Benign Lymphoma Research Articles

Castleman Hastalığı: Nadir Intraabdominal Yerleşim Nedeniyle

Castleman disease (CD) is a rare benign disease with unknown etiology. It is also called angiofollicular lymph node hyperplasia, giant lymph node hyperplasia, lymph node hamartoma, benign giant lymphoma. Histologically, it is classified as hyaline vascular and plasma cell variant, but rarely features of two types can coexist. Most of the cases with unisentric disease are hyaline vascular and most of the cases with multicentric disease are in plasma cell histological type. Although it is frequently located in thorax, it can be found throughout the body. Salivary glands, lungs, pancreas, larynx, parotid gland, meninges, and even limb muscles can be affected as extralymphatic spread. Since it is localized in the middle and anterior mediastinum in the thorax, it should be differentiated from mediastinal autoimmune and neoplastic diseases. In this case report, we aimed to present the radiological findings of a CD case with a rare intraabdominal location.

Environmentally-induced alternative oncogenesis: EROS arrows

The cause of the oncological diseases in children and the specific spectrum of this pathology, with hemangiomas prevailing among benign tumors (BT), and leukemia, lymphomas, and neural tissue tumors among malignant neoplasms (MN), remains unknown. The authors studied the similarities and differences of the connections between environmental factors, benign tumors and MN, as well as the relations between BT and MN. The causality of the so-called “sporadic” fluctuations in the incidence of neoplasms and their relations with environmental factors were revealed. A hypothesis of environmentally-induced alternative oncogenesis is suggested. According to the hypothesis, fetal hemoglobin enhances environmentally-related oxidative stress (EROS), leading to epigenomic regulation disorder of SEMA 7A and MICAL family proteins in the endothelium, axon growth cone, and hematopoietic stem cells.

Intra-abdominal localized hyaline-vascular Castleman disease: imaging characteristics and management of a rare condition.

Castleman disease (CD) is a rare lymphoproliferative disorder of unknown etiology and one of the uncommon causes of nonneoplastic lymphadenopathy. Earlier synonyms of CD included angiofollicular lymph node hyperplasia, giant lymph node hyperplasia, lymphoid hamartoma, benign lymphoma and follicular lymphoreticuloma. This disease was first reported by Castleman et al. in 1954 [1] and later defined by Castleman et al. in 1956 in a series of 13 patients with unicentric hyaline vascular CD presenting with large thymoma-like masses in the anterior mediastinum [2]. The condition was later found to be occasionally associated with hypochromic anemia, hypergammaglobulinemia and bone marrow plasmacytosis [3, 4]. By the late 1960s and the early 1970s, the histological features of the different forms of the disease and the classification in current use had been established [5, 6]. The disease features three main histopathological presentations: hyaline vascular, plasma cell-rich, and mixed variants [6, 7]. The exact incidence of CD is unknown. Association of certain forms of the disease with the human immunodeficiency virus (HIV) and human herpes virus-8 (HHV-8) infections has been long recognized. In 1985, Lachant et al. reported on 2 patients with the acquired immunodeficiency syndrome (AIDS) who developed multicentric CD followed by Kaposi sarcoma [8]. In 1995, Soulier et al. reported frequent coincidence of HHV-8 in 31 patients with multicentric CD [9].

Early lymphoid lesions: conceptual, diagnostic and clinical challenges.

