Monomorphic Population Research Articles

Evolution of Mindsight: Transparent Agents and the Preference to Look at Them

We study the evolution of strategic psychological capabilities in a population of interacting agents. Specifically, we consider agents which are either blind or with mindsight, and either transparent or opaque. An agent with mindsight can observe the psychological makeup of a transparent agent, i.e., its logic, emotions, commitments and other elements that determine how it chooses actions. A blind agent cannot observe and opaque agents cannot be observed. Our assumption that mindsight and transparency are costly and optional exposes a middle ground between standard game theory without mindsight and evolution of preferences theory with obligatory and costless mindsight. We show that the only evolutionarily stable monomorphic population is one in which all agents are blind, opaque, and act-rational. We find that mindsight, transparency, and rule-rational commitments may evolve, albeit only in a portion of the population that fluctuates in size over generations. We reexamine the Ultimatum and Trust games in light of our findings and demonstrate that an evolved population of agents can differ significantly from a population of simplistic payoff-maximizers in terms of psychological traits and economic outcomes.

A universal scaling law determines time reversibility and steady state of substitutions under selection

Monomorphic loci evolve through a series of substitutions on a fitness landscape. Understanding how mutation, selection, and genetic drift drive this process, and uncovering the structure of the fitness landscape from genomic data are two major goals of evolutionary theory. Population genetics models of the substitution process have traditionally focused on the weak-selection regime, which is accurately described by diffusion theory. Predictions in this regime can be considered universal in the sense that many population models exhibit equivalent behavior in the diffusion limit. However, a growing number of experimental studies suggest that strong selection plays a key role in some systems, and thus there is a need to understand universal properties of models without a priori assumptions about selection strength. Here we study time reversibility in a general substitution model of a monomorphic haploid population. We show that for any time-reversible population model, such as the Moran process, substitution rates obey an exact scaling law. For several other irreversible models, such as the simple Wright–Fisher process and its extensions, the scaling law is accurate up to selection strengths that are well outside the diffusion regime. Time reversibility gives rise to a power-law expression for the steady-state distribution of populations on an arbitrary fitness landscape. The steady-state behavior is dominated by weak selection and is thus adequately described by the diffusion approximation, which guarantees universality of the steady-state formula and its applicability to the problem of reconstructing fitness landscapes from DNA or protein sequence data.

Isocitrate dehydrogenase 1 R132H mutation is not detected in angiocentric glioma

Mutations of isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (R132H), have been described in World Health Organization grade II and III diffuse gliomas and secondary glioblastoma. Immunohistochemistry using a mouse monoclonal antibody has a high specificity and sensitivity for detecting IDH1 R132H mutant protein in sections from formalin-fixed, paraffin-embedded tissue. Angiocentric glioma (AG), a unique neoplasm with mixed phenotypic features of diffuse glioma and ependymoma, has recently been codified as a grade I neoplasm in the 2007 World Health Organization classification of central nervous system tumors. The present study was designed to evaluate IDH1 R132H protein in AG. Three cases of AG were collected, and the diagnoses were confirmed. Expression of mutant IDH1 R132H protein was determined by immunohistochemistry on representative formalin-fixed, paraffin-embedded sections using the antihuman mouse monoclonal antibody IDH1 R132H (Dianova, Hamburg, Germany). Known IDH1 mutation-positive and IDH1 wild-type cases of grade II to IV glioma served as positive and negative controls. All 3 patients were male, aged 3, 5, and 15 years, with intra-axial tumors in the right posterior parietal-occipital lobe, right frontal lobe, and left frontal lobe, respectively. All 3 cases showed characteristic morphologic features of AG, including a monomorphous population of slender bipolar cells that diffusely infiltrated cortical parenchyma and ensheathed cortical blood vessels radially and longitudinally. All 3 cases were negative for the presence of IDH1 R132H mutant protein (0/3). All control cases showed appropriate reactivity. IDH1 R132H mutation has been described as a common molecular signature of grade II and III diffuse gliomas and secondary glioblastoma; however, AG, which exhibits some features of diffuse glioma, has not been evaluated. The absence of mutant IDH1 R132H protein expression in AG may help further distinguish this unique neoplasm from diffuse glioma.

