-related neoplasms, it ineffectively addresses HPV-independent malignancies. In this particular population, cytology-based screening remains indispensable. The described case demonstrated subtle cytologic features consistent with endocervical glandular abnormality, ultimately correlating with subsequent histologic findings of HPV-independent GAS. Negative HPV results combined with subtle cytomorphologic changes displayed by some adenocarcinomas on PAP smear could present a significant diagnostic pitfall. Additionally, p16+ expression attributable to aberrant p53 pathways (rather than HPV) may further contribute to potential diagnostic errors. While further research into best practices for early detection of HPV-independent cervical neoplasias should be conducted, this team suggests both clinical survey and referral for cytologic screening following reports of abnormal vaginal bleeding and/or watery discharge and screener education focused on cervical GAS.

Synovial sarcoma- A potential diagnostic pitfall on FNAC

Synovial sarcoma is a malignant mesenchymal tumour with an uncertain origin. It is most commonly seen in the extremities, particularly lower extremities. The diagnosis of synovial sarcoma can be challenging due to its morphological diversity. Histologically, it can be of three subtypes: Monophasic, Biphasic and Poorly differentiated. The transcriptional corepressor, Transducin-Like Enhancer 1(TLE1) is a sensitive and specific marker for synovial sarcoma which helps in distinguishing it from histologic mimics. This case report presents a 48 year old female with swelling over right forearm since 1 year which was misdiagnosed on FNAC as Benign spindle cell lesion, probably Schwannoma. Surgery was done and on histopathological examination, it was diagnosed as Biphasic synovial sarcoma. It was confirmed by TLE1 immunohistochemistry which showed diffuse strong nuclear positivity. FNAC can sometimes fails to sample the epithelial component in biphasic synovial sarcoma, which complicates accurate diagnosis. The exact subtyping of spindle cell tumours is difficult on cytology owing to their complex heterogeneity. Though, Synovial sarcoma is an aggressive tumour, it responds well to treatment including surgery and chemotherapy. Therefore, correct and early diagnosis of synovial sarcoma is vital.

MSH6-proficient crypt foci in MSH6 constitutional mismatch repair deficiency: reversion of a frameshifted coding microsatellite to its wild-type sequence.

The discovery of "mismatch repair deficient (MMRd)-crypt foci" in non-neoplastic intestinal mucosa in Lynch syndrome (LS) has significantly enhanced our understanding of how tumors and tumor immunity form and evolve in LS. In this study, we report the frequent presence of "mismatch repair proficient (MMRp)-crypt foci" in both non-neoplastic and neoplastic intestinal mucosa in a patient with constitutional MMR deficiency (CMMRD), who carried a germline MSH6 pathogenic variant (c.3261dupC) in trans with an MSH6 likely pathogenic variant (c.3724_3726del) and whose tissues were otherwise deficient in MMR globally. The MMRp-crypts occurred at a rate of 1.1/100 crypts in non-neoplastic intestinal mucosa and were readily discernible in adenomas > 1cm. Sequencing analysis revealed normalization of the MSH6c.3261dupC variant in MMRp-adenoma crypts, indicating reverse frameshifting of the exon 5 C8 microsatellite. Interestingly but not surprisingly, the MMRp-adenoma crypts remained microsatellite-instability-high (MSI-H), and shared oncogenic APC mutations with the background MMRd-adenoma. Contrasting with MSH6-CMMRD, no PMS2-CMMRD individuals (0/5) harbored MMRp-crypts. In conclusion, our study documents distinct MMRp-crypts in MSH6-CMMRD, a phenomenon in keeping with MSH6 being a frequent target of MSI-H due to its coding microsatellite and suggesting that MSH6-CMMRD can potentially serve as a unique model system to further our understanding of MSH6's role in MSI-H tumor formation and evolution. Our findings also bear diagnostic implications; when using MMR immunohistochemistry as an ancillary tool in detecting CMMRD, awareness of these MMRp crypts can help avoid diagnostic pitfalls.

Vascular variant of Eagle syndrome: a review.

Eagle syndrome is defined as an elongated styloid process (ESP) that compresses nearby vasculo-nervous structures. The vascular variant of Eagle syndrome can lead to neurological symptoms including syncope, transient ischemic attack, or stroke; however, it has also been associated with other atypical presentations, making its diagnosis challenging. This review aimed to depict the characteristics of patients with the symptomatic vascular variant of Eagle syndrome. The literature search identified 56 reported cases of vascular variants of Eagle syndrome, with a mean age at onset of 51 years (range: 15-85 years), and the male-to-female ratio was 2:4. The ESP was bilateral in 63% of the cases, and the mean length was 48 mm (range: 31-77 mm). Vascular complications were mostly represented by internal jugular vein (IVJ) stenosis (n = 28), followed by internal carotid artery (ICA) dissection (n = 15). Additionally, eight cases of ICA thrombosis and two cases of severe chronic stenosis of the ICA > 90% were reported. Vascular complications may lead to cerebral ischemia due to either a thromboembolic mechanism or, less frequently, reduced blood flow. Laminar cortical necrosis, as a cerebral complication of ICA compression, was exceptionally described in one case, and such an atypical clinical presentation may be regarded as a diagnostic pitfall.

