Aims
PD‐1 inhibitors facilitate immune response against certain tumour types, including melanoma. These drugs have led to prolonged survival but can also result in autoimmune‐type side effects, ...including gastrointestinal inflammation. The histopathological effects of this medication class have not been well studied.
Methods and results
We identified 37 gastrointestinal tract biopsies from 20 patients taking a PD‐1 or PD‐L1 inhibitor and evaluated clinicopathological findings. Diarrhoea was the most common symptom, and endoscopic findings ranged from mild erythema to erosion/ulceration. Common histological findings included lamina propria expansion, villous blunting (if applicable), intra‐epithelial neutrophils and increased crypt/gland apoptosis, although intra‐epithelial lymphocytes were rarely prominent. A few cases showed crypt rupture with resultant histiocytic/granulomatous response. Most patients responded to drug cessation and/or steroids, but follow‐up endoscopies were not performed.
Conclusions
PD‐1/PD‐L1 inhibitors can cause gastritis, enteritis and colitis, similar to other immunomodulatory antibodies (such as CTLA‐4 inhibitors and PI3Kδ inhibitors), but the histological findings vary somewhat among drug classes. Clinical history, lack of prominent intra‐epithelial lymphocytes and crypt rupture may help to distinguish PD‐1 inhibitor gastroenterocolitis from mimics, which include other medication effect, inflammatory bowel disease, graft‐versus‐host disease, cytomegalovirus infection and autoimmune enteropathy.
Here, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (
), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic ...homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models.
Mice with a targeted deletion of
in the pancreas by itself and in the context of two common genetic alterations in PDAC,
and
, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes.
deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant
cooperates with homozygous deletion of
, leading to intraductal papillary mucinous neoplasm (IPMN).
loss in the context of mutant
and
leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from
-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on
loss for dysregulation.
ARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN.
-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.
Perineuriomas of the gastrointestinal tract, formerly known as benign fibroblastic polyps, most commonly occur as polyps on screening colonoscopy, particularly in the distal colon. Gastric examples ...are exceedingly rare. We report the sixth patient with a gastric perineurioma in a 57-year-old female. Histologically, the lesion was composed of bland spindle cells without cytologic atypia or mitotic activity located in the gastric lamina propria. The spindled cells were strongly positive for GLUT1 and focally reactive for epithelial membrane antigen (EMA). The morphologic and immunophenotypic findings were those of gastric perineurioma.
Aims
Appendiceal well‐differentiated neuroendocrine tumours (NETs) are usually incidental and clinically benign. Several studies have reported different risk factors for nodal metastasis. The aim of ...this study was to investigate our appendiceal NETs (App‐NETs) to determine the factors associated with malignant behaviour.
Methods and results
For 120 App‐NETs, we reviewed the clinical presentation and follow‐up, including serum chromogranin A (CgA) levels, and compiled several microscopic variables. Pathological factors were compared with nodal status and time to biochemical recurrence (elevated serum CgA level) by the use of Cox regression. We also reviewed similar App‐NET data in the Surveillance, Epidemiology, and End Results (SEER) Programme. Among our 120 cases, seven patients had positive lymph nodes, and nine developed subsequent elevation of CgA levels; none developed distant metastases or died of disease. Only three patients had grade 2 NETs; none had nodal disease, and one developed an elevated CgA level. Increasing tumour size was associated with an increased risk of nodal disease odds ratio (OR) 4.99, P = 0.0055). All seven node‐positive cases were ≥13 mm. Factors associated with elevated CgA levels included age (OR 1.04, P = 0.041), pT4 disease (OR 10.22, P = 0.033), and nodal disease (OR 24.0, P = 0.012), but not size (OR 2.13, P = 0.072). Of the 1492 reported App‐NETs in the SEER database with data on tumour size, 137 (9%) were pN1; only five of these (4%) were coded as being <5 mm.
Conclusions
Small (<5 mm) App‐NETs that do not invade the serosa or mesoappendix appear to be overwhelmingly benign and low‐grade, requiring neither Ki67 staining nor synoptic reporting. Given their indolent behaviour, different nomenclature or staging may be more appropriate for these NETs.
