C.S. Ng

Most nasal/nasopharyngeal lymphomas are peripheral T-cell neoplasms

Eleven consecutive cases of nasal/nasopharyngeal lymphoma were studied histologically and with a panel of monoclonal antibodies. The disease showed a male predominance and occurred over a wide age range, with a median of 52 years. Five patients had midfacial destructive disease, and six had gross tumor masses involving the nose/nasopharynx. Three cases were classified as small cleaved cell, two cases as mixed cell, five cases as large cell, and one case as immunoblastic lymphoma. Those belonging to the first two categories also satisfied the diagnostic criteria of so-called polymorphic reticulosis. Epithelial invasion, angioinvasion, and coagulative necrosis were demonstrated in seven, eight, and nine cases respectively. Immunohistochemical studies confirmed that the atypical cells of all 11 cases exhibited Tcell markers. All but one case had lost one or more T-cell markers associated with peripheral T cells, particularly Tl and T3. Loss of T-cell markers in the five cases histologically consistent with polymorphic reticulosis provided further support to indicate that the lesion was neoplastic. A significant proportion of cases also expressed the activated T-cell markers 12 (HLA-DR) and interleukin- 2 receptor (IL-2R1).

Kikuchi's lymphadenitis. A morphologic analysis of 75 cases with special reference to unusual features.

Seventy-five cases of Kikuchis lymphadenitis, a self-limiting pseudomalignant condition, were reviewed to determine the spectrum of histologic findings. There were 55 females and 20 males; ages ranged from 9 to 57 years (mean, 25.5). Most patients presented with cervical lymphadenopathy (68 cases). Associated clinical findings were fever (20/52) and leukopenia (15/33). Serum antinuclear antibodies were negative in 15 patients among 16 tested. Among 32 patients with follow-up information, 31 remained well, including one who developed recurrence after 2 years. One patient died of fatal myocardial disease during the active disease. Histologically, the lymph nodes showed paracortical hyperplasia, often associated with a starry-sky appearance resulting from interspersed histiocytes and immunoblasts. The consistent finding was the presence of variable-sized discrete or confluent nodules in the paracortex composed of the following: (a) karyorrhectic and eosinophilic granular debris; (b) histiocytes, many of which were phagocytic and possessed distinctive peripherally placed crescentic nuclei and voluminous cytoplasm containing eosinophilic or karyorrhectic debris (for which we propose the designation crescentic histiocytes), mixed with nonphagocytic histiocytes having twisted or reniform nuclei which were often centrally placed; (c) plasmacytoid monocytes, which were medium-sized cells with eccentrically placed round nuclei and amphophilic cytoplasm; and (d) variable numbers of immunoblasts, which sometimes showed atypia such as irregular nuclear foldings and coarse chromatin. Neutrophils were absent or very sparse. In some nodules, coag-ulative necrosis was present in the center (45 cases). Foamy histiocytes were found in 23 cases, and they predominated in 11. Small clusters of plasmacytoid monocytes were noted in the paracortex in 40 cases. Perinodal inflammation was a common finding, and perinodal involvement by the karyorrhectic process occurred in 15 cases. In addition, we found a number of previously unreported features. Signet-ring histiocytes with clear or homogeneous lightly amphophilic cytoplasm and nuclei compressed into thin crescents, found in seven cases, could mimic signet-ring cell adenocarcinoma. In three cases, some germinal centers were involved by the karyorrhectic process. Foci of lymphocyte-depleted fibrovascular organization were present in eight cases, probably representing the resolving phase of the karyorrhectic process. Despite the broad morphologic spectrum, the intermingling of the distinctive crescentic histiocytes, karyorrhectic debris, and plasmacytoid monocytes in the form of nodules, together with the paucity of neutrophils, are the consistent findings that should permit a confident histologic diagnosis of Kikuchis lymphadenitis.

