bluuebunny/crossref_metadata_2025 huggingface dataset:
Crashing into Discovery: Nesidioblastosis in Adult, Unmasked post-Motor Vehicle Accident - A Case Study and Literature Review
Authors: Mohammed I , Rao D
Published: October 2024

Introduction/Objective

Nesidioblastosis, characterized by pancreatic duct-derived B-islet cell proliferation, typically manifests with hypoglycemic symptoms. While more common in newborns, it can rarely affect adults. Here, we report an incidental finding of nesidioblastosis in a 37-year-old female following abdominal trauma due to a motor vehicle crash (MVC).

Methods/Case Report

A 37-year-old female with no notable medical history presented with blunt abdominal trauma following an MVC. The emergency evaluation revealed a grade 4 traumatic splenic laceration and severe hemoperitoneum. Preoperative lab results showed decreased hemoglobin, elevated white cell count, prolonged prothrombin time, and reduced calcium and magnesium levels. The patient underwent a splenectomy along with a distal pancreatectomy. While grossly unremarkable, microscopic examination revealed maintained acinar architecture with focal hyperplasia around pancreatic ducts. Enlarged acinar cells with pleomorphic nuclei and prominent nucleoli were consistent with focal nesidioblastosis.

Results (if a Case Study enter NA)

NA

Conclusion

Multiple studies have documented the first reported case of nesidioblastosis in adults was in 1975. While its exact incidence is uncertain, most sources suggest a relative frequency of 0.5 – 7% of persistent hyperinsulinemic hypoglycemia, with estimated overall an annual rate of around 9 per 100,000, with a higher occurrence among females. This unusual incidental discovery of nesidioblastosis in an asymptomatic patient undergoing pancreatic resection for unrelated reasons highlights the likelihood of underestimating the actual prevalence of this disease.
Characterizing POLE Mutation-Associated Colorectal Carcinoma: Clinical and Pathologic Insight
Authors: Mohammed I , Rao D
Published: October 2024

Introduction/Objective

Colorectal carcinoma (CRC) is one of the most common cancers and a leading cause of cancer-related death in the United States. Pathogenically, colorectal carcinoma is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alteration. Identification of DNA polymerase mutation leads to the characterization of a new molecular pathway of carcinogenesis named the POLE pathway.

Methods/Case Report

Utilizing the cBioportal platform and Cancer Genome Atlas (TCGA) Firehouse Legacy data, we identified 118 cases of CRC with mutations in the POLE gene. We evaluated the various clinical and pathologic features of POLE mutation-associated CRC.

Results (if a Case Study enter NA)

Within the cohort of 118 cases linked to mutations in the POLE gene, gender distribution reveals that 63 individuals, comprising 53.8% of the sample, are male, while 42 individuals, accounting for 35.9%, are female. Ethnicity breakdown showcases a predominantly White population, with 92 cases (78.6%), followed by 8 cases (6.8%) attributed to Asian-Far East/Indian Subcontinent descent, 5 cases (4.3%) categorized as Asian, and 4 cases (3.4%) each identified as Black and Black or African American. Additionally, one case (0.9%) has an unknown ethnicity, while 4 cases (3.4%) have unspecified racial backgrounds.

The average age at diagnosis is recorded at 48.5 years, with ages ranging from 25 to 85, signifying a broad age spectrum within the affected population. Delving into cancer subtypes, the majority of cases, constituting 64 instances (54.2%), manifest as colon adenocarcinoma, while 38 cases (32.2%) present as rectal adenocarcinoma. Moreover, 9 cases (7.6%) are characterized as colorectal adenocarcinoma, 6 cases (5.1%) are classified as mucinous adenocarcinoma of the colon and rectum, and one case (0.8%) manifests as medullary adenocarcinoma of the colon. This detailed elucidation provides a comprehensive understanding of the demographics and clinical presentation within the cohort affected by POLE gene mutations.

Conclusion

In summary, our research has meticulously examined 118 instances of colorectal carcinoma (CRC) intricately linked to mutations in the POLE gene. Within this cohort, a predominant demographic emerges, with a notable prevalence among individuals of White ethnicity. Delving deeper into the pathological spectrum, colon adenocarcinoma emerges as the prevailing subtype, exemplifying the intricate interplay between genetic aberrations and cancer manifestation.
The Great Mimicker: Goblet Cell Adenocarcinoma of the Appendix Mimicking Mammary Carcinoma in a Patient with a History of Metastatic Breast Cancer
Authors: Zhou X , Du W , Husson M
Published: October 2024

Introduction/Objective

Goblet cell adenocarcinoma of the appendix is a rare and aggressive malignancy with high- grade histological patterns that pose diagnostic challenges due to their resemblance to other tumors. Previous reports have indicated that high-grade goblet cell adenocarcinoma may exhibit similarities to well-differentiated neuroendocrine tumors, and metastatic high-grade goblet cell adenocarcinoma can manifest diverse histologic growth patterns within a single section.

Methods/Case Report

We present a case of an 82-year-old female with a known history of breast cancer with sacral metastasis, presenting with a left upper quadrant “pinching” sensation. Histopathological examination following colectomy showed features of metastatic mammary carcinoma with mixed lobular (pleomorphic and partial signet ring cell type) and ductal features (Figure 1); Notably, different histologic patterns were observed in two tumor deposits, highlighting the complexity of the diagnosis (Figure 2). However, further investigation of the tip of the appendix revealed goblet-like mucinous cells arranged in a tubular growth pattern (Figure 3). Immunohistochemical stains were performed with adequate controls, revealing positive staining for CK20, SATB2, and CDX2, while showing negativity for BRST2, SATB2, GATA3, CK7, PR, ER, and HER2 (Figure 4). These findings corroborate the diagnosis of goblet cell adenocarcinoma.

