Ajay Rawal

Poor correlation of supratherapeutic international normalised ratio and vitamin K-dependent procoagulant factor levels during warfarin therapy.

Patients with a supratherapeutic international normalised ratio (ST‐INR) are at risk for bleeding. ST‐INR is corrected by withholding warfarin therapy and often by supplementing vitamin K or providing vitamin K‐dependent factors; the exact therapeutic decision is based on the extent of the prolonged INR. Currently, ST‐INRs are frequently observed in clinical practice due to the use of sensitive recombinant tissue thromboplastin reagents and automation. However, there are scant data correlating an ST‐INR with various vitamin K‐dependent factors. This prospective cohort study, set in a large tertiary care teaching hospital for the University of Texas Southwestern Medical Center at Dallas, defined the relationship between ST‐INR (>5·0) and measured vitamin K‐dependent procoagulant factors. Prothrombin time, INR and vitamin K‐dependent factors II, VII, IX and X were measured in 78 patients with an INR > 5·0 (ST‐INR) who were on warfarin therapy for more than 2 months. There was no significant relationship between the ST‐INR and levels of important vitamin K‐dependent factors II and X. These data support the recent guidelines that the management of an INR > 5·0 should be driven by the clinical determinants rather than specific INR values per se.

Occult primary medullary thyroid carcinoma presenting with pituitary and parotid metastases: Case report and review of the literature

Medullary thyroid carcinoma (MTC) accounts for <10% of all thyroid malignancies and is derived from the calcitoninproducing C cell [1, 2]. It is of particular interest because of its association with hereditary syndromes, aggressiveness, and refractoriness to adjuvant therapies, and its association with mutations in the RET (rearranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase that may be amenable to therapy with the recently available tyrosine kinase inhibitors (TKI) [3, 4]. Thyroid tumors metastasizing to the pituitary and parotid gland are rare, and medullary thyroid carcinoma metastatic to either site has only been reported in a handful of instances. Here, we report a rare case of an occult MTC, which presented with clinical symptoms associated with synchronous metastases diagnosis.

Expression and Phosphorylation of Eukaryotic Translation Initiation Factor 4E Binding Protein 1 in B-Cell Lymphomas and Reactive Lymphoid Tissues

CONTEXT Cap-mediated messenger RNA translation controlled by the eukaryotic initiation factor 4F (eIF-4F) complex plays a key role in human cancer. eIF-4F activity is controlled by a repressor binding protein (4E-BP1), which promotes translation when phosphorylated. OBJECTIVE To examine the level of expression and phosphorylation of 4E-BP1 in various subtypes of B-cell lymphoma and reactive lymphoid tissues. DESIGN Archival formalin-fixed, paraffin-embedded B-cell lymphoma samples and reactive lymphoid tissues were immunostained and examined for expression of 4E-BP1 and phosphorylated 4E-BP1. Expression of components of the eIF-4F complex and unphosphorylated and phosphorylated 4E-BP1 was confirmed using Western immunoblotting on lysates of frozen lymphoma samples and reactive tissues. RESULTS Immunohistochemical analysis demonstrated weak to undetectable 4E-BP1 staining within benign, reactive germinal centers (N = 10). In contrast, 4E-BP1 was consistently expressed (moderate to strong staining) in 98% of various subtypes of mature B-cell lymphoma (N = 50). 4E-BP1 expression was also demonstrable in all 4 lymph nodes with in situ or partial involvement by follicular lymphoma and in all 12 cases of BCL2-negative lymphoma. The level of phosphorylation of 4E-BP1 in lymphomas, evaluated by immunohistochemistry, was heterogeneous. CONCLUSIONS The immunohistochemical expression pattern of 4E-BP1 exhibits regional and cellular specificity in reactive lymphoid tissues and may offer a diagnostic tool for distinguishing reactive follicles from neoplastic B-cell proliferations.

Testicular extramedullary myeloid cell tumor: report of a case with unique clinicopathologic features and a brief review of the literature.

We report a case of testicular extramedullary myeloid cell tumor in a 37-year-old man who presented with an acute testicular hemorrhage. A pathologic examination revealed no gross tumor mass. A well-differentiated extramedullary myeloid cell tumor infiltrate was seen histologically, localized largely to the seminiferous tubules. The patient had no evidence of any past or concurrent myeloid disorders. The lack of the usual clinical features of a testicular mass and the presence of an intratubular pattern of infiltration can further compound the challenges in diagnosing this entity.

Refractory cytopenias with unilineage dysplasia: a retrospective analysis of refractory neutropenia and refractory thrombocytopenia.

