Extensive Lymphovascular Invasion Research Articles

Presence and extent of lymphovascular invasion in surgical stage I squamous cell carcinoma of the cervix: a comprehensive, international, multicentre, retrospective clinicopathological study

The aim of this study was to determine whether the presence and extent of lymphovascular invasion (LVI) is prognostic in surgical stage I cervical squamous cell carcinoma (SCC). All available tumour slides and/or paraffin blocks from 426 patients with stage I cervical SCC treated surgically with curative intent were collected from 18 institutions and retrospectively analysed. Presence and extent of LVI (focal: <5 spaces, extensive: ≥5 spaces) were assessed on scanning magnification in large haematoxylin-eosin slide sets in 366 cases. Progression-free survival (PFS) was calculated as the time from surgery to first progression or death or last follow-up, whichever occurred first. Overall survival (OS) was defined as the time from surgery to death or last follow-up. Clinicopathologic and statistical analyses were performed on 97 patients with the International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IA and 329 patients with stage IB SCC of the cervix. LVI, both focal and extensive, was more frequent in stage IB than in stage IA (p < 0.001). Patients with stage IB carcinomas with extensive LVI had worse PFS (HR: 2.86) [95% confidence iterval (CI): 1.49, 5.49] (p value: 0.005) and OS (HR: 2.88) (95% CI: 1.38, 6.02) (p value: 0.012) than those with focal or no LVI. In stage IA, in contrast, the presence and extent of LVI did not associate with PFS (p value: 0.926) or OS. Extensive LVI was not statistically correlated with PFS and OS in substages IA1, IA2 or IB2. PFS (HR: 3.7) (95% CI: 1.61, 8.46) (p value < 0.001) and OS (HR: 4.18) (95% CI: 1.58, 11.04) (p value: 0.002) in stage IB1 and PFS (HR: 7.78) (95% CI: 0.87, 69.82) (p value: 0.039) in stage IB3 were diminished in the presence of extensive LVI. In conclusion, in patients with FIGO stage I cervical SCC, the presence and extent of LVI has prognostic significance in stage IB carcinoma, and quantifying LVI is recommended.

Urothelial Carcinoma with Trophoblastic Differentiation-A Report with Review.

Urothelial carcinoma with trophoblastic differentiation is a rare type of urothelial carcinoma that poses a diagnostic challenge. A 50-year-old man presented with hematuria for 4 months duration. Ultrasonography examination showed polypoidal lesions along the right lateral wall and near the right vesicoureteric junction of the urinary bladder. The transurethral resection of the bladder tumor (TURBT) specimen showed marked necrosis and urothelial tumor cells arranged in nests, sheets, and papillae, admixed with multinucleated large cells. Deep muscle and extensive lymphovascular invasion were noted. The tumor cells were diffuse immunopositive for GATA3 and focal positive for p63 and SALL4. Large multinucleated tumor cells were immunopositive for β-hCG, GATA3, inhibin-α, and PLAP, focally positive for SALL4 while negative for p63. The patient denied further treatment and succumbed to the disease after 8 months of the TURBT procedure. We report a rare invasive urothelial carcinoma with trophoblastic differentiation and discuss the differential diagnosis and literature review.

The Presence of Extensive Lymphovascular Invasion is Associated With Higher Risks of Local-Regional Recurrence Compared With Usual Lymphovascular Invasion in Curatively Treated Breast Cancer Patients

Purpose/objectives: Several datasets have demonstrated a correlation between lymph-vascular invasion (LVI) and local-regional recurrence (LRR). Whether the observation of "extensive LVI" is a further and incremental determinant of LRR risk is unknown. We describe clinical outcomes in women with invasive breast cancer stratified by: 1) absence of LVI (neg), 2) LVI focal or suspicious (FS-LVI), 3) usual (non-extensive) LVI (LVI) and 4) extensive LVI (E-LVI).Materials/Methods: Between 12/2009 and 8/2021, 8837 patients with early-stage breast cancer were treated with curative intent and were evaluable. Clinical-pathological details were abstracted by retrospective review. The description of LVI was abstracted from pathology reports. Recurrence and survival outcomes were compared based on the extent of LVI. A matched propensity score analysis compared outcomes between patients with LVI vs. E-LVI.Results: Of the 8837 patients studied, 5584 were neg, 461 had FS-LVI, 2315 had LVI, and 477 had E-LVI. Patient with E-LVI had an adverse risk profile compared to the other groups.The 5- and 10-year local regional recurrence (LRR) cumulative incidence estimates in patients with E-LVI were 9.6% (95% CI: 7.1-13) and 13% (95% CI: 10-17), which were significantly higher than observed in the usual LVI group (6.8% [5.7-7.9] and 10% [8.8-12], respectively). A statistically significant difference in LRR was demonstrated on univariable (HR 1.4, 95% CI [1.03-1.89], p-value 0.029) and multivariable regression analysis (HR 1.62, 95% CI [1.15-2.27], p-value 0.005) when compared to non-extensive LVI.In an alternative approach, we performed a 2:1 propensity-matched analysis comparing LVI to E-LVI patients. The hazard ratio for LRR (HR 1.47 (CI 1.02-2.14, p=0.041) was suggestive of a higher risk with E-LVI.Conclusions: Our work suggests that patients with E-LVI are at a higher risk for LRR than those with usual LVI. For patients who are borderline candidates for regional nodal irradiation or PMRT, the finding of E-LVI might be decisive in favor of intensified treatment.