Chronic lymphocytic leukaemia in the cat: 18 cases (2000–2010)

There is little information regarding the presentation, biologic behaviour, treatment and prognosis in cats with chronic lymphocytic leukaemia (CLL), and further investigation is needed to characterize this disease in cats. The goal of this study was to describe the clinical presentation, response to treatment and prognosis of feline CLL. A multi-institutional retrospective study of 18 cats diagnosed with CLL between 2000 and 2010 was performed. CLL was defined as the presence of a mature lymphocytosis (>9000 lymphocytes µL(-1) ) and confirmation of an immunophenotypically monomorphic or clonal lymphoid population. Each patient was required to also have at least one of the two following criteria: (1) concurrent cytopenia of at least one cell line and/or (2) >15% mature lymphocytes in the bone marrow. Data on signalment, history, clinical signs, clinicopathologic features and response to treatment were reviewed. Median age of the cats at initial presentation was 12.5 years (range: 5-20 years). The most common presenting complaint was chronic weight loss, which was present in 8/18 (44%) cats. Sixteen of 18 (89%) cats were treated with chlorambucil and prednisolone; four of these cats also received vincristine. Two (11%) cats were treated with multi-agent injectable chemotherapy (L-CHOP, l-asparaginase, cyclophosphamide, doxorubicin, vincristine, prednisolone). Eighty-eight percent of cats evaluable for response achieved a complete (nine cats) or partial (six cats) remission. Median overall remission was 15.7 months (range: 1.3-22.8 months). The median overall survival in the 17 cats with follow-up data was 14.4 months (range: 0.9-25.3 months). Results of this study suggest that CLL affects older-aged cats and responds favourably to treatment with oral chlorambucil and prednisolone.

GNAQ and GNA11 mutations in melanocytomas of the central nervous system

Melanocytic tumors in the central nervous system (CNS) include metastatic melanoma and less commonly primary melanocytic tumors, which usually arise from melanocytes of the leptomeninges. The latter include, in order of increasing biologic potential, melanocytomas, melanocytic neoplasms of intermediate grade/differentiation and primary melanomas.(2) Primary leptomeningeal melanocytic neoplasms belong to a larger taxonomic group of benign and malignant tumors arising from melanocytes that are not associated with epithelia. The group also includes blue nevi, melanomas arising in association with blue nevi (so-called “malignant blue nevi”), uveal nevi and uveal melanomas (4, 5, 7). Neoplasms in this group share morphologic features such as predominance of spindled and epithelioid cells, conspicuous pigmentation and absence of epithelial involvement, along with frequent mutations of GNAQ or GNA11, two closely related G-proteins of the Gq family that encode critical amino acids required for the GTPase function of the proteins. GNAQ or GNA11 mutations occur in a mutually exclusive pattern and affect codon 183 in exon 4 or codon 209 in exon 5 of either gene.(7) Mutations at these sites cripple enzymatic function and lead to a constitutively activated GTP-bound state. When in this state, GNAQ and GNA11 act as dominant-acting oncogenes that activate several critical signalling pathways including the MAP-kinase pathway (5, 7). A recent study reported mutations in exon 5 of GNAQ in 6/12 (50%) melanocytomas, 5 of which were in paraspinal locations.(3) We extended this analysis to include exons 4 and 5 of both GNAQ and GNA11. Five cases of CNS melanocytoma were identified from the consultation files of one of the authors (M.K.R.). Sections were cut from formalin-fixed, paraffin-embedded tumor tissue, and stained with hematoxylin-eosin; immunohistochemistry was performed. Tumor DNA was extracted from tissue carefully microdissected from deparaffinized, unstained sections. Direct (Sanger) sequencing for exons 4 and 5 of each of GNAQ and GNA11 was performed using methods described previously.(7) The clinical and pathologic features of the tumors are summarized in Table 1. The tumors occurred in 3 males and 2 females, with a median age of 42 years (range 29-61 years). They were composed of spindle-shaped, oval or epithelioid cells arranged in nests and vague whorls. Tumor cells ranged from amelanotic (Fig. 1a) to conspicuously pigmented (Fig. 1c). Immunohistochemically, all tumors were diffusely positive for S-100 and HMB-45, and negative for epithelial membrane antigen. Mutations were identified in exon 4 of GNAQ (1 case, Fig. 1b) and exon 5 of GNA11 (1 case, Fig. 1d). The mutations [GNAQ:(c.548G>A, p.(Arg183Gln) and GNA11:c.626A>C, p.(Gln209Pro)] are identical to those seen in uveal melanoma and intradermal melanocytic proliferations (6, 7). Our results expand the spectrum of GNAQ and GNA11 mutations that may occur in melanocytomas. To our knowledge, this is the first description of mutations in GNA11 and in exon 4 of GNAQ in melanocytomas. Figure 1 a) Case 1 – A monomorphous population of slightly spindled, amelanotic cells in vaguely whorling array is present (hematoxylin-eosin, x100). Inset - Diffuse cytoplasmic immunolabeling for HMB-45 confirms the melanocytic nature of the tumor cells ... TABLE Clinical and pathologic features of melanocytomas The occurrence of GNAQ and GNA11 mutations in melanocytomas,(3) dermal melanocytic tumors(6, 7) and uveal melanomas(6, 7) suggests the possibility of a developmental link between the cells of origin of these tumors. Indeed, this thesis is supported by the recent description of a developmental pathway in which a subgroup of melanocytes derives from Schwann cell precursors.(1) Although we identified a GNAQ exon 4 mutation in 1 of 5 cases of melanocytoma, exon 4 mutations in either GNAQ or GNA11 are rare in uveal melanomas (7/145, 4.8%) and blue nevi (2/96, 2.1%) (7). Mutational analysis of larger numbers of tumors is required to determine the true incidence of the different mutations in GNAQ and GNA11, and to investigate associations of specific mutations with clinical features, pathologic characteristics, and biologic behavior of melanocytomas.