Fine-needle aspiration of basaloid scalp lesion: Potential diagnostic pitfall

Fine-needle aspiration of basaloid scalp lesion: Potential diagnostic pitfall

Functional hypothalamic amenorrhoea and polycystic ovarian morphology: a narrative review about an intriguing association.

Functional hypothalamic amenorrhoea (FHA) is responsible for 20-35% of all cases of secondary amenorrhoea and, thus, is the second most common cause of secondary amenorrhoea after polycystic ovary syndrome (PCOS). A high number of patients with FHA reveal polycystic ovarian morphology (PCOM) on ultrasound. The combination of amenorrhoea and PCOM can lead to confusion. First, amenorrhoeic women with PCOM fulfil the revised Rotterdam criteria and, thus, can easily be misdiagnosed with PCOS. Moreover, it has been claimed that some women with FHA and concomitant PCOM differ from those without PCOM in terms of endocrine regulation and metabolic traits. The main focus of this article was on studies about FHA, which differentiated between patients with or without PCOM. The aim was to estimate the prevalence of PCOM and to look if it has an impact on pathophysiologic, diagnostic and therapeutic issues as well as on long-term consequences. Peer review original and review articles were selected from PubMed searches for this review. Searches were performed using the search terms 'polycystic AND functional hypothalamic amenorrhoea'. The reference lists of publications found were searched for relevant additional studies. The inclusion criteria for publications were: English language, patients' age ≥ 18 years, year of publication >1980, original studies, validated diagnosis of FHA, and validated diagnosis of PCOM using transvaginal ultrasound. The prevalence of PCOM in women with FHA varied from 41.9% to 46.7%, which is higher than in healthy non-PCOS controls. Hypothetically, the high prevalence might be due to a mixture of silent PCOM, as in the general population, and pre-existing PCOS. Several differences in metabolic and hormonal parameters were found between FHA-PCOM and FHA-non-PCOM patients. While oestrogen deficiency is common to both groups of patients, FHA-PCOM patients have a higher BMI, higher levels of anti-Müllerian hormone (AMH) and testosterone, a higher increase in LH in the course of a GnRH test, and lower sex hormone binding globulin (SHBG) levels than FHA-non-PCOM patients. The differential diagnosis between FHA-PCOM and PCOS, especially PCOS phenotype D (PCOM and oligo-/anovulation without hyperandrogenism), can be challenging. Several parameters have been suggested, which are helpful though not absolutely reliable. They include the typical causes for FHA (excessive exercise, energy deficit, and/or psychological stress), the serum levels of LH, testosterone, and SHBG, as well as the progestin challenge test. Whether FHA-PCOM has a different risk profile for long-term consequences concerning patients' metabolic and cardiovascular situation as well as their bone mass, is unclear. Concerning therapeutic aspects, there are only few data about FHA-PCOM compared to FHA-non-PCOM. To treat anovulation, the use of pulsatile GnRH treatment seems to be equally effective in both groups. Similar to FHA-non-PCOM patients, pulsatile GnRH therapy would be more efficient than exogenous gonadotropins in FHA-PCOM patients. Women with FHA-PCOM present a special sub-population of FHA patients. The diagnostic pitfall of FHA-PCOM should be emphasized in clinical guidelines about FHA and PCOS. The fact that almost half of the women with FHA have an ovarian follicle excess (i.e. PCOM) in face of low gonadotropin serum levels suggests that the intra-ovarian regulation of folliculogenesis is subject to individual variations, for unknown reasons, either genetic or epigenetic. Further studies are needed to investigate this hypothesis. Not applicable.

Aberrant Expression of Pneumocytic Markers (TTF-1 and Napsin-A) in Biliary Duct and Gallbladder Adenocarcinomas; A Potential Diagnostic Pitfall.

Cholangiocarcinomas and gallbladder carcinomas are epithelial tumours with biliary differentiation. On histology and immunohistochemistry, they resemble adenocarcinomas and possess overlapping immunohistochemical profiles. Diagnosing these tumours is best done using appropriate imaging and clinical features with compatible immunohistochemistry. Immuno-staining for thyroid transcription factor-1 (TTF-1) and novel aspartic proteinase of pepsin A (Napsin-A) is believed to be specific for primary pulmonary adenocarcinomas. We herein report uncommon instances of strong and diffuse expression of these markers in two examples of adenocarcinomas arising from the bile duct and gallbladder. A review of the literature and a summary of similar studies relating to aberrant TTF-1 and Napsin-A expression in biliary tract adenocarcinomas are presented.