Primary Endometrial Carcinoma with Signet Ring Cells: A Rare and Unusual Entity

Abstract Introduction/Objective The presence of signet ring cells in an endometrial tumor is suggestive of metastasis, as primary tumors with this morphology are extremely rare. As a result, primary tumors are a diagnosis of exclusion, defined by the presence of signet-ring cells usually associated with mucinous endometrioid carcinoma without clinical or radiographic evidence of metastases from breast, stomach, or colon. Methods/Case Report A 64-year-old woman presented with vaginal bleeding. Ultrasound showed a large, heterogenous uterine mass that was diagnosed as poorly differentiated carcinoma on biopsy. Serum CEA was elevated, and CA-125 was normal. Hysterectomy with salpingo-oophorectomy showed a minor endometrial component of grade 3 endometrioid carcinoma and a predominant component of poorly differentiated carcinoma with signet ring cells. The myoinvasive component consisted of the signet ring cells with pools of acellular mucin. Extensive lymphovascular invasion was noted. Cervix, adnexa, and lymph nodes were free of disease. The signet ring cells were positive for CK7, CK20, and CDX2, and negative for ER and Pax-8. The endometrioid component was positive for ER, Pax-8, and CK7, and negative for CK20 and CDX2. E-cadherin staining was lost in the myoinvasive component of the tumor. Loss of MLH1 and PMS2 nuclear expression was seen, and MLH1 promoter methylation was detected in both components of the tumor. Subsequent colonoscopy and imaging did not reveal any other disease sites. Based on histology, pattern of uterine involvement, and lack of extrauterine disease, a diagnosis of primary poorly-differentiated endometrial adenocarcinoma with signet ring cell features was made. The patient was treated with adjuvant chemotherapy and is currently being followed. Results (if a Case Study enter NA) NA Conclusion We present a rare case of primary signet ring carcinoma of the uterus, a challenging diagnosis made after extensive work-up to rule out metastases. Of the previous 9 reported cases, only one was similar to our tumor with distinct endometrioid and signet ring components. Although these primary endometrial tumors are unified by the presence of signet ring cells, there is considerable immunohistochemical heterogeneity. Some reports suggest the signet ring cells have a Mullerian phenotype, while others, including our case, suggest a gastrointestinal phenotype. In presenting this case, we hope to contribute to this entity’s characterization and bring further awareness that the presence of signet ring cells does not exclude a uterine primary.

The Presence of Extensive Lymphovascular Invasion (LVI) is Associated with Higher Risk of Recurrence in Curatively Treated Breast Cancer Patients

Lymphovascular invasion (LVI) is a pathological feature seen in breast cancer that may be an important step in cancer metastasis. Multiple datasets have demonstrated a correlation between LVI and local-regional recurrence (LRR). Whether the extent of LVI is an incremental determinant of LRR risk is unknown. We describe clinical outcomes in women with invasive breast cancer stratified by: 1) absence of LVI (neg), 2) LVI focal or suspicious (FS-LVI), 3) usual (non-extensive) LVI (LVI) and 4) extensive LVI (E-LVI). Between December 2009 and August 2021, there were 8,837 patients with early-stage breast cancer (T1-2 and N0-2a) were treated with curative intent and were evaluable. Clinical-pathological details were abstracted by retrospective review. The description of LVI was abstracted from pathology reports. Recurrence and survival outcomes were compared based on the extent of LVI. Of the 8837 patients studied, 5584 were neg, 461 had FS-LVI, 2315 had LVI, and 477 had E-LVI. The E-LVI cohort had baseline characteristics suggestive of higher risk such as younger median age, higher proportion of grade 3, more nodal positivity, more mastectomy (67% vs 48%), and higher use of chemotherapy compared to LVI. The cumulative incidence of LRR and DM was highest in the E-LVI group. Using LVI as the reference, the presence of E-LVI, age, tumor size, ER status, grade, mastectomy, and close/positive margins were independent variables for LRR on Cox multivariable regression (Table 1). To assess the effect with an alternate statistical method, we created propensity matched cohorts (matched for age, size, receptors, grade, surgery type, margins and chemotherapy/RT use); a statistical difference in OS was noted between groups with LVI vs E-LVI (HR 1.44 (CI 1.06-1.96, p = 0.018), but not in LRR (HR 1.31 (CI 0.87-1.97, p = 0.2) or DM (HR 1.16 (CI 0.88-1.53, p = 0.3). Our work suggests that patients with E-LVI are at a higher risk for LRR compared to patients with usual LVI, despite maximal standard of care treatment. This is important because E-LVI can be determined from breast specimens, and may help define indications for RNI/PMRT when nodal information is not available.

