Communicating uncertainty in pathology reports: a descriptive study from a specialized cancer center.

Pathologists use certain terminologies to communicate uncertainty in pathology reports. The message conveyed in pathology reports may be interpreted differently by clinicians leading to possible miscommunication. We aimed to compare the interpretation and impact of uncertainty phrases between pathologists and clinicians. A survey with examples of uncertain diagnoses containing ("suspicious for", "indefinite for", "favor", "cannot exclude", "suggestive of", "compatible with", "cannot rule out", "highly suspicious for" and "consistent with") was sent to pathologists and clinicians. For each diagnosis, participants assigned a level of certainty from 1 to 10 and were asked whether they would recommend treatment based on such phraseology. Thirty-six responses (from 7 pathologists, 10 surgeons, 8 pediatric oncologists, 8 medical oncologists, 2 radiation oncologists and 1 diagnostic radiologist) were received. Pathologists had a narrower range of uncertainty compared to clinicians. Wide variation between both groups was seen for all phrases except "compatible with" and "highly suspicious for". 'Indefinite for' showed the lowest mean of certainty (4.67 for pathologists; 4.00 for clinicians) whereas 'consistent with' had the highest (8.83 for pathologists and 9.38 for clinicians). There was a significant difference in the degree of certainty between both groups for "compatible with" (7.83 for pathologists and 9.06 for clinicians, p = .009). For treatment decisions, pathologists and clinicians agreed on initiating treatment when "consistent with" and "compatible with" were used and gave variable responses for the other terms. They proposed opposing treatment recommendations for "favor". Pathologists and clinicians varied in interpretation of uncertainty phrases which may impact treatment.

Unmasking Coincident Hodgkin Lymphoma and Giant Cell Tumor: Insights from [18F] FDG PET/CT.

Tenosynovial giant cell tumors represent a group of typically non-malignant tumors found within the joints and soft tissues. The occurrence of tenosynovial giant cell tumor alongside hematologic malignancies is an infrequent finding. Herein, we report a patient who presented with coinciding Hodgkin Lymphoma (HL) and tenosynovial giant cell tumor before chemotherapy initiation. The case was discovered during initial assessment using [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) imaging for HL staging. An unrelated hypermetabolic mass within the left knee joint led to the discovery of this unusual case, which led to a CT-guided biopsy and tenosynovial giant cell tumor discovery. This was clearly demonstrated in interim and end-of-therapy PET/CT studies when all lymphomatous lesions had resolved but the tenosynovial giant cell tumor remained. This case serves as a reminder of the intricate nature of oncological pathology and emphasizes the need for thorough and vigilant diagnostic evaluation for optimal management plan.

A Rare Case of Nasal Sarcoma with BCOR Internal Tandem Duplication Showing Complete Pathologic Response to the VDC-IE Chemotherapy Protocol.

Sarcoma with BCOR genetic alteration is an exceptionally rare and emerging subtype of sarcoma. It is categorized into two types: BCOR-related gene fusions such as BCOR::CCNB3 sarcomas and other BCOR-rearranged sarcoma and sarcomas with internal tandem duplication of BCOR genes such as infantile undifferentiated round cell sarcomas and primitive myxoid mesenchymal tumors of infancy. BCOR::CCNB3 sarcomas predominantly arise in bone rather than soft tissue and exhibit a higher occurrence in children and adolescent males, whereas sarcomas with BCOR internal tandem duplication show a wider age range but usually arise in the first year of life. Due to their rarity, there is ongoing debate and uncertainty regarding the best treatment approach, with a lack of specific clinical trials addressing these tumors. In this report, we present a unique case of sarcoma with internal tandem duplication of BCOR gene originating in the nasal region. The tumor was successfully and completely resected using the standard VDC-IE chemotherapy protocol, resulting in an unprecedented 100 percent tumor necrosis. The patient has completed the protocol and remains recurrence-free 13 months after diagnosis. This case suggests potential efficacy of the standard VDC-IE protocol in achieving remarkable responses in BCOR rearrangement sarcomas, including the internal tandem duplication subtype. However, further studies are needed to determine the optimal treatment strategies for this disease.

