Replication of HIV-1 in dendritic cell-derived syncytia at the mucosal surface of the adenoid.

Human immunodeficiency virus-type 1 (HIV-1) replicates actively in infected individuals, yet cells with intracellular depots of viral protein are observed only infrequently. Many cells expressing the HIV-1 Gag protein were detected at the surface of the nasopharyngeal tonsil or adenoid. This infected mucosal surface contained T cells and dendritic cells, two cell types that together support HIV-1 replication in culture. The infected cells were multinucleated syncytia and expressed the S100 and p55 dendritic cell markers. Eleven of the 13 specimens analyzed were from donors who did not have symptoms of acquired immunodeficiency syndrome (AIDS). The interaction of dendritic cells and T cells in mucosa may support HIV-1 replication, even in subclinical stages of infection.

Nodular lymphoid hyperplasia of the lung: a clinicopathologic study of 14 cases.

Nodular lymphoid hyperplasia is a controversial entity in which its existence in the lung has been doubted. The current opinion is that most, if not all, such cases represent extranodal marginal zone B-cell lymphomas masquerading as reactive lesions. We found 14 cases of nodular lymphoid hyperplasia in the files of the Pulmonary Department at the Armed Forces Institute of Pathology from 1974 through 1998. All had clinical histories and hematoxylin-eosin slides. In 12 of 14 with paraffin blocks, we applied immunohistochemical antibodies for CD20, CD3, CD43, CD5, bcl-2, bcl-1, CD45RA, and kappa and lambda immunoglobulin light chains. Molecular genetic analysis was performed on paraffin sections in 10 of 14 by the polymerase chain reaction for rearrangements of the immunoglobulin heavy chain gene and the minor and major break-point regions of the chromosomal translocation t (14;18). There were eight women and six men ranging in age from 19 to 80 years (median, 65 yrs). Most lesions (71%) were incidental findings on routine chest x-rays. Most patients (64%) had a single lesion by chest x-ray whereas the remainder had two to three lesions, except for one patient who had "multiple" lesions. There was associated regional lymphadenopathy in five of 14 cases (36%) which, on biopsy, proved to be reactive follicular hyperplasia. The only treatment was surgical excision. Of the seven patients with follow-up information from 8 months to 6 years (mean, 30 mos), none had clinical recurrence and no patient died of disease. The histology and immunophenotype of the lesions were strikingly similar, including abundant reactive germinal centers, intense interfollicular polyclonal plasmacytosis, and a variable degree of interfollicular fibrosis. No case showed a molecular rearrangement of the immunoglobulin heavy chain gene or the minor or major break-point region of the t (14;18). We conclude that nodular lymphoid hyperplasia of the lung, although rare, does exist and deserves its place in the spectrum of reactive pulmonary lesions that ranges from follicular hyperplasia to diffuse hyperplasia of the bronchus-associated lymphoid tissue (lymphoid interstitial pneumonitis).

Epithelioid angiosarcoma of the adrenal glands. A clinicopathologic study of nine cases with a discussion of the implications of finding "epithelial-specific" markers.

Adrenal epithelioid angiosarcomas (AEA) are rare neoplasms. We report the clinicopathologic features of nine cases of AEA. AEA occurred most frequently in the sixth and seventh decades of life (age range, 45-85 years; median, 60); five cases occurred in men and four in women. Presenting symptoms included abdominal mass with or without pain, weight loss, fever, and weakness. Two cases were asymptomatic; one was discovered during evaluation for other disease(s) and the other at autopsy. All neoplasms were nonfunctioning. Radiographic evaluation demonstrated suprarenal or retroperitoneal neoplasms ranging in size from 6 to 10 cm in greatest dimension. Histologically, the neoplasms were invasive, predominantly arranged in solid sheets or nests, and composed of epithelioid cells. Endothelial cell differentiation was suggested by the transition areas between dilated anastomotic vascular spaces and the sheet-like growth, the cytomorphologic similarity between the endothelial cells lining the discernible vascular spaces and those seen in the solid foci, and the presence of intracytoplasmic vacuolization occasionally containing red blood cells. Endothelial derivation was confirmed by immunohistochemistry including Factor VIII-related antigen (FVIII), CD-34 (hematopoetic progenitor cell antigen), and/or Ulex europaeus agglutinin-1 lectin immunoreactivity (UEA-1) and by ultrastructural findings, including rod-shaped microtubulated bodies and intracytoplasmic lumen formation. In addition, cytokeratin reactivity was seen in seven cases, and B72.3 (tumor-associated glycoprotein-72) reactivity was seen in six. Surgical resection was the treatment of choice, occasionally supplemented by chemotherapy. Three patients are presently alive, free of disease, at 13, 11, and 6 years following diagnosis. Three died with metastatic AEA of the lung, and three died of unrelated causes.