Results (if a Case Study enter NA)

NA

Conclusion

In our case, we observed morphological features of goblet cell adenocarcinoma that overlapped with those of established mammary carcinomas. This scenario underscores the diagnostic challenges posed by rare tumors and emphasizes the significance of identifying the low-grade component of goblet cell adenocarcinoma, particularly in patients with a history of metastatic breast cancer.
An unusual liver tumor with challenging morphologic features and immunophenotype: A case report of metastatic HPV-driven basaloid anal squamous cell carcinoma
Authors: Beeter M C , Dhingra S , Amrikachi M , Thrall M
Published: October 2024

Introduction/Objective

Basaloid squamous cell carcinoma (BSCC), a rare subtype of squamous cell carcinoma, occurs most commonly in esophagus, lungs, and head and neck. Anal BSCC is extremely rare and has a 10-20% rate of metastasis. High-risk HPV (HR-HPV) is the main causative agent. BSCC occurrence in an atypical site without a known primary tumor, and with atypical immunoprofile can be a diagnostic challenge.

Methods/Case Report

We report an 83-year-old female with history of breast carcinoma who presented for worsening chest pain. Imaging studies showed pulmonary nodules, 1.8 cm hepatic mass, and pelvic nodules. Liver biopsy showed infiltrating nests of carcinoma with solid and cribriform patterns and luminal necrosis. Some tumor nests had basaloid features with peripheral palisading. Tumor was positive for CK7 and pankeratin; and negative for ER, SOX10, GATA3, GCDFP-15 (Breast markers), CDX2 (GI marker), P63 and P40 (squamous markers), INSM1, Synaptophysin (Neuroendocrine) and TTF1 (lung adenocarcinoma). There was microfocal staining with CK20 and SATB2. Tumor morphology and immunophenotype were not entirely specific to the site of origin. Further search into patient’s medical history showed a recent anal mucosal biopsy revealing a high-grade squamous epithelial lesion with diffuse P16 reactivity. The slides for the anal lesion were reviewed and showed morphologic features similar to the liver biopsy. Additional studies showed both tumors were positive for HR-HPV ISH, P16 (diffuse), and CK5/6 (patchy); and negative for P63. The morphologic features and immunoprofile were supportive of metastasis from HPV-driven BSCC of anus. Subsequent PET Scan revealed a rectal/anal mass.

Results (if a Case Study enter NA)

NA

Conclusion

For tumors with unusual morphology and immunophenotype, complete medical history review, and communication with clinician are important tools in achieving correct diagnosis. HR-HPV ISH is a new tool that can be very useful in reaching correct diagnosis in metastatic anogenital or oropharyngeal squamous carcinomas with basaloid features.
SWI/SNF Altered Gastric Carcinoma with Squamous Differentiation in a young patient with aggressive clinical course
Authors: Centeno L , Misra S , Castillo D , Szeto W , Mannan R
Published: October 2024

Introduction/Objective

Inactivation of SMARCA4 (BRG1) protein subunit of the SWI/SNF complex has been reported in various malignancies affecting multiple organs, often associated with a poor prognosis. We report a rare case of gastric SMARCA4-deficient carcinoma in a young patient, showing squamous differentiation and an aggressive clinical course.

Methods/Case Report

A 28-year-old male presented with epigastric pain and 15-lb weight loss over 3 months. Evaluation revealed a gastric cardia mass, liver lesion, and gastro-hepatic lymph-node. Biopsy of gastric and liver lesions revealed a poorly differentiated carcinoma. Following a course of neoadjuvant chemotherapy, and immunotherapy, total gastrectomy and distal esophagectomy were performed. Grossly, there was a 13 cm mass involving his gastric cardia and body, extending into his distal esophagus. On microscopy, the transmural tumor was arranged as solid sheets, syncytial aggregates, and nests with a focal pseudoglandular pattern in a lymphoplasmacytic rich stroma. Scattered bizarre giant cells were noted, along with brisk mitosis and focal necrosis. Focally, the tumor showed abundant glassy eosinophilic cytoplasm reminiscent of squamoid cells. Two of forty-two lymph nodes were positive for metastatic carcinoma. IHC showed focal positivity for AE1/3, OSCAR, CAM5.2, along with areas staining for p40 and p63; negative for CK7, CK20, CDX2, SATB2, synaptophysin, INSM1, SOX-10, LCA ERG, and SALL4. Nuclear expression for mismatch repair proteins was retained. HER2 was negative (score 0), and PDL-1 CPS score was 40. EBER in-situ hybridization was negative, with retention of INI-1. There was complete loss of SMARCA4 by IHC and next generation sequencing confirmed frameshift alteration of SMARCA4. Final pathologic diagnosis was SMARCA4 deficient poorly differentiated carcinoma with squamous differentiation (ypT3pN1). The patient received adjuvant therapy with Paclitaxel and Ramucirumab. However, his disease progressed, and he succumbed to his illness five months after surgery.

Results (if a Case Study enter NA)

N/A

Conclusion

Our case illustrates that SMARCA4 deficient gastric carcinomas can have heterogeneous morphology, with an aggressive clinical course in young patients. This highlights the importance of early diagnosis and consideration of alternative therapeutic approaches, as these tumors typically do not respond to standard treatments.
Atypical Gastric Glomus Tumor of Uncertain Malignant Potential in A 16-Year-Old Female; A Rare Entity with Unique Findings
Authors: Amin S E , Ahmed A A , Aljumaili Z , Thomas-Ogunniyi J O
Published: October 2024

Introduction/Objective

Gastric glomus tumor (GGT) is a rare mesenchymal tumor that is challenging to diagnose, especially when the immunoprofile overlaps with other more common gastric mesenchymal tumors. The majority of GGT are benign, however, rarely it can be atypical or even malignant. Herein, we present a case of a young female with atypical gastric glomus tumor of uncertain malignant potential.