CD56 (NKH1)-positive hematolymphoid malignancies: An aggressive neoplasm featuring frequent cutaneous/mucosal involvement, cytoplasmic azurophilic granules, and angiocentricity

CD56 (NKH1) expression is a rare phenomenon in malignant lymphomas, mostly confined to those occurring in the nasal or nasopharyngeal region. In this study we provide a detailed clinicopathologic analysis of nine patients with CD56-positive hematolymphoid malignancies occurring in sites other than the upper aerodigestive tract. The disease occurred predominantly in young and middle-aged men (mean age, 40 years) who often presented with swinging fever, skin rash, and/or hepatosplenomegaly, usually in the absence of peripheral lymphadenopathy. There was frequent involvement of the skin and mucosal sites, such as the salivary gland, lungs, and small intestine. The disease pursued a highly aggressive course, with most patients dying within weeks despite cytotoxic therapy. Although the cytologic appearances and immunophenotypic profile varied from case to case, the group of tumors could be unified by two morphologic features, namely, the presence of azurophilic granules in the cytoplasm of the neoplastic cells and the frequent occurrence of angiocentric and angiodestructive infiltrates. Since CD56 reactivity appears to confer a poor prognosis in hematolymphoid malignancies, we recommended inclusion of CD56 antibody in the routine panel for immunophenotypic analysis.

Detection of Epstein-Barr Viral RNA in Malignant Lymphomas of the Upper Aerodigestive Tract

Recent studies have suggested a probable etiologic association between Epstein-Barr virus (EBV) and nasal lymphomas, irrespective of geographic location. This study was performed to investigate the strength of association of EBV with non-Hodgkins lymphomas of the upper aerodigestive tract, based on a large series of cases that have been thoroughly immunophenotyped on frozen tissues. A sensitive in situ hybridization technique was used to detect EBV encoded RNA (EBER) in paraffin sections. Among 30 cases of nasal/nasopharyngeal T-cell lymphoma, 25 (83.3%) were EBER-positive. In the positive cases, most of the neoplastic cells showed strong nuclear signals. Further analysis of this group of tumors showed that all 21 cases (100%) with a CD56+ CD3-phenotype were EBER positive, whereas four of nine cases (44.4%) with a CD56-negative immunophenotype were positive. Only one of 10 cases (10%) of nasal/nasopharyngeal B-cell lymphoma was EBER positive; the positive case was a diffuse mixed-cell lymphoma and could not be distinguished morphologically from the negative cases. Among the 21 cases of lymphoma of the tonsils and back of the tongue (20 B-lineage and one T-lineage), none was EBER positive. In the normal mucosa of the nose/nasopharynx or tonsil (20 cases studied), only very rare EBER-positive small lymphocytes were found in two cases. The almost exclusive detection of EBER in nasal/nasopharyngeal T-cell neoplasms among the lymphomas of the upper aerodigestive tract suggests that EBV probably plays an etiologic role in the pathogenesis of this group of tumors and is not simply a passenger virus, and neither is this merely a site-dependent phenomenon in view of the weak association with nasal/nasopharyngeal B-cell lymphoma.

Expression of natural killer cell markers in non-Hodgkin's lymphomas

One hundred forty-nine cases of non-Hodgkins lymphoma were studied with a panel of monoclonal antibodies, including antibodies to natural killer (NK) cells--anti-NKH1, anti-Leu 7, and anti-Leu 11b. There were 95 B-cell, 51 T-cell, and three null cell lymphomas. Seventeen T-cell lymphomas (33 per cent) expressed NKH1, Leu 7, and/or Leu 11b. None of the B- or null cell lymphomas expressed the NK markers. In comparison with the NK-negative T-cell lymphomas, the NK-positive cases showed a predilection for the nasal and paranasal region. There was a more significant loss of the T-cell markers T3 (peripheral T cell) and T4 (T-helper cell) in NK-positive lymphomas. The difference was due to a high proportion of nasal/paranasal lymphomas, which were associated with a frequent loss of T-cell markers, among the NK-positive cases. However, a similar degree of loss of T-cell markers was observed among NK-positive and NK-negative nasal/paranasal lymphomas. We conclude that expression of NK markers occurs exclusively in a proportion of T-cell lymphomas, but not B-cell or null cell lymphomas. The reason this occurs predominantly in nasal and paranasal lymphomas is unknown.