The O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and clinical outcomes of Ewing sarcoma patients treated with irinotecan and temozolomide.

Background: There remains an unmet need to identify molecular biomarkers in Ewing sarcoma (ES). We sought to assess the influence of the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation on response and progression-free survival (PFS) following initiation of irinotecan and temozolomide (IT), PFS following initiation of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VDC-IE), and overall survival (OS). Materials and methods: Data of advanced ES patients, treated with IT were retrospectively collected. Patients were required to have progression after prior VDC-IE. MGMT promoter methylation was assessed on non-decalcified Formalin-fixed paraffin embedded (FFPE) tissue using methylation sensitive restriction enzyme-quantitative PCR (MSRE-qPCR). Survival was estimated by the Kaplan-Meier method. Results: A total of 20 ES patients underwent MGMT promoter methylation testing, and were eligible for analysis. Five patients (25%) had methylated MGMT, whereas the remaining (15; 75%) had unmethylated promoter. Five (25%) had objective response to IT, with no observed difference by promoter methylation (p = 0.76). Median PFS from initiation of IT for methylated vs. unmethylated MGMT patients was 4.9 and 1.2 months, respectively, p = 0.69. Median PFS from date of initiation of VDC-IE was significantly superior in the methylated group; 27.8 vs. 8.6 months, p = 0.034. Median OS was superior but not statistically significant in the methylated group. Conclusion: MGMT-promoter methylation did not correlate with clinical activity or outcomes following the IT regimen for advanced ES. However, methylated MGMT predicted significantly superior PFS following initiation of the standard VDC-IE protocol.

Challenging Results on FDG PET/CT in a Patient with Uncontrolled Celiac Disease and small bowel adenocarcinoma.

Celiac disease (CD) is a chronic immune-mediated enteropathy that is caused by both environmental (gluten) and genetic (human leukocyte antigen (HLA) and non-HLA genes) factors. Patients may be asymptomatic or exhibit atypical symptoms, necessitating a high index of suspicion for proper diagnosis. The evaluation of CD patients with 18F-FDG PET/CT imaging can be difficult, owing to the fact that this disease is inflammatory in nature. Typical 18F-FDG PET/CT gastrointestinal manifestations of celiac disease include increased multifocal or diffuse bowel uptake, whereas single short segmental uptake is rarely encountered; thus, awareness of this wide range of findings is important to guide physicians through proper management and outcome. We report a case of small intestine adenocarcinoma and known CD complaining of recent episodes of diarrhea and weight loss that had a suspicious small bowel wall thickening that corresponds to a short segmental hypermetabolic process on FDG PET/CT follow-up scan. The patient was then referred to the gastroenterology department and underwent a colonoscopy, a biopsy was taken that revealed CD and was negative for malignancy. Furthermore, 6 months later the abovementioned segmental FDG activity was completely resolved without any treatment received at the given time.

Urinary bladder metastasis from primary breast cancer, a rare and challenging diagnosis. A case report and literature review.

Introduction: and Importance: Liver, lung, bone and brain are usual sites for breast cancer metastases. However, colorectal, prostate and cervical tumors may directly invade the urinary bladder (UB), but hematogenous spread from distant organs like the breast, is extremely rare and may indicate poor prognosis. Case presentation: Here we describe the case of a 78-year-old female patient who was diagnosed with de novo metastatic breast cancer; initially to the bone and pleura with effusion, and then to the brain. Five years after her initial diagnosis, she presented with urinary symptoms and bilateral hydronephrosis. Work up showed diffuse thickening of the UB with no invasion from nearby structures; biopsy confirmed metastatic carcinoma of breast origin. Clinical discussion: Adenocarcinoma of the UB is uncommon. Distinguishing primary adenocarcinoma of the UB from secondary involvement is often challenging. When encountered, involvement by a secondary tumor, either by direct extension or distant metastasis, should be considered. Immunohistochemical stains are essential in reaching an accurate diagnosis. Conclusions: Breast cancer rarely metastasizes to the urinary bladder and prognosis is usually poor. Detailed medical history, imaging, and immunohistochemical studies on biopsy specimen should help reach accurate diagnosis.