Methods/Case Report

A 16-year-old female presented to the emergency with abdominal pain, coffee ground emesis, and melena. Imaging showed a 3.2 cm well-defined gastric mass arising from the muscularis propria.

Results (if a Case Study enter NA)

The FNA biopsy revealed clusters of tumor cells with uniform characteristics, exhibiting distinct cell membranes and eosinophilic to clear cytoplasm, surrounding prominent vasculature.

Immunohistochemical analysis showed that the tumor cells were positive for SMA, synaptophysin, vimentin, calponin, and caldesmon, with weak, patchy positivity for DOG1. CD34 highlighted the vessels separating the tumor cellular clusters into lobules. CD117 and Desmin were negative. The Ki67 proliferation index varied with hotspot foci 25-30%. Morphology and immunoprofile suggest glomus tumor, however, neuroendocrine tumor and epithelioid GIST needed to be excluded.

Subsequent resection specimen showed that the tumor was located within the muscularis propria with extension into the serosal vessels, suggesting vascular invasion, along with foci of cellular spindling and nuclear irregularity are identified. No necrosis noted. Tumor cells were positive for cyclin D1 while negative for myogenin, chromogranin, and DOG1. Overall, findings were consistent with GGT of uncertain malignant potential.

Conclusion

Although GGT are rare, they should be considered in the differential diagnosis of gastric mesenchymal tumors. The presence of diffuse SMA staining can help distinguishing them from GIST. It is crucial to scrutinize for signs of cellular and nuclear atypia, particularly in deeply seated glomus tumors.
Predicting Metastasis and Mortality Risk in Prostate biopsy using genomics and biopsy related factors
Authors: Chacko D , Fidan-Ozbilgin O , Cai D
Published: October 2024

Introduction/Objective

Prostate cancer, the most prevalent cancer among men, is diagnosed through biopsy, yet its predictive accuracy for metastasis and mortality risk remains limited. An approach to stratifying this risk is by combining biopsy data and genetics. The Decipher genomic classifier aids in estimating such risks. This study investigates the correlation between Decipher, biopsy-related factors, and the risk of prostate cancer metastasis or mortality.

Methods/Case Report

50 prostatic adenocarcinoma biopsies were analyzed. Patient age, average tumor volume in positive cores, PSA levels, and Gleason score were documented. Employing Tobit regression with maximum likelihood estimation, the study examined the link between various factors and metastasis/mortality risk of prostatic cancer. Dependent variables encompassed 5, 10, and 15-year risks, while the independent variable was patient age, positive to total core ratio, average tumor volume in positive cores, PSA level, and grade group of the prostate cancer. The model integrated three dummy variables-Grade Group 1, 3, and 4, with Grade Group 2 as reference. Coefficients gauged the distinct impact of Level 1, 3, and 4 diagnoses on outcomes relative to Level 2. Statistical significance was tested conventionally.

Results (if a Case Study enter NA)

Grade Group 1 (Gleason score: 3 + 3):

2.35 percentage point increase in the risk of metastasis within 10 years.

3.51 percentage point increase in the risk of mortality within 15 years.

Grade Group 2

Base level for comparison with other grade groups.

Grade Group 3 (Gleason score: 4 + 3):

No statistically significant difference in the predicting 5 or 10 year risk of metastasis compared to Grade Group 2. No statistically significant difference in the predicting 15 year risk of mortality compared to Grade Group 2.

Grade Group 4 (Gleason score: 4 + 4):

10.07 percentage point increase in the risk of metastasis within 5 years.

17.27 percentage point increase in the risk of metastasis within 10 years.

18.48 percentage point increase in the risk of mortality within 15 years.

Conclusion

The findings suggest combining genomics and grade group can help predict the risk of metastasis and mortality in prostate biopsy. Grade Group 4 diagnosis greatly impacts metastasis and mortality in all timeframes.While Grade Group 1 has a smaller but still significant impact on the 10 and 15 year risk of metastasis and mortality.

However, Grade Group 3 diagnosis does not significantly impact the risk of metastasis in any of the timeframes considered.
NEUROENDOCRINE TUMORS OF THE GENITOURINARY TRACT - A CLINICAL AND PATHOLOGIC REVIEW
Authors: Yilmaz G , Cheng L , Yan L , Gattuso P
Published: October 2024

Introduction/Objective

Neuroendocrine tumors (NETs) of the genitourinary (GU) tract are rarely seen during daily surgical pathology sign-out sessions and comprise a heterogeneous group of neoplasms. We undertook a retrospective study to assess the clinical and pathologic characteristics of this unusual group of neoplasms involving the GU tract.

Methods/Case Report

We performed a retrospective review of the surgical pathology files for NETs of the GU tract between July 1993 and December 2021. Chart review was performed for the clinical and pathologic findings.

Results (if a Case Study enter NA)

A total of 26 patients were identified. There were 18 males and 8 females ranging in age from 43 to 94 years (mean age 69 years). 19/26 (73%) cases were primary tumors; 9 bladder small cell carcinoma, 5 prostatic small cell carcinoma, 4 bladder paragangliomas, and 1 case of small cell carcinoma of the renal pelvis. 7/26 (27%) cases were metastatic tumors; 5 Merkel carcinoma (3 urinary bladders, 2 testes), and 2 small cell carcinoma of the lung to the kidney.