Gliomatosis peritonei as a natural experiment in tissue differentiation

Gliomatosis peritonei (GP) is an unusual condition in which nodules of mature astroglia, often miliary and microscopic in size, are widespread in the peritoneum and abdominal lymph nodes. Its behaviour is benign and it is usually found in association with ovarian teratoma and rarely with teratomas of other organs. Implants grow rapidly and can remain unchanged for life. Astroglia is the main component, but other neural lineage elements and many other tissues can be found. Cells are mature but not terminal, since they express SOX2. Secondary associated lesions include: a) degenerative astrocytic changes, b) granulomatous and follicular chronic inflammatory changes, c) association with hormonally related changes, such as decidual peritoneal metaplasia and endometriosis and d) endothelial and adventitial vascular hyperplasia leading to haemoperitoneum.Two pathogenetic mechanisms are considered: direct seeding of immature neural cells from a primary tumour with subsequent differentiation and metaplasia from peritoneal stem cells. The former proposal is supported by clinicopathologic data such as ample cellular heterogeneity, coexistence of mature astroglia with neural blastema, as well as the shed keratin and hairs from the ovarian neoplasm. However, metaplasia is sustained by a heterozygosity pattern of GP nodules, identical to the normal tissue and different from the coexistent ovarian teratoma. GP would constitute a response to growth factors from teratoma or macrophages. While an implantative origin from ovarian teratoma remains in most cases a more probable mechanism, metaplasia from peritoneal stem cells would explain cases of GP which present a monomorphic astrocytic cell population.

1. Cytomorhologic features of lymphoid neoplasms in the mediastinum and pitfalls in diagnosis

<h3>Background</h3> Lymphoid neoplasms are challenging for most cytopathologists. In the mediastinum, rapid diagnoses have applied through cytology or during frozen sections to separate surgical from non-surgical cases. <h3>Aim</h3> To describe the cytomorphological features of mediastinal lymphoid neoplasms with tissue correlation and relative pitfalls. <h3>Method</h3> Cases of mediastinal neoplasms of guided procedures or frozen sections were reviewed. Smears from guided cytology stained with Diff-Quik and/or Papanicolaou's reagent, and cyto-logical imprints stained with Diff-Quik from frozen tissue specimens were retrieved. Cytomorphological findings were described. These were correlated with histological sections and confirmed by immunohistochemical studies. <h3>Result</h3> Of 50 anterior mediastinal cases, nine interpreted as lymphoproliferative were reviewed, two of which were diffuse large B-cell lymphoma. Two were nodular sclerosing Hodgkin's lymphoma (HD) and the other one was a composite Hodgkin's and non-Hodgkin's lymphoma (NHL). One case was NHL. Two cases were diagnosed with lymphoma versus thymoma. The last case was HD but on tissue correlation and immunohistochemistry panel, revealed embryonal carcinoma with seminomatous areas. <h3>Conclusion</h3> A mixed population of lymphoid cells may be suggestive of NHL. A polymorphous appearance with large cells having lobated nuclei is suggestive of HD. Germ cell tumours in the mediastinum may mimick the cytomorphological features of HD. Reed-Sternberg cells display more irregularly shaped nuclei compared to nuclei of immature germ cells. In a monomorphic population of lymphoid cells the so-called lymphocyte with handles is a neoplastic feature. Occurrence of cells with pale, oval nuclei could be an epithelial cell and should correctly consider thymoma. Awareness of cytomorphological pitfalls of lympho-proliferative lesions with tissue correlation and immunohistochem-istry is almost always crucial.