There are no "benign lymphomas", a fact due to the nature of lymphoid cells to circulate and home as part of their normal function. Thus, benign clonal expansions of lymphocytes are only rarely recognized when localized. Recent studies have identified a number of lymphoid proliferations that lie at the interface between benign and malignant. Some of these are clonal proliferations that carry many of the molecular hallmarks of their malignant counterparts, such as BCL2/IGH and CCND1/IGH translocations associated with the in situ forms of follicular lymphoma and mantle cell lymphoma, respectively. There are other clonal B-cell proliferations with low risk of progression; these include the pediatric variants of follicular lymphoma and marginal zone lymphoma. Historically, early or incipient forms of T/NK-cell neoplasia also have been identified, such as lymphomatoid papulosis and refractory celiac disease. More recently an indolent form of T-cell lymphoproliferative disease affecting the gastrointestinal tract has been described. Usually, CD8(+), the clonal cells are confined to the mucosa. The clinical course is chronic, but non-progressive. NK-cell enteropathy is a clinically similar condition, composed of cytologically atypical NK-cells that may involve the stomach, small bowel or colon. Breast implant-associated anaplastic large cell lymphoma is a cytologically alarming lesion that is self-limited if confined to the seroma cavity. Atypical lymphoid proliferations that lie at the border of benign and malignant can serve as instructive models of lymphomagenesis. It is also critical that they be correctly diagnosed to avoid unnecessary and potentially harmful therapy.

Evaluation diagnostic usefulness of immunoglobulin light chains (Igκ, Igλ) and incomplete IGH D-J clonal gene rearrangements in patients with B-cell non-Hodgkin lymphomas using BIOMED-2 protocol.

Evaluation diagnostic usefulness of immunoglobulin light chains (Igκ, Igλ) and incomplete IGH D-J clonal gene rearrangements in formalin-fixed, paraffin-embedded (FFPE) tissue of patients with B-cell non-Hodgkin lymphomas (B-NHL). This study was performed on samples from 70 patients with B-NHL, including two cases of follicular lymphoma (FL), 20 cases of diffuse large B-cell lymphoma (DLBCL), one case of mantle cell lymphoma (MCL), and 47 cases of B-cell neoplasm (non-classified), which had been previously assessed for complete IGH clonality, and failure to clarify gene rearrangements. We used a gold standard multiplex PCR protocol provided by European Biomedicine and Health (BIOMED-2) Concerted Action Project BMH4-CT98-3936 for improvement of diagnosis and analysis of clonality gene rearrangement in lymphoma malignancies. Our results revealed a total positive monoclonality of 89 % (62/70) in Igκ, Igλ, and 11.4 % (8/70) polyclonality in gene rearrangements assay. The samples with positive clonality consisting (Igκ: 45 %, Igλ: 55 %) in DLBCL, (Igκ: 100 %) in FL, (Igλ: 100 %) in MCL, and (Igκ: 47 %, Igλ: 36 %) in B-cell neoplasm non-classified. None of the incomplete IGH D-J immunoglobulin gene families (0 %) showed monoclonality, and all samples demonstrated polyclonality pattern. Our findings on FFPE tissue revealed that immunoglobulin light chains clonality gene rearrangements assays using BIOMED-2 protocol, could be considered a valuable and reliable method for clonality detection, particularly in cases of failure of complete IGH gene rearrangements analysis. Clonal Ig gene rearrangements assay is applicable for routine diagnostic testing of lymphoproliferative disorders and as a reliable method for differentiating between malignant and benign lymphoma disorders.

Atypical lymphoid proliferations: the pathologist’s viewpoint

Lymphoid proliferations are traditionally thought to be either benign conditions (reactive hyperplasia and lymphadenitis) or malignant lymphomas. However, not all lymphoid lesions at present can be precisely placed into one of these categories. Therefore, in addition to these two extremes, there also exist a third group of lymphoid proliferations – the atypical lymphoid proliferations (AtLP). AtLP is a descriptive term used when it is not possible for the pathologist to differentiate between the benign and the malignant nature of a given lymphoid infiltrate. AtLP represent biologically indeterminate lesions that have some worrisome clinicopathologic features but cannot be interpreted as malignant lymphomas using all criteria currently available. They have some likelihood for subsequent transformation into lymphomas, and therefore AtLP occupy a middle ground between benign and malignant lymphoid proliferations. Nevertheless, sometimes AtLP are not necessarily premalignant and may very well represent a fully benign situation mimicking malignancy. In the author’s opinion, when confronted with a challenging lymphoproliferative lesion, the pathologist should marshall all resources available to interpret it as precisely as possible and therefore place it into one of the two categories: unequivocally benign condition or malignant lymphomas. The resources should include immunohistochemical and molecular studies, obtaining expert opinion and rebiopsy. However, if clinical, morphologic and molecular findings are not sufficient for diagnosis of a benign condition versus lymphoma, the descriptive term AtLP can be used. In the author’s opinion, the use of this descriptive term AtLP may obviate the need to force some lymphoid proliferations (equivocal lesions or mimickers of lymphomas) into either the benign or malignant categories.