Conclusion

The majority of NETs of the GU are primary and urinary bladder to be the most common site. Merkel cell carcinoma appears to have a tendency to metastasize to the GU tract, especially to the testis.
Clinicopathological correlation of three cases of metastatic carcinoma to uterine cervix: An institutional experience
Authors: BENDARI A , Al-Refai R , Sham S , Gomez Marti J , Des Jean R , Harshan M , Mohamed H , Bendari T
Published: October 2024

Introduction/Objective

Metastasis to the female genital tract presents a rare occurrence and poses significant diagnostic hurdles. The uterine cervix, although less frequently implicated, presents additional challenges for metastatic spread owing to its diminutive dimensions, limited vascular perfusion, and abundance of fibrous tissue. Clinical manifestations often include abnormal vaginal bleeding in 62–75% of cases, frequently accompanied by involvement in other anatomical sites. Accurate identification of cervical tumor activity and its primary origin holds paramount importance for precise diagnosis, therapeutic stratagem, and prognostic assessment.

Methods/Case Report

Here we are reporting three cases that were encountered in our institution over a 5-year period. The first patient, a 63-year-old female with a history of breast cancer, six years later exhibited metastatic breast cancer in a cervical polyp, confirmed by positivity for AE1/AE3, GATA3, ER, and negativity for TTF-1, chromogranin, synaptophysin, PAX8, inhibin, calretinin, CDX-2, CD10, desmin, smooth muscle actin, S100, and HMB-45. The second patient, diagnosed with pancreatic adenocarcinoma, two years later manifested cervical metastasis confirmed via positive staining for CK7, CDX2, and focal p63, and did not express PAX8, vimentin, ER, p16, synaptophysin, and chromogranin. The third patient, diagnosed with lung adenocarcinoma, one year later presented with a cervical mass, histologically confirmed as metastatic lung adenocarcinoma via positivity for CK7, Napsin A, and TTF1, and negativity for PAX8, p16, p40, p53, GATA3, and ER.

Results (if a Case Study enter NA)

N/A

Conclusion

Given the challenges of identifying metastasis to the cervix, thorough diagnostic evaluation should be undertaken to differentiate primary versus metastatic disease in women with a history of non-cervical malignancy.
Clinicopathological Characteristics of Small Cell Carcinoma of the Ovary, Hypercalcemic Type – a case Series
Authors: Li X , Madabhushi S , Dimo B , Husson M
Published: October 2024

Introduction/Objective

Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare (<0.01%) and aggressive ovarian tumor primarily affecting young women (median of approximately 24 years), characterized by rapid growth, early metastasis, and association with hypercalcemia in two-thirds of cases. The diagnosis of SCCOHT is challenging due to its rarity and lack of specific clinical symptoms or biomarkers. Our study aims to delineate the clinicopathologic characteristics of SCCOHT based on our case series and add to the existing knowledge.

Methods/Case Report

A retrospective review of University of Pennsylvania Health system pathology database was conducted from 2012 to 2024. Our study identified four patients diagnosed with SCCOHT. Clinical information and histopathologic characteristics were reviewed.

Results (if a Case Study enter NA)

Among the four patients identified, the median age was 24 years, with a median tumor size of 14.5 cm, and all patients presented with weight loss, abdomen bloating, and elevated CA125 levels.

Notably, two patients exhibited hypercalcemia, while one initially presented with normal calcium levels but developed hypercalcemia during disease recurrence. One patient maintained normal calcium levels throughout. Surgical intervention involved bilateral salpingo-oophorectomy in all cases, with pathological staging revealing two patients at pT1a, one at pT1c, and one at pT3c. Histopathological analysis consistently revealed similar morphology, including solid and cystic necrotic neoplasms with diffuse growth or nests/cords of undifferentiated small cells, which displaying vesicular chromatin and prominent nucleoli. Immunohistochemical staining demonstrated loss of BRG1 (SMARCA4) expression in two patients and diffuse positivity for WT1 in all patietns, while negative for cytokeratin, germ cell markers, and melanocytic markers. Genetic test revealed SMARCA4 mutation (p.E 717*, c.3169-1G>A) in one patient.

Conclusion

Small cell carcinoma of the ovary, hypercalcemic type, presents a diagnostic and therapeutic challenge due to its rarity and aggressive nature. Adequate treatment options are currently limited, highlighting the critical need for further research and development of targeted therapies in SCCOHT. Testing for mutations in the SMARCA4 gene is essential for accurate diagnosis of SCCOHT and may uncover new avenues for treatment and management strategies.
An extremely Rare Case of Primary Peritoneal Mucinous Cystadenocarcinoma
Authors: Kumar H , Chen W , Sun S , Satturwar S
Published: October 2024

Introduction/Objective

Primary peritoneal mucinous adenocarcinoma is an extremely rare entity with no well- established treatment protocol. It occurs more commonly in females as compared to males which supports its less understood pathogenesis of arising from heterotopic ovarian tissue or mucinous metaplasia of mesothelial cells.

Methods/Case Report

We present a case of a 31-year-old female who presented with right flank pain after a fall. On imaging studies, a cyst measuring 11.4 x 9.6 x 8.8 cm with an enhancing mural nodule was identified in abdomen (Figure 1). Patient underwent exploratory laparotomy. We received 402.1 grams, 12.5 x 10.0 x 8.0 cm cystic mass.