Reticulum cell neoplasms of lymph nodes: a clinicopathologic study of 11 cases with recognition of a new subtype derived from fibroblastic reticular cells.

Lymph nodes contain nonlymphoid accessory cells including follicular dendritic cells (FDCs), interdigitating dendritic cells (IDCs) and fibroblastic reticular cells (FBRCs). Neoplasms derived from FDCs are uncommon, and those of IDC origin are even more rare. We report the clinicopathologic features of 11 reticulum cell neoplasms, including 2 of FBRC origin. There were seven male patients and four female patients ranging in age from 13 to 73 years. All cases involved lymph nodes (cervical or supraclavicular-6 cases), (abdominal--2 cases), epitrochlear (1 case); two had more than one site of involvement (cervical lymph node and mediastinum--1 case, cervical and abdominal lymph nodes--1 case). One case of FDC tumor had concomitant Castleman's disease, plasma cell variant. Each neoplasm showed similar histology with oval-to-spindle-shaped cells in a storiform or fascicular pattern. Based on immunophenotypic findings, the neoplasms were classified as FDC (five cases), IDC (two cases), FBRC (three cases), and reticulum cell neoplasm, not otherwise specified (one case). The FDC tumors showed immunoreactivity for CD21 or CD35, vimentin, and CD68. The IDC tumors showed strong positivity for S-100 protein and variable positivity for CD68 and CD1a. The cases derived from FBRCs were positive for vimentin, desmin, and smooth-muscle actin. The neoplasm classified as reticulum cell neoplasm, not otherwise specified had similar morphologic features but showed only equivocal positivity for CD68 and vimentin. Follow-up was available for 9 of 11 (82%) cases with a mean of 3.5 years. Four of five patients with FDC tumors were alive with disease when last seen; the fifth is alive and well with no evidence of disease at 4-year follow-up. One patient with IDC tumor had a recurrence in a different nodal site. Two patients with FBRC tumor were disease free at follow-up of 2 years and 8 years, respectively. The patient with reticulum cell neoplasm, not otherwise specified, was alive and disease free 8 years after diagnosis.

Is lymphoplasmacytic lymphoma/immunocytoma a distinct entity? A clinicopathologic study of 20 cases.