Mantle Cell Lymphoma and Involvement of the Orbit and Ocular Adnexa

Orbital and ocular adnexal lymphomas are rare and represent around 1-2% of lymphomas and about 8% of the extranodal lymphomas. However, these entities represent the majority of orbital malignancies. Lymphomas of the ocular adnexal region are primary or secondary lymphomas, and the majority of them are composed of small, mature lymphocytes, which provide a large differential diagnosis. Thus, these entities are not easily distinguished from indolent lymphoid processes such as reactive lymphoid hyperplasia. Extranodal marginal zone lymphoma is the most common lymphoma in the ocular adnexal region. However, this entity cannot be distinguished from benign lymphoid proliferations or other lymphomas composed of small, mature lymphocytes by routine histopathology. We describe a 78-year-old man who presents with bilateral upper eyelid masses, which had been present and grew in size over the past twelve months prior to his presentation. A biopsy of the mass shows a monotonous population of small, mature lymphocytes. The immunohistochemical studies performed on the eyelid mass confirmed a monoclonal proliferation of B cells expressing cyclin-D1; therefore, a final diagnosis of mantle cell lymphoma was rendered. A literature review of mantle cell lymphoma with orbital and ocular adnexal involvement and the diagnostic pitfalls in this area of hematopathology are discussed.

Flowcytometric Immunophenotyping in the Diagnosis of Pediatric Lymphoma: How Reliable Is It and How Can We Optimize Its Use?

We aimed to evaluate the role of flowcytometric immunophenotyping (FCI) as an adjunct to histologic examination in pediatric lymphoma. We conducted a retrospective review of 39 fresh tissue samples and 2 pleural fluids submitted to the histopathology department with a clinical suspicion of lymphoma during a 4-year period, where FCI was performed. The FCI results were correlated with the final histologic diagnosis. The study comprised 38 lymphoid lesions and 3 nonlymphoid tumors. The concordance of FCI for all lesions was 71% and that for non-Hodgkin lymphoma was 75%. When Hodgkin lymphoma was excluded, the correlation was 93.1%. In 3 cases of nonhematologic tumors, FCI was useful in excluding a lymphoma. In one of them, FCI supported the diagnosis of neuroblastoma when CD81, CD9, GD2, and CD56 were added to the FCI panel. FCI produced rapid same-day results with a high sensitivity for benign lymphoid lesions and non-Hodgkin lymphoma. It was not helpful for Hodgkin lymphoma. Although the main application of FCI was to assess lymphoid lesions, it was also useful in the identification of nonlymphoid tumors, especially neuroblastoma. As the prevalence of lymphomas in children differ from that in adults, we believe that the algorithm proposed by us to triage specimens using imprint cytology can optimize the use of FCI in routine pediatric pathology practice.

Clinical presentation of reactive lymphoid hyperplasia (RLH) on the ocular surface – report of 6 cases

Abstract Purpose Reactive lymphoid hyperplasia (RLH), also called inflammatory pseudotumor, benign lymphoma or pseudolymphoma, is a benign and reversible enlargement of lymphoid tissue probably as a reaction to antigen hyperstimulation. RLH consists of dense sheets of small mature lymphocytes with the formation of primary and secondary follicles reminiscent of normal lymph node architecture. In this study we wanted to evaluate the clinical presentation of RLH on the ocular surface. Methods We reviewed 6 patients (3 males, 3 females) with RLH of the ocular surface. The mean age at the time of diagnosis was 28 yrs (range: 8 to 77 yrs). Paraffin sections were stained with H&E and PAS and further evaluated using immunohistochemistry. Results In 2 patients, RLH was confined to the caruncle. One patient presented with a large cyst‐like lesion, another one with a conjunctival nodule near the medial canthus, and in the oldest patient the RLH manifested itself as a pemphigoid‐like conjunctival lesion in the lower fornix. A 26‐years old female patient with a Non‐Hodgkin‐Lymphoma of the left conjunctiva developed conjunctival RLH one month later in the lower fornix of the fellow eye. Follow‐up (1‐11 yrs) was uneventful in all patients. Conclusion In our case series, RLH presented as a singular lesion with varying clinical morphology. Obviously, it has to be carefully distinguished from lymphoma and should be considered in the differential diagnosis even of cyst‐like lesions and at unusual sites such as the caruncle.

