Plexiform architecture in gastrointestinal stromal tumors is not restricted to succinate dehydrogenase-deficient cases

Accumulating evidence reveals the heterogeneous features of gastrointestinal stromal tumors (GISTs), primarily distinguished by their various molecular triggers defining well characterized subgroups. The identification of the pathogenetic group a given GIST belongs to, in combination with the currently adopted GIST prognosticators, is pivotal for the correct management of GIST patients. Epidemiological, anatomical and morphological features are more or less strictly associated with the various possible GIST molecular pathogenesis; therefore, they can concur to addressing molecular analysis or even influence the identification of GIST subsets by themselves. This is particularly true in a cost/benefit perspective aimed at cutting the expenses of pathology labs. Under these circumstances, a correct classical pathological analysis still appears a fundamental step to achieve an optimal GIST characterization.We herein report a gastric epithelioid PDGFRA-mutant GIST displaying the multinodular/plexiform architecture distinctive of succinate dehydrogenase (SDH)-deficient GISTs. Immunohistochemistry and molecular analysis led to the correct tumor characterization. The reported case constitutes a valuable contribution to GIST pathology in that it demonstrates that multinodular/plexiform architecture is not restricted to SDH-deficient GISTs, but can be found also in PDGFRA-mutant ones; this is an event to be aware of, given the predilection for gastric location and epithelioid morphology shared by these two GIST subgroups, only the latter of which includes imatinib-sensitive cases. Keywords: Gastrointestinal stromal tumor, Platelet-derived growth factor receptor alpha, Multinodular architecture, Plexiform architecture, Succinate dehydrogenas

Mesothelioma in Familial Mediterranean Fever With Colchicine Intolerance: A Case Report and Literature Review

A 65-year-old Italian physician affected by Familial Mediterranean fever (FMF) was hospitalized due to progressive abdominal enlargement, which had begun 6 months before admission. Physical examination revealed ascites and bilateral leg edema. Abdominal CT scan showed ascitic fluid and extensive multiple peritoneal implants; peritoneal CT-guided biopsy revealed an epithelial-type malignant mesothelioma. The patient\u2019s past medical history revealed recurrent episodes of abdominal pain and fever from the age of 2. Clinical diagnosis of FMF was suspected at the age of 25, while genetic analysis, performed at the age of 50, confirmed homozygosity for the M694I mutation in the MEFV gene. Treatment with the first line FMF drug colchicine was started and stopped several times because of worsened leukopenia. The patient in fact had a history of asymptomatic leukopenia/lymphopenia from an early age; the intake of colchicine aggravated his pre-existing problem until the definitive suspension of the drug. As for second-line drugs, canakinumab was first prescribed, but due to prescription issues, it was not possible to be administered. When he was given anakinra, there was a worsening of leukopenia leading to septic fever. Systematic literature review indicates that, in most cases, recurrent peritoneal inflammation results in benign peritoneal fibrosis or less commonly in encapsulating peritonitis. There are only a few reported cases of recurrent peritoneal inflammation progressing from FMF to peritoneal mesothelioma (MST). In such cases, intolerance to colchicine or its erratic intake may lead to long-term recurrent inflammation, which usually precedes the development of the tumor, while pre-existing leukopenia, as in our patient, could also be a factor promoting or accelerating the tumor progression. In conclusion, we suggest that in the presence of intolerance or resistance to colchicine, interleukin (IL)-1 inhibition could suppress peritoneal inflammation and prevent MSTs

Autoimmune hepatitis with eosinophilic infiltration responsive to anti-interleukin-5 receptor treatment: a case report and literature review

Inflammatory tissue damage plays a role in the onset, progression, and exacerbation of various chronic autoimmune and metabolic diseases such as autoimmune hepatitis. Here we present a case of autoimmune hepatitis with liver eosinophilic infiltrate in a severe eosinophilic asthma patient who failed conventional immunosuppressive treatment and showed improvement in gastrointestinal symptoms after anti-interleukin-5 receptor treatment. Our case highlights the potential role of eosinophils in initiating or worsening liver inflammation in autoimmune liver disease. The link between eosinophilic inflammation, barrier damage, and chronic autoimmune diseases should be considered in clinical practice

Telocytes are the physiological counterpart of inflammatory fibroid polyps and PDGFRA-mutant GISTs

