Special Considerations in Classification and Workup of Endometrial Carcinomas.

CONTEXT.­: A variety of uncommon malignant endometrial tumors can be challenging to diagnose because of overlapping morphology with more common entities. In some cases, immunohistochemical stains and/or molecular testing allow for more definitive diagnosis or prognostication. OBJECTIVE.­: To review classic morphologic features of uncommon endometrial tumors, pathologic features of these tumors and their mimics, and the evidence for use of immunohistochemistry and molecular testing in the diagnosis of these tumors. DATA SOURCES.­: University of Michigan (Ann Arbor) cases and review of pertinent literature about each entity. CONCLUSIONS.­: Although each of these uncommon endometrial tumors has morphologic mimics, key histologic features, immunohistochemical stains, and molecular testing allow for accurate classification.

KRAS mutation in primary ovarian serous borderline tumors correlates with tumor recurrence.

Oncogenic activation of the mitogen-activated protein kinase (MAPK) pathway due to KRAS or BRAF gain-of-function mutation is frequently found in ovarian serous borderline tumor (SBT) and their extraovarian implants. We investigated mutational status of KRAS and BRAF of the primary ovarian SBTs that had a high stage presentation in correlation with clinical outcome. Among 39 consecutive primary SBTs with either invasive implants (20 cases) or non-invasive implants (19 cases), KRAS and BRAF mutational analysis was informative in 34 cases. Sixteen cases (47%) harbored a KRAS mutation, while 5 cases (15%) had a BRAF V600E mutation. High-stage disease (IIIC) was seen in 31% (5/16) of patients with a KRAS mutation and 39% (7/18) of patients without a KRAS mutation (p = 0.64). KRAS mutations were present in 9/16 (56%) tumors with invasive implants/LGSC versus 7/18 (39%) tumors with non-invasive implants (p = 0.31). BRAF mutation was seen in 5 cases with non-invasive implants. Tumor recurrence was seen in 31% (5/16) of patients with a KRAS mutation, compared to 6% (1/18) of patients without a KRAS mutation (p = 0.04). A KRAS mutation predicted an adverse disease-free survival (31% survival at 160 months) compared to those with wild-type KRAS (94% at 160 months; log-rank test, p = 0.037; HR 4.47). In conclusion, KRAS mutation in primary ovarian SBTs is significantly associated with a worse disease-free survival, independent of the high tumor stage or histological subtypes of extraovarian implant. KRAS mutation testing of primary ovarian SBT may servce as a useful biomarker for tumor recurrence.

Conventional chondrosarcoma of the rib cage and sternum: clinicopathological and molecular analysis of 27 patients treated at a single institution.

Conventional chondrosarcoma of the chest wall is rare, accounting for 15% of cases. Our purpose was to document clinicopathological, imaging and outcome results from a novel set of chest wall chondrosarcomas, and to analyze for IDH mutations and novel molecular alterations. Gross and microscopic pathology, imaging and clinical charts were reviewed. Targeted next-generation sequencing was performed to identify somatic mutations and copy number alterations. The cohort consisted of 27 patients: 16 men and 11 women (mean age 51 years; range 23-76). Palpable mass was the most common presentation. Five were discovered incidentally. Among 20 tumors with complete imaging, 15 arose from a rib and 5 from the sternum. Seven rib tumors were central/intramedullary, 5 were periosteal, 2 were secondary peripheral chondrosarcomas, and one was indeterminate. Among sternal tumors, 4 were central/intramedullary and one was periosteal. Half the periosteal tumors arose from the costochondral junctional cartilage (CCJ). Periosteal chondrosarcomas were sometimes mistaken for extraskeletal masses on initial clinical or radiological examinations. Fifty-nine percent of all tumors were grade 1 and 41% were grade 2. None were dedifferentiated chondrosarcomas. Heterozygous IDH1 mutation was detected in one tumor and heterozygous RAD50 mutation in another. Local recurrence(s) happened in 41% and metastasis in 41%. Grade had strong association with local recurrence (25% grade 1 vs. 64% grade 2 [P = .0447]), metastatic recurrence (19% grade 1 vs. 73% grade 2 [P = .0058]), and survival. Although chest wall chondrosarcomas share morphologic and molecular features with other chondrosarcomas, there is a much higher incidence of periosteal chondrosarcomas. IDH mutant tumors are uncommon. Early diagnosis and margin-negative resection is treatment of choice since chondrosarcomas are chemo- and radioresistant.

