Perianal Paget's disease as spread from non-invasive colorectal adenomas.

AIMS: Paget's disease of the perianal skin is a rare form of extramammary Paget's disease, and may be a primary intraepithelial adnexal neoplasm or secondary due to spread from an underlying colorectal lesion, nearly always colorectal adenocarcinoma. Secondary perianal Paget's disease associated with non-invasive colorectal adenomas is exceedingly uncommon, with only a few reported cases. METHODS AND RESULTS: Herein, we present the clinical and pathological features of the largest series of secondary perianal Paget's disease arising in association with colorectal adenomas. There was gender parity and the median age was 72 years (range = 68-76 years). In all cases, perianal Paget's disease was associated with colorectal adenomas, including three (75%) conventional tubular adenomas and one (25%) tubulovillous adenoma with serrated foci. All adenomas had high-grade dysplasia and one had intramucosal adenocarcinoma (lamina propria invasion; Tis), but all lacked submucosal invasion. The intraepithelial Paget's cells showed a colorectal phenotype by immunohistochemistry in all cases. At follow-up, two patients had no evidence of disease at 6 and 87 months, one had residual perianal Paget's disease at 8 months and one developed invasive adenocarcinoma of the perianal tissue at 36 months. CONCLUSIONS: Similar to its mammary analogue, secondary perianal Paget's disease may arise in association with invasive and/or in-situ colorectal lesions. Although the latter is an uncommon presentation of a recognised rare disease, knowledge of this phenomenon is important to forestall overdiagnosis of invasion and potential overtreatment. The clinical course is variable, such that close follow-up is required.

Cell polarity (the 'four lines') distinguishes gastric dysplasia from epithelial changes in reactive gastropathy.

AIMS: Gastric dysplasia is a risk factor for synchronous and subsequent gastric carcinoma. Distinguishing gastric dysplasia from reactive changes is subject to interobserver disagreement and is a frequent reason for expert consultation. We previously used assessment of surface cell polarity (the 'four lines') as a key feature to decrease equivocal diagnoses in Barrett oesophagus. In the current study, we examined for the presence or absence of the four lines in gastric dysplasia and reactive gastropathy. MATERIALS AND METHODS: The study includes all (n = 91) in-house biopsies with at least gastric dysplasia from the surgical pathology archives of two academic institutions during a 5-year period from 2008 to 2012. A reactive gastropathy group (n = 60) was created for comparison. RESULTS: The dysplasia/neoplasia group was comprised of 14 biopsies of gastric foveolar-type dysplasia, 59 of intestinal-type dysplasia, 14 with dysplasia in fundic gland polyps, three pyloric gland adenomas and one oxyntic gland adenoma. Loss of surface cell polarity was seen in all 88 dysplasia cases with evaluable surface epithelium. All 57 reactive gastropathy cases with evaluable surface epithelium showed intact surface cell polarity except in focal areas directly adjacent to erosions in 17 cases, where the thin wisp of residual surface mucin could not be appreciated on haematoxylin and eosin. CONCLUSION: Surface cell polarity (the four lines) was lost in all gastric dysplasia biopsies with evaluable surface epithelium and maintained in all biopsies of reactive gastropathy. Caution should be taken in using this feature adjacent to erosions in reactive gastropathy.

Erythropoietic protoporphyria in an adult with sequential liver and hematopoietic stem cell transplantation: A case report.

Erythropoietic protoporphyria (EPP) is a rare inherited disorder of the heme biosynthesis pathway resulting in the accumulation of protoporphyrins in the blood, erythrocytes, and other tissues. Because of a gene mutation in the FECH gene, ferrochelatase, the enzyme involved in the final step of heme synthesis, is deficient in these patients. Although the major symptom of this disorder is photosensitivity, rarely, it can cause progressive liver disease requiring liver transplantation (LT). However, LT is not curative and only bone marrow transplantation (BMT) can correct the underlying enzymatic defect. Because liver disease results from accumulation of protoporphyrin in the liver, LT without hematopoietic stem cell transplantation leaves the new liver at risk for similar EPP-related damage. A handful of pediatric patients undergoing sequential LT and stem cell transplantation have been described in the literature; however, to date none has been described in detail in adults. We report a case of an adult male with EPP and liver failure who successfully underwent a sequential liver and hematopoietic stem cell transplantation (HSCT).

