Host Cxcr2-Dependent Regulation of Pancreatic Cancer Growth, Angiogenesis, and Metastasis.

Pancreatic ductal adenocarcinoma (PDAC) manifests aggressive tumor growth and early metastasis. Crucial steps in tumor growth and metastasis are survival, angiogenesis, invasion, and immunosuppression. Our prior research showed that chemokine CXC- receptor-2 (CXCR2) is expressed on endothelial cells, innate immune cells, and fibroblasts, and regulates angiogenesis and immune responses. Here, we examined whether tumor angiogenesis, growth, and metastasis of CXCR2 ligands expressing PDAC cells are regulated in vivo by a host CXCR2-dependent mechanism. C57BL6 Cxcr2-/- mice were generated following crosses between Cxcr2-/+ female and Cxcr2-/- male. Cxcr2 ligands expressing Kirsten rat sarcoma (KRAS-PDAC) cells were orthotopically implanted in the pancreas of wild-type or Cxcr2-/- C57BL6 mice. No significant difference in PDAC tumor growth was observed. Host Cxcr2 loss led to an inhibition in microvessel density in PDAC tumors. Interestingly, an enhanced spontaneous and experimental liver metastasis was observed in Cxcr2-/- mice compared with wild-type mice. Increased metastasis in Cxcr2-/- mice was associated with an increase in extramedullary hematopoiesis and expansion of neutrophils and immature myeloid precursor cells in the spleen of tumor-bearing mice. These data suggest a dynamic role of host CXCR2 axis in regulating tumor immune suppression, tumor growth, and metastasis.

A novel aberration of COL1A1-PDGFB fusion as an insertion in chromosome 15 in one case of dermatofibrosarcoma protuberans involving a rare location.

Dermatofibrosarcoma protuberans (DFSP) is a rare sarcoma of the skin arising from the dermis. Its location is most commonly presented on the trunk of middle-aged adults and rarely on the face. The characteristic genetic aberration in the form of a reciprocal translocation t(17;22)(q21;q13) or a ring fusing the COL1A1 and PDGFB genes is found in 90% of DFSP. We present a case of a 42-year-old man who presented with a DFSP on the left cheek with foci of myxoid-fibrosarcomatous transformation. A conventional chromosomal analysis revealed a complex karyotype without a supernumerary ring chromosome or a linear translocation t(17;22). Comparative genome hybridization and fluorescence in-situ hybridization revealed the fusion of COL1A1 and PDGFB probes inserted in chromosome 15. This is a unique case of DFSP characterized by a rare body location, unique histopathological features, and novel chromosome COL1A1-PDGFB insertion, and may help guide future diagnostic and patient care modalities.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy, and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience, and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate" and 52 (25%) "rarely appropriate" and 43 (20%) having "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision to order specific tests rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-the AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Review of the medical literature and assessment of current utilization patterns regarding the use of two common fluorescence in situ hybridization assays in the diagnosis of dermatofibrosarcoma protuberans and clear cell sarcoma.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a tumor of intermediate malignancy, which in selected circumstances can pose difficulty in diagnosis. Clear cell sarcoma (CCS) is a very rare aggressive soft tissue sarcoma that can be difficult to distinguish histologically from melanoma. METHODS: The current literature on t(17;22) COL1A1-PDGFB fluorescence in situ hybridization (FISH) assay in DFSP was reviewed. Also reviewed was the current literature on dual color break-apart EWSR1 FISH assay in CCS. Finally, the current utilization patterns of these tests was assessed in attendees of the American Society of Dermatopathology annual meeting (Chicago, 2016). RESULTS: The literature indicates that (17;22) COL1A1-PDGFB FISH assay has limited value for classic DFSP, where the diagnosis can be established by routine morphology and immunohistochemistry. Given the high specificity of the EWSR1 FISH assay and significant complexity in the diagnosis of CCS, this ancillary study is helpful in distinguishing CCS from melanoma. CONCLUSIONS: In attendees, t(17;22) COL1A1-PDGFB FISH testing for classic cases of DFSP is appropriately not being used by respondents. However, the literature sustains that it is useful in selected circumstances in which a definitive diagnosis is challenging. The majority of respondents are utilizing the EWSR1 FISH assay to distinguish CSS from melanoma as is supported by the literature.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate," 52 (25%) "rarely appropriate" and 43 (20%) "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Diffuse Papular Eruption of the Face and Eyelids.

A 68-year-old Caucasian woman presented with a 1-month history of a facial and neck eruption (Figure 1A). Her face was covered with 3-mm monomorphic, pink, shiny, papules and rare pustules on an erythematous background. The eruption extended down the neck, her conjunctivae were injected, and her lid margins were inflamed. She had no history of rosacea.

Duodenal gangliocytic paraganglioma with lymph node metastases: A case report and comparative review of 31 cases.