Gastroblastoma of the Pylorus: A Case Report and Review of the Literature.

Gastroblastoma is an extremely rare biphasic tumor that typically occurs in the stomach in patients between the ages of 10 and 30. Only 16 cases have been reported previously. These tumors are important to diagnose and distinguish from more aggressive neoplasms; although numbers are small, prognosis appears excellent overall with complete excision, with only occasional metastasis and/or local recurrence. We report a case of gastroblastoma in a 26-year-old male arising from the pylorus and extending through the first and second portions of the duodenum. This is the first case to be reported from this specific location.

Isolated Terminal Ileitis in Children.

Isolated terminal ileitis in adults is a well described entity that rarely progresses to Crohn disease (CD), and pediatric literature on this topic is very limited. We describe the prevalence, clinical, endoscopic, histologic, and radiological features, along with long-term outcome of isolated terminal ileitis in our institution. We reviewed charts of 956 children who underwent colonoscopy from 2013 to 2017. Thirty-three children had isolated histologically-defined terminal ileitis. Seventeen children were diagnosed with CD and 16 children had idiopathic terminal ileitis. Children with CD had higher prevalence of abnormal C-reactive protein levels, severe inflammation, and radiological evidence of bowel wall thickening compared with children with idiopathic ileitis. Children with idiopathic ileitis did not develop CD over a follow-up period of 83 months. In contrast to adults, CD is common in children with isolated terminal ileitis and those with idiopathic ileitis do well over long-term.

Correlative Assessment of p53 Immunostaining Patterns and TP53 Mutation Status by Next-Generation Sequencing in High-Grade Endometrial Carcinomas.

TP53 mutations are frequently identified in the copy number-high molecular subgroup of endometrial carcinomas (ECs). P53 immunohistochemistry (IHC) is a widely used surrogate marker reflecting the mutational status of TP53 , and recent reports have shown ~95% concordance between the two methods in ECs. While these results are promising, studies evaluating the correlation between different p53 IHC staining patterns and comprehensive next-generation sequencing results are still limited. We compared the p53 IHC staining patterns, scored as wild-type, diffuse nuclear overexpression, null/complete absence, and cytoplasmic, to next-generation sequencing results reported by FoundationOneCDx in 43 high-grade ECs: 20 serous ECs, 9 mixed ECs with a serous component, 4 carcinosarcomas with a serous component, and 10 grade 3 endometrioid ECs. The concordance of p53 IHC and TP53 mutation status was 100% (43/43) overall, including 100% (33/33) concordance in tumors with a serous component and 100% (10/10) in endometrioid ECs. Among the 35 tumors with aberrant p53 expression the most commonly observed pattern was diffuse nuclear overexpression seen in 69% (24/35), followed by cytoplasmic staining in 17% (6/35), and complete absence of staining (null) in 14% (5/35) of tumors. Of the 6 tumors with cytoplasmic staining, 4 corresponded to missense mutations within the DNA binding domain (V157F in 2 tumors, and S127P and R280S, in 2 tumor each), while 2 corresponded to nonsense mutations in the tetramerization domain (p.E339*). Our results further support that p53 IHC can serve as an accurate predictor of TP53 alterations in ECs to aid the molecular-based tumor classification and the distinction between tumor histotypes, both of which play an important role in the assessment of clinical prognosis and therapeutic decision making. In addition, our data suggest, that the type and position of TP53 mutation may not directly correlate with the observed p53 IHC pattern in all tumors, and that there may be alternative mechanisms for cytoplasmic localization (other than mutations involving the nuclear localization domain), possibly due to conformational changes or posttranslational modifications of the aberrant p53 protein.

Molecular testing of soft tissue tumors.