Nodal imaging in the neck: recent advances in US, CT and MR imaging of metastatic nodes

The presence of lymph node metastasis in the neck in patients with head and neck cancer is an important prognostic determinant in staging cancers and in planning surgery and chemo- and radiotherapy for the cancer patients. Therefore, metastatic nodes should be effectively differentiated from benign lymphadenopathies and nodal lymphomas. Here, we review recent advances in the diagnostic imaging of metastatic nodes in the neck, with emphasis placed on the diagnostic performance of MR imaging, Doppler sonography, and CT.

Paraffin immunohistochemistry as an adjunct to hematopathology.

In the past two decades, there have been a number of dramatic advances in immunology that have subsequently affected immunohistochemistry. These have had a substantial impact on all phases of laboratory medicine, especially surgical pathology. Many hospital laboratories use immunohistochemical analysis on paraffin-embedded tissue sections as routinely as other special histochemical techniques. Hematopathology, in particular, has become increasingly reliant on the immunohistochemical antibody technique. This method aids in the identification of lineage-associated or lineage-restricted antigens in hematolymphoid neoplasms. The demonstration of kappa or lambda light-chain restriction is a good indicator of monoclonality in B-cell processes, aiding in the distinction between benign reactive hyperplasia and malignant lymphoma. Increasing numbers of antibodies that react to cluster differentiation cell surface antigens have become available for use in paraffin-embedded sections, obviating the need for frozen tissue in many cases. This facilitates the collection, processing, shipping, and storage of tissue specimens for immunohistochemical studies. This report will discuss the basic concepts in the immunohistochemical technique and show its applicability to hematopathology. It will also describe the most relevant antigens/antibodies and how they are used in antibody panels for the diagnosis of benign and malignant hematolymphoid lesions.

Semi-automatic Quantitation of Nucleolar Organizer Regions in Non-Hodgkin's Lymphomas

Nucleolar organizer regions may be useful in the diagnosis and classification of non-Hodgkin's lymphomas. In this study of 46 cases we applied morphometric analysis with quantitation of physical descriptors of the nuclear profile (area, perimeter) and both number and area of stained nucleolar organizers therein enclosed to a series of lymphomas and benign lymphoid infiltrates. While nuclear outlines were manually traced small organizer regions within the nuclear profiles were semi-automatically outlined by a thresholding procedure subjected to manual override. This results in determination of number, area and perimeter of organizer regions. Data were corrected for section thickness effects and a stereologic (three-dimensional) analysis was additionally performed. We found an increase in mean number and area of nucleolar organizers per nucleus in high grade lymphomas compared to benign infiltrates and lower grade lymphomas. Volume and thickness corrected data showed a decrease in organizer number with concomitant increase in organizer volume in the higher grade lymphomas. Multivariate analysis of the cases, previously classified histologically, showed that clear resolution could be obtained, on the basis of physical descriptors, both between as well as within groups of the three tumor grades.