Cut surface showed an unilocular cyst filled with seromucinous fluid and 4.0 x 2.5 x 1.7 cm friable excrescences. Histologic examination showed an adenocarcinoma arising from background mucinous cystadenoma. The tumor cells were positive for AE1/AE3, CK7, CK20, villin (focal), PAX8 (focal), p53 (wild-type) and negative for WT-1, AMACR, CDX-2, TTF-1, GATA-3, inhibin and calretinin. ER and PR immunostains were positive in the ovarian-type stroma in the background mucinous cystadenoma. As the radiology work-up was negative for any other tumor in the pelvis or other sites, the diagnosis of primary peritoneal cystadenocarcinoma was rendered. Molecular analysis showed presence of KRAS and TP53 mutations. Patient is doing well at 6 months follow-up without any recurrence.

Results (if a Case Study enter NA)

NA

Conclusion

This case is an extremely rare case of primary peritoneal mucinous cystadenocarcinoma and thus requires consideration that it should be included in the differential diagnosis of peritoneal tumors.
Reflex Testing of Endometrial Carcinoma For Next Generation Sequencing: An Institutional Experience
Authors: Brunetti A
Published: October 2024

Introduction/Objective

Endometrioid carcinoma is now separated into four subgroups based on molecular profiling. These subgroups (POLE mutant [POLEmut], mismatch repair-deficient [MMRd], p53 abnormal [p53abnl], and no specific molecular profile [NSMP]) have been shown to be diagnostically and prognostically relevant. This is especially highlighted by the inclusion of molecular classification into the 2023 FIGO staging for EMCA. In conjunction with our gynecologic oncologists (gynonc) and colleagues in molecular pathology, we developed and implemented a reflex process by which next generation sequencing (NGS) is done on all hysterectomies performed at our institution for EMCA.

Methods/Case Report

In collaboration between gynonc, molecular diagnostics, surgical pathology and operations personnel, an order set was built within our LIS. At the time of sign-out, the gynecologic pathologist (GYNP) selects the block for NGS testing and orders the cuts for NGS, digital scanning of the corresponding H&E and the NGS testing. Histology in turn processes the cuts, scans the H&E and transfers the material for NGS. The digital slides are stored in an accessible repository and annotated by the GYNP. Results of NGS testing are released into the patient’s EMR and molecular/histologic correlation is subsequently performed by the GYNPs.

Results (if a Case Study enter NA)

In the period between 1/1/23 and 2/28/24, we processed 131 EMCA cases through this pathway. Of 103 endometrioid-type EMCA reflexed during this period, 7 were classified as POLEmut, 23 as MMRd, 13 as p53abnl, and 60 as NSMP. 16 cases required re-review of IHC and/or NGS results due to discrepancies. 4 p53abnl cases required upstaging according to the new FIGO, while no POLEmut cases required downstaging as they were all stage I.

Conclusion

Overall, our pilot pathway was considered a success and continues. We believe our process can serve as a framework for other institutions and can be applied to other malignancies.
A Case Report of Inflammatory Myofibroblastic Tumor Mimicking Leiomyosarcoma of the Uterus
Authors: Poonam F , Devi A , Farooq S , Chen S
Published: October 2024

Introduction/Objective

Inflammatory myofibroblastic tumor (IMT) of the uterus is a rare entity that presents significant diagnostic challenges due to its infrequency and has the potential for being misdiagnosed as a leiomyoma, endometrial stromal tumor, or myxoid leiomyosarcoma, resulting in undertreatment or overtreatment.

Methods/Case Report

We present a case report of a 50-year-old woman with a history of anemia due to heavy menstruation caused by fibroids, who underwent hysterectomy. The concurrent pelvic wash cytology raised suspicious for myxoid leiomyosarcoma.

Results (if a Case Study enter NA)

Macroscopic examination revealed both well and poorly circumscribed nodules, ranging upto 4.7 cm in maximum dimension. Cut surfaces exhibited a spectrum of appearances, including tan-pink, whorled and rubbery, as well as soft, hemorrhagic, edematous, and mucinous areas with necrosis. Microscopically, the tumor exhibited myxoid spindle cell proliferation, in the background of lymphoplasmacytic inflammatory infiltrates. She was diagnosed with IMT metastasis to left fallopian tube, ovary, and omentum. Immunohistochemical (IHC) analysis further confirmed the diagnosis, showing strong and diffuse cytoplasmic positivity for ALK (anaplastic lymphoma kinase), caldesmon, and smooth muscle actin. This case underscores the critical importance of accurate diagnosis in guiding appropriate treatment strategies. Moreover, given the morphological overlap with other uterine tumors, the identification of ALK rearrangement emerges as a pivotal diagnostic marker, distinguishing IMT from its mimics such as leiomyoma, leiomyosarcoma and smooth muscle tumor of uncertain malignant potential (STUMP).

Enhancing our understanding of the histomorphological features and ALK immunostaining of uterine IMT is essential for optimizing patient management and outcomes.

Conclusion

IMT in the female genital tract can mimic other more common benign and malignant tumors like leiomyoma, leiomyosarcoma, and endometrial stromal sarcoma. Familiarity with clinical and histologic features and the use of ALK immunostaining can be critical for correct diagnosis.
Next-generation sequencing (NGS) of anaplastic thyroid carcinoma identifies unreported mutations in 25 recurring genes
Authors: Jansen S , Zhang X , Chen N , Hammer R , Pavlick D C , Hiemenz M , Dougherty K C , Dooley L M
Published: October 2024

Introduction/Objective

Anaplastic thyroid carcinoma (ATC) is a rare, aggressive form of thyroid cancer. Our prior work identified 6 molecular clusters of ATC with a possible de novo group. Secondary analysis of NGS data from 713 ATC cases was undertaken to identify less frequent and unreported gene mutations.