Endometrial serous carcinoma with extensive squamous differentiation mimicking primary endometrial squamous cell carcinoma: Clinicopathological and molecular analysis of a case with literature review

In the histological assessment of endometrial carcinoma, the presence of squamous differentiation is generally considered inconsistent with a serous histotype. Herein, we report a case of endometrial serous carcinoma with extensive squamous differentiation mimicking squamous cell carcinoma, with literature review.A 67-years-old-woman underwent hysterectomy, bilateral salpingo-oophorectomy, sentinel lymph node resection, omental and peritoneal biopsies, due to a 8cm endometrial mass. Histologically, the tumor showed squamous carcinoma features with positivity for squamous cell markers (p40, p63, cytokeratin-5/6, cytokeratin-34βE12) and negativity for Müllerian markers (PAX8, estrogen receptor, progesterone receptor). No immunohistochemical/molecular alterations typical ofendometrioid carcinoma (i.e., PTEN loss, mismatch repair deficiency, nuclear β-catenin expression,POLEmutation) were observed. P53 showed aberrant pattern and p16 showed basal positivity. The tumor infiltrated the myometrium full-thickness with extensive lymphovascular space invasion. Surprisingly, the sentinel lymph node metastasis showed overt serous carcinoma features. Additional sampling of the endometrial mass revealed a minor. In conclusion, serous carcinoma may show diffuse squamous differentiation. In the case of suspected primary endometrial squamous cell carcinoma, an extensive sampling is warranted.

S2242 Taking Caution at Road’s End: Incidental Finding of Appendiceal Goblet Cell Tumor on Colonoscopy

Introduction: Appendiceal cancer is uncommon and rarely diagnosed on colonoscopy. We present a case of incidentally discovered goblet cell adenocarcinoma of the appendix and its subsequent management. Case Description/Methods: 81-year-old male presented to GI clinic for persistent epigastric pain and reflux. Symptoms had been worsening for several years and were refractory to medical therapy. He denied unintentional weight loss, nausea, melena, or a family history of colorectal cancer. He had 9 colonoscopies between 1999 and 2016 for rectal bleeding due to hemorrhoids and diverticulosis, with a single 2mm TA removed in 2016 and 5-year follow-up advised. Repeat EGD and colonoscopy were scheduled, during which the appendiceal orifice (AO) had a “heaped-up” appearance and was biopsied with cold forceps. Histology revealed goblet cell adenocarcinoma (GCA.) CT of the abdomen and pelvis showed a mildly enlarged appendix, no LAD, and no evidence of metastasis. The patient underwent a laparoscopic right hemicolectomy. Pathology clarified that carcinoma extended from appendix to mesoappendix and cecum with extensive lymphovascular and perineural invasion. Resected margins and 19 resected lymph nodes were negative for malignancy and ultimately staged pT4aN0 (IIB). Colonoscopy 1 year later revealed healthy ileocolonic anastomosis without signs of polyps or other masses (Figure). Discussion: Appendiceal cancer is categorized into 2 types: epithelial and neuroendocrine. GCA histologically has features of both. Incidence is rare, reportedly 0.05/100,000/year. It is usually an incidental finding following appendectomy for acute appendicitis and uncommonly found via colonoscopy. The AO is a key endoscopic landmark that should be identified on all colonoscopies to ensure completeness. Endoscopists should have a low threshold to biopsy abnormal-appearing tissue surrounding the AO. While no established risk factors for GCA, cases report an association with schistosomiasis and caucasian proclivity. Clinical diagnosis is difficult as presentations range from abdominal pain to appendicitis. Swift work-up and therapy are essential as appendiceal GCA can aggressively spread nodally or intraperitoneally. While evidence-based guidelines are not available, current management is similar to that of colon cancer with hemicolectomy for localized disease, adjuvant chemotherapy based on the surgical pathology, and post-treatment surveillance. We hope this case highlights the rarity of appendiceal GCA and the need for evidence-based guidelines.Figure 1.: A) Appendiceal orifice with “heaped-up” appearance B) Healthy ileocolonic anastamosis C) Clusters of goblet-like mucinous cells with invasion into and through the lamina propria (10X) D) High power view (20X) of cohesive groups of goblet-like mucinous cells. Nuclear atypia is mild and mitotic figures are inconspicuous E) Cytokeratin AE1/AE3 highlights the colonic mucosa and the infiltrative goblet-cell tumor (10X) F) Chromogranin highlights scattered endocrine cells (10X).