In vivo expression of the B7 costimulatory molecule by subsets of antigen-presenting cells and the malignant cells of Hodgkin's disease

The B-lymphocyte/accessory-cell activation antigen B7 (BB1) has been shown in vitro to stimulate T-lymphocyte proliferation and cytokine production via CD28 present on the latter cells. In this study, benign lymphoid tissues, lymphomas, and extralymphoid inflammatory sites were examined immunohistochemically using anti-B7 and other relevant monoclonal antibodies. B7 was expressed by benign transformed germinal center B cells, as it was by B cells of follicular lymphomas. B7 was also expressed by a subpopulation (a mean of 31% to 65%) of macrophages and dendritic cells in a variety of lymphoid tissues. It was present in abundance on all macrophages constituting sarcoid granulomas in lymph nodes. In extralymphoid inflammation, 17% to 35% of macrophages expressed B7 only weakly. Cases of Hodgkin's disease showed expression of B7 by the majority of Reed-Sternberg cells or malignant mononuclear variants, a phenomenon that potentially contributes to the lymphocytic accumulation that is a feature of this condition. CD28+ T cells were seen in all areas where T cells were present. B7+ and CD28+ cells colocalized in, for example, lymphoid follicles, lymph node paracortex, sarcoid granulomas, and Hodgkin's disease tissue, indicating a potential for cellular interaction via these molecules at these sites.

Sensitivity and specificity of immunostaining in the diagnosis of mantle zone lymphoma.

The diagnosis of mantle zone lymphoma is sometimes difficult to make solely on the basis of morphology because the mantle zone pattern may be present in other disorders such as benign mantle zone hyperplasia, follicular center cell (FCC) lymphomas, and Castleman disease. To distinguish mantle zone lymphoma from the other disorders mentioned previously, the authors performed immunoperoxidase studies on B-5-fixed, paraffin-embedded sections or cryostat sections of lymph nodes from nine patients with a diagnosis of mantle zone lymphoma. The results then were compared with the immunostaining pattern seen in FCC lymphomas and various benign lymphoid hyperplasias. A monoclonal proliferation of mantle zone cells, as shown by staining for immunoglobulin light chains, was noted in the mantle zones and interfollicular areas in all six cases from which cryostat sections were available. The cells in the residual follicular centers uniformly had a polyclonal light chain marking pattern. Two novel monoclonal antibodies (LN-1 and LN-2) that identify FCCs and B-cells in B-5-fixed, paraffin-embedded tissues also were used in this study. Of the six cases in which the monoclonal antibodies could be used, the cells in the residual follicles were uniformly LN-1 positive, LN-2 positive, while the mantle zone and interfollicular cells were almost completely LN-1 negative, LN-2 positive. The data suggest that mantle zone lymphomas are a distinctive neoplasm of monoclonal B-cells of non-FCC origin. The authors conclude that immunostaining is a sensitive technic for identifying a malignant neoplasm of B-cells in the mantle zone and interfollicular areas. In addition, the method is relatively specific and useful for distinguishing mantle zone lymphoma from similar-appearing disorders such as benign mantle zone hyperplasias and certain FCC lymphomas.

Lymphoreticular tumors of the orbit

Lymphoreticular tumors in the orbit are uncommon. Only 42 patients were identified from over 2000 patients with tumors of lymphoid tissue seen between 1958 and 1979. The patients were divided into 3 groups: primary malignant, secondary malignant, and benign lymphoma. In the primary malignant lymphoma groups, there were 24 patients with a median age of 64 (40 to 87) years and a 2.4:1 female to male ratio: 2 cases were bilateral. In 19 (79%) patients with the lymphoma limited to one orbit the tumor was controlled in every case with doses from 25 to 45 Gy. There were no serious complications. Subsequently lymphoma developed at other sites in 7 (37%) patients. The 5 and 10 year cause specific actuarial survival rates were 70 and 62%. In the 8 patients with secondary malignant lymphoma, the orbital disease was controlled by irradiation, although all patients required further treatment and died of their disease. Radiotherapy controlled all 7 patients with benign lymphoma without any complications.

Cutaneous Pseudolymphoma

The diagnosis of cutaneous lymphoreticular infiltrative lesions is difficult. There are many diagnoses possible, and oftentimes it is difficult to distinguish between a malignant lymphoma cutis and any of the many benign lymphomas. This article deals with a patient who was diagnosed as having metastatic small-cell carcinoma. Because of the inconsistency between the pathologic diagnosis of malignancy and the benign clinical findings and course, a wide ablative excision of the lesion was done and the surgical specimen was studied thoroughly by numerous pathologists. Even then the diagnosis could not be clearly established. The differential diagnosis of cutaneous lymphomatoses is discussed.