Lymphadenopathy of Kimura's disease

Kimuras disease is an important category of reactive lymphadenopathy in the Oriental population. The enlarged nodes are mostly located in the head and neck region. Salient pathological changes include florid germinal centers, Warthin-Finkeldey type polykaryocytes, vascularization of germinal centers, increased postcapillary venules in the paracortex, eosinophilic infiltration, and sclerosis. The pathology of Kimuras disease is quite different from that of angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma). Immunoperoxidase studies show IgE reticular networks in germinal centers. Nondegranulated surface IgE-positive mast cells are present in the paracortex. The authors propose that Kimuras disease represents an aberrant immune reaction to an as yet unknown stimulus. Although the individual histological features are nonspecific, the constellation of features is highly characteristic of Kimuras disease. Since lymphadenopathy can herald involvement of other tissues and the prognosis is excellent, accurate diagnosis of this disease in lymph node biopsies may spare the patients unnecessary radical surgery.

Large B-cell lymphomas with a high content of reactive T cells

Twenty-one cases of large, B-cell lymphoma with an unusually high content of reactive T lymphocytes are described in this report. Fifteen patients presented with lymphoma in nodal sites and six patients presented with lymphoma in extranodal sites. With two exceptions, all patients were more than 50 years of age. The male to female ratio was 1:2. Histologically, isolated to small groups of large lymphoid cells were intermingled with many small lymphocytes. The large cells were neoplastic and exhibited B-lineage markers; immunoglobulin light chain restriction could be demonstrated in two thirds of the cases. There was a rich infiltrate of immunophenotypically mature T lymphocytes that comprised more than 50% of the cellular population. The T lymphocytes ranged from small cells with dark, round nuclei to slightly larger cells with elongated, irregular nuclei. There were occasional medium-sized blastic cells. There was also a variable infiltrate of histiocytes with or without epithelioid features, eosinophils and plasma cells, and increased vascularity. The peculiar morphologic features were also reproduced in other sites in the four patients for whom additional histologic materials were available for examination. We postulate that the abundance of T cells results either from a florid host reaction or from cytokine secretion by the neoplastic B cells, attracting T cells to the vicinity. The morphologic and immunologic features mimic those of a variety of benign lymphoproliferative diseases, angioimmunoblastic lymphadenopathy and lymphomas arising in angioimmunoblastic lymphadenopathy, peripheral T-cell lymphoma, secondary B-immunoblastic lymphoma, and Hodgkins disease. Careful morphologic evaluation and immunophenotypic studies using leukocyte antibodies reactive in paraffin-embedded sections are of great assistance in determining a diagnosis.

In situ localization of epstein-barr virus encoded RNA in non-nasal/nasopharyngeal CD56-positive and CD56-negative T-cell lymphomas