Retraction: Regulatory T Cells in the Human Immune System

Regulatory T () cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting antitumor immunity. cells characterized by expression of the transcription factor Foxp3 play a key role in immune homeostasis. Rather than a monomorphic population strictly determined by Foxp3 as a 'master regulator', the emerging view is one of cells as a population with many levels of complexity. Distinct subphenotypes of cells are found in different anatomical locations. This review will focus on these novel aspects of cell diversity, and discuss recent findings regarding human cells, including the ontogeny and development of cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by cell subsets and factors that regulate cell lineage commitment. We also will discuss future studies that are needed for the successful therapeutic use of human cells.

Mutationally Activated TYK2 From T-ALL Specimens Exhibits Tranformative Capacity in Cell Lines and Primary Cell Models and T-Lineage Expansion in Mice

Abstract 74 Background:First-line therapy for T-cell acute lymphoblastic leukemia (T-ALL) fails in 25% of children and more than 50% of adults despite improvements in clinical outcomes due to intensification of therapy. Development of new and improved therapeutic regimens will require 1) new gene targets relevant to the pathogenesis of T-ALL, 2) targeted therapeutic agents with activity against those gene targets, and 3) effective models for pre-clinical development of these gene targets and therapies. Current in vivo models of T-ALL recapitulate derangements in the Notch signaling pathway but modeling alternative pathways of T-ALL leukemogenesis are lacking. We report that tyrosine kinase 2 (TYK2) is vital for the maintenance of T-ALL growth and viability, and we have developed a mouse model based on an activating mutation of TYK2 found in a T-ALL specimen. This mouse model will be useful for further exploration of the biological role of TYK2 in T-ALL pathogenesis as well as pre-clinical evaluation of TYK2 inhibitors as components of T-ALL therapy regimens. Methods: Sequence analysis of TYK2 in T-ALL cell lines and patient samples revealed a diversity of TYK2 point mutations. These mutations were located just outside of or within the FERM domain (V15A, G36D, G36R, S47N, R425H), the pseudokinase domain (V731I), and the kinase domain (E957D, and R1027H). Identified point mutant were cloned and introduced into Ba/F3 cells for assessment of transformative capacity. The point mutant E957D was ectopically expressed via retroviral transduction in primary murine bone marrow hematopoietic progenitor cells and co-cultured on OP9-DL1 stromal cell layers to assay the effect of this mutation on in vitro T-lineage development and expansion. A murine transduction/transplantation model was developed to investigate the effect of TYK2 E957D in vivo. Results: Introduction of the point mutants into Ba/F3 cells revealed that 7/8 (all except R425H) transformed cells to factor-independent growth. Transformed cells displayed constitutive phosphorylation of TYK2, STAT1, STAT3, and ERK1/2. Treatment of transformed cells with JAK Inhibitor I revealed extreme sensitivity of cells to this TYK2 kinase inhibitor as well as reduction of TYK2 AND STAT1 phosphorylation. Ectopic expression of TYK2 E957D enhanced in vitro T cell development and subsequent expansion of mature T cells on OP9-DL1 stromal cell layers as compared to TYK2 WT or empty vector. Fifty percent of mice transplanted with bone marrow ectopically expressing TYK2 E957D died at 7 months post-transplant with evidence of hematologic malignancy characterized by massive expansion of the thymus and infiltration of the bone marrow with a monomorphic population of cells. In comparison, none of the mice transplanted with wild-type TYK2 were adversely affected. Conclusions: We demonstrate that mutations in TYK2 in T-ALL can confer constitutive activity to the TYK2 signaling pathway, which can play a functional role in the pathogenesis of T-ALL. Ectopic expression of TYK2 E957D leads to enhanced expansion of T cells and mice expressing this point mutant in the hematopoietic compartment die from hematologic malignancy with grossly enlarged thymuses after a long period of latency. This model could complement the arsenal of currently available T-ALL models and may represent and the latency of disease may allow a search for cooperating elements leading to transformation. Small-molecule kinase inhibitors with activity against TYK2 reduce the growth of these TYK2-dependent cells. Hence, we have defined a new, oncogenic signaling pathway in T-ALL cells that can be readily modulated by kinase inhibitors. Cumulatively, these data offer new therapeutic options for T-ALL patients while simultaneously providing novel insights into the biology of T-cells and the TYK2-STAT1 signaling cascade. Disclosures:Druker:Novartis:; Bristol-Myers Squibb:; Ariad Pharmaceuticals: Consultancy; OHSU patent #843: Mutated ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership, OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t; Cylene: Consultancy.