Low-grade appendiceal mucinous neoplasm (LAMN) is an enigmatic tumor that lacks the capacity for classic invasion but can dissect through the appendiceal wall, causing pseudomyxoma peritonei (PMP). ...Most large studies of the histologic spectrum of LAMN and its rate of associated PMP include cases submitted from outside institutions, potentially skewing their findings. We identified 117 cases of LAMN at our institution. Hematoxylin and eosin-stained slides from each were reviewed, and clinical and pathologic parameters were noted. The patients were 76 females and 41 males, with a mean age of 60 years. Presenting symptoms were available for 113 patients; the majority (56%) were symptomatic, typically with abdominal pain. Ninety-one tumors (78%) were grossly dilated, and the entire appendix was submitted in 88 (75%) cases. Median lesion size was 5.5 cm. Ninety-two cases (79%) demonstrated epithelial denudation; these were often markedly dilated and contained intraluminal or mural microcalcifications. Thirty-two (27%) had a mucosal Schwann cell proliferation. On the basis of the American Joint Committee on Staging eighth edition cancer staging manual, of 117 cases, 66% were staged as pTis, 9% as pT3, 24% as pT4a, and 2% as pT4b. Ten cases (9%) were associated with histopathologic evidence of disseminated PMP. Only 1 patient died of disease, while 3 were alive with disease at last follow-up. Previous LAMN studies have utilized both departmental and extradepartmental material; our single-institution review demonstrated lower rates of PMP than some prior studies. Some LAMNs may be markedly dilated with extensive denudation, making the diagnosis difficult to confirm microscopically and ultimately requiring submission of the entire appendix for histologic evaluation.
Small cell neuroendocrine carcinoma of the prostate (SCNECP) is a rare, aggressive subtype of prostate carcinoma. Most SCNECP arise from conventional prostate adenocarcinoma (CPAC) treated with ...androgen deprivation therapy (ADT).
We identified four cases of CPAC treated with ADT, which evolved to SCNECP with liver metastasis. The average interval between the diagnosis of CPAC and SCNECP was 102 months (range: 12 to 168). Histologically, the tumors showed nests of cells with high nuclear:cytoplasmic ratios, granular chromatin, and frequent mitoses. All cases were synaptophysin, chromogranin, and AE1/AE3 positive, with a Ki-67 labeling index ≥70%. NKX3.1 was negative in all but one case and TTF-1 was positive in half. Weak ERG positivity by IHC was seen in one case which also demonstrated the TMPRSS2-ERG gene rearrangement; all other cases were negative for ERG by IHC. Serum prostate specific antigen (PSA) levels were normal to near-normal in all. The median interval between the diagnosis of SCNECP and death was 3.25 months (range: 0.75 to 26).
Our case series highlights the importance of considering a prostate primary, even in the setting of normal PSA levels and loss of prostate markers, when diagnosing neuroendocrine carcinoma in the liver. Further, we emphasize the significance of diagnosing SCNECP that metastasizes to the liver, as it portends a particularly dismal prognosis.
Appendiceal neuroendocrine neoplasms (NENs) can present with various growth patterns including the traditional triad of histologic patterns-insular, trabecular and tubular. A small cluster pattern ...was also found in this study and the literature on this specific morphology is limited. In this study, we conducted a comprehensive review of appendiceal NENs from our institution over a ten-year period. Clinical and demographic data were obtained from medical records. Immunohistochemical stains were performed with antibodies specific for synaptophysin, chromogranin, INSM1, CD56, serotonin and peptide YY. The small cluster pattern was found in 29.4 % of all cases evaluated. The tumor cells in these cases were predominantly located at the distal tip of the appendix, associated with fibrous obliteration. These tumors were smaller in size and tended towards less advanced tumor stage, with reduced incidence of lymphovascular and/or perineural invasion. Chromogranin expression was identified in 76 % of these cases. There is a heterogeneous hormone profile with 46.7 % serotonin and 33.3 % peptide YY. In conclusion, the small cluster pattern NENs present with unique histological features and hormone expression profile. Among the various neuroendocrine markers, INSM1 showed superior diagnostic performance, with high sensitivity and minimal non-specific staining.
•Appendiceal NENs present unique diagnostic challenges due to their distinct anatomic, histologic and pathologic attributes.•Small cluster pattern NETs can present inconspicuously, and are associated with fewer high-risk prognostic features.•Small cluster pattern NETs demonstrate a heterogeneous hormone profile: serotonin or PYY-positive, and double-negative.•INSM1 showed superior diagnostic performance for appendiceal NETs, with high sensitivity and minimal non-specific staining.
Abstract
Objectives
To systematically evaluate gynecologic malignancies (adnexal or uterine) causing gastrointestinal (GI) signs (eg, mass on colonoscopy) or symptoms (eg, bloody stools) clinically ...mimicking a GI primary malignancy.
Methods
The archives of 2 institutions were retrospectively reviewed for gynecologic malignancies clinically manifesting as colonic lesions. For each case, available radiologic, endoscopic, and histologic findings were recorded.