The myelodysplastic syndromes (MDS) are stem cell disorders characterized by ineffective hematopoiesis and peripheral cytopenias [1]. Over 10 000 cases per year are diagnosed in the United States [2]. The incidence rises to 20–50/100 000 per year over the age of 60 [3]. The current World Health Organization (WHO) classification (2008) [4,5] includes a new diagnostic category of MDS: refractory cytopenias with unilineage dysplasia (RCUD), defined by 410% morphological dysplasia limited to a single myeloid lineage, 51% peripheral blood blasts, 55% bone marrow blasts, and unior bi-cytopenia (pancytopenia is not allowed). RCUD is further subdivided into refractory anemia (RA), refractory neutropenia (RN), and refractory thrombocytopenia (RT), according to the dominant peripheral cytopenia. While RA with ring sideroblasts (RARS) meets RCUD criteria, it is kept separate given its distinctive morphologic features. RA and RARS represent the majority of cases of MDS with unilineage dysplasia; RN and RT are considered rare, and extreme caution is recommended in making these latter diagnoses [4]. It is postulated that RN and RT exhibit low-risk features similar to RA/RARS. However, there is very limited clinical information reported about these new categories, and none from the United States. We report the incidence, presenting clinical and pathological features, clinical course, and outcomes of patients with RN and RT diagnosed and followed at a single center in the United States. We performed a retrospective review of 293 consecutive patients diagnosed with MDS (1992–2009) at the Minneapolis Veterans Affairs Medical Center (VAMC), with approval from the institutional human subjects committee. Cytopenias were defined as hemoglobin 510.0 g/dL, absolute neutrophil count 51.86 10/L, and platelet count 51006 10/L [6,7]. Diagnostic and follow-up peripheral smears and bone marrow specimens were reviewed by both hematopathologists (A.R. and H.M., blinded to clinical information) to re-confirm the diagnosis. Statistical analysis was performed using GraphPad Prism 5.0 (GraphPad Software Inc., San Diego, CA). Differences between groups were compared using a two-tailed t-test. The probabilities of overall survival (OS) were determined using the Kaplan– Meier method and compared by log-rank (Mantel– Cox) test. Amongst 293 consecutive patients diagnosed with MDS, five (1.7%) with RN and six (2.0%) with RT were identified, and compared with 27 (9.2%) patients diagnosed with RA/RARS during the same period (Supplementary Table S1). In studies of isolated cytopenias (other than anemia) in MDS published prior to the WHO 2008 classification, the incidence of isolated thrombocytopenia was reported to range from 1% [8] to 8.9% [9]. Fenaux et al. [10] reported the incidence of ‘RN/RT’ as 3.2% (eight RN, two RT, amongst 312 patients with MDS). However, since publication of the WHO 2008

Burned out testicular seminoma presenting as a primary gastric malignancy.

In contrast to primary gastric adenocarcinomas, germ cell tumors are potentially curable even when metastatic. It is therefore essential for clinicians and pathologists to be aware of the spectrum of unusual manifestations of germ cell malignancies. Here we report on a 55-year-old man who presented with clinical and endoscopic features indicative of a primary gastric carcinoma. Surprisingly, the ulcerative mucosal lesion was found to be due to a metastasis from an occult, “burned-out” testicular seminoma. This case describes the radiological and pathological features that helped differentiate this rare situation from the much more common gastric adenocarcinoma, and extends the diagnostic possibilities that must be considered in patients presenting with gastric ulcers.

Melanoma Tumor Seeding After Punch Biopsy

A 65-year-old man presented with an asymptomatic pigmented lesion of unknown duration located on the left mid back. Clinical examination revealed a 1.59 1.2-cm well-circumscribed, asymmetric, nonulcerated brown plaque with variegated coloration (Figure 1). A blue– white veil, irregular pigment globules, and regression structures were visualized using dermoscopy. Because of clinical suspicion of malignant melanoma, three scouting 4-mm punch biopsies were performed within the lesion. Two of three specimens showed invasive nodular melanoma with a Breslow depth of 0.71 mm. Fourteen days later, the tumor was excised down to the fascia with 1-cm lateral margins. Histologic examination of this excision revealed a tumor with a Breslow depth of 1.8 mm, but neoplastic melanocytes were also identified extending down the fibroinflammatory reaction from a previous punch biopsy tract into the subcutaneous fat with a Breslow depth of 9.0 mm (Figure 2). All margins were clear of tumor. Positron emission tomography–computed tomography (PET-CT) was negative for metastasis. Surgical oncology performed a wide excision and sentinel lymph node sampling. No residual tumor was present in the wide excision, and the sentinel lymph node biopsy was negative for metastatic disease. The patient declined further nodal basin dissection. Oncology ultimately opted not to “upstage” the patient based on biopsy seeding and maintained tumor classification as T2a. The patient declined adjuvant therapy. Six months later, there was no Figure 1. 1.59 1.2-cm plaque on left mid back.