Lymphosarcoma associated with Heterobilharzia americana infection in a dog

Hepatic T-cell lymphosarcoma with involvement of regional lymph nodes and concurrent schistosomiasis were diagnosed in an 11-year-old male neutered mixed-breed dog with a history of chronic weight loss, inappetence, vomiting, and diarrhea. Trematode ova present in the hepatic parenchyma and mesenteric node were surrounded by sheets of neoplastic lymphocytes while those in the intestinal wall were surrounded by large numbers of non-neoplastic lymphocytes. Immunohistochemistry revealed that both the neoplastic and hyperplastic populations were T lymphocytes. The ova were identified by fecal saline sedimentation as Heterobilharzia spp., and fecal ova shedding resolved after praziquantel anthelmintic treatment. The lymphoma progressed despite chemotherapy, and the dog was euthanized after developing neurologic signs and a necropsy was performed. A monomorphic population of neoplastic T cells expanded and replaced normal architecture in the liver and spleen, surrounded nerve roots within the cauda equina, and infiltrated the meninges of the brain. The presence of schistosome ova embedded within neoplastic T-cell infiltrates suggests that, as previously reported in human schistosomiasis, heterobilharziasis may be associated with neoplasia.

Solitary mastocytoma in an adult with an unusual clinical presentation

To the Editor: A 30-year-old woman presented with a 10-year history of headaches, flushing, and anaphylaxis triggered by exercise, stress, heat, or scalp friction. Recently, she noticed a poorly circumscribed scalp mass. Computed tomography imaging confirmed a 3.3- × 1.5-cm subcutaneous mass, without bone involvement. The mass fluctuated in size (up to 10 cm), and episodes of anaphylaxis occurred with manipulation. Interestingly, the patient experienced no flushing or anaphylaxis while pregnant, but her symptoms returned after delivery. A punch biopsy specimen of the skin obtained from the edge of the tumor showed subtle histopathologic changes with a mild perivascular, perifollicular lymphocytic infiltrate and scattered mast cells (Fig 1). Surgical resection was performed and revealed a scalp mass with lobulated appearance. Histopathologically the tumor was composed of a dense monomorphous population of mast cells, with abundant granular cytoplasm; positive Giemsa and tryptase stains confirmed the diagnosis of mastocytoma (Fig 2). Postoperatively, the patient made a complete recovery and had no further symptoms at 27 months’ follow-up.Fig 2A and B, Intraoperative photographs of the solitary mastocytoma in vivo and after surgical resection. C and D, Hematoxylin-eosin sections showing dense population of mast cells with round nuclei, bland chromatin, and abundant granular cytoplasm. D (insert), There is diffuse immunoreactivity to mast cell tryptase.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Solitary mastocytoma is primarily a disease of young children, with adult cases rarely reported.1Pandhi D. Singal A. Aggarwal S. Adult onset, hypopigmented solitary mastocytoma: report of two cases.Indian J Dermatol Venereol Leprol. 2008; 74: 41-43Crossref PubMed Scopus (2) Google Scholar Lesions are typically cutaneous, involving the extremities, face, scalp, and trunk. Cutaneous mastocytomas may be associated with systemic disease, but up to 15% of patients with a mast cell disorder may develop a solitary mastocytoma without systemic involvement.2Castells M.C. Extracutaneous mastocytoma.J Allergy Clin Immunol. 2006; 117: 1513-1515Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar In our case, a diagnosis of concurrent systemic mastocytosis was suspected, but not confirmed. The bone marrow biopsy specimen showed few clusters of mast cells (>15 cells). The serum tryptase level ranged from 11 to 14 ng/mL; therefore, under the World Health Organization (WHO) threshold of 20 ng/mL. Thus, by WHO criteria, one major criterion was met (clusters of >15 mast cells), but no minor criteria were satisfied for the diagnosis of systemic mastocytosis.3Valent P. Horny H.P. Li C.Y. Longley J.B. Metcalfe D.D. Parwaresch R.M. et al.Mastocytosis.in: Jaffe E.S. Harris N.L. Stein H. Vardiman J.W. World Health Organization Classification of Tumors: Tumours of the Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, France2001: 291-300Google Scholar Molecular studies showed no D816V mutation in the KIT gene and no evidence of the FEP1L1-PDGFRA fusion transcript. Adult-onset mastocytoma has a less favorable rate of spontaneous resolution compared with the childhood lesions, and surgical excision may be necessary.1Pandhi D. Singal A. Aggarwal S. Adult onset, hypopigmented solitary mastocytoma: report of two cases.Indian J Dermatol Venereol Leprol. 2008; 74: 41-43Crossref PubMed Scopus (2) Google Scholar Preoperative collaboration with the anesthesiology team is important to avoid hemodynamic instability during surgical manipulation. Our patient was premedicated with oral cetirizine. It is noteworthy that in this case the tumor became evident only years after the onset of nonspecific clinical symptoms. The initial histopathologic changes were very subtle, offering only a hint of what would later be seen in the surgical specimen. This fact may be explained by the superficial nature of the biopsy and illustrates the necessity of close follow-up and clinical-pathologic correlation when similar findings are encountered on the biopsy specimen. Interestingly, the patient had a complete lack of symptoms during pregnancy, with symptoms returning postpartum. To our knowledge, this is the first report of concurrent solitary mastocytoma and pregnancy, with complete control of mastocytoma-related symptoms during pregnancy. It has been previously reported that pregnancy may worsen the symptoms of mastocytosis.4Donahue J.G. Lupton J.B. Golichowski A.M. Cutaneous mastocytosis complicating pregnancy.Obstet Gynecol. 1995; 85: 813-815Crossref PubMed Scopus (19) Google Scholar, 5Worobec A.S. Akin C. Scott L.M. Metcalfe D.D. Mastocytosis complicating pregnancy.Obstet Gynecol. 2000; 95: 391-395Crossref PubMed Scopus (37) Google Scholar