Results
We identified 16 cases: 13 biopsies and 3 resections. The masses were localized in the rectosigmoid (14 cases 88%), right (1 case 6%), and transverse (1 case 6%) colon. Gastrointestinal-type complaints included abdominal pain, weight loss, hematochezia, and obstruction; 1 case was asymptomatic and found during screening colonoscopy. Nine patients (56%) had no known prior gynecologic malignancy, and in only 2 of these patients was there some clinical suspicion of a noncolonic primary malignancy. Most cases (13 81%) were serous carcinoma, usually high-grade adnexal or primary peritoneal. Six cases (38%) directly extended into the colon, and 7 (44%) metastasized; route of spread was unclear in the others. Only 1 case (6%) showed mucosal involvement, and none showed desmoplasia or dirty necrosis. Four of the 13 serous carcinomas (31%) showed psammoma bodies.
Conclusions
Advanced gynecologic malignancies, most commonly serous carcinoma, can rarely manifest as GI lesions. Clues to noncolonic origin on biopsy include lack of colonic mucosal involvement/dysplasia, desmoplasia, or dirty necrosis.
Background
Peritoneal dissemination of low-grade appendiceal mucinous neoplasms (LAMNs), sometimes referred to as pseudomyxoma peritonei, can result in significant morbidity and mortality. Little is ...known about the natural history of localized (non-disseminated) LAMNs.
Objective
The goal of this study was to evaluate the risk of peritoneal recurrence in patients with localized LAMNs.
Methods
We performed a multi-institutional retrospective review of patients with pathologically confirmed localized LAMNs. Baseline characteristics, pathology, and follow-up data were collected. The primary endpoint was the rate of peritoneal recurrence.
Results
We identified 217 patients with localized LAMNs. Median age was 59 years (11–95) and 131 (60%) patients were female. Surgical management included appendectomy for 124 (57.1%) patients, appendectomy with partial cecectomy for 26 (12.0%) patients, and colectomy for 67 (30.9%) patients. Pathology revealed perforation in 46 patients (37.7% of 122 patients with perforation status mentioned in the report), extra-appendiceal acellular mucin (EAM) in 49 (22.6%) patients, and extra-appendiceal neoplastic cells (EAC) in 13 (6.0%) patients. Median follow-up was 51.1 months (0–271). Seven (3.2%) patients developed a peritoneal recurrence, with a median time to recurrence of 14.4 months (2.5–47.0). Seven (15.2%) patients with histologic evidence of perforation had recurrence, versus no patients (0%) without perforation (
p
< 0.001); five (10.2%) patients with EAM versus two (1.2%) patients without EAM (
p
= 0.007), and one (7.7%) patient with EAC versus six (2.9%) patients without EAC (
p
= 0.355) had recurrence.
Conclusions
This multi-institutional study represents the largest reported series of patients with localized LAMNs. In the absence of perforation or extra-appendiceal mucin or cells, recurrence was extremely rare; however, patients with any of these pathologic findings require careful follow-up.
The SWItch/Sucrose Non-Fermentable (SWI/SNF) complex is a multimeric protein involved in transcription regulation and DNA damage repair. SWI/SNF complex abnormalities are observed in approximately ...14–34 % of pancreatic ductal adenocarcinomas (PDACs). Herein, we evaluated the immunohistochemical expression of a subset of the SWI/SNF complex proteins (ARID1A, SMARCA4/BRG1, SMARCA2/BRM, and SMARCB1/INI1) within our PDAC tissue microarray to determine whether SWI/SNF loss is associated with any clinicopathologic features or patient survival in PDAC. In our cohort, 13 of 353 (3.7 %) PDACs showed deficient SWI/SNF complex expression, which included 11 (3.1 %) with ARID1A loss, 1 (0.3 %) with SMARCA4/BRG1 loss, and 1 (0.3 %) with SMARCA2/BRM loss. All cases were SMARCB1/INI1 proficient. The SWI/SNF-deficient PDACs were more frequently identified in older patients with a mean age of 71.6 years (SD = 7.78) compared to the SWI/SNF-proficient PDACs which occurred at a mean age of 65.2 years (SD = 10.95) (P = 0.013). The SWI/SNF-deficient PDACs were associated with higher histologic grade, compared to the SWI/SNF-proficient PDACs (P = 0.029). No other significant clinicopathologic differences were noted between SWI/SNF-deficient and SWI/SNF-proficient PDACs. On follow-up, no significant differences were seen for overall survival and progression-free survival between SWI/SNF-deficient and SWI/SNF-proficient PDACs (both with P > 0.05). In summary, SWI/SNF-deficient PDACs most frequently demonstrate ARID1A loss. SWI/SNF-deficient PDACs are associated with older age and higher histologic grade. No other significant associations among other clinicopathologic parameters were seen in SWI/SNF-deficient PDACs including survival.
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