Partial breast irradiation: An updated consensus statement from the American brachytherapy society

PurposeIn recent years, results with mature follow-up have been reported for several Phase III trials randomizing women to receive whole breast irradiation (WBI) versus varying modalities of partial breast irradiation (PBI). It is important to recognize that these methods vary in terms of volume of breast tissue treated, dose per fraction, and duration of therapy. As such, clinical and technical guidelines may vary among the various PBI techniques. MethodsMembers of the American Brachytherapy Society with expertise in PBI performed an extensive literature review focusing on the highest quality data available for the numerous PBI options offered in the modern era. Data were evaluated for strength of evidence and published outcomes were assessed. ResultsThe majority of women enrolled on randomized trials of WBI versus PBI have been age >45 years with tumor size <3 cm, negative margins, and negative lymph nodes. The panel also concluded that PBI can be offered to selected women with estrogen receptor negative and/or Her2 amplified breast cancer, as well as ductal carcinoma in situ, and should generally be avoided in women with extensive lymphovascular space invasion. ConclusionsThis updated guideline summarizes published clinical trials of PBI methods. The panel also highlights the role of PBI for women facing special circumstances, such as history of cosmetic breast augmentation or prior breast irradiation, and discusses promising novel modalities that are currently under study, such as ultrashort and preoperative PBI. Updated consensus guidelines are also provided to inform patient selection for PBI and to characterize the strength of evidence to support varying PBI modalities.

Endometrial Adenocarcinoma with Pattern of Invasion Resembling Adenoma Malignum

Endometrial adenocarcinoma with a glandular invasion pattern resembling adenoma malignum of cervix is a deceptively benign and highly differentiated form of endometrioid adenocarcinoma which can be resistant to radiation therapy and exhibit a deep invasion pattern. We report a 57-year-old female who was a biopsy-proven case of FIGO grade 2 endometrial adenocarcinoma with 4 cm cervical involvement, who underwent whole pelvic radiation therapy followed by hysterectomy. Her hysterectomy sections revealed conventional endometrioid adenocarcinoma with a deceptively bland pattern of well-spaced, branching glands with myometrial invasion up to 90%. Extensive lymphovascular space invasion was identified and cervical stroma was involved. Immunohistochemistry was consistent with an endometrial origin. The final diagnosis was endometrial adenocarcinoma with adenoma malignum pattern of invasion. It is not clear whether the gland morphology was due to radiation treatment however, the widespread and extensive invasion makes it imperative to recognize that these patients need to be vigilantly followed up. It is important to recognize this entity because these deeply invasive and benign appearing glands can be resistant to the conventional approach of radiation treatment and highlights the fact that the patient needs to be cautiously staged and accordingly treated. Keywords: Endometrial adenocarcinoma; Minimal deviation; Adenoma malignum; Uterus; Pelvic radiotherapy

Recurrence and Survival Rates for 1400 Early Breast Tumors Treated with Intraoperative Radiation Therapy (IORT).

IntroductionIntraoperative radiotherapy (IORT) permits accurate delivery of radiation therapy directly to the tumor bed. We report local, regional, and distant recurrence data along with overall and breast cancer-specific survival for 1400 tumors treated with x-ray IORT.MethodsA total of 1367 patients with 1400 distinct tumors were enrolled in a registry trial. All received breast conservation surgery and low-energy 50 kV x-ray IORT. To be eligible for excision plus IORT as the only local treatment, histopathology had to confirm tumor size ≤30 mm, margins ≥2 mm, negative lymph nodes, and no extensive lymphovascular invasion. Patients who failed any parameters were referred for additional surgery and/or whole breast radiation therapy (WBRT).ResultsThere were 64 ipsilateral local recurrences, 60 were in the IORT only group, 7 axillary recurrences, and 7 distant recurrences. Forty-one local recurrences were within the same quadrant as the index cancer. Twenty-three were in different quadrants. With 62 months of median follow-up, the 5-year Kaplan–Meier probability of any event for all 1400 tumors was 5.27%. For 1175 patients who received IORT only, it was 5.98%. For favorable subtypes, it ranged from 2.41 to 4.31%. Multivariate analysis revealed that biologic subtype luminal A and the addition of WBRT significantly reduced the risk of local recurrence.ConclusionsThe local, regional, and distant recurrence rates observed were comparable to those reported in the literature for IORT but higher than those reported for standard forms of WBRT, hypofractionated treatment, or APBI. IORT benefits include convenience, decreased exposure to medical environments, and low complication rates.

Does Lymph Node Assessment Change the Prognostic Significance of Extensive LVSI and p53 Mutation in Endometrial Cancer?