Primary Clear Cell Sarcoma of the Lung: a Case Report.

BACKGROUND: Clear Cell Sarcoma of Soft Tissue (CCSST), or melanoma of the soft part, is a rare, aggressive tumor that originates in the aponeurosis and fasciae of the distal parts of the extremities. Reports from other sites of the body are rare. OBJECTIVE: We are reporting an extremely rare tumor that presented as a central left-sided lung mass and found to be clear cell sarcoma of soft tissue. METHODS: We report a 24-year-old male patient presented with recurrent attacks of left-sided chest pain associated with cough and dyspnea. RESULTS: Imaging showed a central left-sided 8*5.5*5 cm lung mass. The age of the patient and the radiological characteristics of the lesion were suggestive of a benign pathology. After histopathological assessment of the lesion, suspicion of the malignant process was raised, mainly melanoma of soft part and PEComa. The patient underwent left-sided pneumonectomy. The postoperative histological examination, immunohistochemical findings including positive staining for S-100, HMB-45, and Melan-A, and positive FISH study for EWSR1 gene rearrangements supported the diagnosis of CCSST originating primarily in the major fissure of left the lung. CONCLUSION: The rarity of CCSST in general and tumors originating in the lung primarily raise the challenges in hypothesizing a differential diagnosis, choosing proper investigations and treatment methods. The histological examination, immunohistochemical, and cytogenetics of the tumor are mandatory to reach the final diagnosis.

Intratumoral talimogene laherparepvec injection with concurrent preoperative radiation in patients with locally advanced soft-tissue sarcoma of the trunk and extremities: phase IB/II trial.

BACKGROUND: Soft-tissue sarcomas (STS) in the extremities and trunk treated with standard-of-care preoperative external beam radiation therapy (EBRT) followed by surgical resection are associated with local and distant relapses. In preclinical studies, oncolytic virotherapy in sarcoma has demonstrated antitumor effects via direct intratumoral oncolysis and cytotoxic T-cell-mediated immune responses. Talimogene laherparepvec (TVEC) is a replication-competent, immune-enhanced, oncolytic herpes simplex virus type 1 engineered for intratumoral injection; it has been approved by the FDA for the treatment of locally advanced and metastatic melanoma. METHODS: We explored a novel combination of TVEC with standard-of-care EBRT administered preoperatively in patients with locally advanced STS of the extremities and trunk in a phase IB/II clinical trial. Thirty patients with primary STS >5 cm for which EBRT was indicated to achieve negative margins were enrolled. FDA-approved TVEC doses were used. Immune correlative studies in peripheral blood, biopsy and resected tumor tissues were performed. RESULTS: No dose-limiting toxicity was observed. Adverse events were similar to those reported in prior studies with TVEC. One patient with myxoid liposarcoma exhibited a partial response. Seven of the 29 (24%) evaluable patients achieved 95% pathological necrosis. None of the patients developed a herpes infection due to the treatment. Eight of the 29 (27%) patients developed postoperative wound complications, which is consistent with previous studies. None of the patients developed local recurrence after surgical resection of the primary sarcoma. 2-year progression-free and overall survival were 57% and 88%, respectively. Caspase-3 demonstrated increased expression of both in TVEC-treated tissue samples as compared with control samples treated with radiation alone. CONCLUSION: Preoperative intratumoral TVEC with concurrent EBRT for locally advanced STS is safe and well-tolerated. This combination treatment may enhance immune responses in some cases but did not increase the proposed rate of pathological necrosis. The Caspase-3 biomarker may be associated with a positive effect of TVEC in sarcoma tumor tissue and should be explored in future studies. TRIAL REGISTRATION NUMBER: NCT02453191.

ALK-Positive Histiocytosis: A Case Report and Literature Review.

