Castleman's disease and related disorders

Three disorders that bear the eponym of Castleman's disease (CD) are discussed. The localized CD of hyaline-vascular (HV) type features an architecturally abnormal, hypervascular lymphoid tissue with burned-out germinal centers, and presents as an asymptomatic, slowly growing mass. It may represent a lymphoid hyperplasia associated with excessive angiogenesis. The localized CD of plasma cell (PC) type, instead, features an architecturally recognizable lymph node with solid sheets of PCs and presents with systemic manifestations of inflammation and B cell hyperreactivity. It appears as a localized chronic reaction to unknown antigens. "Multicentric" CD indicates a clinicopathologic entity characterized by the histology of CD of "mixed" type, a predominantly lymphadenopathic presentation consistently involving peripheral nodes, manifestations of multisystem involvement, and an idiopathic nature. It is best considered as a systemic B cell lymphoproliferation, which probably arises in a setting of immunoregulatory deficit, and may result in the outgrowth of clonal B cell populations. An attempt is presented to place the latter two forms of CD in the larger perspective of idiopathic PC disorders, by taking into account both the nature of the diseases (hyperplastic, dysplastic, neoplastic) and the lymphocyte traffic system that is involved (bone marrow-bound, mucosa-associated or peripheral-node-bound). In such a scheme, localized CD, PC type, and multicentric CD appear as a hyperplastic and a dysplastic disorder, respectively, of peripheral-node-bound B cells, related to, and often associated with, primary nodal plasmacytoma and osteosclerotic myeloma (so-called POEMS, Takatsuki's or Crow-Fukase's syndrome).     

Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251.

PURPOSE: To define the activity and feasibility of brief-duration high-intensity chemotherapy for adults with small noncleaved, non-Hodgkin's lymphoma (SNC) and the L3 variant of acute lymphocytic leukemia (L3 ALL). PATIENTS AND METHODS: Seventy-five adults with either SNC or L3 ALL (median age, 44 years) were treated with an aggressive regimen that consisted of one cycle of cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide; high-dose methotrexate, vincristine, dexamethasone, and either doxorubicin or etoposide/cytarabine; or intrathecal triple therapy with prophylactic CNS irradiation. RESULTS: All 24 patients with L3 ALL and the 30 of 51 patients with SNC confirmed by central histologic review were included in this analysis. Forty-three of 54 patients achieved complete response (CR) (18 of 24 with ALL and 25 of 30 with SNC), and 28 are alive and in continuous CR with a median follow-up of 5.1 years. Hematologic toxicity was profound, and nonhematologic toxicity was notable, with 10 of 75 patients treated developing significant neurologic toxicity consisting of transverse myelitis in five patients, CNS toxicity in three, and severe peripheral neuropathy in two. All patients who did not achieve CR died of the disease, and all recurrences occurred within 16 months of the end of treatment. Responses and toxicities were similar in the patients with both lymphoma and leukemia. CONCLUSION: Aggressively delivered chemotherapy is potentially curative in as many as half of patients with SNC and the L3 ALL variant. This treatment regimen had considerable neurologic toxicity and has been modified.     

Use of anti-inflammatory and non-narcotic analgesic drugs and risk of non-Hodgkin's lymphoma (NHL) (United States)

Objective: To examine whether exposures to anti-inflammatory and non-narcotic analgesic drugs are associated with risk of non-Hodgkin's lymphoma (NHL). Methods: A case–control study was conducted among women living in upstate New York. The study involved 376 cases of NHL identified through the New York State Cancer Registry and 463 controls randomly selected from the Medicare beneficiary files and New York State driver's license records. Information regarding use of common medications in the past 20 years and potential confounding variables was obtained by telephone interview. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using an unconditional logistic regression model. Results: There were non-significant increases in risk associated with ever use of cortisone injections and oral cortisone (OR = 1.44 (Cl 0.98–2.11) for injections and 1.21 (CI 0.73–2.00) for oral cortisone, although there was no clear dose–response relationship with either type. On the other hand, the risk of NHL progressively increased with the frequency of use of non-steroidal anti-inflammatory and non-narcotic analgesic drugs (NSAID/NNAD) (p-value for trend 0.008). Women who used any of these medications daily for more than 10 years had an OR of 1.90 (CI 1.01–3.57), compared with those who used it less than once a month on average. The risk associated with long-term use was most pronounced for ibuprofen, intermediate for aspirin, and least for acetaminophen. Conclusions: Because the population-attributable risk associated with NSAID/NNAD use is potentially large, our results need to be verified in further epidemiologic studies.     