Lymphoplasmacytic lymphoma/immunocytoma (LLI) was defined initially as a small B-cell lymphoma with plasmacytoid or plasmacytic features. Because other types of small B-cell lymphoma, particularly marginal zone B-cell lymphoma may exhibit plasmacytic differentiation, the revised European-American lymphoma classification and World Health Organization has defined LLI more narrowly to exclude other small B-cell lymphomas. The goal of this study was to reevaluate LLI as a clinicopathologic entity. Twenty cases were selected from 43 previously diagnosed as "small lymphocytic lymphoma, plasmacytoid" or "immunocytoma" from 1985 to 1998. Cases fulfilling the criteria for B-cell small lymphocytic lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, or other types of B-cell lymphoma were excluded. The histopathology and immunoreactivity for CD20, CD79a, CD3, CD43, CD23, CD5, kappa, lambda, and immunoglobulins (Ig's) M, G, and A were reviewed, in addition to available clinical findings. There were 13 men and seven women, with a mean age of 69 years. Five patients had documented Waldenström's macroglobulinemia (WM). Three architectural patterns were observed. Pattern A (seven of 20) showed open sinuses, small follicles, and hemosiderosis; pattern B (four of 20) showed hyperplastic follicles; and pattern C (nine of 20) showed diffuse effacement. Epithelioid histiocytes were prominent in patterns B and C but absent in A. Cytologically, six of 20 were polymorphous with 10% to 40% transformed cells; 14 of 20 were lymphoplasmacytic. Five cases showed minor foci of monocytoid B cells. One case showed a composite histology of LLI and small lymphocytic lymphoma. Amyloid was present in two cases. All cases were CD20 and/or CD79a immunoreactive, with two of 20 positive for CD43. Twelve cases were kappa monoclonal and eight cases were lambda monoclonal. Twelve of 17 cases that could be evaluated were positive for IgM and five were positive for IgG. All cases were negative for CD5 and CD23 with the exception of the one case with a composite histology. Eleven of 20 patients with available follow-up died of disease (median, 48 months), and eight of 20 are alive with disease at a follow-up of 6 months to 2 years. LLI does appear to represent a distinct clinicopathologic entity even though it shows morphologic heterogeneity and overlapping features with marginal zone B-cell lymphoma and small lymphocytic lymphoma. Recognition of LLI is important because the overall prognosis may be worse than for other types of small B-cell lymphomas.

Lymphoid changes of the nasopharyngeal and palatine tonsils that are indicative of human immunodeficiency virus infection. A clinicopathologic study of 12 cases.

We report 12 cases in which the histomorphologic changes of the nasopharyngeal tonsils (adenoids) or palatine tonsils suggest infection with the human immunodeficiency virus (HIV). The patients included 10 men and two women, aged 20 to 42 years (median, 33 years). The clinical presentation included airway obstruction, pharyngitis, fever, and a tonsillar or adenoidal mass lesion. Histologic evaluation of the excised adenoids or tonsils in 10 of the cases demonstrated a spectrum of changes including florid follicular hyperplasia, follicle lysis, attenuated mantle zone, and the presence of multinucleated giant cells (MGC). The latter characteristically localized adjacent to the surface or tonsillar crypt epithelium. Two of the 12 cases showed marked lymphoid depletion with absent germinal centers, plasmacytosis, and stromal vascular proliferation. Immunohistochemical evaluation for HIV p24 core protein showed reactivity in 10 of 12 cases localized to follicular dendritic cell network (FDC), the MGC, scattered interfollicular lymphoid cells, and cells identified within the surface or crypt epithelium. Localization of viral RNA by in situ hybridization paralleled the HIV p24 immunohistochemical findings. Additional significant findings included the presence of both CD-68 and S-100 protein in the MGC and the presence of S-100 protein in dendritic cells. Other than HIV, no microorganisms were identified. At the time of presentation, eight patients were not known to be a risk for HIV infection, nor were they known to be HIV infected or suffering from AIDS. In these patients, HIV infection was suspected on the basis of the histologic changes seen in the resected tonsillar and adenoidal tissue. Serologic evaluation (by enzyme-linked immunosorbent assay), confirmed the presence of HIV infection. Our findings suggest the possibility of HIV dissemination through the upper aero-digestive tract mucosa via target cells, such as intraepithelial dendritic cells, submucosal macrophages, and T-lymphocytes. Subsequent presentation of viral antigens to the tonsillar and adenoidal lymphoid tissues results in enlargement of these structures that clinically may simulate a neoplastic proliferation but causes histomorphologic changes that are highly suspicious for HIV infection even in asymptomatic HIV-positive patients.

Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases.

