Increasing access to pathology services in low- and middle-income countries through innovative use of telepathology.

INTRODUCTION: In low- and middle-income countries (LMICs), surgical care can be limited by access to pathology services. In Uganda, the pathologist-to-population ratio is less than 1 to 1 million people. The Kyabirwa Surgical Center in Jinja, Uganda, created a telepathology service in collaboration with an academic institution in New York City. This study demonstrated the feasibility and considerations of implementing a telepathology model to supplement the critical pathology needs of a low-income country. METHODS: This was a retrospective, single-center study of an ambulatory surgery center with pathology capability using virtual microscopy. The remote pathologist (also known as a telepathologist) controlled the microscope and reviewed histology images transmitted across the network in real time. In addition, this study collected demographics, clinical histories, the surgeon's preliminary diagnoses, and the pathology reports from the center's electronic medical record. RESULTS: Nikon's NIS Element Software was used as a dynamic, robotic microscopy model with a video conferencing platform for communication. An underground fiber optic cable established Internet connectivity. After a two-hour tutorial session, the lab technician and pathologist were able to proficiently use the software. The remote pathologist read (1) pathology slides with inconclusive reports from external pathology labs, and (2) tissues labeled by the surgeon as suspicious for malignancy, which belonged to patients who lacked financial means for pathology services. Between April 2021 and July 2022, tissue samples of 110 patients were examined by a telepathologist. The most common malignancies on histology were squamous cell carcinoma of the esophagus, ductal carcinoma of the breast, and colorectal adenocarcinoma. CONCLUSION: With the increasing availability of video conference platforms and network connections, telepathology is an emerging field that can be used by surgeons in LMICs to improve access to pathology services, confirming histological diagnosis of malignancies to ensure appropriate treatment.

Whole-exome analysis of metaplastic breast carcinomas with extensive osseous differentiation.

AIMS: Metaplastic breast carcinoma (MBC) is a rare type of triple-negative breast cancer that shows vast histological and genetic heterogeneity. Osseous differentiation can be found in different subtypes of MBC. Whether MBCs with osseous differentiation are underpinned by specific genetic alterations has yet to be defined. The aim of this study was to investigate the repertoire of somatic mutations and copy number alterations (CNAs) in three MBCs with extensive osseous differentiation. METHODS AND RESULTS: Tumour and normal DNA samples from three MBCs with extensive osseous differentiation were subjected to whole-exome sequencing. Somatic mutations, CNAs and mutational signatures were determined by use of a validated bioinformatics pipeline. Our analyses revealed clonal TP53 hotspot mutations associated with loss of heterozygosity of the wild-type allele coupled with mutations affecting genes related to the Wnt and/or the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathways in all cases analysed. All cases showed a dominant mutational signature 1, with two cases showing a secondary signature 3 in addition to other features of homologous recombination DNA repair defects. The oncostatin M receptor gene, which plays a role in mesenchymal differentiation and bone formation, was found to be mutated in two MBCs with extensive osseous differentiation and in none of 35 previously published 35 MBCs. CONCLUSION: Our findings suggest that MBCs with osseous differentiation have somatic mutations similar to those of other forms of MBC.

Resolution of whipple disease-induced pulmonary hypertension following antibiotic therapy.

Whipple disease is a disorder caused by Tropheryma whipplei, a ubiquitous Gram-positive bacillus. In addition to gastrointestinal manifestations, many other systems may be involved in Whipple disease. Pulmonary hypertension (PH) is a rare manifestation of Whipple disease, and its clinical course is not well established. We report a case of a 45-year-old woman who presented with typical gastrointestinal manifestations of Whipple disease, which was diagnosed by duodenal biopsy. She was also noted to have elevated pulmonary arterial pressures on transthoracic echocardiography. There was no evidence of left-sided valvular disease, hypertrophy, or dyskinesis, and there was no evidence of endocarditis. The patient was started on intravenous ceftriaxone for 6 weeks and then transitioned to oral trimethoprim-sulfamethoxazole for a year. The patient demonstrated clinical improvement, endoscopic and histologic improvement, and also resolution of PH. This is the third reported case of PH that is convincingly secondary to Whipple disease that resolved after appropriate antibiotic therapy.

Benign phyllodes tumour in a transgender woman receiving hormonal therapy.

We present a case of a transwoman taking hormonal feminisation therapy for over 20 years, who underwent surgical excision of a benign phyllodes tumour of the breast. Hormones progesterone and oestrogen act on breast epithelium to increase proliferation. For ciswomen, endogenous and exogenous oestrogen exposure over a lifetime is associated with increased risk for certain benign and malignant breast pathologies. Transwomen taking hormonal therapy may also be at an increased risk of breast disease.