Primary vascular tumors of lymph nodes other than Kaposi's sarcoma. Analysis of 39 cases and delineation of two new entities.

Primary vascular tumors of lymph nodes other than Kaposi's sarcoma are very rare, as attested to by only a handful of case reports in the literature. Based on an analysis of 39 such cases, we could distinguish five major groups. Hemangiomas of capillary/cavernous, lobular capillary, and cellular types were composed of compact aggregates of blood-filled vessels, variable in size, that replaced the nodal architecture partly or almost completely; some appeared to have originated in the hilum or medulla. These hemangiomas either represented incidental findings in lymph nodes or were seen with solitary lymph node enlargement; the evolution was benign with no recurrence. A distinctive benign lesion occurring exclusively in inguinal lymph nodes, which we propose designating "angiomyomatous hamartoma," showed replacement of the nodal parenchyma by smooth muscle cells and fibrous tissue, in continuity with exuberant proliferation of muscular vessels in the hilum. Epithelioid vascular tumors, characterized by plump endothelial cells with dense eosinophilic cytoplasm and numerous vacuoles, exhibited a range of differentiation, from hemangioma with well-formed vascular channels (with or without tissue eosinophilia) to hemangioendotheliomas composed predominantly of cords and sheets of tumor cells lying in a hyaline-myxoid matrix. Epithelioid hemangioendothelioma was particularly likely to be mistaken for metastatic carcinoma, and local recurrence could occur. A variant, the spindle and epithelioid hemangioendothelioma, was characterized by the presence of an additional component of spindle cells. Another tumor we found, polymorphous hemangioendothelioma, is a previously uncharacterized borderline malignant vascular tumor exhibiting solid, primitive vascular and angiomatous patterns and relatively bland cytologic features. Lymphangiomas of lymph nodes usually showed simultaneous multifocal and extra-nodal involvement and were characterized by cystic endothelium-lined spaces filled predominantly with lymph fluid. It is important to recognize these primary vascular tumors of lymph nodes to avoid mistaking them for a variety of benign vasoproliferative lesions, Kaposi's sarcoma, angiosarcoma, and metastatic cancer.     

The role of radiation therapy in the treatment of early stage large cell lymphoma

Nineteen patients with localized non-Hodgkin's lymphoma large cell type classified by the international formulation in group D (5) and group G (14) were treated with extended field radiation therapy. These patients have been followed for 168 months with range from 12 to 168 months from initiation of treatment. In G category of the formulation, the overall survival is 83 per cent at 5 and 10 years and recurrence-free survival is 75 per cent at 10 years. Sixteen of the patients were stage I and three were stage II. Two patients died without evidence of recurrence. Four patients recurred and two of these died of disease. Thirteen of the 19 patients are alive and recurrence free. Bulk of disease had no apparent influence on the response to irradiation. We believe that the early pathological stage large cell lymphoma of the G and D type international formulation are appropriate candidates for radical radiation therapy and benefit from this approach to treatment.     

Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer

Several steps in the clinical evolution of human neoplasia are associated with a variety of recurrent chromosomal defects that could prove essential to the understanding of cancer. We found 15 types of nonrandom chromosomal abnormalities in a study of 71 patients with follicular lymphoma; 10 of the types appeared to influence the histopathological findings, clinical course, or response to treatment. A translocation, t(14;18), observed in 85 percent of all patients appeared to be the main determinant of a follicular pattern. Ten patients with a t(14;18) as a single defect had the histologic features of follicular small cleaved-cell lymphoma. Most did not require treatment for one to four years, because their tumors had an initial indolent course. In contrast, patients with follicular small cleaved-cell lymphoma with t(14;18) and deletion 13q32 acquired the hematologic features of leukemia and had an acceleration of the disease. A deletion 6q together with a complete or partial trisomy 7 or trisomy 12 (or both) was associated with the clinically more aggressive follicular mixed small- and large-cell or large-cell histologic type, which often evolves from follicular small-cell lymphoma. A complete or partial trisomy 3, 18, or 21 correlated almost exclusively with follicular large-cell lymphoma. In all follicular stages, a trisomy 2 or duplication 2p often accompanied an accelerated clinical course and a poor response to treatment. This study suggests that several discrete genomic defects may govern the evolution of a patient's malignant disease.     