We report a retrospective clinicopathologic study of 108 primary thyroid gland lymphomas (PTLs), classified using the REAL and proposed WHO classification schemes. The patients included 79 women and 29 men, with an average age of 64.3 years. All patients presented with a thyroid mass. The PTLs were classified as marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) or MZBL (n = 30), diffuse large B-cell lymphoma (DLBCL) with MZBL (n = 36), DLBCL without MZBL (n = 41), and follicle center lymphoma (FCL; n = 1). Excluding the FCL, features of lymphomas of MALT-type were identified in all groups, despite a follicular architecture in 23% of cases. Lymphocytic thyroiditis (LT) was identified in 94%. Ninety-one percent of patients presented with stage IE or IIE disease, whereas 69% had perithyroidal soft tissue infiltration. All patients were treated with surgical excision followed by adjuvant therapy (76%): chemotherapy (15%), radiation (19%), or a combination of radiation and chemotherapy (42%). Disease-specific survival was 82% at last follow up (mean, 82.8 mos) and 79% at 5 years. Statistically, stages greater than IE, presence of DLBCL, rapid clinical growth, abundant apoptosis, presence of vascular invasion, high mitotic rate, and infiltration of the perithyroidal soft tissue were significantly associated with death with disease. No patients with MZBL or stage IE disease died with disease. In summary, PTLs typically occur in middle- to older-aged individuals as a thyroid mass, with a predilection for females. Despite their histologic heterogeneity and frequent simulation of other lymphoma subtypes, virtually all PTLs are lymphomas of MALT-type arising in the setting of LT. Mixed DLBCL and MZBL are common. Overall, PTLs have a favorable outcome with appropriate therapy, but prognosis depends on both clinical stage and histology. MZBL and stage IE tumors have an excellent prognosis, whereas tumors with a large cell component or DLBCL or stage greater than IE have the greatest potential for a poor outcome.

Inflammatory pseudotumor of lymph nodes: a study of 25 cases with emphasis on morphological heterogeneity.

The clinicopathological and immunohistochemical findings in 25 cases of inflammatory pseudotumor of lymph nodes (IPT) are presented. The patients were 13 women and 12 men between 8 and 81 years of age. Clinically, symptoms of prior infection, fatigue, abdominal pain, weight loss, fever of unknown origin, pelvic inflammatory disease, or nausea and night sweats were obtained in 15 patients, whereas six patients presented with asymptomatic lymphadenopathy. In four additional patients, no clinical information was obtained. The involved nodes included cervical, supraclavicular, inguinal, mesenteric, and mediastinal lymph nodes. In two cases, there was synchronous involvement of separate lymph node groups (inguinal and cervical in one case and cervical and mediastinal in another case), whereas in a third patient there was synchronous involvement of the spleen and a paraaortic lymph node. Histologically, the lesions were characterized by a fibrosing/inflammatory process that showed marked heterogeneity and striking variation from case to case. Based on their histological features, the lesions could be classified into three different groups: Stage I was characterized by the appearance of single or multiple small foci containing a spindle cell proliferation admixed with a prominent inflammatory background, with complete preservation of the remainder of the nodal architecture; stage II was characterized by more diffuse involvement of the lymph node with a marked inflammatory response admixed with a prominent myofibroblastic proliferation leading to subtotal effacement of the nodal architecture, often with extension of the process beyond the capsule into perinodal fat; and stage III was characterized by almost complete replacement of the lymph node by diffuse sclerosis with scant residual inflammatory elements and total loss of the normal nodal architecture. Immunohistochemical studies in 20 cases showed a striking number of vimentin- and actin-positive myofibroblastic cells with moderate increase in CD20/CD45+ small lymphocytes and polyclonal plasma cells in the stage I lesions, the emergence of numerous CD68+ histiocytes admixed with lymphocytes, plasma cells, and abundant fibromyofibroblastic cells in the stage II lesions, and only few remaining scattered CD68+ histiocytes and fibroblasts in the stage III lesions. Our findings suggest that inflammatory pseudotumor of lymph node represents an evolving, dynamic process that may adopt different morphological appearances depending on its stage of evolution. Recognition of the various stages of this process may be of importance for differential diagnosis with other fibrosing/inflammatory conditions of lymph nodes.