A Rare Case of Breast Metastatic Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumor (GIST) is one of the most common spindle cell neoplasms of the alimentary system, and can arise anywhere along the gastrointestinal tract (GI). Its incidence rate is up to 22 cases per million, with a minor geographic variation. GIST is thought to originate from interstitial cell of Cajal, and its pathogenesis is related to molecular defects, such as KIT receptor tyrosine kinase or platelet-derived growth receptor alpha gene activation. While the majority of GISTs are known to show a benign disease course, metastases of high-grade forms to different organ systems have been seldom reported. We present a case with an unprecedented metastasis of GIST to the breast. The patient is a 62-year-old female with a history of the primary resection of GIST from the small intestine. Her disease course was initially complicated by multiple metastases, solely localized to the liver for which she had a living-donor liver transplant. The tumor harbored both KIT exon 11 and exon 17 mutation. Fourteen months post-transplant, the patient was found to have metastatic GIST on her breast biopsy. GIST metastasis to the breast is extremely rare. A consideration of this spindle cell neoplasm as a differential is recommended when clinical suspicion arises. The pathophysiology, current diagnostic tool, grading system, and treatment of this tumor are discussed.

Measuring Invasive Breast Carcinoma on Core Biopsy-Is It Necessary?

CONTEXT.­: Pathologic tumor size is significant in the treatment of breast carcinoma and is routinely measured on excision. OBJECTIVE.­: To analyze the need for measuring size of invasive mammary carcinoma on biopsy. DESIGN.­: Nine hundred twenty-two cases of invasive carcinoma whose size was measured (greatest linear measurement) on biopsy and excision was correlated, including imaging when available (110 cases). RESULTS.­: Patient mean age was 62 years. Most (90%; 830 of 922) carcinomas were ductal and sampled by ultrasound and graded as follows: well, 13% (113 of 922); moderately, 58% (532 of 922), and poorly differentiated, 28% (258 of 922); 19 microinvasive not graded. Tumor mean size was 7.5 mm on biopsy and 14.4 mm on excision. Biopsy modality was as follows: ultrasound, 7.8 mm (92%, 844 of 922); mammotome, 3.3 mm (7%, 65 of 922); and magnetic resonance imaging, 5.9 mm (1%, 13 of 922). Size comparison on biopsy versus excision was biopsy > excision: 8% (72 of 922), biopsy = excision: 10% (95 of 922), and biopsy < excision: 82% (755 of 922). Half (36 of 72) of the biopsy > excision tumors were less than 5 mm, 96% (726 of 755) of biopsy < excision tumors were greater than 5 mm, while those equal on both were predominantly (88%, 84 of 95) less than 10 mm, 20% (19 of 95) of which were microinvasive. Stage changed in 600 cases, staging based on excision in 581 (63%), and staging based on biopsy in 19 (2%). Radiologic-pathologic correlation (n = 110) showed perfect concordance in 11 (10%), 83 (75%) were ±1 to 2 mm, and 16 (15%) were ± more than 3 mm. Difference between the biopsy and excision ranged from a lower limit of 1.3 mm for T1a tumors to 18 mm for T2. CONCLUSIONS.­: While most carcinomas are larger on excision, 18% (167 of 922) are larger or equal on biopsy. Factors predictive of biopsy > excision tumors include stage 1 tumors (P < .001), especially less than 5 mm, and sampled by mammotome. We recommend measuring invasive carcinoma on biopsy and excision.

Variability in the identification of lymphovascular space invasion for early stage cervical cancer.