BACKGROUND: The diagnosis of soft tissue tumors is challenging, especially when the evaluable material procured is limited. As a result, diagnostic ancillary testing is frequently needed. Moreover, there is a trend in soft tissue pathology toward increasing use of molecular results for tumor classification and prognostication. Hence, diagnosing newer tumor entities such as CIC-rearranged sarcoma explicitly requires molecular testing. Molecular testing can be accomplished by in situ hybridization, polymerase chain reaction, as well as next generation sequencing, and more recently such testing can even be accomplished leveraging an immunohistochemical proxy. CONCLUSION: This review evaluates the role of different molecular tests in characterizing soft tissue tumors belonging to various cytomorphologic categories that have been sampled by small biopsy and cytologic techniques.

Approach to Fine Needle Aspiration of Giant Cell-rich Tumors of Soft Tissue.

Giant cells may be found in a wide variety of reactive and neoplastic soft tissue lesions. Because of their distinct histomorphology, they often stand out in procured samples such as fine needle aspirates. The giant cells themselves may be benign or neoplastic. However, the presence, type, and quantity of giant cells are usually not specific and in some cases can even be misleading when making a diagnosis. The aim of this review is to guide the practicing cytopathologist in narrowing their differential diagnosis when encountering one of these challenging giant cell-rich lesions of the soft tissue.

Rare Presentation of Rosai-Dorfman Disease in Soft Tissue: Diagnostic Findings and Surgical Treatment.

Introduction and Importance. Rosai-Dorfman disease (RDD) is a rare, benign type II histiocytosis characterized by the infiltration of S100+ histiocytes and emperipolesis. The disease may present in the lymph nodes (nodal RDD), in extranodal sites, or in both nodal and extranodal sites. Among those patients who present exclusively in extranodal sites, only a minority of cases present in the soft tissue. Case Presentation. An 18-year-old female presented to orthopedic oncology clinic with a chief complaint of a mass located in her lower back. The patient underwent excision of the lumbosacral mass. Pathologic review demonstrated emperipolesis of lymphocytes and plasma cells within enlarged, eosinophilic histiocytes in a background of lymphoplasmacytic infiltration and collagenous stroma. Immunohistochemical staining demonstrated S100+ and CD163+ histiocytes, consistent with diagnosis of soft tissue RDD. Clinical Discussion. Histologically, RDD is generally characterized by emperipolesis-the presence of intact lymphocytes within the histiocyte cytoplasm-and a mixed infiltrate of S100+ histiocytes, mononuclear cells, plasma cells, and lymphocytes. Although soft tissue RDD may histologically resemble nodal RDD, soft tissue RDD also demonstrates some notable histologic differences including the lack of nodal architecture, the presence of increased fibrosis and collagen deposition, and generally fewer RDD cells. Conclusion. This case presentation demonstrates one few reports of isolated soft tissue RDD within the lumbosacral region without associated lymphadenopathy or skin changes and highlights the heterogeneity that still exists in the treatment paradigm of extranodal RDD.

Minimally Invasive Ovarian-Preserving Approach for the Management of a Sclerosing Stromal Tumor in an Adolescent: A Case Report.

BACKGROUND: Sclerosing stromal tumors (SSTs) are rare benign ovarian tumors that occur in adolescents and young adults. They are often treated with unilateral salpingo-oopherectomy due to concern for malignancy. CASE: A 13-year-old postpubertal female presented with sharp, constant abdominal pain with physical exam concerning for a lower abdominal mass. An ultrasound revealed a 9.7-cm solid, heterogenous left ovarian mass. The abdomen and pelvis CT confirmed the findings and showed a predominantly cystic mass arising from the left adnexa. During surgery, a smooth and distinct mass arising from the left ovary was encountered without abnormal findings in surrounding structures. A cystectomy was performed, and intraoperative findings showed no evidence of malignancy. Based on the lab, imaging, and surgical findings, staging and salpingo-oopherectomy were not pursued. SUMMARY AND CONCLUSION: Given the benign nature of SSTs, it is important to entertain the diagnosis in adolescents presenting with clinically congruent ovarian masses. The minimally invasive approach allows for sparing of the ovary in the adolescent population.

Cellular angiofibroma arising in the anorectal region: clinicopathologic and immunohistochemical analysis of five cases.