Methods/Case Report

Deidentified NGS results of 713 ATC cases were obtained from Foundation Medicine (FoundationOne CDx). The results were analyzed for frequency of gene mutations. A search of the literature and genomic databases (TCGA, NCI Genomic Data Commons, and cBioPortal) was performed to determine gene association with thyroid cancers including ATC.

Results (if a Case Study enter NA)

There are 25 gene mutations present in 5 or more cases that have not previously been reported in ATC and one gene found, MTAP, which has been discussed in a limited number of cases. The gene mutations found are listed from highest to lowest frequency (14.77% to 0.69%) as follows: MTAP, LRP1B, ASXL1, NUP93, MUTYH, NOTCH3, RAD21, CRKL, PIK3R1, FANCA, STAG2, BRCA2, FGF4, FGF3, FGF19, FBXW7, BRCA1, BCORL1, QKI, VHL, PRKN, GATA6, NKX2_1, KDM5C, CCND3, and BAP1. There are also 99 other gene mutations with 4 or fewer cases (0.14% to 0.77%) that have not previously been associated with ATC. MTAP was previously reported to be lost by immunohistochemistry in 6/27 (22.2%) ATC cases; MTAP loss was also reported to indicate a potential CDKN2A abnormality. Our larger data set supports that MTAP is lost in ATC with 98.6% of MTAP- deleted ATC also harboring CDKN2A deletion and 92.3% showing CDKN2B deletion (p-values < 0.0001), supporting MTAP and CDKN2A/B are often deleted together. Other significant genes include the hereditary cancer genes MUTYH, FANCA (autosomal recessive), and BRCA1/2 (autosomal dominant) and genes associated with clonal hematopoiesis. ASXL1 and STAG2 have previously been unreported in ATC while others such as DNMT3A, TET2, and BCOR were also present in our dataset.

Conclusion

Our findings demonstrate 124 genes mutated in ATC that have not been previously reported. Besides the previously reported MTAP in 6 cases, genes associated with hereditary cancer and clonal hematopoiesis were identified. MTAP is located adjacent to CDKN2A/B and is often codeleted with MTAP at a much higher frequency than previously reported. Identifying associations with other diseases could improve surveillance and options for earlier therapy of ATC. Finally, these findings warrant further research to determine their role in the pathogenesis and treatment targets of ATC.
Anaplastic thyroid carcinoma: a genome-based search for new targeted therapy options
Authors: Zhang X , Jansen S , Chen N , Dooley L M , Hammer R , Pavlick D C , Hiemenz M , Dougherty K C
Published: October 2024

Introduction/Objective

Anaplastic thyroid carcinoma (ATC) is a rare, aggressive thyroid cancer. Precision medicine, particularly gene-targeted therapy has emerged as a promising avenue in cancer treatment. However, few targeted therapies have been approved for ATC. Here, we present a genome-based search for new targeted therapy options using next-generation sequencing (NGS) data of 727 ATC cases.

Methods/Case Report

Deidentified NGS results in 727 ATC cases were obtained from Foundation Medicine. A search of the literature and genomic databases (TCGA, My Cancer Genome, and DGIdb) was performed to analyzed frequency of gene mutations and corresponding gene targeted drugs.

Results (if a Case Study enter NA)

Remarkably, 99.17% of the 727 ATC cases had at least one targeted drug option available. Among the 254 unique genes identified with pathogenic mutations, 150 (59.06%) were found to have at least 1 corresponding targeted drug. Among the top 35 most frequently mutated genes (frequency > 2.0%), 27 (80.00%) had available targeted therapies. Notably, most drug categories (70.83%) exhibited multi-gene targeting capabilities. The drug categories based on the percentage of genes targeted from highest to lowest are Serine/Threonine and Tryosine kinase inhibitors, therapeutic antibodies, MEK inhibitors, CDK inhibitors, AKT inhibitors, PI3K inhibitors and immunotherapies. There are an additional 16 drug categories that target 1 to 5 of the 35 frequently mutated genes identified.

Of particular interest is MTAP, a previously unreported frequently mutated gene which is most often deleted (14.77%). Several drugs are undergoing phase 1 and/or phase 2 clinical trials for MTAP-deleted solid tumors. MTAP loss holds promise for identifying expanding therapeutic options in ATC.

Conclusion

Our genome-based analysis indicates that 99.17% of the 727 ATC cases have targeted drug options, targeting 59.06% of identified gene mutations. Among the 24 categories of targeted drugs 17 (70.83%) target more than one gene. The 2018 FDA approval of combination BRAF/MEK inhibitor therapy for management of BRAF V600E-positive ATC was a major first step in gene targeted therapies. Besides that, Tyrosine kinase inhibitors, mTOR inhibitor, PPAR-γ agonist, ALK inhibitor, VEGF inhibitor and several combined treatment and immunotherapeutic agents are currently being tested in ATC clinical trials. These promising findings highlight the expanding repertoire of gene-targeted therapy options in ATC and emphasizes the importance of combined strategies and identifying driver mutations.
Regional distribution of anaplastic thyroid cancer in the United States
Authors: Kovalenko M , Hammer R , Chen N , Haithcoat T , Dooley L M
Published: October 2024

Introduction/Objective

Anaplastic thyroid cancer (ATC) is an aggressive rare malignancy found in less than 2% of thyroid cancer patients. Its low occurrence rate presents challenges for collecting sufficiently large cohorts at a single institution, making statistical analysis about the disease’s spread, geographical distribution, and prevalence difficult. Nationwide data lakes such as Oracle EHR Real-World Data (ORWD, formerly Cerner Real World Data) offer a boost in cohort sizes and an opportunity to study ATC’s geographical distribution and assess regional differences.