Gangliocytic paraganglioma (GP) is a rare tumor of uncertain origin most often located in the second portion of the duodenum. It is composed of three cellular components: Epithelioid endocrine cells, spindle-like/sustentacular cells, and ganglion-like cells. While this tumor most often behaves in a benign manner, cases with metastasis are reported. We describe the case of a 62-year-old male with a periampullary GP with metastases to two regional lymph nodes who was successfully treated with pancreaticoduodenectomy. Using PubMed, EMBASE, EBSCOhost MEDLINE and CINAHL, and Google Scholar, we searched the literature for cases of GP with regional lymph node metastasis and evaluated the varying presentations, diagnostic workup, and disease management of identified cases. Thirty-one cases of GP with metastasis were compiled (30 with at least lymph node metastases and one with only distant metastasis to bone), with age at diagnosis ranging from 16 to 74 years. Ratio of males to females was 19:12. The most common presenting symptoms were abdominal pain (55%) and gastrointestinal bleeding or sequelae (42%). Twenty-five patients underwent pancreaticoduodenectomy. Five patients were treated with local resection alone. One patient died secondary to metastatic disease, and one died secondary to perioperative decompensation. The remainder did well, with no evidence of disease at follow-up from the most recent procedure (except two in which residual disease was deliberately left behind). Of the 26 cases with sufficient histological description, 16 described a primary tumor that infiltrated deep to the submucosa, and 3 described lymphovascular invasion. Of the specific immunohistochemistry staining patterns studied, synaptophysin (SYN) stained all epithelioid endocrine cells (18/18). Neuron specific enolase (NSE) and SYN stained most ganglion-like cells (7/8 and 13/18 respectively), and S-100 stained all spindle-like/sustentacular cells (21/21). Our literature review of published cases of GP with lymph node metastasis underscores the excellent prognosis of GP regardless of specific treatment modality. We question the necessity of aggressive surgical intervention in select patients, and argue that local resection of the mass and metastasis may be adequate. We also emphasize the importance of pre-surgical assessment with imaging studies, as well as post-surgical follow-up surveillance for disease recurrence.

A Yellow Papular Eruption on the Arms, Legs, and Neck: A Rare Masquerader.

A 54-year-old Caucasian woman with a medical history of mitral valve prolapse presented with a 5-year history asymptomatic papules. There was no family history of similar lesions. Physical examination revealed >100, 2- to 4-mm, firm, yellow, dermal papules located on the neck, antecubital and popliteal fossae, flexor surface of both forearms, and inner aspect of the thighs (Figure 1). There was no skin laxity. A 4-mm punch biopsy was obtained from the left thigh for histologic examination. Findings showed a focal increase in the concentration of elastic fibers highlighted by Verhoeff Van Gieson stain (Figure 2). There was no fragmentation, calcification, or phagocytosis of elastic fibers. There was also no evidence of actinic elastosis. A section stained with hematoxylin and eosin appeared relatively unremarkable. These findings were consistent with late-onset focal dermal elastosis.

Sixty-five thousand shades of gray: importance of color in surgical pathology diagnoses.

Digital whole slide imaging (WSI) is a diagnostic modality that has gained acceptance as a tool for use in some areas of surgical pathology such as remote consultations. Accurate control of color representation of digitally rendered images of histologic sections is considered an important parameter of WSI. Currently, professional societies, physicians, and other stakeholders are in the process of establishing clinical guidelines outlining the use of these devices, which include color integrity and color calibration of scanners and viewing devices. Although color is a component of surgical pathology diagnoses, it was posited that pathologists could accurately diagnose surgical specimens without color. To test this hypothesis, 5 pathologists were presented breast biopsy specimens from 20 patients consisting of 22 separate tissue specimens and WSI of 158 hematoxylin and eosin-stained slides imaged at ×20. No special stains were included. The pathologists reviewed each case using a 16-bit grayscale monitor and rendered a diagnosis for each case. Diagnoses were compared to the original light microscopy diagnoses and scored for concordance. A 92.7% concordance was observed. Discordant diagnoses represented well-known areas of diagnostic disagreement in breast pathology as well as known limitations of WSI. The research demonstrated that surgical pathologists did not rely primarily on color to render accurate diagnoses of breast biopsy cases but rather used architectural features of tissue and cellular morphology to reach a diagnostic conclusion. This research did not suggest that color is an unimportant factor in pathology diagnosis, but its importance may be overstated.

Cancers of major salivary glands.

Major salivary gland malignancies are a rare but histologically diverse group of entities. Establishing the diagnosis of a malignant salivary neoplasm may be challenging because of the often minimally symptomatic nature of the disease, and limitations of imaging modalities and cytology. Treatment is centered on surgical therapy and adjuvant radiation in selected scenarios. Systemic therapy with chemotherapeutic agents and monoclonal antibodies lacks evidence in support of its routine use.

Malignant paraganglioma of the bladder: a case report and review of the literature.