Cellular angiofibroma (CA) is a rare, benign mesenchymal tumor with a predilection to the distal female and male genital tract. Extragenital examples of CA, including anorectal CAs, are exceedingly rare and documented mainly as single case reports. Herein, we analyze the clinicopathological and immunohistochemical features of 5 anorectal CAs. There were 4 males and one female ranging in age from 45 to 70 (median, 58) years at the time of surgery. Tumors arose in the superficial tissues of the anorectal (n = 3) and perianal (n = 2) regions. The tumors were well circumscribed ranging from 2 to 6.7 (median, 5.4) cm. All demonstrated a low to moderately cellular proliferation of cytologically bland spindled cells within a variably dense collagenous and focally myxocollagenous stroma and small- to medium-sized vessels featuring perivascular collagen deposition. Two cases showed degenerative and/or inflammatory changes. All 5 tumors strongly expressed CD34 and androgen receptor proteins, more variably expressed estrogen (n = 5) and progesterone (n = 4) receptor proteins and desmin (n = 3), and focally expressed alpha-smooth muscle actin (n = 3), GATA-3 (n = 2), and p16 (n = 1). Retinoblastoma protein expression was reduced (n = 4) (compared with expression in endothelial cells) or completely lost (n = 1). All patients were treated with simple surgical excision, and the 2 study members with follow-up data showed no evidence of local recurrence over a postoperative follow-up interval of 23 and 73 months. In comparison with conventional genital tract CA, our 5 anorectal CAs occurred mostly in males, were generally less cellular, and appear to follow a similar uneventful clinical course.

Minimal uterine serous carcinoma and endometrial polyp: a close clinicopathological relationship.

Frequently involving an endometrial polyp, minimal uterine serous carcinoma (MUSC) represents the earliest recognizable forms of endometrial serous carcinoma. The aim of this study was to provide a comprehensive morphological and clinical outcome assessment of MUSC involving endometrial polyp. A total of 77 fully staged MUSCs involving endometrial polyp were identified, including 53 MUSCs confined to polyp and 24 nonpolyp confined tumors. Extrauterine disease was found in 17% (9/53) of polyp-confined MUSCs compared to 41.7% (10/24) of nonpolyp confined tumors (p = 0.02). Lymphovascular invasion was observed in 3.8% (2/53) of polyp-confined cases compared to 25% (6/24) of nonpolyp confined cases (p = 0.047). Lymph node metastasis was observed in 11.3% (6/53) of polyp-confined cases, compared to 29.2% (7/24) of nonpolyp confined cases (p = 0.058). Positive pelvic washing cytology was seen in 18.9% (10/53) of polyp-confined versus 37.5% (9/24) of nonpolyp confined tumors (p = 0.078). Overall, 58 of 77 (75.3%) patients had low tumor stage (57 stage I cases and 1 stage II case) and only two patients (3.5%) had a recurrence. In contrast, 19 of 77 (24.7%) patients had advanced stage (stage III or IV) disease and 17 (89.5%) patients had recurrence (p < 0.0001). Only one of 57 low-stage patient (1.7%) versus 11 of 19 high-stage patients (57.8%) died of the tumor (p < 0.0001). Five of 53 (9.4%) patients with polyp-confined MUSC and 7 of 24 (29.2%) patients with nonpolyp confined MUSC died of the disease (p = 0.03). In conclusion, while a small percentage of MUSCs exist without the involvement of an endometrial polyp, a close topographic relationship between MUSC and the endometrial polyp is confirmed in this largest series, supporting the theory that most if not all MUSCs arise in an EMP. Patients with MUSC without extrauterine spread have an excellent prognosis. Compared to patients with MUSC confined to an endometrial polyp, patients with MUSC extending to the background endometrium have a significantly higher risk for high-stage disease at presentation.

Reproducibility of scoring criteria for HER2 immunohistochemistry in endometrial serous carcinoma: a multi-institutional interobserver agreement study.