I. Colorectal Benign Non-epithelial Tumors

From 1968 to August, 1977, 10 cases of colorectal non-epithelial tumors were experienced at our institute. They included two cases of leiomyomas, four cases of lipomas, and a case of benign lymphoma, pneumastosis cystoides and two cases of endometriosis.Leiomyomas, which located in the rectum, were diagnosed preoperatively by means of rectal biopsies.Three of four cases of lipomas, which located in the transverse colon, were examined endoscopically. Although the characteristic endoscopic appearances of the lipomas are said to be smooth, soft and pliable consistency with normal overlying mucosa, two of three cases showed shallow ulceration and reddness over the mass, that resulted in macroscopic resemblance to adenomatous polyps. When the lower half of the mass was smooth with shallow irregular ulceration on the upper half, endoscopic diagnosis of lipoma rather than adenomatous polyp was suggested. Endoscopic diagnosis of lipomas were difficult without careful observation. One of the lipomas was successfully removed via the colonoscope. The endos-copic removal may be very useful for diagnosis and treatment in selected cases of the nonepithelial tumors.

CASTLEMAN'S LYMPHOMA AMONG JAPANESE POPULATION

Since our report on Castlemans lymphoma in 1958, a total of 53 cases by 36 authors have appeared in the Japanese literatures. Among them our first case, whose tumor was found in the pelvic cavity, would be the first patient ever reported in Japan. The outstanding histological features of Castleman's lymphoma consists of variegated morphology of germinal centers due to peculiar capillary proliferation, multicentric germinal centers in a lymph follicle showing a chimerical figure and expansive growth of lymph follicles by compressing interfollicular area. Among these Japanese population, we have noticed the highest age incidence between 10-19 years, with somewhat female predominance, the most preferential site in the upper part of the body, and, as compared to the other ethnical subjects, more frequent tumor multiplicity and less usual plasma cell type of the tumor. A possible pathogenesis that Castleman's lymphoma could be "a benign lymphoma" in contrast to malignant lymphomas is emphasized from various aspects.

Malignant and benign lymphomas of the eye, eyelid, and orbit (author's transl)

Twenty-three lymphomas of the eye, eyelid, and orbit were chosen study from biopsy material of the Department of Pathology, University of Kiel, and the Lymph Node Registry in Kiel. There were 12 malignant non-Hodgkin's lymphomas and 11 benign lymphomas. Catamnestic examination confirmed the histologic diagnosis in all 11 cases of benign lymphoma. Eleven of the malignant lymphomas represented immunocytomas and were therefore a low-grade malignancy. In contrast, there was only one case of malignant lymphoma of high-grade malignancy, which was diagnosed as centroblastic lymphoma. The immunocytoma was retrobulbar in one third of our cases and conjuctival in only 2 cases, whereas benign lymphoma had developed in the conjunctiva in 7 of 11 cases. Immunocytoma represents a tumor composed of lymphocytes and plasma cells or plasmacytoid cells. PAS-positive globular inclusions are usually found in the nucleus and/or cytoplasm of the plasma cells or plasmacytoid cells.

Primary lymphoreticular tumours in the orbit

This paper reviews 46 cases of primary lymphoreticular tumours presenting in the orbit treated at the Christie Hospital between 1932 and 1969. Primary control of the orbital disease was readily achieved with a single exposure of 800 rad of orthovoltage X-rays to a single anterior field of 7 cm diameter and no case recurred in the orbit. The extent of the disease is a more important factor than the exact histological diagnosis in determining the prognosis, but none of five cases of benign lymphoma has developed disease elsewhere in a period of 5-7 years after treatment. The prognosis is good with a crude five-year survival of 54 percent, but if the disease is initially confined to the orbit 70 percent survive five years.