Extranodal sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) of the head and neck.

We report 14 cases of extranodal sinus histiocytosis with massive lymphadenopathy involving a variety of head and neck sites. The patients ranged in age from 3 to 70 years (median, 43 years). Nine cases occurred in women and five occurred in men. The clinical presentation varied depending on the site of occurrence and included nasal obstruction, stridor, proptosis, ptosis, decreased visual acuity, facial pain or tenderness, cranial nerve deficits, mandibular tenderness, and mass lesions. Head and neck sites involved by disease included the nasal cavity, paranasal sinuses, nasopharynx, parotid gland, submandibular gland, larynx, temporal bone, infratemporal fossa, pterygoid fossa, meninges, and orbital region. The majority of patients presented with involvement of more than one site. Nodal involvement was identified in four patients. Special stains for microorganisms were negative. The sinus histiocytosis with massive lymphadenopathy cells demonstrated an immunophenotypic profile supporting derivation from macrophage/histiocytic lineage. Treatment varied and included surgical excision with or without adjuvant therapy (chemotherapy, radiotherapy) or steroids. Several patients required more extensive surgery as a result of extension of their disease to adjacent structures or due to recurrent disease. Twelve patients are alive and either free of disease or have persistent disease. Two patients died, one as a result of complications of disease.

Antiapoptotic marker Bcl-X(L), expression on Reed-Sternberg cells of Hodgkin's disease using a novel monoclonal marker, YTH-2H12.

Inhibitors of apoptosis may regulate tissue differentiation and promote cell survival in neoplasia. A new apoptosis inhibitor of the bcl-2 gene family, bcl-X(L), was recently found in some types human neoplasia but not in normal tissue. We investigated bcl-X(L) expression in 419 cases of normal and neoplastic lymphoid lesions using immunohistochemistry with the monoclonal antibody bcl-X(L) (YTH-2H12). Ninety-four percent (141/150) of classic Hodgkin's disease (HD) were positive for bcl-X(L) with strong intensity in most Reed-Sternberg (RS) cells. Forty-eight percent (38/80) of nodular lymphocyte predominance (LPHD) were positive. In the non-Hodgkin's lymphomas (NHL), bcl-X(L) was expressed in a low percentage of cases (< 20%), with the exception of follicle center lymphoma, grade III/III (78%). All reactive hyperplastic lesions were negative for bcl-X(L). RS cells, which expressed bcl-X(L), were not labeled by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). We found RS cells expressing bcl-X(L) were absent of DNA fragmentation (apoptosis). Our data provide evidence that bcl-X(L) is abnormally expressed in the RS cells of HD and some types of NHL raising speculation that inhibition of apoptosis may be important in the pathogenesis of lymphoma, specifically HD. In addition, the previously reported correlation between bcl-X(L) and Epstein-Barr virus expression in HD was not supported by this study.

Expression of CD44 (HCAM) in small lymphocytic and mantle cell lymphoma.

Small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL) are small B-cell lymphomas that share many morphological and immunophenotypic features, both expressing the T-cell antigen CD5. Because of this, there is speculation that these two lymphomas may have a common origin, both arising from the mantle zone of the lymph node. CD44 (HCAM), a glycoprotein "homing receptor," has been reported as a marker of small B-cell lymphomas for determining behavior as well as the nodal cell of origin. Intensity of CD44 expression also has been correlated with dissemination of lymphoma. We studied 50 cases with classic features of SLL (30 cases) or MCL (20 cases). Immunophenotypic analysis was performed on paraffin sections. All cases of MCL and SLL were CD20 positive; CD5 was expressed in 19 of 25 (76%) SLL and 11 of 15 (73%) MCL. Cyclin D1 was expressed in 11 of 17 (76%) MCL and no cases of SLL. CD43 coexpression was seen in 27 of 29 (93%) SLL and 17 of 19 (89%) MCL. CD23 was positive in 25 of 28 (89%) SLL and 2 of 20 (10%) MCL. Bcl-2 was positive in 18 of 22 (82%) SLL and 15 of 16 (94%) MCL. CD44 was positive with moderate to strong intensity in 11 of 30 SLL and 15 of 20 MCL. Peripheral blood involvement did not correlate with CD44 immunoreactivity. MCL tended to have intense CD44 immunoreactivity, whereas SLL tended to show weaker CD44 intensity. This trend in the intensity of CD44 in MCL suggests that CD44 may be helpful in distinguishing SLL from MCL and possibly elucidating the origin of these CD5-positive B-cell neoplasms.