Targeted anti-human epidermal growth factor receptor 2 (HER2) therapy has recently been proven to improve progression-free and overall survival of patients with advanced stage or recurrent endometrial serous carcinoma. To date, no specific pathology HER2 testing or scoring guidelines exist for endometrial cancer. However, based on evidence from the recent successful clinical trial and comprehensive pre-trial pathologic studies, a new set of HER2 scoring criteria have been proposed for endometrial serous carcinoma-distinct from the existing breast and gastric cancer-specific criteria. We present the first study assessing interobserver agreement of HER2 scores using the proposed serous endometrial cancer-specific scoring system. A digitally scanned set of 40 HER2-immunostained slides of endometrial serous carcinoma were sent to seven gynecologic pathologists, who independently assigned HER2 scores for each slide following a brief tutorial. Follow-up fluorescent in situ hybridization (FISH) for HER2 gene amplification was performed on cases with interobserver disagreement when a 2+ HER2 score was assigned by at least one observer. Complete agreement of HER2 scores among all 7 observers was achieved on 15 cases, and all but one case had an agreement by at least 4 observers. The overall agreement was 72.3% (kappa 0.60), 77.5% (kappa 0.65), and 83.3% (kappa 0.65), using four (0 to 3+ ), three (0/1+ , 2+ , 3+ ), or two (0/1+ , 2/3+ ) HER2 scoring categories, respectively. Based on the combination of HER2 immunostaining scores and FISH, the interobserver disagreement may have potentially resulted in a clinically significant difference in HER2 status only in three tumors. We conclude, that the proposed serous endometrial cancer-specific HER2 scoring criteria are reproducible among gynecologic pathologists with moderate to substantial interobserver agreement rates comparable to those of previously reported in breast and gastric carcinomas. Our findings significantly strengthen the foundation for establishing endometrial cancer-specific HER2 scoring guidelines in the future.

Does Specimen Type Have an Impact on HER2 Status in Endometrial Serous Carcinoma? Discordant HER2 Status of Paired Endometrial Biopsy and Hysterectomy Specimens in the Presence of Frequent Intratumoral Heterogeneity.

A recent clinical trial showed prolonged progression-free survival in human epidermal growth factor receptor 2 (HER2)-positive advanced stage and recurrent endometrial serous carcinomas when trastuzumab was added to traditional chemotherapy. Approximately one third of these tumors are HER2-positive and have been described to show unique characteristics of HER2 protein expression and gene amplification, including significant intratumoral heterogeneity, in recent studies. However, currently, there are no standard protocols for the selection of optimal specimen type or algorithm for HER2 testing in endometrial serous carcinomas. The current study aimed to evaluate the concordance of HER2 status between endometrial biopsy/curettage and subsequent hysterectomy specimens in endometrial serous carcinoma. A total of 57 patients with endometrial serous carcinoma with available HER2 status were identified during the study period, 14 of which (14/57, 25%) were HER2-positive by immunohistochemistry and/or fluorescent in situ hybridization (FISH). The final study cohort consisted of 40 paired endometrial biopsies/curettings and hysterectomies to include all 14 HER2-positive tumors and 26 selected HER2-negative tumors to represent an equal distribution of HER2 immunohistochemical scores. HER2 FISH was performed on all tumors with an immunohistochemical score of 2+. HER2 immunohistochemical scores, heterogeneity of HER2 expression, FISH results, and the overall HER2 status were compared between the 2 specimen types. HER2 status was successfully assigned in both specimen types in 37 cases, as three specimens showed inadequate FISH signals. Concordant HER2 status was observed in 84% of cases (31/37), with identical HER2 immunohistochemical scores in 65% (26/40) of tumors. Among the 6 tumors with a discordant HER2 status, 2 were HER2 negative in the biopsy and positive in the hysterectomy, and 4 were HER2-positive in the biopsy and negative in the hysterectomy. The false-negative rate would be 15.4% and 26.7% if only the biopsy or only the hysterectomy would be the basis for the result, respectively. Intratumoral heterogeneity of HER2 protein expression was present in 22 tumors (55%), including all cases with a discordant HER2 status. The concordance rate of HER2 status between paired endometrial biopsies/curettings and hysterectomies of endometrial serous carcinoma is lower than the reported rates of breast cancer, and comparable to those of gastric carcinomas. Frequent heterogeneity of HER2 protein expression combined with the possibility of a spatially more heterogenous sampling of endometrial cavity in biopsies and curettings, and the potential differences in specimen handling/fixation between the 2 specimen types may explain our findings. HER2 testing of multiple specimens may help identify a greater proportion of patients eligible for targeted trastuzumab therapy and should be taken into account in future efforts of developing endometrial cancer-specific HER2 testing algorithm.

