The spectrum of pathological diagnoses in non-sentinel axillary lymph node biopsy: A single institution's experience.

Although axillary lymphadenopathy is a common clinical encounter, systemic evaluation of non-sentinel lymph node biopsy is sparse. We reviewed our institution's 15-year experience to delineate the spectrum of diagnoses in non-sentinel axillary lymph nodes. 1165 non-sentinel axillary lymph node biopsies were retrieved and the diagnosis and relevant clinical information was reviewed. This spectrum of diagnoses was further stratified by gender, age, and oncologic history. The spectrum of diagnoses included: breast carcinoma (27.6%), lymphoma (29.2%), melanoma (3.5%), other carcinoma (2.9%), sarcoma (0.4%), and benign changes (36.3%). The most common diagnoses in men were lymphoma (61.8%) and benign changes (23.6%); while in women they were benign change (41.2%), breast carcinoma (37.8%) and lymphoma (16.7%). Besides benign changes, lymphoma and breast carcinoma were most common in women younger and older than 30 years, respectively. In patients with a history of malignancy, the most common diagnoses were metastasis from the known tumor and benign change; while in patients with a negative oncologic history and female patients without a history of breast cancer, the diagnosis was generally either lymphoma or benign change. Anaplastic large cell lymphoma was rare but may be mistaken as metastatic carcinoma thus a high index of suspicion is warranted. Thus through retrospective review of a large cohort of non-sentinel axillary lymph node biopsies, we described the spectrum of pathological entities based on the gender, age, and clinical history, which could provide valuable information for further work-up of axillary lymph node biopsy.

Cutaneous involvement in multiple myeloma (MM): A case series with clinicopathologic correlation.

BACKGROUND: Disease-specific skin lesions are rare in patients with multiple myeloma (MM). OBJECTIVE: We sought to further characterize the clinical and pathologic features of patients with cutaneous involvement with MM. METHODS: We identified 13 patients with cutaneous lesions of MM. RESULTS: Cutaneous lesions consisted of pink, red, and violaceous papules, nodules, and/or plaques that varied in size. Histopathology revealed atypical plasma cells with occasional plasmablastic features. MM had aggressive biologic features and was at an advanced stage in the majority of patients. Despite aggressive management, including chemotherapy and stem-cell transplantation, most patients died of progressive disease within a few months after the development of cutaneous lesions. LIMITATIONS: The study group was relatively small. CONCLUSIONS: Cutaneous involvement with MM is associated with aggressive biologic behavior and short survival.

Effect of time to infusion of autologous stem cells (24 vs. 48 h) after high-dose melphalan in patients with multiple myeloma.

High-dose melphalan (HD-Mel) is considered the current standard of care among the preparative regimens used in autologous peripheral blood stem cell transplantation (SCT) for multiple myeloma (MM), but optimal time and schedule of administration is not defined. We retrospectively analyzed outcomes and toxicities of HD-Mel administered on day -2 vs. day -1 before autologous stem cells infusion. A total of 138 consecutive MM patients treated at Penn State Hershey Cancer Institute between 2007 and 2010 were included in this study. No difference in time to hematopoietic recovery, common SCT-related toxicities, and clinical outcomes was seen between patients who received HD-Mel on day -2 (group A, n = 47), and those who received it on day -1 (group B, n = 91). Prompt and full hematopoietic recovery occurred even when stem cells were infused between 8 and 24 h after completion of chemotherapy. In the absence of prospective and randomized data, we conclude that a single I.V. infusion of HD-Mel on day -1 is a safe and effective practice, and the so-called 'day of rest' before the transplant appears not to be necessary.

Perceived levels of pain associated with bone marrow aspirates and biopsies.

BACKGROUND: Little is known about the degree of pain experienced by patients undergoing a bone marrow aspiration and biopsy (BMAB). OBJECTIVE: To evaluate the effectiveness of several strategies aimed at reducing the pain score. METHODS: We conducted a retrospective analysis of 258 consecutive adult patients who underwent BMAB via 6 different approaches, the first 5 of which were performed by one physician. Group A received local anesthesia with 1% lidocaine hydrochloride (5 mL) and a 5-minute wait time before the procedure; group B received local anesthesia with a double dose (10 mL) of lidocaine; group C received 5 mL of local anesthesia with a 10-minute wait; group D received 5 mL of local anesthesia plus a topical spray with ethyl chloride; group E received oral analgesia and anxiolysis 30 minutes before the procedure in addition to the group A dosage of lidocaine; and group F received the same anesthesia as did group A, but the BMAD was performed by a less experienced practitioner. RESULTS: On a 0 to 10 scale, the mean pain level among the 258 patients was 3.2 (standard deviation = 2.6). Rate of complications was low (<1%). Several strategies failed to improve the pain level, including the administration of a double dose of local anesthesia, waiting longer for the anesthesia effect, and the additional use of a topical anesthetic spray or oral analgesia and anxiolysis. Pain levels were not increased when the procedure was done by a less experienced practitioner. Younger age and female gender were associated with higher pain levels. CONCLUSIONS: Given that the average level of perceived pain during BMAB is low to moderate (approximately 3 on a 0-10 scale), the routine use of conscious sedation for this procedure may not be indicated. Several strategies aimed at reducing the pain level, including doubling the dose of anesthesia and using an oral prophylactic regimen of analgesia and anxiolysis, failed to improve pain scores.