Telehematopathology in a clinical consultative practice.

We studied a series of 60 telepathology cases sent in consultation to the Department of Hematopathology from January 1, 1995, through July 31, 2000. Cases from the United States and the world representing academic, private, military, and federal sectors were reviewed. Ninety percent of patients were adults (54 of 60), and male patients outnumbered female patients 2 to 1. Ages were from 1 to 79 years (mean, 42 years). Forty-three cases were lymph nodes (72%), 14 were bone marrow or peripheral blood (23%), and 3 were from other sites (5%). Twenty-seven of the consultant diagnoses were benign (27 of 60). Twenty-nine were malignant (non-Hodgkin lymphoma, Hodgkin disease, and "other malignancy" groups), and 4 were nondiagnostic. Glass slide/paraffin tissue blocks were available in only 35 (58%) of 60 cases. The concordance rate for diagnostic telehematopathology cases with subsequent glass slide/paraffin block follow-up was 91% (29 of 32 cases). The discordance rate was 9% (3 of 32). This finding shows a high degree of diagnostic accuracy for consultative telehematopathology. Of 118 images analyzed, 58 were considered very good/good (49%), 32 were poor/very poor (27%), and 28 were fair (24%). Poor images had suboptimal resolution, color, or technical quality of transmission, and most poor images were low-power images. Additional case problems included insufficient immunoperoxidase stain availability, selection, and labeling; transmitted field selection; specimen preparation and staining; presence or absence of accompanying clinical data; and availability of ancillary studies such as flow cytometric, cytogenetic, and molecular data. From this analysis, the following recommendations are offered. To optimize telehematopathology consultation, include any additional information that have a significant influence on the final consultant diagnosis. Include any pertinent clinical information, laboratory data, special stains, immunoperoxidase stains, and molecular data. Select representative and diagnostically significant low-power and high-power fields for an accurate diagnosis. Label every immunostain or special stain submitted. Always send glass slides and tissue blocks when requested by the consultant. Optimize telemedicine microscopy and computer equipment with appropriate technical expertise, training, and support. In conclusion, the field of telepathology offers an exciting and potentially powerful solution to the problem of national and global subspecialty consultation. Hematopathology is potentially well suited to this technologically advanced marriage of computer and Internet technologies with modern microscopy, molecular diagnostics, immunophenotypic profiling, and the consultant pathologist.

Bcl-2 immunohistochemistry in a surgical series of non-small cell lung cancer patients.

The bcl-2 gene is implicated in oncogenesis by its ability to prolong cell survival through the inhibition of apoptosis, without increasing cell proliferation. An association between immunohistochemical staining for bcl-2 protein and the histological type and prognosis of non-small cell carcinoma was hypothesized by Pezzella et al. (N Engl J Med 329:690-694, 1993). In a case series, we stained formalin-fixed, paraffin-embedded tumor tissue from 106 surgical non-small cell lung cancer patients with an antibody to bcl-2 protein (DAKO clone 124, Carpinteria, CA). The resulting bcl-2 staining data were evaluated for associations with demographic, histological, immunohistochemical, and genetic features, including p53 mutations. Bcl-2 staining was observed in tumors from 29 of 106 (27%) of subjects, but was significantly less frequent in subjects' adenocarcinoma histology (8 of 55, 14.6%) (P = .007). This finding persisted after adjustment for age, gender, stage, grade, smoking history, and disease-free survival. In univariate analyses, no association was seen with age, weight, body mass index, gender, or pack-years smoking; tumor grade, stage, or patient performance status; p53 or c-erbB2 immunohistochemical staining, or p53 mutations. These data agree with earlier reports that bcl-2 staining is less common in adenocarcinomas; however, our data do not support the hypothesis that bcl-2 staining confers a better prognosis overall, in squamous cell carcinoma, or in an older patient population.