Exocrine pancreas in type 1 and type 2 diabetes: different patterns of fibrosis, metaplasia, angiopathy, and adiposity.

The endocrine and exocrine compartments of the pancreas are spatially related but functionally distinct. Multiple diseases affect both compartments, including type 1 diabetes (T1D), pancreatitis, cystic fibrosis, and pancreatic cancer. To better understand how the exocrine pancreas changes with age, obesity, and diabetes, we performed systematic analysis of wellpreserved tissue sections from the pancreatic head, body, and tail of organ donors with T1D (n = 20), type 2 diabetes (T2D, n = 25), and donors with no diabetes (ND, n = 74). Among ND donors, we found that acinar-to-ductal metaplasia (ADM), angiopathy, and pancreatic adiposity increased with age, while ADM and adiposity also increased with BMI. Compared to age- and sex-matched ND organs, T1D pancreata had greater acinar atrophy and angiopathy with fewer intralobular adipocytes. T2D pancreata had greater ADM, angiopathy, and total T lymphocytes, but no difference in adipocyte number, compared to ND organs. While total pancreatic fibrosis was increased in both T1D and T2D, the pattern was different with T1D pancreata having greater periductal and perivascular fibrosis, whereas T2D pancreata had greater lobular and parenchymal fibrosis. Thus, the exocrine pancreas undergoes distinct changes as individuals age or develop T1D or T2D.

Clinicopathological study of blue nevi of the gastrointestinal (GI) tract: first case series.

AIM: Blue nevus (BN) is a benign melanocytic proliferation that is typically cutaneous. Extracutaneous BN is infrequent and is reported in the mucosa of various organs. Gastrointestinal (GI) tract BN is rare. Here, we describe the clinicopathological findings of the largest series of GI tract BNs. METHODS: A search of our Pathology Data System (1984-2019) identified six GI tract blue nevi. Clinical information, pathology reports and available H&E-stained section slides were reviewed. RESULTS: Lesions predominated in the middle-aged adults (mean 54, range 27-80) with a slight female predominance (66%). Most cases arose in the rectum and colon (83%), with one gastric lesion (17%). Four cases were identified during endoscopic examination performed either for screening or for unrelated symptoms (66%). Two patients presented with rectal bleeding (33%) unassociated with the BN. Endoscopically, most lesions appeared as superficial hyperpigmented areas (83%). One case was described as abnormal mucosa (17%). Microscopically, the mucosa was involved in all of the cases (100%). One case showed submucosal extension in addition to the mucosal component (17%). Lesions showed a proliferation of bland spindle cells with abundant granular pigment. No nuclear atypia or mitoses were identified. Immunostains showed immunoreactivity for melanocytic markers. Follow-up information available for five patients showed no recurrences to date (mean follow-up 1 year). CONCLUSIONS: BN is a benign melanocytic proliferation. It is important to be aware of the occurrence of such lesions outside of the skin and consider the possibility of BN when pigmented lesions are encountered in the GI tract.

Lymphocytic and collagenous colitis in children and adolescents: Comprehensive clinicopathologic analysis with long-term follow-up.

