Tertiary lymphoid neogenesis is a component of pulmonary lymphoid hyperplasia in patients with common variable immunodeficiency.

BACKGROUND: Despite reducing pneumonia and other infections, antibody replacement does not appear to treat pulmonary lymphoid hyperplasia (PLH) in patients with common variable immunodeficiency (CVID). The pathogenesis and optimal treatments remain to be clarified. OBJECTIVE: We aimed to better understand the pathology of CVID-associated lung disease. Tertiary lymphoneogenesis, although a component of interstitial lung disease associated with autoimmune diseases, has not previously been explored in patients with CVID. METHODS: We examined the clinical characteristics and pathologic findings of 6 patients with CVID with nodular/infiltrative lung disease who had biopsy specimens demonstrating PLH. RESULTS: In these subjects regions of PLH contained distinct B- and T-cell zones, with B-cell predominance in 1 patient and T-cell predominance in the others. Colocalization of Ki67, Bcl6, and CD23 within this ectopic lymphoid architecture demonstrated tertiary lymphoneogenesis with active centers of cellular proliferation. One patient received rituximab with improved pulmonary radiologic findings. CONCLUSION: Ectopic lymphoid tissue forming germinal centers suggest tertiary lymphoneogenesis in CVID-associated lung disease. B cell-targeted therapy might disrupt CVID-associated lymphoid hyperplasia.

Identifying predictive factors for posttransplant lymphoproliferative disease in pediatric solid organ transplant recipients with Epstein-Barr virus viremia.

Epstein-Barr virus (EBV) viremia (EV) in pediatric solid organ transplant (SOT) recipients is a significant risk factor for posttransplant lymphoproliferative disease (PTLD) but not all patients with EV develop PTLD. We identify predictive factors for PTLD in patients with EV. We conducted a retrospective chart review of all pediatric SOT recipients (0 to 21 y) at a single institution between 2001 and 2009. A total of 350 pediatric patients received a SOT and 90 (25.7%) developed EV. Of EV patients, 28 (31%) developed PTLD. The median age at transplant was 11.5 months in the PTLD group and 21.5 months in the EV-only group (P=0.003). Twenty-three (37%) EV-only patients had immunosuppression increased before EV, compared with 28 (100%) of PTLD patients (P<0.001). The median peak EBV level was 3212 EBV copies/10 lymphocytes for EV-only and 8392.5 EBV copies/10 lymphocytes for PTLD (P=0.005). All patients who developed PTLD had ≥1 clinical symptoms. Younger age at transplant, increased immunosuppression before EV, higher peak EBV level, and presence of clinical symptoms have predictive value in the development of PTLD in SOT patients with EV.

Localization of BRCA1 protein in breast cancer tissue and cell lines with mutations.

BACKGROUND: The breast and ovarian cancer susceptibility gene (BRCA1) encodes a tumor suppressor. The BRCA1 protein is found primarily in cell nuclei and plays an important role in the DNA damage response and transcriptional regulation. Deficiencies in DNA repair capabilities have been associated with higher histopathological grade and worse prognosis in breast cancer. METHODS: In order to investigate the subcellular distribution of BRCA1 in tumor tissue we randomly selected 22 breast carcinomas and tested BRCA1 protein localization in frozen and contiguous formalin-fixed, paraffin embedded (FFPE) tissue, using pressure cooker antigen-retrieval and the MS110 antibody staining. To assess the impact of BRCA1 germline mutations on protein localization, we retrospectively tested 16 of the tumor specimens to determine whether they contained the common Ashkenazi Jewish founder mutations in BRCA1 (185delAG, 5382insC), and BRCA2 (6174delT). We also compared co-localization of BRCA1 and nucleolin in MCF7 cells (wild type) and a mutant BRCA1 cell line, HCC1937 (5382insC). RESULTS: In FFPE tissue, with MS110 antibody staining, we frequently found reduced BRCA1 nuclear staining in breast tumor tissue compared to normal tissue, and less BRCA1 staining with higher histological grade in the tumors. However, in the frozen sections, BRCA1 antibody staining showed punctate, intra-nuclear granules in varying numbers of tumor, lactating, and normal cells. Two mutation carriers were identified and were confirmed by gene sequencing. We have also compared co-localization of BRCA1 and nucleolin in MCF7 cells (wild type) and a mutant BRCA1 cell line, HCC1937 (5382insC) and found altered sub-nuclear and nucleolar localization patterns consistent with a functional impact of the mutation on protein localization. CONCLUSIONS: The data presented here support a role for BRCA1 in the pathogenesis of sporadic and inherited breast cancers. The use of well-characterized reagents may lead to further insights into the function of BRCA1 and possibly the further development of targeted therapeutics.