While high-intermediate risk (HIR) early stage endometrial cancer patients achieve excellent outcomes with adjuvant vaginal brachytherapy (VBT), the recent PORTEC2 update suggested factors such as extensive lymphovascular space invasion (LVSI) and abnormal p53 expression predict for poorer outcomes and that these patients should be treated with external beam radiation therapy (EBRT), rather than VBT. Our study aims to determine if patients with these risk factors who undergo a lymph node assessment prior to receiving adjuvant therapy show similarly high recurrence rates.We identified 97 patients with FIGO 2009 stage IA grade 3, stage IB grade 1-2, and stage IIIC (with positive LN only but no other stage II or III factors) endometrial cancer who underwent surgical resection including lymph node assessment from 2009 to 2018 at our institution. We reviewed the LVSI status and extent, and the p53 status in these patients. Local failure (LF), regional failure (RF) distant metastasis (DM), and overall survival (OS) were compared using Kaplan-Meier.Median follow up was 52 months. The median OS was not reached. The 3-year cumulative incidence of failure were: 3.3% LF, 7.1% RF and 2.2% DF. Patients with any LVSI had poorer OS (P < 0.01, increased rates of LF (P < 0.02) and increased rates of RF (P < 0.04). Extent of LVSI also correlated with OS, LF, RF and DM, where patients with extensive LVSI has worse outcomes when compared with patients with limited LVSI (P = 0.04, P = 0.04, P = 0.04, P = 0.01, respectively). Abnormal p53 correlated with increased rates of LF (P < 0.02). Patients who had both abnormal p53 and any LVSI had worse OS (P > 0.0010), increased LF (P = 0.047) and RF (P < 0.01), compared to patients who had neither risk factor. 47% of the entire patient cohort and 50% of patients with extensive LVSI or abnormal p53 received radiation therapy. No patients who completed EBRT experienced in-field recurrences.Patients with HIR early stage endometrial cancer treated at our institution have had excellent outcomes. However, a small group of patients with unfavorable risk factors such as abnormal p53 expression and/or LVSI have worse outcomes, even with lymph node assessment, suggesting that these factors can aid in the selection of patients who may derive benefit from intensification of treatment. EBRT may be beneficial in this high risk population, as no patients who completed EBRT in our study had in field recurrences.C. Hui: None. M. Mendoza: None. R. Von Eyben: None. P. Hammer: None. B. Howitt: None. E.A. Kidd: Advisory Board; Varian Brachytherapy Advisory Board.

Primary testicular carcinoid tumor with marked lymphovascular invasion.

Testicular carcinoid tumors are very rare, accounting for less than 1% of all testicular tumors. We report a rare case of a testicular carcinoid tumor with extensive lymphatic invasion. A 42-year-old man presented with a painless, enlarged right testicular mass. There was no history of injury or discomfort in this region. Right radical orchiectomy was performed, which showed a well-defined, non-encapsulated solid white mass with calcification (7.0 × 4.5 × 3.5 cm) and absence of cystic components. Microscopic examination using hematoxylin and eosin staining of the tumor sections identified organoid, trabecular, and solid patterns with rosette formation. Extensive multifocal lymphatic invasion was observed. Immunohistochemistry was positive for synaptophysin, chromogranin, and CD56. Testicular carcinoid tumors usually show good prognoses; however, there was extensive lymphovascular invasion in this case. Thus, in the case of unusual presentation of the disease, close follow-up is necessary.

Comprehensive genomic profiling and prognostic analysis of cervical gastric-type mucinous adenocarcinoma.

Gastric-type mucinous adenocarcinoma (GAS) is an uncommon cervical adenocarcinoma, which is not associated with human papillomavirus (HPV) infection. Compared with HPV-associated cervical adenocarcinoma, GAS has characteristics of larger volume, deep invasion, and easy to metastasize to distant sites. Also, GAS is typically resistant to chemo/radiotherapy. Few studies have reported the molecular genetic characteristics of GAS. In order to investigate the molecular genetic characteristics of GAS and reveal its possible pathogenesis, 15 GAS patients were enrolled from Peking University People's Hospital (2009-2019) and examined with next-generation sequencing (NGS). Based on the clinicopathologic feature analysis, we found that the presence of lymph node metastasis and extensive lymphovascular invasion were associated with poor survival outcomes of GAS (p = 0.0042 and p = 0.005, respectively). Based on the NGS testing, our results showed that the most frequently mutated gene was TP53 (8/15, 53.3%), followed by STK11, CDKN2A, and ARID1A. STK11 mutations were more frequent in well-differentiated GAS (33.3% vs. 0.0%, p = 0.026) and patients with extensive lymphovascular invasion (33.3% vs. 0.0%, p = 0.044). Survival analysis revealed that STK11 mutations were significantly associated with the poor prognosis of GAS (p = 0.01). Our results also showed that mutations in the target drug were detected in 53.3% of GAS patients. Patients with ERBB2 amplification (13.3%) presented the highest level of evidence according to OncoKB recommendations. These results indicate that the genomic alterations of GAS mainly involved the cell cycle and PI3K/AKT signaling pathways, and some therapeutic candidates were identified in GAS patients.