Methods/Case Report

We searched ATC distribution across US regions defined by ZIP codes recorded in ORWD using multiple coding parameters, including ICD9, ICD10, and SNOMED as well as direct text searches for “anaplastic thyroid carcinoma”. We analyzed the geographical associations defined by ORWD (region) with sex, race, and age of ATC onset using the Fisher’s exact test. We combined 10 regions into 4 representative groups because of the small sample size. The groups are West Coast including the Rockies, Midwest from North Dakota to Texas, East Coast, and New England.

Results (if a Case Study enter NA)

Search for ATC condition codes in ORWD produced only 200 region-coded patient records across the US using multiple methods to try and identify cases. The mid-section of the US and coastal regions shows the highest numbers of ATC patients while New England and South regions show the lowest. While more women have ATC overall, the East Coast group has significantly more males (p value = 0.04). ATC is a predominantly white disease (79.8% overall) with black population increasing in East Coast group and other races (Asian/Undeclared) in West Coast (p-value < 0.001). There appears to be no significant association between age of ATC onset and the geographical groups.

Conclusion

The data shows geographic differences in distribution of ATC although this preliminary analysis neither explains the nature of these differences nor allows for a clearer view. The rarity of the disease complicates data analysis. This study was also limited by number of cases retrievable from the database itself and lack of granularity in coding available for ATC to find cases of interest, highlighting the difficulty of accurate tumor classifications in large data lakes. Further research into geographical distribution and environmental factors (radioactivity, pollution) of thyroid cancer using more advanced tools, such as GeoSpark, are planned.
Rare Encounter: A Study of Oral Cavity Kaposi Sarcoma in Two Cases
Authors: Jabbar M , Yin J , Zenezan D , Proca D , Kuklani R
Published: October 2024

Introduction/Objective

Kaposi Sarcoma (KS) of the oral cavity, is an unusual vascular endothelial neoplasm and is the most common malignancy affecting the skin and internal organs in patients with AIDS. The tumor is caused by Human herpesvirus 8 (HHV-8). It rarely metastasizes and can be treated and totally cured by treating the AIDS disease.

The oral cavity may be the only/ first site of KS, and therefore, is important in the diagnosis. The lesions present as multiple red-purple macules that develop into plaques or nodules. The hallmark microscopic features are spindle cell proliferation and irregular small, vascular slits, which often run parallel to the epithelium, as well as extravasated RBCs, with hemosiderin deposition and hyaline globules in 50% of lesions. HHV-8 nuclear staining is positive in all cases, which is crucial to differentiate it from other conditions with positivity for spindled cell markers: CD34, CD31, ERG, and FVIII R. The tumor can also be positive for lymphatic-specific markers (D2-40, LYVE-1, VEGFR3, and PROX1)

Methods/Case Report

We reviewed retrospectively archived cases from our TUH oral pathology database with available H&E slides diagnosed for Kaposi sarcoma between 2013 – 2023. We retrieved two confirmed cases, and we reviewed the slides and clinical information.

Results (if a Case Study enter NA)

Data were colleceted and analysed.

Conclusion

Incorporating Kaposi sarcoma into the differential diagnosis of pigmented red-purple vascular lesions in the oral cavity is of paramount importance. Detection of Kaposi sarcoma in this region bears significant prognostic implications, often serving as an initial sign of Kaposi sarcoma and indicating HIV infection. Lesions typically localize on the palate and gingiva.

Heightened awareness of this clinical entity is crucial for facilitating early detection and treatment with antiretroviral drugs. Furthermore, the differential diagnosis for lesions with similar clinical presentations encompasses a broad spectrum, including benign conditions such as pyogenic granuloma, hemangioma, bacillary angiomatosis, and even granulation issue, as well as malignant tumors like angiosarcoma. It is noteworthy that considering Kaposi sarcoma in this context prompts pathologists to prioritize ordering stains for HHV-8. This diagnostic approach is supported by the exceptional sensitivity and specificity of HHV-8 stains, which exhibit 99% sensitivity and 100% specificity for diagnosing Kaposi sarcoma, while consistently yielding negative results in all other entities within the differential diagnosis.
Co-existence of Myelodysplastic Disorders and Plasma Cell Neoplasms: Case Series
Authors: Baban Y , jum’ah H , Ayub S
Published: October 2024

Introduction/Objective

The development of myelodysplastic syndrome (MDS) in patients with plasma cell neoplasm (PCN) receiving treatment is well reported. However, co-occurrence of both, without any chemotherapy history, is sparsely documented in the literature. We aim to highlight the possible association between both.

Methods/Case Report

Database search was done using Epic Slicer-Dicer for cases with biopsy proven co-existing MDS and PCN (from 2010-2022). The patients’ charts were reviewed to collect and analyze the clinical features.

Results (if a Case Study enter NA)

We identified 3 patients, all in their seventies on presentation:

First patient: man, presented with unexplained chronic anemia. Serum protein electrophoresis (SPEP) showed elevated levels of monoclonal IgG kappa (4.2 g/dl). Evaluation of the BM biopsy revealed MDS with low blasts (WHO-5) with IgG plasma cell myeloma (56% Kappa-restricted plasma cells). Chromosome analysis revealed normal karyotype. Molecular studies were not done.

Second patient: man, with Rheumatoid Arthritis and anemia. SPEP revealed biclonal IgG lambda (2.0 g/dl). BM biopsy indicated 5-8% lambda-restricted plasma cell proliferation. Anemia was managed with darbopoetin, but without improvement. The patient did not get chemotherapy. Follow-up BM biopsy was done, showing MDS with low blasts and ringed sideroblasts (WHO-5) alongside the PCN. FISH showed two abnormal IGH rearrangement populations.