ALK positive histiocytosis is a relatively new histiocytic proliferation disease with a characteristic gene translocation involving fusion of the ALK gene with different partners, mostly KIF5B. We report a case of ALK-positive histiocytosis with literature review. A 27-year-old male patient presented mainly with progressive lower limb weakness. Imaging studies showed an intradural extramedullary enhancing lesion at the L3 level. A 1.5 cm mass was excised from the sensory nerve root in the filum terminale at the level of L3. Histologic examination showed infiltration of the nerve by numerous histiocytes with moderate to abundant eosinophilic to clear-foamy and variably-vacuolated cytoplasm with irregular-to-smooth contoured nuclei. The histiocytes were positive for CD68 and ALK1 and negative for S100 and CD1a. KIF5B-ALK fusion was detected by real time-polymerase chain reaction. The patient is asymptomatic nine months after surgical excision. This is the first reported localized case occurring in the nerve root of an adult patient, thus expanding the clinical manifestations of this disease. An integrated histological, immunohistochemical and molecular approach is recommended for diagnosis. We recommend performing ALK1 immunohistochemical stain on all histiocytosis cases to increase awareness and detection of this newly described entity.

Retrospective implementation of the Milan system for reporting salivary gland cytopathology; a review of 5 years in a specialized cancer center.

BACKGROUND: The Milan system for reporting salivary gland cytopathology (MSRSGC) aims to standardize terminology, facilitate communication, and optimize management by providing risk of malignancy (ROM) for each category. Our retrospective cohort aims to study the reproducibility of reporting using the MSRSGC and to calculate the ROM for each category. METHODS: Cases of fine needle aspiration (FNA) of salivary glands and related cervical lymph nodes were retrieved from our files between 2015 to 2019. From a total of 63 cytology cases, 57 cases had available material for cytological reexamination of which 45 cases had follow up data. All cases were reviewed independently by two pathologists and reclassified based on the MSRSGC. The reclassification of cases for both pathologists was compared and the ROM for each diagnostic category was calculated. RESULTS: The 57 cases were studied. Both pathologists had initial concordance in classification of 52 of 57 cases. The remainder five cases were concurred upon after combined review. The cases were classified as: Non Diagnostic (ND); (n = 8), Non Neoplastic (NN); (n = 7), Atypia of Undetermined Significance (AUS); (n = 8), Neoplasm Benign (NB) (n = 10), Salivary Gland Neoplasm of Uncertain Malignant Potential (SUMP) (n = 5), Suspicious for Malignancy (SM) (n = 1) and Malignant (M) (n = 18). The ROM was: ND: (33.3%); NN: (0%); AUS (33.3%); NB (0%); SUMP (25%); SM (100%) and M (100%). CONCLUSION: Applying the MSRSGC is reproducible which facilitates standardization of reports and stratifying cases preoperatively. In general, the ROM for our cases was close to that reported in the literature.

The epidemiology of lymphoma in Jordan: A nationwide population study of 4189 cases according to World Health Organization classification system.

OBJECTIVE/BACKGROUND: Lymphoma is a common human cancer that shows a variable geographic incidence worldwide. It is the fourth most common cancer in Jordan. Systemic reports of descriptive epidemiology on lymphoma from the Middle East are limited. METHODS: A nationwide multi-institutional retrospective study was conducted covering all major hospitals and laboratories that provide diagnostic services. We collected data on all cases diagnosed with lymphoma between 2014 and 2019. The included variables were patients' age, gender, anatomic site, and the histologic type according to the World Health Organization classification system. RESULTS: A total of 4189 cases were diagnosed with lymphoma. There was a statistically significant gender difference (p < .05), as 57.5% of patients were males. The peak incidence occurred at age 25-55 years. There were 1,652 (39%) cases of Hodgkin lymphoma (HL) and 2,537 (61%) of non-Hodgkin lymphoma (NHL), where nodular sclerosis (67%) and diffuse large B-cell lymphoma (53%) were the most common subtypes, respectively. The average age-adjusted incidence rates per 100,000 population were 8.01 for all lymphomas, 4.33 for NHL, and 3.16 for HL and all remained stable over the 6 years. CONCLUSION: HL is the most common lymphoma in Jordan, with a percentage higher than most of reported studies in Asian and Western countries. It also shows a unimodal distribution of age-specific incidence rates, with a single peak in young adults. The incidence rate of HL is higher than Eastern countries but comparable to the West. In contrast, NHL demonstrates a lower incidence rate than Western countries but a similar distribution of subtypes, as mature T/natural killer-cell lymphomas were rare.

Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy and short-course radiotherapy followed by resection has been gaining recognition in the treatment of rectal cancer. Avelumab is a fully human immunoglobulin that binds Programmed Death-Ligand 1 (PD-L1) and prevents the suppression of the cytotoxic T cell immune response. This phase II trial evaluates the safety and pathologic response rate of short-course radiation followed by 6 cycles of mFOLFOX6 with avelumab in patients with locally advanced rectal cancer (LARC). METHODS: This study is prospective single-arm, multicenter phase II trial adopting Simon's two-stage. Short-course radiation is given over 5 fractions to a total dose of 25 Gy. mFOLFOX6 plus avelumab (10 mg/kg) are given every 2 weeks for 6 cycles. Total mesorectal excision is performed 3-4 weeks after the last cycle of avelumab. Follow up after surgery is done every 3 months to a total of 36 months. Adverse event data collection is recorded at every visit. RESULTS: 13 out of 44 patients with LARC were enrolled in the first stage of the study (30% from total sample size). All patients met the inclusion criteria and received the full short-course radiation course followed by 6 cycles of mFOLFOX6 plus avelumab. 12 out of the 13 patients completed TME while one patient had progression of disease and was dropped out of the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33-73) years. The first interim analysis revealed that 3 (25%) patients achieved pathologic complete response (pCR) (tumor regression grade, TRG 0) out of 12. While 3 (25%) patients had near pCR with TRG 1. In total, 6 out of 12 patients (50%) had a major pathologic response. All patients were found to be MMR proficient. The protocol regimen was well tolerated with no serious adverse events of grade 4 reported. CONCLUSION: In patients with LARC, neoadjuvant radiation followed by mFOLFOX6 with avelumab is safe with a promising pathologic response rate. Trial Registration Number and Date of Registration ClinicalTrials.gov NCT03503630, April 20, 2018. https://clinicaltrials.gov/ct2/show/NCT03503630?term=NCT03503630&draw=2&rank=1 .

Short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma.

BACKGROUND: Current standard practice for locally advanced rectal cancer (LARC) entails a multidisciplinary approach that includes preoperative chemoradiotherapy, followed by total mesorectal excision, and then adjuvant chemotherapy. The latter has been accompanied by low compliance rates and no survival benefit in phase III randomized trials, so the strategy of administering neoadjuvant, rather than adjuvant, chemotherapy has been adapted by many trials, with improvement in pathologic complete response. Induction chemotherapy with oxaliplatin has been shown to have increased efficacy in rectal cancer, while short-course radiation therapy with consolidation chemotherapy increased short-term overall survival rate and decreased toxicity levels, making it cheaper and more convenient than long-course radiation therapy. This led to recognition of total neoadjuvant therapy as a valid treatment approach in many guidelines despite limited available survival data. With the upregulation (PDL-1) expression in rectal tumors after radiotherapy and the increased use of in malignant melanoma, the novel approach of combining immunotherapy with chemotherapy after radiation may have a role in further increasing pCR and improving overall outcomes in rectal cancer. METHODS: The study is an open label single arm multi- center phase II trial. Forty-four recruited LARC patients will receive 5Gy x 5fractions of SCRT, followed by 6 cycles of mFOLFOX-6 plus avelumab, before TME is performed. The hypothesis is that the addition of avelumab to mFOLFOX-6, administered following SCRT, will improve pCR and overall outcomes. The primary outcome measure is the proportion of patients who achieve a pCR, defined as no viable tumor cells on the excised specimen. Secondary objectives are to evaluate 3-year progression-free survival, tumor response to treatment (tumor regression grades 0 & 1), density of tumor-infiltrating lymphocytes, correlation of baseline Immunoscore with pCR rates and changes in PD-L1 expression. DISCUSSION: Recent studies show an increase in PD-L1 expression and density of CD8+ TILs after CRT in rectal cancer patients, implying a potential role for combinatory strategies using PD-L1- and programmed-death- 1 inhibiting drugs. We aim through this study to evaluate pCR following SCRT, followed by mFOLFOX-6 with avelumab, and then TME procedure in patients with LARC. TRIAL REGISTRATION: Trial Registration Number and Date of Registration: ClinicalTrials.gov NCT03503630, April 20, 2018.