Lack of genetic homozygosity in prepubertal teratomas: divergent pathogenesis distinct from that of teratomas in adolescents.

In adults, both immature and mature ovarian teratomas show frequent genetic homozygosity consistent with tumorigenesis involving germ cells after meiosis I. Investigation into genetic zygosity of various teratomas in children has been limited. Thirteen sacrococcygeal, 12 ovarian, and 3 testicular teratomas in children 18 years or younger were retrieved from our departmental archives and histologically reviewed. Tumor and paired normal tissues were microdissected and subjected to short tandem repeat (STR) genotyping. DNA genotyping was informative in 12 sacrococcygeal teratomas, 8 ovarian teratomas, and 3 testicular teratomas. Sacrococcygeal teratomas included seven mature teratomas, four immature teratomas, and one mixed germ cell tumor with patient age ranging from 0 days to 3 years. All but two patients were female. Ovarian teratomas included five mature and three immature teratomas with patient age ranging from 2 to 18 years. Testicular teratomas included two mature teratomas and one immature teratoma with patient age ranging from 3 months to 3 years. All sacrococcygeal, testicular, and ovarian teratomas in patients younger than 4 years showed no evidence of genetic homozygosity by STR genotyping. In contrast, all four ovarian teratomas in patients older than 9 years showed either partial or complete homozygosity. In conclusion, unlike adolescent and adult ovarian teratomas, prepubertal sacrococcygeal and gonadal teratomas lack genetic homozygosity, supporting the hypothesis that teratomas before puberty develop at an early stage of germ cell development different from that of teratomas in adolescents and adults.

Synovial Myxoma: Found in Canines, Rabbits, and Now Humans Too?: A Case Report.

CASE: A 63 year-old woman presented with a multiple-year history of right knee pain and effusions and pain refractory to numerous knee aspirations and an arthroscopic synovectomy. The patient underwent a 2-incision synovectomy and intralesional resection. A pathologic review of the specimens revealed an infiltrative tumor of basophilic, cluster of differentiation 68-positive synovial cells embedded within a myxoid stroma with low proliferative activity, most consistent with a synovial myxoma. CONCLUSIONS: This case report of a synovial myxoma-a benign, slow growing but locally aggressive mass that is most commonly found in canines-indicates that the lesion may occasionally occur in humans.

HER2 testing of gynecologic carcinosarcomas: tumor stratification for potential targeted therapy.

A recent phase II clinical trial showed increased progression-free survival in patients with HER2-positive endometrial serous carcinoma receiving trastuzumab in addition to carboplatin-paclitaxel chemotherapy. Similar to endometrial serous carcinomas, carcinosarcomas of the female genital tract have a dismal prognosis and could potentially benefit from new targeted therapeutic approaches. We aimed to systematically evaluate the characteristics of HER2 expression/amplification in gynecologic carcinosarcomas using standardized staining methods and scoring criteria. Tumors from 80 patients (65 uterine, 15 tubo-ovarian) were included, containing a serous (60%), endometrioid (10%), clear cell (3%), undifferentiated (3%), neuroendocrine (1%), or mixed (24%) carcinoma, and either a homologous (46%), or a heterologous (54%) sarcoma component. HER2 scores were assigned to both components per the 2007 and 2013 ASCO/CAP breast scoring criteria. A total of 13 cases (12 uterine, 1 ovarian, 16%) were HER2 positive (either by immunohistochemistry or FISH) using the 2013 criteria, while only 10 cases (9 uterine, 1 ovarian, 13%) were HER2 positive per the 2007 criteria. Nine cases showed a change in their HER2 immunohistochemical score between the two scoring systems, including two cases with a change in the overall HER2 status from negative (2007) to positive (2013). Heterogeneity of HER2 protein expression was observed in 38% of HER2-positive tumors, and a lateral/basolateral membranous staining pattern was common. The sarcoma component showed 2+, equivocal HER2 expression in five cases, one of which also demonstrated HER2 amplification by FISH. All HER2-positive carcinosarcomas had either a serous or a mixed carcinoma component, and all but one HER2-positive tumors were of uterine primaries. Our study demonstrates that gynecologic carcinosarcomas share similarities in their HER2 expression/amplification profiles to endometrial serous carcinomas, which should be taken into account when assessing their HER2 status to ensure appropriate patient selection for potential targeted HER2-based therapies in the future.