We recently reported a group of non-nasal/nasopharyngeal hematolymphoid malignancies expressing the natural killer cell marker CD56, characterized by frequent extranodal localization, angiocentricity, and aggressive clinical course (HUM PATHOL 23:798-804, 1992). Because we have shown a very strong association of Epstein-Barr virus (EBV) with CD56-positive T-cell lymphomas of the nose nasopharynx, we asked whether a similar association also occurs with the non-nasal CD56-positive T-cell lymphomas. In situ localization of EBV encoded RNA (EBER) was performed on paraffin sections of 15 such cases, including the nine previously reported cases and six new cases (three showing prominent hepatosplenic involvement and three showing involvement of one or more extranodal sites, such as the parotid gland, tonsils, gastrointestinal tract, skeletal muscle, and testis). A case was considered positive when the majority of the tumor cells showed nuclear signal. Ten cases showed EBER positivity, and all but one of them were negative for CD3 and other T-cell markers, except CD2. Only one of four cases showing a CD3-positive phenotype was EBER positive. Of the remaining two CD3-negative EBER-negative cases, one showed a histiocytic phenotype and the other was positive for multiple T-cell markers. Among 15 cases of CD56-negative non-nasal peripheral T-cell lymphoma studied for comparison, six were CD3-negative, among which three showed EBER positivity. All nine CD3-positive cases were EBER negative. Five cases (three CD3 positive and two CD3 negative) showed rare isolated (< 1%) EBER-positive tumor cells. We conclude that among non-nasal T-cell lymphomas, EBV is strongly correlated with CD56 positivity (66.7% v 20%), and the positive cases almost always show an immunophenotype identical to that commonly observed in nasal lymphomas (CD2 positive, CD3 negative, and CD56 positive). Thus, EBV may play an etiologic role in these CD56-positive lymphomas. There is also a correlation between EBER positivity and CD3 negativity, irrespective of the CD56 status. The presence of isolated EBER-positive cells in CD56-negative T-cell lymphomas, occurring at a frequency similar to that reported in the European population, probably represents secondary infection of tumor cells.

Reactive hemophagocytic syndrome: A study of 7 fatal cases

&NA; Reactive hemophagocytic syndrome is a clinico‐pathologic entity characterized by systemic proliferation of non‐neoplastic histiocytes showing phagocytosis of hemopoietic cells, resulting in blood cytopenia. It is best known to be associated with virus infection, but other associated diseases have also been implicated. The clinical and pathological findings of 7 fatal cases are described. The syndrome affected both sexes of a wide age range, and all patients had fever. Significant laboratory findings were blood cytopenia, abrupt drop in the blood cell counts, deranged liver function tests and abnormal coagulation profile. The associated diseases were diverse: two patients had bacterial infection; two had peripheral T‐cell lymphoma; one had disseminated undifferentiated carcinoma of the ovary; one had both tuberculosis and disseminated nasopharyngeal carcinoma, and one had no obvious underlying disease. It is postulated that lymphokines secreted by lymphoid cells or tumor cells may be responsible for the systemic activation of histiocytes. The differential diagnosis from malignant histiocytosis is discussed.

Utility of a paraffin section-reactive CD56 antibody (123C3) for characterization and diagnosis of lymphomas

Although expression of CD56 (neural cell adhesion molecule, a natural killer cell marker) is uncommon among lymphomas, this feature has defined a distinctive and important category of lymphoma: the putative natural killer (NK) cell lymphoma, which shows a predilection for the upper aerodigestive tract, skin, skeletal muscle, and other extranodal sites and pursues an aggressive clinical course. Thus far, CD56 expression can be reliably analyzed only on fresh or frozen tissues. In this study, we evaluated the sensitivity and specificity of a CD56 antibody, 123C3, when applied on routine formalin-fixed, paraffin-embedded tissues for analysis of lymphomas, by comparing the staining results with those obtained on frozen tissues using the CD56 antibody NKH1. The 123C3 antibody worked on paraffin sections only with prior antigen retrieval using a pressure cooker or a microwave oven. Among 32 CD56+ T/NK cell lymphomas and one CD56+ B-lymphoblastic lymphoma, the neoplastic cells showed crisp membrane staining with 123C3 in all cases. None of the 24 CD56- T-cell lymphomas and 50 CD56-B-cell lymphomas stained with 123C3. In normal or reactive lymphoid tissues from a variety of sites, there were few small lymphocytes (< 0.1%) that showed cell membrane staining with 123C3, although occasional plasma cells might show cytoplasmic staining. We conclude that with suitable antigen retrieval procedures, 123C3 can be reliably applied on routine paraffin sections for detection of CD56 expression in lymphomas. Furthermore, this antibody can be used to support a diagnosis of lymphoma or to detect residual disease for cases of CD56+ T/NK cell lymphoma in which the neoplastic lymphoid cells are small and show minimal atypia, especially in small biopsies.