Novel Double Central Ray Amputation of the Third and Fourth Digits: Case Report and Literature Review.

Whenever partial hand amputations for soft tissue sarcomas are attempted, special consideration should be given to achieve a balance between complete resection associated with negative margins and preservation of functionality to the patient so that the hand can support the contralateral intact hand for bimanual activities. This difficult decision is even more challenging within the limited anatomical confines of the hand. Based on our literature review, this is the first case of double central 3rd and 4th ray amputation, as far as we know with good hand function, evaluated by the Musculoskeletal Tumor Rating Scale.

Metastatic poorly differentiated chordoma: the eyes do not see what the mind does not know

Chordoma is a rare tumor. It has unique clinical, pathological and immunohistochemical characteristics. Accurate diagnosis is essential as the tumor shows an aggressive clinical course and requires a multimodal therapeutic approach. A case with wide spread distant metastatic disease that was initially thought to represent metastatic thyroid carcinoma is presented. Appropriate clincopathologic correlation and the histologic findings raised the possibility of poorly differentiated chordoma. The diagnosis was confirmed by immunohistochemistry for INI-1 and Brachyury. The approach to the diagnosis emphasizing the clinical and pathologic findings of this case is discussed and reviewed in the context of the published literature.

Metastatic poorly differentiated chordoma: the eyes do not see what the mind does not know.

Chordoma is a rare tumor. It has unique clinical, pathological and immunohistochemical characteristics. Accurate diagnosis is essential as the tumor shows an aggressive clinical course and requires a multimodal therapeutic approach. A case with wide spread distant metastatic disease that was initially thought to represent metastatic thyroid carcinoma is presented. Appropriate clincopathologic correlation and the histologic findings raised the possibility of poorly differentiated chordoma. The diagnosis was confirmed by immunohistochemistry for INI-1 and Brachyury. The approach to the diagnosis emphasizing the clinical and pathologic findings of this case is discussed and reviewed in the context of the published literature.

Simultaneous detection of single-nucleotide variant, deletion/insertion, and fusion in lung and thyroid carcinoma using cytology specimen and an RNA-based next-generation sequencing assay.

BACKGROUND: Molecular testing for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion is routinely performed in patients with stage IV lung adenocarcinoma to assess their eligibility for targeted therapy. Fine-needle aspiration (FNA)-derived material frequently is the only pathologic material available. The identification of genomic aberrations in thyroid nodules from FNA smears may help stratify cancer risk and spare patients from a second surgery. In the current study, the authors tested nucleic acid extracted from the cytology smears of lung and thyroid carcinomas for simultaneous detection of single-nucleotide variant, insertion/deletion, and gene fusion using an RNA-based next-generation sequencing assay. METHODS: A total of 27 cases (17 lung and 10 thyroid carcinomas, the majority of which had known variants) were tested. Areas of interest were scrapped from stained smears using a scalpel. Total nucleic acid was extracted. Gene fusion and mutational analysis was performed using the Comprehensive Thyroid and Lung FusionPlex Assay. Data were analyzed using the analysis pipeline provided by the vendor. Eleven cases with available formalin-fixed, paraffin-embedded (FFPE) tissue were tested in parallel. RESULTS: Gene fusions were detected in 6 cases; common single-nucleotide variants in EGFR, RAS, and BRAF in 14 cases; and in-frame deletions within EGFR in 3 cases. A concordance rate of 100% was observed between FNA and FFPE tissue. CONCLUSIONS: Cytology preparations can be a reliable source for the detection of both DNA and RNA aberrations. The ability to simultaneously detect multiple types of genomic variants is crucial for patients with advanced cancer and maximizes the usefulness of cytology specimens. Cancer Cytopathol 2018;126:158-69. © 2018 American Cancer Society.