Chronic Generalized Lymphadenopathy in a Child-Progressive Transformation of Germinal Centers (PTGC).

BACKGROUND: Enlarged lymph nodes are a common complaint in a Pediatrician's office. Diagnosis of reactive lymphadenopathy secondary to infectious, inflammatory, immune dysregulation calls for clinical investigation, including a thorough history, physical exam, imaging, and less often, a biopsy of the lymph node. Here we discuss a rare presentation of extensive generalized, chronic, waxing, and waning lymphadenopathy diagnosed as Progressive Transformation of Germinal Centers (PTGC) and the course of illness over eight years follow up period. DISCUSSION: Progressive Transformation of Germinal Centers (PTGC) is considered a benign condition, but extensive recurrent generalized lymphadenopathy in a very young child has not been reported before. This case demonstrates the importance of long-term follow-up and tailoring the diagnostic work-up and management based on new signs and symptoms. Here we focus on the clinical considerations and management of complex presentation of a common clinical finding.

Mast cell leukemia with novel BRAF variant and concomitant atypical KIT variant.

Mast cell leukemia (MCL) is a leukemic variant of systemic mastocytosis defined by mast cells ≥ 20% of marrow nucleated cells. Its incidence is < 1% of all systemic mastocytosis cases [1]. Clinical characteristics and treatment of the disease are not well established and overall prognosis is very poor. We report a case of de novo mast cell leukemia with novel BRAF variant, concomitant KIT exon 9 missense mutation and complex cytogenetic abnormalities. After careful review of the literature we have not found any prior reports of concomitant BRAF and KIT variants, and complex cytogenetic abnormalities in MCL. This case provides evidence that MCL can have wide spectrum of genetic abnormalities as well as accumulation of mutations in various genes including BRAF. This finding may have significant implications for the understanding of pathogenesis, diagnosis, as well as targeted therapy of MCL.

A rare case of atypical chronic myeloid leukemia associated with t(8;22)(p11.2;q11.2)/ BCR-FGFR1 rearrangement: A case report and literature review.

Myeloid/lymphoid neoplasm with t(8;22)(p11.2;q11.2)/BCR-FGFR1 is an extremely rare diagnosis, with few reported cases to date. In contrast to other FGFR1-partner rearrangements that are associated with chronic eosinophilic leukemia, acute myeloid leukemia, and/or lymphoblastic lymphoma, patients with BCR-FGFR1 have a myeloproliferative disorder that closely resembles chronic myeloid leukemia (CML). The current report describes a rare case of a 61 year old man with an atypical CML phenotype associated with t(8;22)(p11.2;q11.2)/BCR-FGFR1. A literature review is presented to enhance the awareness of this rare diagnostic entity.

Unexpected Short-Tandem-Repeat Patterns in Posttransplant Chimerism Testing: Investigation of 3 Cases with Help from Forensic Science.

Chimerism testing by short tandem repeats (STRs) is used to monitor engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). Generally, STR alleles are stable and transferred from parent to child or from donor to recipient. However, 3 cases did not follow this norm. Additional work-up with help from forensic literature solved these mysteries. In case 1, the patient received HSCT from his son. The son shared STR alleles in 22/23 loci except Penta E, which was explained by repeat expansion in the son. In case 2, the patient had been in remission for 14 years after HSCT for lymphoma and developed repeat expansion in CSF1PO in granulocytes. In case 3, a pre-HSCT patient demonstrated 3 alleles, with 2 peaks taller than the third, in the FGA locus (chromosome 4). A combination of a triallelic variant and leukemia-associated trisomy 4 explained the finding. STR number variants are rare and clinically inconsequential but can overlap malignancy-associated, clinically significant changes.

An Immunohistopathologic Study to Profile the Folate Receptor Beta Macrophage and Vascular Immune Microenvironment in Giant Cell Arteritis.