OBJECTIVE: To evaluate the inter- and intra-rater variability of lymphovascular space invasion (LVSI) in early stage cervical cancer. METHODS: We identified invasive cervical cancer tissue samples from radical hysterectomies in our institutional pathology database. The cases were stained with Hematoxylin & Eosin (H&E) and immunostains (CD-31 and D2-40). They were evaluated for the presence of LVSI by 6 pathologists on 3 separate occasions: with H&E staining only, then with H&E and immunostained specimens, and finally using a shared written criterion for diagnosis of LVSI. With 80 cases, a two-sided 95% confidence interval for the Kappa of 0.7 with a precision of 0.1 on each side was estimated. RESULTS: Stage distribution was: IA 10%, IB 85%, and IIA 5%. The majority of cases were squamous cell carcinoma (55%), followed by adenocarcinoma (39%) and adenosquamous or other histology (6%). The mean inter-rater Kappa was 0.41 (95% CI: 0.37-0.45) for H&E. Usage of immunohistochemistry made a statistically significant improvement in the mean Kappa, but it still remained low: 0.52 (p = 0.02). Adding evaluation criteria for LVSI did not significantly increase the mean Kappa: 0.49 (p = 0.16). The mean intra-rater variability of H&E staining alone compared with H&E staining plus immunostaining was 0.53 (range: 0.43-0.64). The mean Kappa comparing H&E staining and H&E staining with criteria was 0.50 (range: 0.40-0.59). CONCLUSIONS: We noted high inter- and intra-rater variability in the diagnosis of LVSI underscoring the challenges of LVSI diagnosis. Considering the significance assigned to LVSI and its implication for treatment, comprehensive guidelines with regards to determination of LVSI status are of paramount importance.

Impact of pathological response after neoadjuvant chemotherapy on adjuvant therapy decisions and patient outcomes in gastrointestinal cancers.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is frequently used in gastrointestinal cancers (GIC), and pathological, radiological, and tumor marker responses are assessed during and after NAC. AIM: To evaluate the relationship between pathologic, radiologic, tumor marker responses and recurrence-free survival (RFS), overall survival (OS), adjuvant chemotherapy (AC) decisions, and the impact of changing to a different AC regimen after poor response to NAC. METHODS AND RESULTS: Medical records of GIC patients treated with NAC at Mount Sinai between 1/2012 and 12/2018 were reviewed. One hundred fifty-six patients (58.3% male, mean age 63 years) were identified. Primary tumor sites were: 43 (27.7%) pancreas, 62 (39.7%) gastroesophageal, and 51 (32.7%) colorectal. After NAC, 31 (19.9%) patients had favorable pathologic response (FPR; defined as College of American Pathologists [CAP] score 0-1). Of 107 patients with radiological data, 59 (55.1%) had an objective response, and of 113 patients with tumor marker data, 61 (54.0%) had a ≥50% reduction post NAC. FPR, but not radiographic or serological responses, was associated with improved RFS (HR 0.28; 95% CI 0.11-0.72) and OS (HR 0.13; 95% CI 0.2-0.94). Changing to a different AC regimen from initial NAC, among all patients and specifically among those with unfavorable pathological response (UPR; defined as CAP score 2-3) after NAC, was not associated with improved RFS or OS. CONCLUSIONS: GIC patients with FPR after NAC experienced significant improvements in RFS and OS. Patients with UPR did not benefit from changing AC. Prospective studies to better understand the role of pathological response in AC decisions and outcomes in GIC patients are needed.

Effects of growth hormone secretion on body composition in patients with Crohn's disease.

Crohn's disease is a multisystem disorder characterized by chronic intestinal inflammation. Accumulation of mesenteric fat occurs in patients with Crohn's disease, although the mechanisms underlying site-specific changes in adipose deposition are unclear. To investigate whether there are alterations in site-specific adipose deposition in patients with Crohn's disease and to determine hormonal influences that may underlie such changes, we investigated body composition and serum hormone levels in 20 men with Crohn's disease (mean age, 45 +/- 2 yr) and 20 age-, gender-, and body mass index-matched normal controls (mean age, 43 +/- 3 yr). None of the Crohn's patients was receiving glucocorticoid therapy. Subjects underwent hourly GH sampling for 12 h beginning at 2000 h and fasting serum IGF-I and testosterone measurements. Body composition was assessed by quantitative computed tomography of the abdomen and bioelectrical impedance analysis. In the Crohn's disease and control subjects, mean serum GH levels were 1.07 +/- 0.2 and 1.7 +/- 0.2 ng/ml (P = 0.06), serum IGF-I levels were 162.7 +/- 10.5 and 194.8 +/- 15.7 ng/ml (P = 0.1), and serum testosterone levels were 489 +/- 33 and 514 +/- 38 ng/ml (P = NS), respectively. Percentage body fat was significantly higher in the Crohn's patients (21 +/- 0.8% vs. 17.7 +/- 0.9%, respectively; P = 0.013). Intraabdominal fat (IAF) was significantly higher in the Crohn's subjects vs. controls (115 +/- 11 vs. 69 +/- 7 cm(2), respectively; P = 0.001). The ratio of intraabdominal to total body fat was higher in the Crohn's subjects than in the controls (0.4 +/- 0.1 vs. 0.3 +/- 0.1, respectively; P = 0.025). Subcutaneous fat area was similar in the two groups. IAF was higher in Crohn's patients even when controlling for testosterone and mean serum GH. Mean serum GH contributed independently to the differences in IAF (P = 0.001). The ratio of IAF to total body fat remained higher in the Crohn's subjects when controlling for serum testosterone, but was no longer significant in a model that also included IGF-I and mean serum GH. GH levels contributed independently to the differences in the intraabdominal to total body fat ratio (P = 0.02). In the Crohn's patients, serum GH correlated negatively with intraabdominal and total body fat and the ratio of intraabdominal to total body fat. Crohn's disease is associated with an increase in central fat accumulation, with more IAF and a higher ratio of intraabdominal to total body fat compared with controls. Although serum GH levels were similar in the two groups, GH contributed significantly to the abdominal fat measurements. These data show that GH has an important role in modulating visceral fat distribution in patients with Crohn's disease.