Cutaneous basal cell carcinosarcoma: case report and literature review

Carcinosarcomas are malignant neoplasms with biphasic carcinomatous and sarcomatous or sarcoma‐like components. In general, the sarcomatous component is accepted to be the result of divergent mesenchymal differentiation of the epithelial component. Although well characterized in some anatomic locations (e.g. uterus, upper aerodigestive tract and lung), carcinosarcomas of the skin are rare. Reported epithelial components include squamous, adnexal, neuroendocrine and basaloid. Including this case, only 47 cases of primary cutaneous basal cell carcinosarcoma have been reported in the literature to date. We performed an extensive immunophenotypic evaluation in our case, which confirmed the previously reported coexpression of p53 in both components, and revealed a hitherto unreported coexpression of p16 and p63. Additionally, this report reviews the clinical, pathologic, immunophenotypic characteristics and outcomes of the basal cell carcinosarcomas reported in the literature, in order to emphasize the overall uniform characteristics and clinical behavior of this neoplasm.

Necrosis of uninvolved bone marrow following filgrastim administration in a patient with Burkitt lymphoma undergoing chemotherapy.

A 62-year-old male with a new diagnosis of stage IA Burkitt lymphoma (submandibular lymph nodes) commenced chemotherapy according to the R-hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin and dexamethasone) protocol. His staging bone marrow biopsy demonstrated no morphological or immunophenotypic evidence of lymphoma. Per protocol, he was started on filgrastim at 480 lg/d on day 6. As his neutrophils recovered (by day 16), he began experiencing severe diffuse bone pain necessitating the use of narcotic medications. He remained afebrile. Filgrastim was discontinued on day 17. The laboratory tests showed a marked elevation of lactate dehydrogenase (LDH, 224 iu/l on day 16 to 2789 iu/l on day 20), a rise in alkaline phosphatase (66 u/l on day 16 to 361 u/l on day 21) and a drop in the platelet count (to 34 9 10/l from 74 9 10/l) and haemoglobin concentration (99 g/l from 116 g/l). There was no clinical or laboratory evidence of sepsis, haemolysis or disseminated intravascular coagulation. The peripheral blood film was leucoerythroblastic. A bone marrow biopsy performed on day 22 demonstrated a clearly demarcated focus of coagulative bone marrow necrosis with associated haemorrhage involving 33–50% of the entire biopsy length. The image (haematoxylin & eosin, 920 objective) shows a sharp interface between viable (on the right) and necrotic bone marrow tissue (on the left). With supportive care, there was complete resolution of bone pain and normalization of LDH, alkaline phosphatase and blood counts. The patient received additional cycles of chemotherapy without filgrastim, without any recurrence of this complication, and is in a continued clinical remission at 2 years follow-up. While the clinicopathological entity of bone marrow necrosis is often associated with an underlying haematological malignancy of the marrow, this patient had no identifiable marrow involvement by lymphoma. The lack of recurrence with subsequent cycles of chemotherapy (which were administered without filgrastim) strongly suggests that filgrastim was the likely aetiological factor. A heightened awareness of the association of bone marrow necrosis with filgrastim is important, given the expansion of clinical uses of filgrastim in the treatment of malignancy and benign neutropenias and for peripheral blood stem cell mobilization.

Thrombocytosis in myelodysplastic and myelodysplastic/myeloproliferative syndromes

Thrombocytosis at diagnosis is uncommon in myelodysplastic (MDS) and myelodysplastic/myeloproliferative (MDS/MPD) syndromes. We conducted a retrospective analysis to determine the clinical and haematopathological features of such patients, and the effect of thrombocytosis on prognosis. Of the 388 patients diagnosed with MDS from 1980 – 2006, 31 presented with thrombocytosis. The majority (71%) had low risk features and a low incidence of spontaneous bleeding or thrombo-embolic events. Compared to a case-matched control group of MDS and MDS/MPD patients without thrombocytosis of similar ages and IPSS scores, patients with thrombocytosis had a slightly lower probability of progression to a higher grade of MDS (P = 0.03), equivalent risk of transformation to acute myeloid leukemia (AML), and a trend (P = 0.07) towards longer overall survival (median 35.4 months compared to 27.6 months for controls).