Recurrent precursor-B acute lymphoblastic leukemia presenting as a cervical malignancy.

A 59 year old woman with a history of acute lymphoblastic leukemia in remission presented with right flank pain. An abdominal ultrasound showed mild to moderate right hydronephrosis due to obstruction, and computed tomography scan showed a bulky mass near the cervix, concerning for cervical or uterine malignancy. A Papanicolaou smear was suspicious for malignancy, and immunocytochemical stains were positive for terminal deoxynucleotidyl transferase (TdT) and cluster of differentiation (CD)-10, focally positive for CD34 and CD79a, and negative for CD3, CD20, and paired box protein-5 (PAX-5). Cervical biopsies showed an infiltrating population of cells with immunophenotype similar to the cells on cervical cytology. The cytologic and histologic workup was compatible with infiltration of the uterine cervix by recurrent precursor-B acute lymphoblastic leukemia. A bone marrow biopsy showed normocellular marrow without evidence of tumor or infiltrative disease. Complete blood count and peripheral blood smear showed no evidence of leukemic involvement. Acute lymphoblastic leukemia diagnosed on cervical Pap smear has been very rarely reported. The majority of cases of hematologic malignancy involving the uterine cervix present with vaginal bleeding. To our knowledge, only three cases of recurrent precursor-B acute lymphoblastic leukemia in the uterine cervix have been reported, two of which occurred in pediatric patients. One pediatric patient presented with vomiting and abdominal pain, and was found to have hydronephrosis on imaging. This is perhaps the first case of precursor-B acute lymphoblastic leukemia diagnosed on cervical cytology in an adult patient with hydronephrosis and without vaginal bleeding.

Postoperative cardiac homograft involvement in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare multisystem disorder which is known to affect the skin, lungs, bone, pituitary gland, retroperitoneum and cardiovascular system. The case is described of a patient with ECD who had previously undergone a Ross procedure for presumed endocarditis involving the aortic valve and aortic root. The patient subsequently developed arthralgias, abdominal pain (requiring an exploratory laparotomy) and polydipsia. Furthermore, he developed progressive, symptomatic stenosis of the pulmonic homograft. A reoperative replacement of the homograft was required. The clinically suspected diagnosis of ECD was confirmed by a pathologic analysis of the explanted pulmonary homograft, and also (retrospectively) of previously resected mesenteric tissue. It is postulated that the patient may have developed ECD as a result of an immunologic reaction to the homograft tissue used for the Ross procedure.

Thymomas diagnosed during pregnancy: two cases in young women without paraneoplastic or autoimmune disease.

We report 2 cases of thymomas diagnosed during pregnancy. Neither of these 2 patients had paraneoplastic autoimmune conditions or previous neoplasia. The first patient had a 7.3-cm lymphocyte-predominant thymoma with capsular invasion. The second patient was diagnosed through fine needle aspiration biopsy after computed tomography showed multiple mediastinal masses. Although cases of thymoma during pregnancy have been reported, the exact cause has yet to be elucidated. We review the clinical, radiologic, pathologic, and immunohistochemical findings-including those of podoplanin, estrogen receptor, and progesterone receptor-of 2 previously unreported cases, as well as discuss the relationship of malignancy and pregnancy and review the available literature regarding pregnancy and thymoma.

BRCA1 protein and nucleolin colocalize in breast carcinoma tissue and cancer cell lines.