The prognostic role of ERG immunopositivity in prostatic acinar adenocarcinoma: a study including 454 cases and review of the literature.

TMPRSS2/ERG fusion is among the most frequent genetic anomalies in prostate adenocarcinomas. Although positive immunostaining for ERG has been shown to tightly correlate with ERG fusion status, the clinical and prognostic significance of a positive ERG stain remains undetermined. The significance of ERG immunostaining in 454 consecutive prostate adenocarcinomas from radical prostatectomies (RPs) using tissue microarrays, herein, is evaluated. A separate set of 59 cases of incidental prostate adenocarcinoma detected on transurethral resection of prostate with a Gleason score of 6 was also included. ERG translocation was significantly more common in peripheral zone cancer in comparison with cancer of the transitional zone (33% in RP versus 5% in transurethral resection of prostate specimens). In the RP cohort, although ERG positivity was significantly associated with younger age at presentation and lower prostate-specific antigen values, it showed no association with Gleason score or with pathologic stage. In multivariate analysis, biochemical recurrence was only associated with the final RP Gleason score and elevated prostate-specific antigen levels and was unrelated to neither ERG positivity or to its staining intensity. In our hands, ERG positivity was unrelated to either aggressive local tumor characteristics or a worse outcome. Our results, as well as an extensive review of the related literature showing conflicting findings, seem to indicate that ERG immunopositivity cannot be considered as an important prognostic factor in prostate cancer.

Primary Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) of the penis: a report of an extraordinarily unusual site and a literature review of extraskeletal Ewing's sarcoma.

Ewing's sarcomas/primitive neuroectodermal tumors (ES/PNETs) arise from a multipotent progenitor cell and are considered to be of neuroectodermal derivation. Most tumors commonly arise in the skeletal system, which are the classic ES/PNET and occasionally occur in the soft tissue of extraskeletal sites, which are named extraskeletal Ewing's sarcomas (EES/PNET). This study reports a case of a 28-year-old man with primary EES/PNET of the penis.

Prognostic factors in T1 bladder urothelial carcinoma: the value of recording millimetric depth of invasion, diameter of invasive carcinoma, and muscularis mucosa invasion.

pT1 bladder urothelial carcinomas represent a heterogeneous group of tumors with different biologic behaviors, and identifying the subset of tumors that carries a high risk of disease recurrence and progression is therefore important. We evaluated the prognostic significance of substaging 86 cases of pT1 bladder urothelial carcinoma based on different pathologic parameters. The mean tumor depth was 1.1 mm, and the mean diameter of the invasive focus was 2.2 mm. The mean number of tissue fragments with invasion was 4.4. Lymphovascular invasion and concomitant carcinoma in situ were present in 13% and 45% of cases, respectively. Although 56% of patients recurred, 18% experienced disease progression. Multivariate analysis showed a significant association between muscularis mucosa invasion (P = .007), depth of invasion (P = .0001), diameter of invasive focus (P = .014), and progression. Furthermore, depth of invasion more than 3 mm was significantly associated with progression of disease, achieving a sensitivity of 31%, specificity of 99%, and predictive value of 79%. In comparison, the cutoff values for the diameter of invasive carcinoma that correlated best with outcome was 6 mm for progression. Lastly, combining both variables showed a strong prognostic accuracy where it predicted 94% of recurrences. Importantly, all cases with depth of invasion more than 3 mm and diameter more than 6 mm progressed. Lymphovascular invasion or concomitant carcinoma in situ did not correlate with outcome. From the current data, we do recommend reporting muscularis mucosa invasion whenever possible. Alternatively, tumor depth and tumor diameter should be included in the final pathology report in individual cases in which muscularis mucosa invasion cannot be assessed.