Presumptive histiocytic neoplasm with unusual immunophenotype in a cat

True histiocytic proliferative diseases have been infrequently documented in the cat, with progressive histiocytosis and histiocytic sarcoma representing the bulk of the reported cases. A 5-year-old, neutered male domestic shorthair cat presented with a 1-month history of anorexia, depression, mucosal pallor and persistent non regenerative anemia. On admission, the cat appeared depressed, icteric, dyspneic and had moderate splenomegaly. The cat had a severe, temporarily regenerative anemia, and a blood smear evaluation revealed numerous neutrophil- and monocyte-phagocytosed erythrocytes. Splenic and bone marrow aspirate smears were predominated by a monomorphic population of individual or aggregated round-to-oval cells, likely of histiocytic origin that often phagocytosed erythrocytes and leukocytes. A comprehensive immunocytochemical staining panel failed to definitively identify the neoplastic cells. This report emphasizes the clinical course, the sequential hematological abnormalities, the cytology and the unusual immunophenotype of a presumptive histiocytic sarcoma in a cat.

Pathology Quiz Case 1

A 6-MONTH-OLD BOY PRESENTED TO HIS PRImary care pediatrician with a raised, nontender, draining lesion on the anterior aspect of the right side of his neck. The lesion was present at birth, but it had recently become more raised and erythematous. There was no history of drainage from the lesion. Two weeks before presentation, the patient had an upper respiratory infection. Physical examination revealed a soft, orange, erythematous 1.5 1.0-cm lesion along the anterior border of the right sternocleidomastoid muscle at the level of the hyoid bone (Figure 1). There were no other cutaneous findings. The patient was referred to pediatric otolaryngology. Ultrasonography demonstrated bilateral lymphadenopathy, which was attributed to the recent upper respiratory infection. No sinus tract or cystic structure was visible. The history, appearance, and location of the lesion were consistentwithabranchialcleft sinus,andthepatientwasscheduled for surgical treatment. At the time of surgery, a probepatent opening in the skin was not identified, and careful dissection failed to identify a sinus tract or an underlying cystic mass. The abnormal tissue that was suspected to contain the tract was removed. On histopathologic examination, sections of skin demonstrated a proliferation of monomorphous round to oval cells with clear cytoplasm and centrally located nuclei infiltrating and expanding the papillary dermis and extending into the reticular dermis (Figure 2). Giemsa staining revealed purple metachromatic cytoplasmic granules within the monomorphous cell population (Figure 3). Immunohistochemical staining of these cells demonstrated the presence of CD117 (c-kit) (Figure 4). What is your diagnosis?