PDGFRA mutations in the gastrointestinal (GI) tract can cause GI stromal tumour (GIST) and inflammatory fibroid polyp (IFP). Hitherto no cell type has been identified as a physiological counterpart of the latter, while interstitial Cajal cells (ICC) are considered the precursor of the former. However, ICC hyperplasia (ICCH), which strongly supports the ICC role in GIST pathogenesis, has been identified in germline KIT-mutant settings but not in PDGFRA-mutant ones, challenging the precursor role of ICC for PDGFRA-driven GISTs. Telocytes are a recently described interstitial cell type, CD34+/PDGFRA+. Formerly considered fibroblasts, they are found in many organs, including the GI tract where they are thought to be involved in neurotransmission. Alongside IFPs and gastric GISTs, GI wall \u201cfibrosis\u201d has been reported in germline PDGFRA-mutants. Taking the opportunity offered by its presence in a germline PDGFRA-mutant individual, we demonstrate that this lesion is sustained by hyperplastic telocytes, constituting the PDGFRA-mutant counterpart of germline KIT mutation-associated ICCH. Moreover, our findings support a pathogenetic relationship between telocyte hyperplasia and both IFPs and PDGFRA-mutant GISTs. We propose the term \u201ctelocytoma\u201d for defining IFP, as it conveys both the pathogenetic (neoplastic) and histotypic (\u201ctelocytary\u201d) essence of this tumour, unlike IFP, which rather evokes an inflammatory-hyperplastic lesion

Telocytes as possible precursors of PDGFRA-mutant gastrointestinal mesenchymal tumors

Based on the morphologic/immunophenotypic evidence produced so far, a precursor role of TCs not only for IFPs, but also for PDGFRA-driven GISTs appears more than a pure hypothesis. However, further studies (especially ultrastructural) are warranted to definitively settle this issue

Telocytes as possible precursors of PDGFRA-mutant gastrointestinal mesenchymal tumors\u2014rejoinder

We read with interest the reply by Manley et al to our letter supporting telocytes (TCs) as possible precursors of gastrointestinal mesenchymal tumors [1], [2]. We would like to clarify that the tumors we think derive from TCs along with inflammatory fibroid polyps (IFPs) are actually PDGFRA-mutant gastrointestinal stromal tumors (GISTs), that is, \u201cgenuine\u201d GISTs (concurring to form this tumor group together with the other GIST subtypes, distinguished by diverse pathogenetic mechanisms, which likewise feature distinctive morphology and clinical features). Therefore, in this regard, the definition \u201cPDGFRA-mutant polyps arising sporadically and syndromically within the stomach and diagnosed as GISTs,\u201d ascribed to us by Manley and colleagues, is inaccurate. Actually, PDGFRA-mutant GISTs are in most cases not polypoid, rather constituting intramural masses, with clear-cut histologic and immunophenotypical features [3]. We have recently produced morphogenetic evidence of the origin of these tumors, along with typical IFPs, from TCs, exploiting the opportunity offered by the concurrent presence of a prominent TC hyperplasia [4]. In the same article, we proposed to define IFP as \u201ctelocytoma\u201d because this term conveys both the neoplastic and histotypic natures of these tumors. Conversely, tumors typical of PDGFRA-mutant syndrome whose nosology is less straightforward are the fibrous tumors defined as GISTs by De Raedt and colleagues [5] and described also by Carney and Stratakis [6] and by ourselves [7]. These tumors not only do not exhibit morphologic features typical of GISTs but also do not express CD117 and DOG1; in addition, they have been found mostly in the small intestine, unlike PDGFRA-mutant GISTs, which show a strong predilection for the stomach. We have previously discussed in depth this issue, supporting these \u201cfibrous tumors\u201d as a possible variant of IFP [7]. In conclusion, in our opinion, PDGFRA mutations can determine 3 types of lesions in the gastrointestinal tract: (1) typical PDGFRA-mutant GIST, (2) typical IFP (telocytoma) and its variant formerly defined as \u201cfibrous tumors\u201d, and (3) TC hyperplasia. Of note, the latter and the \u201cfibrous tumors\u201d variant of IFP (telocytoma) hitherto have been described exclusively in germline PDGFRA mutant settings, that is, in PDGFRA-mutant syndrome

Prognostic Importance of Histologic Vascular Invasion in Papillary Thyroid Carcinoma