Giant cell arteritis (GCA) is a chronic immune-mediated disease of medium-to-large sized arteries that affects older adults. GCA manifests with arthritis and occlusive symptoms of headaches, stroke or vision loss. Macrophages and T-helper lymphocytes infiltrate the vascular wall and produce a pro-inflammatory response that lead to vessel damage and ischemia. To date, there is no GCA biomarker that can monitor disease activity and guide therapeutic response. Folate receptor beta (FRB) is a glycosylphosphatidylinositol protein that is anchored on cell membranes and normally expressed in the myelomonocytic lineage and in the majority of myeloid leukemia cells as well as in tumor and rheumatoid synovial macrophages, where its expression correlates with disease severity. The ability of FRB to bind folate compounds, folic acid-conjugates and antifolate drugs has made it a druggable target in cancer and inflammatory disease research. This report describes the histopathologic and immunohistochemical methods used to assess expression and distribution of FRB in relation to GCAimmunopathology. Formalin-fixed and paraffin-embedded temporal artery biopsies from GCA and normal controls were stained with Hematoxylin and Eosin to review tissue histology and identify pathognomonic features.Immunohistochemistry was used to detect FRB, CD68 and CD3 expression. A microscopic analysis was performed to quantify the number of positively stained cells on 10 selected high-power-field sections and their respective locations in the arterial wall. Lymphohistiocytic (LH) inflammation accompanied by intimal hyperplasia and disrupted elastic lamina was seen in GCA with none found in controls. The LH infiltrate was composed of approximately 60% lymphocytes and 40% macrophages. FRB expression was restricted to macrophages, comprising 31% of the total CD68+ macrophage population and localized to the media and adventitia. No FRB was seen in controls. This protocol demonstrated a distinct numerical and spatial pattern of the FRB macrophage relative to the vascular immune microenvironment in GCA.

Neuroleukemiosis: Diagnosis and management.

An exceedingly rare manifestation of leukemia, termed neuroleukemiosis, involves peripheral nerve infiltration by leukemic cells. Patients with neuroleukemiosis typically present with a peripheral neuropathy and/or chloromatous masses. The diagnosis is supported by, and established with, electrophysiologic testing, imaging, histopathology, and immunophenotyping. We present the case of 21 year old male with multiply relapsed M4 type of acute myelogenous leukemia (AML) who presented with extremity pain and was subsequently found to have multiple cervical, thoracic, and lumbosacral nerve root masses. A diagnosis of neuroleukemiosis was established via CT-guided biopsy and immunophenotyping. The patient's neuroleukemiosis responded well to chemotherapy, donor lymphocyte infusions, and spinal irradiation. The literature is reviewed regarding this interesting and rare clinical condition.

Nonsecretory and Light Chain Escape in Patients With Multiple Myeloma.

BACKGROUND: Multiple myeloma (MM) is characterized by the secretion of monoclonal protein by malignant plasma cells in the vast majority of cases. We identified and analyzed patterns of disease relapse and progression associated with disappearance of the paraprotein ("nonsecretory [NS] escape"), or conversion from production of intact Ig molecule to its associated light chain ("LC escape"). PATIENTS AND METHODS: We retrospectively reviewed medical records and a database of 791 consecutive patients with symptomatic MM. RESULTS: Twenty-eight (3.5%) patients had disease evolution associated with either NS (n = 13) or LC (n = 15) escape. The event occurred at a median of 37 months (range, 3-156 months) after the diagnosis of MM, and after a median of 3 chemotherapy regimens (range, 1-8 regimens). Presence of extramedullary disease at progression was detected in 8 (29%) patients. Sensitivity to chemotherapy before and after escape was present in 21 (75%) and 14 (50%) patients, respectively. After a median follow-up of 55 months, 19 (68%) patients died, and progressive MM was the cause of death in 18 patients. The median overall survival after escape was 20 months (95% confidence interval, 9-25 months), and no significant difference was found between the NS and LC groups (P = .44). The median overall survival after diagnosis of MM was worse in patients with NS/LC escape than in those without escape (52 vs. 94 months; P = .018). CONCLUSIONS: Our study describes the largest series of NS and LC escape in MM to date. The development of this phenomenon is associated with more aggressive clinical features, frequent resistance to chemotherapy, and worse clinical outcome.

A case of vasculopathy of unknown etiology associated with fatal hydrops fetalis and review of the literature on intimomedial mucoid degeneration.

Non-immune hydrops fetalis (NIHF) has a high mortality rate [1]. Many etiologies of NIHF have been identified, including cardiovascular abnormalities, severe anemia, and genetic defects. In patients with cardiovascular etiology, structural malformations lead to fluid accumulation resulting in increased intravascular hydrostatic pressure. We report a fatal case of NIHF in a 31 week gestational age, Caucasian neonate with heart remodeling associated with a stenotic vasculopathy of the right pulmonary artery. The artery revealed partial occlusion with vascular wall abnormalities, including disarrayed smooth muscle fibers, hyperplasia within the tunica media, and myxoid change within the media and intima. Identical vasculopathy was also identified within a mesenteric artery, and this contributed to hemorrhage and early ischemic necrosis of the small intestine, discovered on postmortem examination.