Hyalinizing clear cell carcinoma: A case report and review of the literature

Hyalinizing clear cell carcinoma (HCCC) is a low-grade malignancy with infiltrative growth pattern. It affects mainly the minor salivary glands of adult women. The most frequent locations of this tumor are the palate and tongue. HCCC shows a poorly circumscribed, infiltrative, and essentially monomorphic population of clear cells with few mitoses and almost no nuclear or cellular pleomorphism. These cells form trabeculae, cords, islands, and/or nests, circumscribed by variable amounts of hyalinized fibrous bands with foci of myxohyaline stroma. S-100 protein, muscle-specific actin, smooth muscle actin, myosin, and calponin are consistently negative, which strongly indicates the absence of myoepithelial cell differentiation in this tumor. We present a case of HCCC affecting the upper vestibule in a 53-year-old man. The patient was treated by surgery and postoperative radiation and did not show recurrence or distant metastases 3 years after treatment. Discussed also are the clinical and pathologic features of this tumor along with the differential diagnosis and a literature review.

Post‐transplant Burkitt lymphoma is a more aggressive and distinct form of post‐transplant lymphoproliferative disorder

Although the literature reports a low incidence of Burkitt lymphoma (BL) as a post-transplant lymphoproliferative disorder (PTLD), this entity appears to be different from other monomorphic PTLDs (M-PTLDs), both in its aggressive clinical presentation and its distinct pathologic profile. Patients with BL, diagnosed in the post-transplant setting, (patients aged ≤ 18 years) were retrieved from the pathology archives at Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center from 1982 to 2010. Clinical outcomes were obtained along with pathologic review. Twelve patients with pediatric BL in the post-transplant setting (9 boys, 3 girls) were retrieved. The patients displayed a monomorphic population of small to intermediate-sized, noncleaved, lymphoid elements with a "starry-sky" pattern. The immunophenotype for patients available to the study was CD20+ (n = 9/10), CD10+ (n = 8/8), bcl-6+ (n = 11/11), with a near 100% Ki-67/MIB-1 proliferation index (n = 7/7), and negative for TdT (n = 7/7). Most pretransplant Epstein-Barr virus titers were negative (n = 8/10), with post-transplant titers positive in all tested patients (n = 11), and with positive Epstein-Barr-encoded RNA in situ hybridization in most cases (n = 9/11). The median time from transplantation to diagnosis was 52 months (range, 6-107 months). Nine patients were currently alive after immediate antineoplastic chemotherapy, with median disease-free time of 93 months from diagnosis (range, 2-199 months). BL-PTLD had a higher Epstein-Barr virus incidence compared with sporadic and immunodeficiency-associated BL and represented a distinct monomorphic PTLD. Although some M-PTLDs can be managed less aggressively with decreased immunosuppression alone, immediate lymphoma-specific chemotherapy was associated with a favorable outcome and was strongly recommended.

Glacial History of the North Atlantic Marine Snail, Littorina saxatilis, Inferred from Distribution of Mitochondrial DNA Lineages

The North Atlantic intertidal gastropod, Littorina saxatilis (Olivi, 1792), exhibits extreme morphological variation between and within geographic regions and has become a model for studies of local adaptation; yet a comprehensive analysis of the species' phylogeography is lacking. Here, we examine phylogeographic patterns of the species' populations in the North Atlantic and one remote Mediterranean population using sequence variation in a fragment of the mitochondrial cytochrome b gene (607 bp). We found that, as opposed to many other rocky intertidal species, L. saxatilis has likely had a long and continuous history in the Northwest Atlantic, including survival during the last glacial maximum (LGM), possibly in two refugia. In the Northeast Atlantic, several areas likely harboured refugial populations that recolonized different parts of this region after glacial retreat, resulting in strong population structure. However, the outlying monomorphic Venetian population is likely a recent anthropogenic introduction from northern Europe and not a remnant of an earlier wider distribution in the Mediterranean Sea. Overall, our detailed phylogeography of L. saxatilis adds an important piece to the understanding of Pleistocene history in North Atlantic marine biota as well as being the first study to describe the species' evolutionary history in its natural range. The latter contribution is noteworthy because the snail has recently become an important model species for understanding evolutionary processes of speciation; thus our work provides integral information for such endeavours.