Two splenic lesions in need of clarification: hamartoma and inflammatory pseudotumor

This short review is dedicated to a precise pathologic characterization of 2 uncommon and poorly defined lesions of the spleen and to their distinction from histologically similar processes. Splenic hamartoma represents an abnormally formed red pulp and is characterized by the presence of sinus-like structures lined by CD8(+) endothelia. The great variety of its morphologic appearances may result from the preponderant growth of one or another of the several components of the red pulp, ie, CD34(+) capillaries, myoid cells and macrophages. Therefore, it is proposed that "cord capillary hemangioma," myoid angio-endothelioma, and histiocyte-rich tumors are part of the spectrum of splenic hamartoma. Inflammatory pseudotumor (IPT) of the spleen is a reactive lesion, probably of multiple etiologies, characterized by a mixture of inflammatory cells and a minor, disorganized component of spindle cells. The latter include fibroblasts, SMA(+) myofibroblasts, and CD68(+) spindled histiocytes, establishing a close similarity with the IPT of the lymph node. This benign process needs to be distinguished from 2 others that have a predominant spindle cell component arranged in parallel bundles: the IPT-like follicular dendritic cell tumor, which is consistently associated with Epstein-Barr Virus; and the inflammatory myofibroblastic tumor, also often Epstein-Barr Virus-related and similar to those of the soft tissues, lung and other organs. These 2 lesions are neoplastic and therefore have a potentially worse prognosis than IPT.     

Three immunostaining techniques for the localization of leukocyte common antigen in formalin-fixed, paraffin-embedded dermatological biopsy specimens

Although leukocyte common antigen is a valuable discriminant between lymphoreticular proliferations and other histologically similar neoplasms, several publications have described difficulties in adequately labeling this determinant in formalin-fixed, paraffin-embedded tissues. We studied 662 paraffinized cutaneous and noncutaneous neoplasms for the presence of leukocyte common antigen, using an extended avidin-biotin-peroxidase complex (ABC) method, a combined ABC-peroxidase-antiperoxidase technique, and a biotin-strept-avidin procedure. Each of the three immunohistochemical techniques produced effective results in the detection of leukocyte common antigen in all malignant lymphomas, but none of them produced false-positive staining in nonhematopoietic lesions. These results suggest that antibodies to leukocyte common antigen are highly specific and that the methods employed in this study allow for excellent diagnostic sensitivity in the recognition of cutaneous lymphomas.     

Primary malignant lymphoma arising in postmastectomy lymphedema. Another facet of the Stewart-Treves syndrome

In rare cases, primary malignant lymphomas may arise in the soft tissues. Only one previous case has arisen in the context of chronic lymphedema. Because of the clinical appearance of such lesions, which resemble violaceous nodular or plaquelike tumors, they may be confused clinically with lymphedema-associated angiosarcomas occurring after radical mastectomy (Stewart-Treves syndrome). Furthermore, the histologic appearance of some lymphomas and angiosarcomas may also be similar. We studied two women with primary postmastectomy lymphedema-related malignant lymphoma in the soft tissues of the upper arm. These tumors arose 11 and 30 years, respectively, after radical removal of ductal mammary carcinomas. Histologically, one neoplasm mimicked metastatic carcinoma or epithelioid angiosarcoma; whereas the other was initially confused with a variety of pathologic entities, including vasculitis, epithelioid hemangioma, and malignant fibrous histiocytoma. The lymphoid nature of both lesions was confirmed by immunoreactivity for leukocyte common antigen in addition to the B-lymphocyte marker, L26. Conversely, vascular and epithelial determinants were absent. One patient's disease pursued an indolent course; she died of unknown causes but with no evidence of lymphoma at last follow-up. The second patient is currently in remission on chemotherapy. Awareness of the existence of lymphedema-related malignant lymphoma and familiarity with methods used for its distinction from epithelioid vascular sarcomas should prevent unnecessary surgery.