An immunohistochemical analysis of folate receptor beta expression and distribution in giant cell arteritis - a pilot study.

BACKGROUND: Giant cell arteritis (GCA) is a chronic vasculitis of large and medium vessels in which no targetable biomarkers exist to allow selective treatment, predict disease activity and monitor therapeutic responses. The accessibility of the temporal artery (TA) for biopsy allows morphologic studies to characterize macrophages and T cells in the microenvironment of the arterial wall. We evaluated the expression of folate receptor beta (FRB), a candidate diagnostic/therapeutic biomarker, compared its expression with key macrophage markers and correlated it with GCA severity. METHODS: Formalin-fixed paraffin-embedded tissue sections were examined from 6 patients with GCA and 2 controls. Immunohistochemistry was performed using FRB, ETB, CD68 and CD3 antibodies to evaluate for activated macrophages and T cells, assess FRB distribution along the intima, media and adventitial layers and composition of inflammatory infiltrates. We compared the expression of FRB, ETB and CD68 in GCA versus negative controls and in severe (with visual loss) versus mild (without visual loss) disease. RESULTS: In GCA, moderate to severe inflammation was accompanied by >90% destruction of the internal elastic lamina. Macrophages comprised 36.3 ± 4.1% while CD3+ lymphocytes accounted for 61.7 ± 4.1% of total leukocytes. FRB was selectively expressed in macrophages and localized to the adventitia. GCA patients had marginally increased median FRB (9.8 cells/hpf vs. 0; p=0.095), ETB (20.5 vs. 0; p=0.095) and CD68 (38.8 vs. 5; p=0.071) expression versus controls. ETB was found in endothelial cells, smooth muscle cells and macrophages in intima/media. FRB positively correlated with ETB (r=0.90; p-0.037) and CD68 levels (r=0.90; p=0.037). ETB expression positively correlated with CD68 (r=1.0; p<0.0001). There was no difference in FRB between severe and mild GCA. CONCLUSION: FRB is a potential diagnostic and therapeutic biomarker with restricted expression in GCA macrophages. FRB+ macrophages localized to the adventitia and their expression correlated with ETB and CD68 macrophages, suggesting that they contribute to GCA pathogenesis.

Isolated sciatic neuropathy as an initial manifestation of a high grade B-cell lymphoma: A case report and literature review.

Sciatic nerve neuropathy due to infiltrating of a high grade B-cell lymphoma is a very rare situation and has not often been reported. We report a case with a previous history of indolent lymphoma who presented with isolated sciatic nerve neuropathy and was found to have diffuse large B cell lymphoma involving the sciatic nerve. Although the current case is not a primary sciatic nerve lymphoma given the systematic involvement shown on MRI and PET/CT scan, the case represents a neurolymphomatosis of the sciatic nerve given the direct invasion of the lymphoma cells into the sciatic nerve. Due to the rarity of this condition, we subsequently reviewed related literatures.

Clinical Implications of CD30 Expression in Aggressive B-Cell Lymphomas.

BACKGROUND: US Food and Drug Administration approval of brentuximab vedotin for treatment of CD30-positive relapsed/refractory lymphomas, including classical Hodgkin lymphoma and anaplastic large cell lymphoma, initiated significant interest in researching CD30 expression in other therapy-resistant or relapsed lymphomas. We evaluated CD30 expression in 116 cases of aggressive B-cell lymphomas diagnosed at Penn State Milton S. Hershey Medical Center between 2000 and 2012 with the purpose of assessing the benefit of treatment with brentuximab. PATIENTS AND METHODS: We studied CD30 expression in types of aggressive B-cell lymphomas not previously studied, including Burkitt lymphoma, high-grade (grade III) follicular lymphoma, mixed grade III follicular lymphoma/diffuse large B-cell lymphoma (DLBCL), posttransplantation lymphoproliferative disease large B-cell lymphoma, and primary mediastinal large B-cell lymphoma. RESULTS: CD30 expression was found in 37.5% of DLBCL and 46.2% of other non-DLBCL aggressive B-cell lymphomas. CONCLUSION: Expression of CD30 in patients with both DLBCL and other aggressive B-cell lymphomas and the absence of MYC oncogene-driven proliferation in the majority of these tumors suggests that brentuximab may be a particularly effective form of targeted therapy in the subset of patients with high CD30 expression.