Nephrogenic Adenoma: A Pitfall on Frozen Section of Urethral Strictures.

Urethral strictures are a common cause of urinary obstruction which can be treated with surgical resection. Frozen sections are rare and pose a diagnostic challenge to pathologists due to the presence of benign lesions such as nephrogenic adenoma. We retrospectively examined all specimens of urethral stricture resections submitted to pathology at our institution from 2012 to 2022 (n = 258). Final pathology reports were searched to identify patients with dysplasia, carcinoma, or nephrogenic adenoma. When available, frozen section reports were also examined and compared to the final report, and additional clinical history and microscopic images were collected for patients with nephrogenic adenoma. Nephrogenic adenoma was identified in 3.8% (10/258) of urethral stricture resections. Dysplasia was identified in one patient who underwent two separate resections, and squamous cell carcinoma was found in one resection. Intraoperative frozen section was requested in 3.4% of resections (9/258). In two resections, an initial diagnosis of squamous cell carcinoma was initially favoured, however when reviewed with a genitourinary pathologist the diagnosis was changed to "reactive process" with a final diagnosis of nephrogenic adenoma. Nephrogenic adenoma can be challenging on frozen section due to variable architectural patterns, inflammation, and reactive changes. While urethral strictures are relatively common, their assessment by frozen section is rare and pathologists may lack familiarity with the variable morphology of benign entities that can be seen on frozen section resulting in their misinterpretation. We highlight this potential diagnostic pitfall and demonstrate the value of a second opinion prior to definitive frozen section diagnosis of malignancy.

How reliable is the distinction between thoracolumbar AO type A3 and A4 fractures? A systematic literature review.

The AOSpine classification divides thoracolumbar burst fractures into A3 and A4 fractures; nevertheless, past research has found inconsistent interobserver reliability in detecting those two fracture patterns. This systematic analysis aims to synthesize data on the reliability of discriminating between A3 and A4 fractures. We searched PubMed, Scopus, and the Web of Science for studies reporting the inter- and intra-observer reliability of detecting thoracolumbar AO A3 and A4 fractures using computed tomography (CT). The search spanned 2013 to 2023 and included both primarily reliability and observational comparative studies. We followed the PRISMA guidelines and used the modified COSMIN checklist to assess the studies' quality. Kappa coefficient (k) values were categorized according to Landis and Koch, from slight to excellent. Of the 396 identified studies, nine met the eligibilitycriteria; all were primarily reliability studies except one observational study. Interobserver k values for A3/A4 fracturesvaried widely among studies (0.19-86). The interobserver reliability was poor in two studies, fair in one study, moderate in four studies, and excellent in two studies. Only two studies reported intra-observer reliability, showing fair and excellent agreement. The included studies revealed significant heterogeneity in study design, sample size, and interpretation methods. Considerable variability exists in interobserver reliability for distinguishing A3 and A4 fractures from slight to excellent agreement. This variability might be attributed to methodological heterogeneity among studies, limitations of reliability analysis, or diagnostic pitfalls in differentiating between A3 and A4. Most observational studies comparing the outcome of A3 and A4 fractures do not report interobserver agreement, and this should be considered when interpreting their results.

Aberrant CD45 Immunoreactivity in Neuroendocrine Neoplasms: A Diagnostic Pitfall-Report of 10 Specimens and Clinical Recommendations.

Leukocyte common antigen (LCA), or CD45, is classically thought of as a leukocyte-exclusive protein, and as such, CD45 immunohistochemistry (IHC) is often used as a key differentiator between non-Hodgkin lymphomas (NHLs) and morphologically similar neuroendocrine neoplasms (NENs). Herein, we report our experience regarding aberrant CD45 immunoreactivity in a series of NENs. A natural language search was used to retrieve desired archival patient files. All prior NENs which had a positive neuroendocrine diagnosis or IHC results (synaptophysin, chromogranin, CD56, and/or neuron-specific enolase), as well as CD45 staining performed, were reviewed for possible CD45 positivity (n = 686). Among these 686 NENs, 10 were aberrantly positive for CD45 staining. CD45 showed nuclear, cytoplasmic, and/or membranous staining in tumor cells. The significance of such staining is unclear. Albeit for a minority of patients, pathologists should be aware that NENs may aberrantly stain with CD45 and thereby pose a diagnostic pitfall. Therefore, broadening routine IHC panels is recommended to differentiate NENs more clearly from NHLs.