Microscopic colitis (MC) is characterized by chronic watery diarrhea, endoscopically normal findings, and abnormal histology. While mostly encountered in adults, pediatric cases are rare and may show varying presentations. Our pathology data system was searched from 1984 to 2019 for patients ≤18 years of age with a lymphocytic colitis (LC) or collagenous colitis (CC) pattern of injury. Twenty-seven cases (23 LC and 4 CC) were retrieved. LC was more prevalent than CC (85% vs 15%, respectively) and affected slightly younger individuals (mean, 9.8 years versus 12.25 years). Immune dysregulation was documented in 11 (41%) patients. Most patients presented with watery diarrhea (n = 26, 96%) and either abdominal pain (n = 18, 67%), nausea/vomiting (n = 5, 19%), flatulence (n = 6, 22%), and/or weight loss (n = 1, 4%). A subset of patients (n = 10, 37%) demonstrated endoscopic abnormalities. Histologically, some patients with LC and CC displayed focal cryptitis or crypt abscess formation (n = 7, 26%) and focally increased crypt apoptosis (n = 9, 33%) in the absence of chronic injury. Clinical follow-up data were available for 23 (85%) patients with variable clinical responses recorded. Only 8 patients experienced complete symptom resolution. Twelve patients (11 LC and 1 CC) had subsequent biopsy material; of which, one developed histologic features of inflammatory bowel disease and another was found to have a CTLA-4 deficiency. Our study shows that pediatric patients with MC may have atypical clinical, histologic, and endoscopic findings and variable clinical responses. Underlying inflammatory and/or genetic conditions may be eventually unmasked, and genetic testing may be helpful in a small subset of patients.

Granulomatosis with Polyangiitis Manifesting as a Symptomatic Sellar Mass in a Young Woman.

A pituitary mass is a rare and poorly understood complication of granulomatosis with polyangiitis (GPA). Here we describe the case of a young woman with GPA who presented with signs and symptoms initially suggestive of meningitis but was ultimately found to have hypopituitarism and an enlarging sellar mass. She underwent transsphenoidal biopsy, which revealed an abundance of sterile inflammation and necrosis consistent with GPA-related inflammation. This case demonstrates a rare complication of GPA, i.e., a pituitary mass, initially mimicking meningitis. GPA-related pituitary involvement has an unknown pathogenesis and can have debilitating long-term consequences including chronic hypopituitarism and vision impairment, highlighting the need for further research.

The "Race" Toward Diversity, Inclusion, and Equity in Pathology: The Johns Hopkins Experience.

With 3.8% black trainees in 2012, pathology had significantly fewer trainees from groups underrepresented in medicine compared to other specialties. To address this, faculty in the Johns Hopkins Department of Pathology established an outreach program and funded rotation for students underrepresented in medicine and from disadvantaged groups. The aims were to increase exposure to the field and improve diversity, inclusion, and equity in pathology. A 1-month rotation for students underrepresented in medicine was established in 2013. Rotation schedules tailored to each rotator's interests included resident conferences and individual faculty meetings. In 2016, a proactive outreach program was established. Faculty visited historically black medical schools and underrepresented in medicine student groups at other institutions, where they gave a "Careers in Pathology" presentation targeted to second- and third-year medical students. Faculty also attended underrepresented in medicine student conferences and participated in high school student programs to further expand the underrepresented in medicine pipeline into medicine and pathology. Since 2016, fourteen outreach presentations have been delivered. The number of rotators increased from 1 in 2013 to 18 in July 2019. Rotators self-identified as African, African American, Hispanic, and Native American. Most were second- to fourth-year medical students, and 1 was a pathology resident. Six rotators are currently pathology residents, and others are strongly considering applying to pathology. The outreach efforts account for the success of our rotation, which, in turn, has had a positive impact on interest in pathology. However, we recognize barriers to retention and intend to incorporate additional professional development activities to further address equity.

Iatrogenic Kaposi's Sarcoma in an HIV-Negative Young Male With Crohn's Disease and IgA Nephropathy: A Case Report and Brief Review of the Literature.

BACKGROUND: Kaposi's sarcoma (KS) is a vascular tumor arising in association with human herpesvirus-8 (HHV-8) infection, and different variants show different clinical presentations. Isolated intestinal KS in the background of Crohn's disease (CD) is exceedingly rare with only 3 cases reported in the English literature (from 1966 to 2016). CASE PRESENTATION: Herein, we report a case of intestinal KS in a 21-year-old HIV-negative Ethiopian male with a long-standing history of steroid therapy for his underlying IgA nephropathy. Recent gastrointestinal biopsies confirmed an additional diagnosis of CD. Despite the addition of Infliximab to his therapy, his CD remained refractory, and a laparoscopic-assisted ileocolectomy was performed to alleviate a partial small bowel obstruction. Examination of his terminal ileum demonstrated a polypoid mass with adjacent incidental ileal submucosal nodules. These nodules were composed of plump spindle cells with scattered mitoses and vascular channels with extravasated red blood cells. Intratumoral hyaline globules were also noted. Immunohistochemistry revealed HHV-8 positivity, confirming the histologic impression of KS. CONCLUSIONS: Here we report the fourth case of KS in CD in an HIV-negative patient and only the third case of isolated intestinal KS in the setting of CD. A review of the literature suggests that attenuation of immunosuppressive therapy may be adequate management of iatrogenic KS in the absence of a systemic HHV-8 infection.