The breast and ovarian cancer susceptibility gene BRCA1 encodes a tumor suppressor. BRCA1 protein, which is involved in DNA damage response, has been thought to be found primarily in cell nuclei. In the present investigation, immunohistological studies of BRCA1 protein in frozen breast cancer tissue and MCF7 and HeLa cell lines revealed BRCA1 expression in both nucleoli and nucleoplasmic foci. Immunoelectron microscopic studies of estrogen-stimulated MCF7 cells demonstrated BRCA1 protein localization in the granular components of the nucleolus. Moreover, immunofluorescence of BRCA1 and nucleolin double-labeling showed colocalization in both nucleoli and nucleoplasmic foci in breast tumor cells and asynchronously growing MCF7 and HeLa cells. Multiparameter analysis of BRCA1 and nucleolin in relation to cell cycle position (DNA content) showed expression during G1-S and persistence of BRCA1 during G2/M. After gamma-irradiation of MCF7 cells, BRCA1 protein dispersed from nucleoli and nucleoplasmic foci to other nucleoplasmic sites, which did not colocalize with nucleolin. Small interfering RNA-mediated knockdown of BRCA1 protein resulted in decreased immunofluorescence staining, which was confirmed by Western blotting. The observed colocalization of BRCA1 and nucleolin raises new possibilities for the nucleoplasm-nucleolus pathways of these proteins and their functional significance.

Rarity of malignant mesothelioma prior to the widespread commercial introduction of asbestos: the Mount Sinai autopsy experience 1883-1910.

BACKGROUND: Most malignant mesotheliomas are related to asbestos exposure. Whether malignant mesothelioma occurs in the absence of asbestos exposure remains unsettled. To address this question we reviewed a series of 2,025 autopsies performed at the Mount Sinai Hospital between 1883 and 1910, prior to the widespread commercial introduction of asbestos. METHODS: Retrospective autopsy review. RESULTS: No cases of malignant mesothelioma were identified in 2,025 autopsies performed between 1883 and 1910. CONCLUSIONS: Malignant mesothelioma was rare prior to the widespread commercial introduction of asbestos.

Laparoscopic antrectomy for the treatment of type I gastric carcinoid tumors.

BACKGROUND: While the optimal treatment for type I gastric carcinoid tumors remains controversial, there is evidence to suggest that in multifocal disease, antrectomy may not only control local disease but also may lead to enterochromaffin-like cell (ECL) hyperplasia regression compared to medical and endoscopic treatments. MATERIALS AND METHODS: A single institution retrospective review of eight consecutive patients with multifocal type I gastric carcinoid tumor patients with no evidence of metastatic disease was performed from 2005 to 2006. All of these patients underwent laparoscopic antrectomy with Billroth II reconstruction. Patients' preoperative gastrin, chromogranin A levels, and biopsy and surgical specimen slides were compared with postoperative laboratory and biopsy slides. Pathology slides were reanalyzed by a blinded pathologist from our institution for evidence of tumor and ECL hyperplasia regression. RESULTS: All patients tolerated the procedure well with no reoperations or mortalities. Six of eight patient complained of mild reflux which was treated medically. One of eight had a mild wound infection which resolved with a course of cephalexin. Gastrin levels significantly decreased (98.9%) in all patients (P = 0.001). Furthermore, chromogranin A levels also significantly decreased (81.4%). Eight of eight patients showed no evidence of carcinoid tumor after surgery at mean biopsy follow-up of 17 mo (range 2-35 mo), however there was ECL hyperplasia after resection. Four of eight patients (50%) showed regression of ECL hyperplasia on postop biopsy, while the remaining four of eight showed no evidence of regression. CONCLUSIONS: This is the largest case series to investigate the surgical, clinical, and histologic outcomes of laparoscopic antrectomy in type I gastric carcinoid. Our data suggest that laparoscopic antrectomy is a safe and minimally invasive approach to treat nonmetastatic type I gastric carcinoid. All patients had no evidence of gross or microscopic disease at follow-up biopsy and almost half had regression of ECL hyperplasia at follow-up suggesting that antrectomy may be sufficient to prevent tumor recurrence. However, continued regular endoscopic surveillance and medical follow-up of patients with ECL hyperplasia are recommended.

The changing face of post-transplant lymphoproliferative disease in the era of molecular EBV monitoring.