Clinicopathologic and molecular characterization of NTRK-rearranged thyroid carcinoma (NRTC)

Primary thyroid neoplasms with actionable NTRK rearrangements are rare, and their clinical behavior, histologic characteristics, and molecular landscape are not well understood. We report an institutional series of eleven NTRK-rearranged thyroid carcinomas (NRTC) by performing clinicopathologic review and next-generation sequencing for targeted mutations and gene rearrangements. The NRTC encompass a histomorphologic spectrum of ten papillary thyroid carcinomas (PTC), including one with high-grade features, and one secretory carcinoma (SC), in ten adults and one adolescent. All NRTC were characterized by an unusual multinodular growth pattern, extensive lymphovascular invasion, and cervical lymph node metastases at initial presentation. Immunophenotypically, while most cases were positive for TTF1 and PAX8, the SC case was negative/weak for these markers and instead diffusely expressed GATA3, mammaglobin and S100. Observed gene rearrangements included ETV6-NTRK3 (n = 4, including the SC), TPR-NTRK1 (n = 2), RBPMS-NTRK3 (n = 2), SQSTM1-NTRK1 (n = 1), SQSTM1-NTRK3 (n = 1), and EML4-NTRK3 (n = 1). Mutation profiling revealed a concurrent TERT promotor mutation C228T in two (22%) patients and a novel frameshift MEN1 deletion in one. All patients received total thyroidectomy and radioactive iodine. Despite frequent development of persistent/recurrent disease (9 cases, 82%) and distant metastases (6 cases; 55%), no tumor-related death occurred over a median (range) follow-up of 44 (11 to 471) months. Three patients received NTRK inhibitor therapy, with the SC case showing complete resolution and two other patients experiencing 33% and 69.7% decrease of disease burden. Although the range of features is variable, NRTC appear to be clinically aggressive tumors with high metastatic rate but relatively low mortality with NTRK inhibitor therapy. The histologic findings of multinodular growth and extensive lymphovascular spread, seen in all NRTC, including PTC and SC, may serve as useful histomorphologic clues to prompt NTRK status testing. We also present the first report of concurrent TERT promotor activating mutation which did not appear to confer entrectinib resistance to NRTC.

Malignant Perivascular Epithelioid Cell Tumor Mimicking Renal Cell Carcinoma: A Diagnostic Pitfall

Abstract We describe a case of metastatic malignant renal perivascular epithelioid cell tumor in a 56-year-old male. Computed tomography initially revealed bilateral heterogeneous enhancing kidney masses, the right one significantly larger than the left. The patient underwent a right radical nephrectomy. Upon gross examination, the mass was infiltrating into the surrounding fat and had a heterogeneous cut surface with multiple hemorrhagic foci. Histologically, majority of cells were highly atypical with abundant clear cytoplasm, pleomorphic nuclei, and enlarged prominent nucleoli. Extensive lymphovascular invasion was noted. Based on morphology, the diagnosis of renal cell carcinoma, Fuhrman grade 4, with extensive rhabdoid and focal sarcomatoid features was rendered. Follow-up computed tomography demonstrated a hypodense area within the right hepatic lobe, which upon resection showed identical morphology to the renal mass, except for focal areas of prominent epithelioid cells with abundant eosinophilic cytoplasm. Immunohistochemistry of both resection specimens (kidney and liver) demonstrated positive staining for Melan-A, HMB-45, and epithelial membrane antigen, focal positive staining for TFE3, and negative staining for PAX8 and cytokeratin. The initial diagnosis of renal cell carcinoma was amended to malignant epithelioid angiomyolipoma with hepatic metastasis. The diagnosis of angiomyolipoma/perivascular epithelioid cell tumor is particularly problematic owing to the large number of potential mimics. Immunohistochemistry for myomelanocytic differentiation should be considered in the context of kidney lesions with epithelioid and spindled cell morphology.