Although paragangliomas of the bladder are uncommon, malignant paragangliomas of this anatomic site are exceedingly rare, with a mere 37 previously reported cases. We report the case of a 58-year-old man with a malignant paraganglioma of the bladder who sought care secondary to gross hematuria; however, misdiagnosis of this tumor resulted in hypertensive crisis during cystoprostatectomy. Not only does this case present a unique malignant paraganglioma of the bladder, but also it discusses the clinical ramifications when misdiagnosed. Like pheochromocytomas, extra-adrenal paragangliomas can manifest with similar sympathetic stimulation; this becomes a serious complication for clinicians resecting these tumors in unusual locations without proper histologic diagnosis. Additionally, we discuss the unique clinical and pathologic findings of our patient and comprehensively review the previously published cases comparing clinical and pathologic features. Several interesting findings are identified including average age at diagnosis, gender predilection, presenting symptoms, size at diagnosis, and common sites of metastasis.

Undifferentiated Embryonal Sarcoma of Liver.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare malignant hepatic tumor. A 47 year old male presented with symptoms of sour taste in his mouth, occasional nausea, indigestion and 15-pound weight loss over two months. He had an unremarkable upper gastrointestinal endoscopy. Imaging showed a large liver mass in the left hepatic lobe that was resected and then reported as UESL. He went on to develop lung metastases and was initially treated with doxorubicin and ifosfamide followed by switching of therapy to gemcitabine and docetaxel due to progression of disease. He had a good response after two cycles and went on to receive four more cycles, achieving stable disease. We can therefore conclude that the combination of gemcitabine and docetaxel is a potential therapeutic option for patients with UESL.

Myeloid-derived suppressor cells contribute to Staphylococcus aureus orthopedic biofilm infection.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature monocytes and granulocytes that are potent inhibitors of T cell activation. A role for MDSCs in bacterial infections has only recently emerged, and nothing is known about MDSC function in the context of Staphylococcus aureus infection. Because S. aureus biofilms are capable of subverting immune-mediated clearance, we examined whether MDSCs could play a role in this process. CD11b(+)Gr-1(+) MDSCs represented the main cellular infiltrate during S. aureus orthopedic biofilm infection, accounting for >75% of the CD45+ population. Biofilm-associated MDSCs inhibited T cell proliferation and cytokine production, which correlated with a paucity of T cell infiltrates at the infection site. Analysis of FACS-purified MDSCs recovered from S. aureus biofilms revealed increased arginase-1, inducible NO synthase, and IL-10 expression, key mediators of MDSC suppressive activity. Targeted depletion of MDSCs and neutrophils using the mAb 1A8 (anti-Ly6G) improved bacterial clearance by enhancing the intrinsic proinflammatory attributes of infiltrating monocytes and macrophages. Furthermore, the ability of monocytes/macrophages to promote biofilm clearance in the absence of MDSC action was revealed with RB6-C85 (anti-Gr-1 or anti-Ly6G/Ly6C) administration, which resulted in significantly increased S. aureus burdens both locally and in the periphery, because effector Ly 6C monocytes and, by extension, mature macrophages were also depleted. Collectively, these results demonstrate that MDSCs are key contributors to the chronicity of S. aureus biofilm infection, as their immunosuppressive function prevents monocyte/macrophage proinflammatory activity, which facilitates biofilm persistence.

The pathology milestones and the next accreditation system.

CONTEXT: In the late 1990s, the Accreditation Council for Graduate Medical Education developed the Outcomes Project and the 6 general competencies with the intent to improve the outcome of graduate medical education in the United States. The competencies were used as the basis for developing learning goals and objectives and tools to evaluate residents' performance. By the mid-2000s the stakeholders in resident education and the general public felt that the Outcomes Project had fallen short of expectations. OBJECTIVE: To develop a new evaluation method to track trainee progress throughout residency using benchmarks called milestones. A change in leadership at the Accreditation Council for Graduate Medical Education brought a new vision for the accreditation of training programs and a radically different approach to the evaluation of residents. DATA SOURCES: The Pathology Milestones Working Group reviewed examples of developing milestones in other specialties, the literature, and the Accreditation Council for Graduate Medical Education program requirements for pathology to develop pathology milestones. The pathology milestones are a set of objective descriptors for measuring progress in the development of competency in patient care, procedural skill sets, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice. CONCLUSIONS: The milestones provide a national standard for evaluation that will be used for the assessment of all residents in Accreditation Council for Graduate Medical Education-accredited pathology training programs.

Reticulated lesion as an early diagnostic sign for giant cell arteritis.

We report a case of giant cell arteritis (GCA) in an elderly woman. The patient presented to her dermatologist with a reticulated, purpuric patch on her frontal-temporal scalp and forehead that was associated with unilateral head pain. A punch biopsy of the lesion was suspicious for GCA, which was later confirmed by temporal artery biopsy. This case highlights a potential early cutaneous finding of GCA that may aid the clinician in the diagnosis before more severe complications occur.