Pediatric PTLD is often associated with primary EBV infection and immunosuppression. The aim was to retrospectively review the spectrum of histologically documented PTLD for two time intervals differentiated by changes in use of molecular EBV monitoring. Eleven of 146 patients (7.5%) in 2001-2005 (Era A) and 10 of 92 (10.9%) in 1993-1997 (Era B) were diagnosed with PTLD. The median age at liver transplantation (0.8 and 0.9 yr, respectively) and the median duration between liver transplant and diagnosis of PTLD (0.6 and 0.7 yr, respectively) were similar in both eras. However, patients in Era A presented with significantly less advanced histological disease compared to patients in Era B (p=0.03). Specifically, nine patients (82%) in Era A had Pl hyperplasia/polymorphic PTLD, whereas in Era B, six had advanced histological disease (five monomorphic and one unclassified). Three transplant recipients in Era B died secondary to PTLD, whereas there were no PTLD-related deaths in Era A (p=0.03). Heightened awareness of risk for PTLD, alterations in baseline immunosuppression regimens, implementation of molecular EBV monitoring, pre-emptive reduction in immunosuppression and improved therapeutic options may have all contributed to a milder PTLD phenotype and improved clinical outcomes.

Pagetoid reticulosis after radiotherapy of primary cutaneous anaplastic large-cell lymphoma.

We describe a 60-year-old man with a history of primary cutaneous anaplastic large cell lymphoma on the chest, who presented with a new scaly red plaque on the same site 11 years after radiation therapy. Histological examination revealed a dense epidermotropic infiltrate of atypical mononuclear cells consistent with pagetoid reticulosis. Immunohistochemistry revealed the infiltrate to be CD4, CD8, and CD30. Remarkably, all the atypical cells were strongly CD30, and furthermore, the CD30 cells were found exclusively in the epidermis. In the initial cutaneous anaplastic large cell lymphoma lesion, the CD4, CD8, and focally CD30 atypical cells were well confined within the dermis with no epidermal component. To our knowledge, the present case seems to be the first description of pagetoid reticulosis presenting at the site of a previously treated dermal anaplastic large cell lymphoma. This case also represents an extreme presentation of epidermotropism and CD30 expression in pagetoid reticulosis.

In vitro chemoresistance testing in well-differentiated carcinoid tumors.

BACKGROUND: Well-differentiated, "typical" carcinoid tumors traditionally have a very poor response to chemotherapy. We hypothesized that tumor specimens from well-differentiated carcinoid tumors would be highly resistant to the effects of chemotherapy when tested against a variety of antineoplastic agents in vitro. METHODS: Ninety-eight typical carcinoid specimens were surgically harvested, cultured, and tested against antineoplastics in vitro. (3)H-Thymidine incorporation was used to assess the percentage of cell-growth inhibition (PCI) of tested specimens. PCI was used to determine if specimens had extreme drug resistance (EDR), intermediate drug resistance (IDR), or low drug resistance (LDR) to each reagent against which they were tested. RESULTS: Seventy specimens generated results. Each was tested with an average of six drugs. The mean proportions of drugs classified as LDR, IDR, and EDR were 0.48 (range 0-1), 0.34 (range 0-1), and 0.18 (range 0-0.80), respectively. The mean numbers of drugs per specimen exhibiting LDR, IDR, and EDR chemoresistance were 2.7, 2.1, and 1.2, respectively. 57 of 70 specimens (81%) had LDR to at least two drugs. 5-FU had the highest frequency of low chemoresistance at 69%, followed by doxorubicin at 67%. Low in vitro resistance to chemotherapeutics was prevalent among typical carcinoids, while EDR was comparatively infrequent. CONCLUSIONS: This implies that there may be less clinical chemoresistance and more chemosensitivity among typical carcinoid tumors than clinical trials have previously revealed. These findings warrant additional investigations assessing the response of carcinoid tumors to assay-guided chemotherapy regimens.

Pulmonary manifestations of light chain deposition disease.

Light chain deposition disease (LCDD) is a rare condition characterized by extracellular light chain deposition in tissues. Patients commonly have an underlying plasma cell dyscrasia, and produce excess levels of monoclonal light chains. Renal involvement is the most common clinical manifestation. Rarely, light chains are deposited in the lung. We present the pathologic and radiographic findings of three patients with biopsy-proven pulmonary light chain disease and a review of the literature.

T-cell PTLD presenting as acalculous cholecystitis.

We report a five-yr-old child, presenting three yr after heart transplant with acalculous cholecystitis. Histology revealed EBV negative T-cell PTLD. The disease involved the gallbladder, liver, lungs, and mesenteric lymph nodes. He was treated with chemotherapy, went into remission, but relapsed after 11 months and died.

Renal benign epithelial nodal inclusions.