S2275 All at Once: Dual Novel Diagnosis of Crohn’s Disease and Colonic Adenocarcinoma in a 22-Year-Old Man

INTRODUCTION: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States. Mucinous adenocarcinoma makes up 10-15% of all CRC and disproportionately affects younger adults. One study found that those aged 25 and younger who developed CRC present acutely and when compared to older adults, were diagnosed at a more advanced stage and carried a poorer prognosis.[1] Crohn’s disease frequently presents in ages 20-29 and can increase risk of CRC. CASE DESCRIPTION/METHODS: A 22 year old male with no significant past medical history presented to ED with intermittent abdominal pain, diarrhea and weight loss. Initial labs revealed leukocytosis, elevated CRP/ESR and positive fecal occult blood test. CT imaging revealed hepatic flexure stricture with dilation of the ascending colon and distal ileum with enlarged ileocolic lymph nodes (Figure 1). Colonoscopy revealed moderate stenosis at the hepatic flexure with significant inflammation and ulceration which prevented a pediatric colonscopy from traversing. Descending colon had scattered moderate inflammation. Two days following the colonoscopy, the patient developed a bowel perforation which required emergent exploratory laparotomy with open right hemicolectomy and diverting loop ileostomy. Surgical findings included terminal ileum perforation, dense stricture at the hepatic flexure with adherence to the underlying duodenum without fistula. Pathology report revealed adenocarcinoma in the ascending colon invading into the visceral peritoneal surface, with extensive lymphovascular invasion. The cancer was staged at G3pT4aN2a. The uninvolved terminal ileum revealed active inflammation consistent with Crohn’s disease. Genetic testing was only positive for polysomy of chromosome 17. He was ultimately diagnosed with mucinous adenocarcinoma with signet ring cell features in the setting of newly diagnosed Crohn’s disease (Figure 2). DISCUSSION: This is a rare case of advanced mucinous adenocarcinoma with signet ring features of the ascending colon in a 22-year-old with previously undiagnosed Crohn’s disease. This demonstrates the importance and difficulty of considering CRC in the differential when working up a young adult for GI symptoms as the newly diagnosed Crohn’s disease seemed to fit our patient’s presentation perfectly.Figure 1.: Stricture at the hepatic flexure with dilation of the ascending colon and distal ileum.Figure 2.: Signet ring cells.

1365 A Rare Case of Neuroendocrine Tumor Originating in Liver Diagnosed by ERCP Using a Spyglass Direct Visualization System

INTRODUCTION: Neuroendocrine carcinoma is predominantly found in the gastrointestinal tract (54-75%) with 44%, 19%, 16%, 10% and 7% in the small intestines, rectum, appendix, colon and stomach respectively. Primary liver neuroendocrine carcinoma comprises around 0.3% of all neuroendocrine tumors. This is a case of a neuroendocrine carcinoma with a focus of cholangiocarcinoma presenting as a biliary stricture diagnosed by ERCP using the spyglass visualization system. CASE DESCRIPTION/METHODS: A 75 year old female with a prior history of rheumatoid arthritis presented with persistent nausea, vomiting, diarrhea and abdominal pain and a 20 lb weight loss since December 2017. An ultrasound revealed intrahepatic biliary ductal dilation in the left lobe with no visible mass and a coarse hepatic echotexture. A subsequent MRI of the abdomen demonstrated left lobe intrahepatic biliary ductal dilation with a hypointense 1 cm region within the liver parenchyma associated with a biliary stricture. The biliary stricture in the left hepatic branch was visualized with the spyglass direct visualization cholangioscope introduced through an ERCP scope. Biopsies obtained through the cholangioscope revealed high grade dysplasia. The patient underwent a left lobectomy of liver with hepatic artery and portal lymph node dissection. Lymph nodes were negative for malignancy. The biliary stricture was from a high grade neuroendocrine carcinoma with a microscopic focus of cholangiocarcinoma with extensive lymphovascular and perineural invasion. The margin of the bile duct and hepatic hilum were involved by neuroendocrine carcinoma. Post operative PET scan showed a small focus of activity without any signs of distant metastasis. DISCUSSION: SpyGlass direct visualization system is a relatively new technique in ERCP. Recently published prospective data confirm that the overall success rates for adequate tissue sampling is nearly 90%. ERCP has limitations for sampling lesions in the bile duct without direct visualization. Conventional ERCP biliary sampling yields are 20% to 30% for cytology brushing to approximately 50% with a combined brush/standard biopsy forceps approach. If sampling is negative, the choice is either radical surgery or continual observation with an MRI. Nowadays, ERCP with spyglass technique and targeted direct visualization biopsy affords vastly higher yields. Direct visualization is now the gold standard to obtain biopsy samples in cases of biliary strictures.

Invasive Mammary Carcinoma With Paneth Cell–Like Eosinophilic Cytoplasmic Granules: Is It an Entity?