A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma.

BACKGROUND: The KRAS oncogene is a driver mutation and is present in greater than 90% of pancreatic ductal adenocarcinomas (PDAC). A subset of these tumors, however, do not harbor mutations in KRAS (wild type KRAS). Studies have shown that patients with mutated KRAS have a poorer survival on first-line gemcitabine-based chemotherapy compared to wild type KRAS. In this study, we examined a cohort of patients with PDAC at our institution who were either wild type or mutant for the KRAS gene and assessed for differences in survival and response to different chemotherapeutic regimens. METHODS: We examined clinical records of patients treated at the Abramson Cancer Center of the University of Pennsylvania from 2013 to 2017. Patients with a pancreatic mass and a histologic diagnosis of pancreatic or pancreaticobiliary adenocarcinoma were identified. Thirty-nine patients with PDAC who underwent tumor sequencing at Penn Medicine's Center for Personalized Diagnostics (CPD) were selected for further study. Twelve patients were identified whose tumors were KRAS wild type. Twenty-seven patients with PDAC whose tumors harbored KRAS mutations were selected as controls (KRAS mutant). RESULTS: We noted a longer overall survival (OS) among KRAS wild type patients compared to KRAS mutant patients (P=0.026). This was independent of the age at diagnosis, patient gender, stage of diagnosis, tumor morphology, mismatch repair (MMR) status, and chemotherapeutic regimen. CONCLUSIONS: Similar to previously reported studies, PDAC with a KRAS wild type mutational profile has a better prognosis with a longer OS. This improved prognosis is independent of the protocol utilized in therapy for these patients. Our findings suggest that future clinical trials in pancreatic cancer should take into consideration the presence of KRAS mutations in their pre-planned analysis when assessing the efficacy of a novel therapeutic approach. This may be a crucial factor in trial concepts and outcomes.

Well-child care clinical practice redesign for young children: a systematic review of strategies and tools.

BACKGROUND AND OBJECTIVE: Various proposals have been made to redesign well-child care (WCC) for young children, yet no peer-reviewed publication has examined the evidence for these. The objective of this study was to conduct a systematic review on WCC clinical practice redesign for children aged 0 to 5 years. METHODS: PubMed was searched using criteria to identify relevant English-language articles published from January 1981 through February 2012. Observational studies, controlled trials, and systematic reviews evaluating efficiency and effectiveness of WCC for children aged 0 to 5 were selected. Interventions were organized into 3 categories: providers, formats (how care is provided; eg, non-face-to-face formats), and locations for care. Data were extracted by independent article review, including study quality, of 3 investigators with consensus resolution of discrepancies. RESULTS: Of 275 articles screened, 33 met inclusion criteria. Seventeen articles focused on providers, 13 on formats, 2 on locations, and 1 miscellaneous. We found evidence that WCC provided in groups is at least as effective in providing WCC as 1-on-1 visits. There was limited evidence regarding other formats, although evidence suggested that non-face-to-face formats, particularly web-based tools, could enhance anticipatory guidance and possibly reduce parents' need for clinical contacts for minor concerns between well-child visits. The addition of a non-medical professional trained as a developmental specialist may improve receipt of WCC services and enhance parenting practices. There was insufficient evidence on nonclinical locations for WCC. CONCLUSIONS: Evidence suggests that there are promising WCC redesign tools and strategies that may be ready for larger-scale testing and may have important implications for preventive care delivery to young children in the United States.