Myocarditis with checkpoint inhibitor immunotherapy: case report of late gadolinium enhancement on cardiac magnetic resonance with pathology correlate.

BACKGROUND: Nivolumab is a human IgG4 anti-programmed cell death protein-1 (PD-1) monoclonal antibody that works by augmenting the immune response against tumour cells. It has the potential of causing multiple autoimmune-related events, including cardiac. However, the real incidence and diagnosis of cardiac complications remains unclear. CASE SUMMARY: A 47-year-old woman with a history of carotid artery dissection and metastatic melanoma presented with acute heart failure. One year prior to presentation, she had received one cycle only of checkpoint inhibitor therapy with both ipilimumab and nivolumab, and nivolumab only was restarted 4 months prior to presentation. On admission, she was hypotensive, tachycardic due to atrial tachycardia and with pulmonary oedema. An echocardiogram revealed a left ventricular ejection fraction of 26%. Cardiovascular magnetic resonance (CMR) demonstrated a non-ischaemic pattern of late gadolinium enhancement (LGE), most consistent with myocarditis. The diagnosis of immunotherapy-mediated cardiac toxicity was highly considered and immunosuppressive therapy was initiated. However, she went into refractory cardiogenic shock and did not survive. An autopsy performed with samples from areas of myocardium with and without LGE on the CMR, found correlation. DISCUSSION: According to the literature, cardiac complications develop in less than 1% of patients treated with checkpoint inhibitors, with a 0.06% incidence reported in nivolumab specifically. However, it may be higher, given the lack of cardiac monitoring during treatment. We present the first case demonstrating direct histological correlation of T-lymphocytic infiltration with areas of LGE on CMR. Future investigation using CMR for early detection of inflammation and left ventricular dysfunction may help to diagnosis disease earlier.

Minimal microsatellite shift in microsatellite instability high endometrial cancer: a significant pitfall in diagnostic interpretation.

Mismatch-repair deficiency testing plays a critical role in the identification of proband in Lynch Syndrome families and triaging patients with high stage or recurrent solid malignancies for check point inhibitor (Pembrolizumab) immunotherapy. We compared microsatellite shift patterns of microsatellite instability PCR analysis at 5 NCI recommended loci between microsatellite instability high endometrial carcinoma (n = 50) and microsatellite instability high colorectal cancer (n = 19). The endometrial cancer cohort included 45 endometrioid, 1 serous, and 4 clear cell carcinomas. Overall, 52% (26/50) of microsatellite instability high endometrial cancers showed minimal microsatellite shift (defined as a one to three nucleotide repeat shift at an involved locus) observed at least at one locus. Among microsatellite instability high endometrial cancers with minimal microsatellite shift, the frequencies at each involved locus were D2S123 (21/21, 100%), D17S250 (10/11, 89%), D5S346 (11/12, 92%), BAT25 (9/12, 80%), and BAT26 (8/21, 45%). Noticeably, 11 of the 26 cases (42%) showed only minimal shift. Among microsatellite instability high endometrial cancers with minimal microsatellite shift, 65% (17/26) had combined MLH1 and PMS2 loss, 8% (2/26) had combined MSH2 and MSH6 loss, 13% (3/26) had MSH6 loss and 15% (4/26) had loss of PMS2 by immunohistochemistry. In contrast, only 16% (3/19) had minimal microsatellite shift seen in colorectal cancer cohort with corresponding loss of MLH1/PMS2, MSH2/MSH6, or MSH6. Overall, 15% (7/50) of microsatellite instability high endometrial carcinomas showed isolated loss of MSH6 in contrast to 7% (1/15) seen in microsatellite instability high colorectal carcinomas. In conclusion, microsatellite instability high endometrial carcinomas have a significantly higher frequency of minimal microsatellite shift that coincides with a high percentage of combined loss of MLH1/PMS2. Microsatellite instability high endometrial cancers also have more frequent loss of MSH-6. Diagnostically, recognition of minimal microsatellite shift is crucial for accurate interpretation of microsatellite instability PCR data of endometrial carcinoma.