Abstract Breast carcinomas with Paneth cell–like eosinophilic cytoplasmic granules are rare and commonly reported in association with acinic cell carcinoma or microglandular adenosis. Paneth cell–like differentiation has been described outside the GI tract, including lung, liver, pancreas, lacrimal glands, and prostate. Very little is known about the significance of these granules and whether they represent a metaplastic or possibly a therapy-related change. There are only 45 reported cases involving the breast, mostly individual case reports or 2 to 3 case series. Although the clinical experience is limited, most of the reported cases seem clinically indolent. Here we present a 74-year-old female with a mammographically detected 1.1-cm left breast retroareolar mass for which she underwent a biopsy and subsequent lumpectomy with axillary dissection. Histology revealed an invasive ductal carcinoma, with Paneth cell–like eosinophilic PAS-positive cytoplasmic granules in the background of extensive ductal carcinoma in situ (DCIS). Similar granules were seen in some ducts involved by DCIS. Invasive carcinoma and DCIS were present throughout the 5.5-cm lumpectomy beyond the grossly measured 4.0-cm mass. There was extensive lymphovascular invasion and tumor was present at all the surgical resection margins. Twelve of the 13 axillary lymph nodes had macrometastases. The tumor was ER and PR positive and HER2 negative. Clinically, there were extensive bony metastases involving the skull, spine, sternum, iliac bones, and femur. There were also multiple lung nodules and mediastinal lymph nodes that were positive for metastasis on biopsy. The patient is still undergoing chemotherapy and radiotherapy 6 months following surgical excision. Our case demonstrates the heterogeneity of this entity as the clinical course in our patient has been very aggressive. A collaborative effort must be established to compile a larger case series to better our understanding of this increasingly reported histological observation and whether it represents a distinct entity.

SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma

Small cell carcinoma of the ovary, hypercalcemic type is a rare, aggressive malignancy which usually occurs in young women and is characterized by mutations in SMARCA4, with few other alterations. We recently encountered uterine tumors with morphologic, immunohistochemical, and genetic similarities to small cell carcinoma of the ovary, hypercalcemic type. Herein we report the clinicopathologic and molecular features (using a targeted massively parallel sequencing [MPS] assay) of these tumors. The cases were diagnosed on cervical and endometrial biopsies (n = 2, 34, and 29 years) or hysterectomy and bilateral salpingo-oophorectomy (n = 3, 25, 33, and 58 years). The tumors were composed of sheets of large atypical epithelioid cells with prominent rhabdoid morphology, indistinguishable from the “large cell” variant of small cell carcinoma of the ovary, hypercalcemic type. In three cases, the ovaries were pathologically examined to exclude a primary ovarian malignancy. Immunohistochemically, four of four cases showed SMARCA4 loss, and were negative or only focally positive for keratins, EMA, and claudin-4. One of three cases was positive for WT-1. Targeted MPS was successfully performed on 4 of 5 tumors, and showed recurrent mutations in SMARCA4, with few other alterations. Of the cases diagnosed on hysterectomy, all had extensive lymphovascular invasion, extra-uterine spread, and marked infiltrative growth. These tumors were uniformly aggressive; all patients died of disease (median survival 7 months, range 1–43 months). We propose this entity be called “SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus)”, a term which describes both the tumor's underlying molecular abnormality and its morphology. Its unique clinicopathologic and molecular features differentiate it from other related malignancies, including undifferentiated endometrial carcinoma, small cell carcinoma of the ovary (hypercalcemic type), and epithelioid sarcoma. We review and discuss previously reported “rhabdoid tumors of the uterus;” while they are a heterogenous group of tumors, some of them are likely examples of this entity. Correctly identifying cases of SMARCA4-deficient uterine sarcoma from histologic mimics is important as it may have prognostic, predictive, and germline implications.

2 Massive Cardiac Metastases of an Untreated, Inflammatory Breast Cancer in a Young Patient: A Case Report of Autopsy Findings and Review of the Literature

Inflammatory breast carcinoma is a rare, aggressive form of breast cancer with a rapid onset and a poor prognosis. Extensive lymphovascular invasion characterizes this disease process. Cardiac involvement is rare and usually is clinically unknown until autopsy examination. A case report of a 47-year-old Hispanic woman with inflammatory breast carcinoma and widely metastatic disease, including extensive cardiac involvement is presented. A literature review of this disease and the mechanism of retrograde pulmonary/mediastinum lymphatic microembolism is included. A literature review on the benefits of better access to medical care for underserved populations is also discussed. At the time of autopsy, metastases involving the lungs, liver, and mediastinal lymph nodes, as well as pleural and pericardial effusions were observed grossly. Microscopic examination confirmed massive cardiac metastases, including involvement of the myocardium. Additionally, unexpected involvement of multiple other organs was identified, including dermal lymphatic permeation of abdominal skin. Inflammatory breast cancer is an aggressive, rapidly progressive, and often fatal disease. Cardiac metastases are rare with inflammatory breast carcinoma, and the mechanism of cardiac dysfunction requires further study. This case illustrates the known devastating nature of this disease. It also provides the opportunities to study the cardiac dysfunction associated with myocardial metastases, and the need for improved access to medical care in underserved populations for early detection and treatment of disease.