There are 3 case series reports describing benign epithelial inclusions in nodal sinuses of perinephric lymph nodes of pediatric patients. The majority of these inclusions were observed in perinephric lymph nodes removed during nephrectomies from pediatric patients with Wilms' tumors. We report 2 cases of benign renal tubular epithelial inclusions located in the perinephric hilar lymph nodes. One of our cases is, to our knowledge, the first case of benign renal epithelial inclusions reported in an adult patient.

Primary MALT Lymphoma of the Breast Treated with Definitive Radiation.

We are reporting a case of a 59-year-old woman, with a family history of breast cancer, who presented with extranodal marginal zone lymphoma (MALT) of the left breast. She received definitive radiation therapy and remains without evidence of disease. Here, we present a case and review the current literature to determine the optimal treatment of this rare presentation of MALT.

PET scan-positive cat scratch disease in a patient with T cell lymphoblastic lymphoma.

In patients who have history of lymphoma, a positive positron emission tomography (PET) scan is frequently considered as good evidence for relapse and/or persistent disease. Thus, lymph node biopsy is not always done to confirm the diagnosis of relapse or refractory lymphoma before a patient is subjected to further chemotherapy. We report a case of patient with history of T cell lymphoblastic lymphoma who presented again with inguinal lymphadenopathy and positive study on positron emission tomography suggestive of lymphoma relapse. This was pathologically proven to be cat scratch disease. This case suggests that in the immunocompromised patients who had history of lymphoma, infectious etiology should be ruled out for PET scan-positive lymphadenopathy.

MALT Lymphoma of the Bladder: A Case Report and Review of the Literature.

The presentation of a MALT lymphoma in the bladder is exceedingly rare. Furthermore, the optimal treatment of primary MALT confined to the bladder remains to be defined. Here, we report a case of a 65-year-old female with primary MALT lymphoma treated with definitive radiation therapy. The patient received a total dose of 30 Gy in 20 equal daily fractions to the bladder and tolerated the treatment well. In addition, we have extensively reviewed the relevant literature to better define the optimal management of this rare disease. In conclusion, primary MALT lymphoma of the bladder represents a rare malignancy with excellent prognosis if detected at an early stage. For early stage disease, definitive radiation represents an excellent treatment modality with a minimal side-effect profile.

Extranodal follicular dendritic cell tumor of the tonsil: report of a diagnostic pitfall and literature review.

Follicular dendritic cell tumor (FDCT) usually arises in the dendritic reticulum cells of the lymph nodes. Extranodal cases are rare; only 24 cases have been reported in the head and neck region, and most are in the oropharynx. Nine cases of primary FDCT of the tonsil have been reported in English-language literature, to which we add the 10th case. This 77-year-old white woman presented with a tonsillar mass that was misdiagnosed as squamous cell carcinoma. She underwent neoadjuvant radiotherapy plus combined oropharyngeal and mandibular resection with radical neck dissection. Eight years later, she presented with dyspnea and was found to have a lung mass with hilar lymphadenopathy. A biopsy specimen was taken from the hilar lymph nodes, and histologic analysis yielded results similar to those found in the original tumor. Immunohistochemical analysis confirmed that FDCT was present at both sites. We wish to highlight this potential diagnostic pitfall because the treatment and prognosis for FDCT are vastly different from the treatment and prognosis for squamous cell carcinoma of the tonsil.

Primary bone marrow B-cell lymphoma: report of four cases.

Bone marrow involvement is infrequent at presentation in cases of diffuse large B-cell lymphoma. We report four adult patients with diffuse large B-cell lymphoma in whom bone marrow involvement with hematologic manifestations was the predominant clinical feature at presentation. Three patients presented with a leukoerythroblastic blood picture and one with pancytopenia. In each case, the unusual hematologic manifestations, with bone marrow replacement and the presence of immature forms in the peripheral blood, led to consideration of alternative hematologic diagnoses, including acute granulocytic leukemia in three cases and a myelodysplastic syndrome in one. The correct diagnoses were established by immunohistochemistry on formalin-fixed, paraffin-embedded bone marrow for two cases and by flow cytometry on aspirated bone marrow or peripheral blood lymphocytes for the other two. Diffuse large B-cell lymphoma should be considered in the differential diagnosis of unusual hematologic presentations, particularly in the elderly.