Chromosome analysis revealed normal karyotype. Molecular studies were not done.

Third patient: woman, with pancytopenia. SPEP indicated monoclonal protein IgG lambda (1.8 g/dl). BM biopsy revealed 10% lambda-restricted plasma cell proliferation, coexisting with MDS with increased blasts grade 2 (WHO-5). Molecular studies showed: 2-FLT3 L601_K602insNFREYEYDL and ASXL1 E635fs*15. Chromosome analysis revealed normal karyotype.

No in common clinical findings found during chart reviewing the cases.

Conclusion

Further investigating the underlying pathology, bone marrow microenvironment, and molecular and cytogenetics abnormalities in a larger number of patients with co-existing MDS and PCN is important. Also, if there was an association, it is important to study the sequence of occurrence between them.
DEVELOPMENT OF SYSTEMIC MASTOCYTOSIS AFTER BONE MARROW TRANSPLANTATION FOR AN ACUTE MYELOID LEUKEMIA: DONOR DERIVEN DISEASE OR SYSTEMIC MASTOCYTOSIS WITH AN ASSOCIATED MYELOID NEOPLASM
Authors: Rusnak K R , Nozad S
Published: October 2024

Introduction/Objective

Systemic mastocytosis may have variable presentation ranging from an indolent disease to an aggressive form. Systemic mastocytosis with an associated myeloid neoplasm can occur simultaneously, or within an interval of a myeloid neoplasm and should meet the diagnostic criteria of both entities.

Methods/Case Report

Herein, we present a patient with history of acute myeloid leukemia with KMT2A(11q23) amplification who initially underwent an allogeneic hematopoietic stem cell transplantation from a matched sibling donor. One year later, the patient developed isolated central nervous system relapse, as well as evidence of molecular relapse in the bone marrow and underwent a second allogeneic transplantation, but this time, from a matched unrelated donor.

The 100 days post second transplant bone marrow biopsy was negative for involvement by acute myeloid leukemia and the chimerism study revealed evidence of total engraftment with 100% donor cells. Additionally, Fluorescence in situ hybridization analysis detected no evidence of KMT2A amplification. However, morphologic examination of the bone marrow biopsy demonstrated involvement by systemic mastocytosis with multiple dense aggregates of CD117 and tryptase positive mast cells showing spindled cell morphology. Mast cells were positive for CD25 and demonstrated negative expression of CD2 and CD30. PCR analysis of the peripheral blood did not detect evidence of KIT mutation, but serum tryptase was elevated.

Results (if a Case Study enter NA)

NA

Conclusion

This case highlights a rare instance of systemic mastocytosis in the setting of remission from an acute myeloid leukemia in a post transplantation bone marrow and represents a diagnostic challenge. While development of systemic mastocytosis in a patient with prior history of an acute myeloid leukemia suggests the possibility of systemic mastocytosis with an associated myeloid neoplasm, some other features including the complete remission and total engraftment of the post transplantation bone marrow with 100% donor cells, raise the possibility of a donor driven disease.
Myeloid Sarcoma of Conjunctiva in a patient with JAK2-positive myeloid neoplasm: two distinct myeloid neoplasms sequentially arising from a common precursor
Authors: Hanan A , Altaf S , Khan A , Zhang X , Cocker R
Published: October 2024

Introduction/Objective

Myeloid sarcoma (aka granulocytic sarcoma or chloroma), a rare type of myeloid neoplasm is characterized by the presence of myelogenous blastic cells outside of the bone marrow either before, during or after the development of leukemia. Presentation in the orbit is extremely rare, unlike other body parts. We report a case of myeloid sarcoma of conjunctiva in a patient with JAK2-positive myeloid neoplasm.

Methods/Case Report

An 84-year-old man presented with bilateral conjunctival masses which on biopsy showed diffuse involvement by blasts, immunohistochemically expressing positivity for myeloperoxidase, CD33, CD68, CD34 (partial), CD117 (partial) but were non-reactive to CD15, CD3 and PAX5. Next generation sequencing (NGS) revealed mutations in NRAS, ASXl1 and TET2 genes, consistent with the diagnosis of myeloid sarcoma (MS) of the conjunctiva. While patient’s past medical history included status post radiation and chemotherapy for prostate cancer and colonic adenocarcinoma respectively. it was also significant for a JAK 2 positive myeloproliferative neoplasm (MPN), six-years prior to current presentation. At the time he was treated with hydroxyurea for 5 years but developed neutrophilic leukocytosis and transfusion-dependent anemia. Subsequently a treatment regimen including ruxolitinib and pacritinib was initiated but without clinical and hematological improvements. NGS of the initial JAK2-positive MPN revealed ASXL1, JAK2 and TET2 mutations. Of note are the similarities and variations in the molecular signatures of patient’s initial MPN and current conjunctival MS. While the two neoplasms carried an identical TET2 mutation with highest variant allelic frequency, they are different in other mutations.

Results (if a Case Study enter NA)

NA

Conclusion

Our case illustrates an unusual manifestation of myeloid sarcoma localized to the conjunctiva. The identification of clonal relatedness on NGS with distinct mutations, adds complexity to our understanding of tumor origin. It highlights a series of events which may have contributed to this phenomenon, including consequence of therapy, clonal evolution with molecular discordance or origin as a totally independent entity. This report underscores the importance of genetic profiling in guiding prognosis and treatment strategies in such settings.