Stochasticity in the adaptive dynamics of evolution: the bare bones

First a population model with one single type of individuals is considered. Individuals reproduce asexually by splitting into two, with a population-size-dependent probability. Population extinction, growth and persistence are studied. Subsequently the results are extended to such a population with two competing morphs and are applied to a simple model, where morphs arise through mutation. The movement in the trait space of a monomorphic population and its possible branching into polymorphism are discussed. This is a first report. It purports to display the basic conceptual structure of a simple exact probabilistic formulation of adaptive dynamics.

Fine needle aspiration cytology of insular carcinoma of thyroid

Poorly differentiated (insular) thyroid carcinoma is defined as a thyroglobulin-producing non-follicular non-papillary thyroid carcinoma, having an intermediate behavior between well-differentiated and anaplastic carcinomas. FNAC is widely used as aid for workup of thyroid gland lesion. However, scant information is available in the literature about cytologic findings of this rare entity. Ten cases of surgically resected insular carcinoma with a corresponding cytology were selected. The cytologic smears and histological sections were reviewed for presence of cytomorphologic features including cellularity, predominant cytoarchitectural pattern, additional cytologic co-patters pattern, cell size, cell shape, nuclear pleomorphism, nuclear/cytoplasmic (N/C) ratio, chromatin pattern, amount of cytoplasm, mitotic figures, colloid, background debris, nuclear grooves, and intranuclear pseudoinclusions. In all the cases, the cells were arranged predominantly in solid clusters. Focal microfollicular pattern was identified in five cases of which three cases showed presence of inspissated colloid within the follicles. Singly scattered malignant cells and bare nuclei were seen in all cases. Cells were monomorphic, round with high N/C ratio, finely granular chromatin and inconspicuous nucleoli. Background showed presence of cellular debris in two cases. Mitotic figures were obvious and atypical mitosis was also identified. Cellular smears composed of monomorphic population of small cells arranged in large clusters and sheets with high N/C ratio and high mitosis suggest the possibility of insular carcinoma. Background cellular debris/necrosis also supports the diagnosis. Cell block preparation in these cases may be of additional help in accurate diagnosis.

Cytodiagnosis of intracranial metastatic adenoid cystic carcinoma: Spread from a primary tumor in the lacrimal gland

Adenoid cystic carcinoma (ACC) of the lacrimal gland is a rarely encountered orbital tumor. It invades intracranially more frequently than carcinomas of other glands in the head and neck. A 61-year-old man underwent right orbital exenteration for a tumor in the supraorbital region. He had lost all records and presented to us with a diffuse swelling in the right forehead, six years later. Fine-needle aspiration cytology of the right frontal swelling revealed monomorphic population of small, slightly atypical cells, arranged in multilayered groups with abundant fine intercellular metachromatic substance between cell groups. There were hyaline globules of varying size with attached tumor cells. Cytological diagnosis of metastatic intracranial ACC with a lacrimal gland primary was suggested. Biopsy of the swelling confirmed our cytological diagnosis of ACC with perineural, vascular and lymphatic invasion. Thus, the authors report this case of intracranial metastasis of ACC of the lacrimal gland to remind neurosurgeons planning intervention that this disease shows a tendency to invade intracranially.

Long-term Treatment of Chronic Lymphocytic Leukemia in a Green-winged Macaw (Ara chloroptera)

A 32-year-old green-winged macaw (Ara chloroptera) was diagnosed with chronic lymphocytic leukemia based on progressive lymphocytosis and the presence of a monomorphic population of well-differentiated lymphocytes in the bone marrow of a clinically normal bird. Chemotherapy was initiated because of rapidly increasing peripheral lymphocyte counts. In addition to oral prednisone (1 mg/kg once daily), oral chlorambucil (1 mg/kg twice weekly) was initiated but was discontinued after 6 weeks because of thrombocytopenia. The leukocyte count was stabilized for 29 weeks with the concurrent use of oral cyclophosphamide (5 mg/kg 4 d/wk) and daily prednisone, and the bird exhibited a good quality of life. The bird died shortly after the chemotherapy was inadvertently discontinued. The neoplastic cells from this macaw stained positive for CD-3 antibody and negative for Bla.36, suggesting the leukemia was of T-cell origin. This is the first report of long-term treatment of a macaw with cyclophosphamide and documents thrombocytopenia in a macaw secondary to chlorambucil treatment.