Pulmonary fibrosis after bone marrow transplantation responsive to treatment with prednisone and cyclosporine.

Interstitial pneumonitis and biopsy-proven pulmonary fibrosis developed in a 35-year-old man with acute myeloblastic leukemia 4 months after conditioning with total body irradiation, etoposide and cyclophosphamide and allogeneic marrow transplantation from an HLA-identical sister. The patient had no evidence of graft-versus-host disease. Under treatment with cyclosporine and prednisone the patient became asymptomatic and radiographic changes of the chest normalized. Following discontinuation of immunosuppressive treatment the patient again became dyspneic, and chest radiographs showed bilateral diffuse interstitial infiltrates. Concurrently there was a rise in serum transaminases. Treatment with prednisone again resulted in resolution of all symptoms and normalization of radiographic and hepatic function abnormalities. This case indicates that late onset interstitial pneumonitis may respond to immunosuppressive therapy. Conceivably, such pulmonary disease may represent the first or only manifestation of chronic graft-versus-host disease.

Loss of tumor suppressor gene expression in high-grade but not low-grade non-Hodgkin's lymphomas.

The products of the MTS1/CDKN2 and retinoblastoma (RB) tumor suppressor genes, p16 and pRB, act as agonists in controlling the late G1 cell cycle checkpoint. Inactivation of either gene occurs in a wide range of human malignant neoplasms. Data on the expression of both genes in the same set of malignant lymphoid neoplasms are scarce. We studied the p16/pRB pathway in low-grade and high-grade non-Hodgkin's lymphomas, using immunohistochemical techniques. Paraffin sections of 9 reactive lymph nodes and 43 low-grade and 60 high-grade malignant lymphomas were reacted with antibodies against pRB and p16. All benign lymph nodes showed a normal pattern of RB and MTS1/CDKN2 expression. Of 101 evaluable lymphomas, only a single high-grade tumor displayed loss of RB reactivity. Loss of p16 was identified in 14 of 55 evaluable high-grade lymphomas but not in any of the low-grade lesions. All but 3 of the RB- and p16-negative cases were diffuse large cell lymphomas, for an abnormality rate of 55% in this category. While loss of RB function was a rare event in human lymphomagenesis, p16 was absent in some 25% of high-grade non-Hodgkin's lymphomas; diffuse large cell lymphomas were the primary target of tumor suppressor gene inactivation.

Myelodysplastic syndrome with acquired hemoglobin H disease. Evolution through megakaryoblastic transformation into myelofibrosis.

A 64-year-old man was found to have a hemolytic anemia with a hematocrit of 0.28 (28%) during a routine evaluation. One month before this his hematocrit had been normal. Further studies revealed a myelodysplastic syndrome and acquired hemoglobin H disease. Eighteen months later this transformed into acute megakaryoblastic leukemia with disappearance of hemoglobin H, and shortly thereafter he had myelofibrosis develop. Acquired hemoglobin H disease, which is an alpha-thalassemia-like syndrome, results in the formation of an unstable hemoglobin composed of beta chain tetramers. This condition has been associated with preleukemia, sickle cell anemia, and hematologic malignancies. Although idiopathic myelofibrosis also has been described as a setting in which this thalassemic syndrome occurs, the present case is unusual in that the myelofibrosis was preceded by refractory anemia with leukemic transformation.

Auto anti-M. Clinical and serologic findings of seven patients from one hospital and review of the literature.