OBJECTIVE: To conduct a retrospective study of 39 patients with papillary carcinoma of the thyroid with histologic vascular invasion (VI+) and 361 patients without any sign of vascular invasion (VI−). SUMMARY BACKGROUND DATA: In the present study, we undertook a retrospective analysis of papillary carcinoma of the thyroid to assess whether histologically determined vascular invasion can be considered a predictive factor for prognosis. METHODS: By means of a retrospective study, we evaluated the department's database of patients with papillary thyroid carcinoma who had undergone total thyroidectomy from January 1993 to December 1999. RESULTS: Group I consisted of papillary carcinoma without any sign of vascular invasion (VI−) comprising 361 patients. Group II consisted of papillary carcinoma with vascular invasion (VI+) comprising 39 patients. At the time of diagnosis, we observed no metastases in patients with VI−, whereas a pulmonary metastasis was observed in 1 patient with VI+ (P = 0.0023). In 3.6% patients with VI− and in 20.5% patients with VI+, we observed recurrences in the regional lymph nodes (P < 0.001); we observed 6 (1.66%) distant metastases in patients with VI− and in the 12.8% patients with VI+ (P < 0.001). Three patients with VI+ (7.7%) and 2 patients with VI− (0.6%) died of tumor-related causes; these figures were found to be statistically significant (P < 0.001). CONCLUSIONS: In papillary carcinoma, it should be noted that histologic vascular invasion may be considered as a sign of an increased tendency toward hematogenic invasion and consequent increase in the relative percentage of metastases; ultimately, this means a poorer prognosis. In the presence of risk factors indicating a possible increase in biologic aggressiveness, adequate postoperative treatment and close follow up become essential

Emergency surgery for colorectal cancer does not affect nodal harvest comparing elective procedures: a propensity score-matched analysis

PURPOSE: About 30% of colorectal cancers (CRCs) present with acute symptoms. The adequacy of oncologic resections is a matter of concern since few authors reported that emergency surgery in these patients results in a lower lymph node harvest (LNH). In addition, emergency resections have been reported with a longer hospital stay and higher morbidity rate. We thus conducted a propensity score-matched analysis with the aim of investigating LNH in emergency specimens comparing with elective ones. Secondary aim was the comparison of morbidity and hospital stay. METHODS: Eighty-seven consecutive R0 emergency surgical procedures were matched with elective CRCs using the propensity score method and the following covariates: age, sex, stage, and localization. Groups were compared using univariate and multivariate analyses. Outcome measures were LNH, nodal ratio, Clavien's morbidity grades, and hospital stay. RESULTS: Emergency patients presented more metastatic nodes compared with elective ones (p 0.017); however, both presented a comparable mean LNH. Multivariate analysis documented that a T stage ≥3 was the only variable correlated with a nodal positivity (OR 6.3). On univariate analysis, emergency CRCs had a longer mean hospital stay compared with elective resections (p 0.006) and a higher rate of Clavien ≥4 events (p 0.0173). Finally, emergency resection and an age >66 years were variables independently correlated with a mean hospital stay >10 days (OR, respectively, 3.7 and 3.5). CONCLUSIONS: Emergency CRC resections were equivalent to the elective procedures with respect to LNH. However, emergency surgery correlated with a longer mean hospital stay. Graphical abstract Emergency and Elective resections for CRC provide similar LNH

Collagenous colitis and atezolizumab therapy: an atypical case.

Immune checkpoint inhibitors such as anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), anti-PD-1 (programmed cell death protein 1), and PD-L1 (programmed cell death protein-ligand 1) are emerging drugs that have radically changed treatment and prognosis of different types of tumors. However, despite their considerable benefits, immune checkpoint inhibitors are associated with numerous side effects involving several organs. Gastrointestinal toxicities represent some of these most common adverse events. While clinical presentation usually ranges from mild diarrhea to life-threatening colitis, typical endoscopic and histologic findings of immune-mediated colitis often resemble those of inflammatory bowel diseases. However, less common patterns are lymphocytic colitis and, rarely, collagenous colitis. Physician and pathologists must be aware of the wide spectrum of clinical and histological findings that may be encountered in immune-related gastro-intestinal toxicities. We report a rare and atypical case of collagenous colitis occurred in a woman affected by stage IV lung adenocarcinoma, on atezolizumab therapy