Auto-anti-M antibodies are not commonly documented serologically. A review of the literature reveals only ten cases with no consistent clinical or laboratory findings. In their institution, over a 12-year period, the authors have identified this autoantibody in seven patients, suggesting that it may not be such a rare entity but rather may be underdiagnosed. In this article the authors describe the pertinent clinical and serologic findings in their seven patients, as well as review the salient features of the previously reported cases.

Acute infectious mononucleosis. CD30 (Ki-1) antigen expression and histologic correlations.

Lymph nodes from patients with acute infectious mononucleosis (AIM) typically show marked paracortical expansion and a prominent immunoblastic proliferation that can occur in nodules and sheets, as well as within sinuses. The marked immunoblastic proliferation, coupled with Reed-Sternberg-like cells and a polymorphous inflammatory cell background, may simulate either non-Hodgkin's lymphoma or Hodgkin's disease. A recently described entity, Ki-1-positive lymphoma, or large cell anaplastic lymphoma, shares some clinicopathologic and phenotypic features with AIM and must be considered in the differential diagnosis. The present case describes a 20-year-old male who had signs and symptoms consistent with AIM, which he was later proven serologically to have, but whose cervical lymph node showed features suspicious for large cell anaplastic lymphoma. In addition, the Ki-1 (CD30) antigen was expressed by some of the atypical immunoblasts, further raising this possibility.

The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies.

Immunohistochemistry is increasingly used as an aid in the diagnosis of small-cell lung carcinoma (SCLC). Previous studies have investigated immunohistochemical staining of SCLC with small numbers of antibodies, but few have examined large series with a broad panel of antibodies. For this reason, the authors examined the distribution and intensity of staining of 20 open-lung biopsy (OLB) and 21 transbronchial biopsy (TBB) specimens of SCLC with a panel of epithelial, neuroendocrine, and hormonal markers. Small-cell lung carcinoma stained most frequently with epithelial markers, followed by neuroendocrine and hormonal markers. Similar percentages of OLB and TBB specimens stained for keratin (100% each) and epithelial membrane antigen (100% and 95%, respectively). Unexpectedly, BER-EP4 stained 100% of OLB specimens. Chromogranin A was the most frequent neuroendocrine marker in OLB and TBB specimens (60% and 47%, respectively) followed by neuron-specific enolase (60% and 33%), Leu-7 (40% and 24%), and synaptophysin (5% and 19%). No neuroendocrine immunohistochemical reactivity was found in 24% of TBB specimens and 20% of OLB specimens. Bombesin was the most sensitive hormonal marker (45% of OLB specimens). These results show that keratin, epithelial membrane antigen, and BER-EP4 are reliable epithelial markers for SCLC in both TBB and OLB specimens. In addition, negative staining for neuroendocrine markers, because it can occur in as many as 25% of cases, should not deter the diagnosis of SCLC.

Histologically discordant lymphomas with B-cell and T-cell components.

We describe the clinical, histologic, immunophenotypic, and genotypic features of five cases of histologically discordant lymphomas with B-cell and T-cell components. Three patients presented with B-cell lymphoma; T-cell lymphoma subsequently developed. One patient presented with T-cell lymphoma; B-cell lymphoma subsequently developed. One patient presented with synchronous B-cell and T-cell lymphomas. There were three men and two women. The median age at the initial diagnosis of lymphoma was 66 years. The mean interval between the development of the two lymphomas was 83 months. All patients died of disease. The mean survival was 96 months after the initial diagnosis of lymphoma and 14 months after the diagnosis of the histologically discordant lymphoma. Epstein-Barr virus was found in two cases--the B-cell lymphoma in the patient who presented with synchronous lymphomas, and the subsequent T-cell lymphoma in one of the patients who presented with B-cell lymphoma. Based on the results of immunophenotypic and genotypic analyses, these cases likely represent the occurrence of two distinct lymphoid neoplasms rather than histologic progression of the same neoplastic clone. Furthermore, a subset of these cases are Epstein-Barr virus-associated.