Riccardo Manconi

Inaccuracy of death certificate diagnoses in malignancy: An analysis of 1,405 autopsied cases

In 1,405 patients who died at the General Hospital of Trieste in 1974 and 1978, malignant neoplasm was revealed at autopsy. Clinical diagnosis was accurate in 54 per cent of these patients. The tumor was clinically suspected in 19 per cent and was undiagnosed in 27 per cent. The accuracy of the clinical diagnoses varied significantly according to the primary site and type of tumor; accuracy was inversely related to the age of the patient and varied also according to the department of the hospital to which the patient had been admitted. This latter variation is age-dependent, too. In the past decades clinical diagnosis of malignancy has not greatly improved, although the autopsy rate has almost everywhere strongly decreased, representing a heavy handicap in the epidemiologic research on cancer as a cause of death.

Demonstration of S-100 protein distribution in human lymphoid tissues by the avidin-biotin complex immunostaining method.

Immunoreactivity for S-100 protein was investigated immunohistochemically in a series of 49 fixed and paraffin-embedded normal, reactive, and neoplastic human lymphoid tissue specimens. The avidin-biotin complex immunoperoxidase method was used, with overnight (12-hour) incubation with a commercially available antiserum to S-100 protein. In addition, cryostat sections were tested with DRC 1 monoclonal antibody to dendritic reticulum cells (DRCs) in three cases and with OKT6 antibody to interdigitating reticulum cells (IRCs) in nine cases. All tissues, including lymph nodes, tonsils, adenoid, spleens, appendices, thymuses, and tissues containing nodular reactive lymphoid infiltrates, demonstrated a consistent immune staining pattern. A striking network composed of dendritic processes that showed finely granular S-100 protein immunoreactivity was observed in most of the follicular germinal centers; a similar dendritic pattern was observed in the follicular centers when the corresponding frozen sections were immunostained with DRC 1. In the extrafollicular areas, the S-100-positive cells topographically and morphologically resembled the IRCs that were demonstrated by OKT6 antibody in the corresponding frozen sections. The results seem to indicate that cells topographically and morphologically similar to IRCs and DRCs in human lymphoid tissues from different sites share immunoreactivity for S-100 protein. The present study confirms the unexpected presence of S-100 protein in dendritic cells of follicular germinal centers by a simple and currently available method.

S-100 protein, fibronectin, and laminin immunostaining in lymphomas of follicular center cell origin

Forty‐nine paraffin‐embedded biopsy specimens of involved nodal and extranodal tissue (bone marrow, spleen, and liver) from 13 patients with follicular center cell lymphomas (FCCL) and 14 with small lymphocytic lymphomas (SLL), including 11 cases with chronic lymphocytic leukemia, were tested for Sg100 protein immunoreactivity. Analysis for fibronectin and laminin immunoreactivities was limited to the lymph node biopsy specimens. In FCCL, S‐100‐positive dendritic reticulum cells (DRCs) were found in 23 of the 26 tissue specimens examined, regardless of the involved sites and the growth pattern. Cases with completely or predominantly follicular pattern were usually associated with a spherical meshwork pattern of S‐100‐positive DRCs; in the FCCL specimens with a diffuse pattern (lymph nodes and bone marrow) as well as in the specimen areas with a minimally follicular tumor pattern, S‐100‐positive DRCs were consistently fewer in number and composed loosely aggregated nests. No S‐100‐positive DRCs were found in all the biopsy specimens in SLL. Concerning fibronectin and laminin immunostainings, results showed that no differences were present between areas of follicular and diffuse neoplastic growth and that the neoplastic growth of FCCL maintained for each antiserum the same distribution pattern as that seen in normal follicles. Analysis of the microenvironmental components as revealed with antisera used in the current study—particularly with anti‐S‐100 protein antiserum—appears to be a useful adjunct for the identification of FCCL in paraffin‐embedded biopsy specimens, especially in extranodal sites.

Heterogeneous immunostaining patterns of follicular dendritic reticulum cells in human lymphoid tissue with selected antibodies reactive with different cell lineages.

A comparative immunohistologic study of the cell density and distribution pattern of follicular dendritic reticulum cells (DRCs) within their follicular microenvironments (germinal centers and mantle zones) was performed by immunoperoxidase technique with a selected panel of antibodies either operationally specific for DRCs (DRC-1) or reported as having additional immunoreactivity with DRCs (antibodies to B- and T-cells, leukocytes, monocytes/macrophages, desmosomal components, and S-100 protein). Twenty-five biopsy specimens, including reactive lymph nodes and tonsils as well as normal spleen tissue, were analyzed. Serial frozen sections were tested either with single antibodies or paired monoclonal reagents in double-labeling procedures. Our results consistently indicated that DRCs positive for Leu M3 and BA-2 antibodies were confined to the central portion of germinal centers, whereas DRCs immunoreactive for S-100 protein and desmoplakin 1 and 2 were localized mostly in the central and pericentral portion of germinal centers. All the DRCs extending from the central portion of germinal centers to the mantle zones were labeled with DRC-1 and, unexpectedly, with OKB7 antibodies. Other immunostainings, such as those for HLA-DR antigens, common leukocyte antigen, and Leu 3a, were not contributory in defining topographic differences of DRCs within the follicle. The consistent heterogeneity of the labeling patterns appears to suggest a possible in situ immunophenotypic grouping of DRCs, and the concept of their possible heterogeneity appears to be corroborated.

Non‐Hodgkin's lymphoma in the elderly. A retrospective clinicopathologic study of 50 patients

The pathologic and clinical findings of 50 patients aged 65 or older (median, 71.5 years) with non‐Hodgkins lymphomas (NHL) are reported. These patients formed 27% of all cases of NHL seen in a single institution over a 7‐year period. Forty patients presented with nodal and 10 with extranodal NHL. According to the Ann Arbor system, 20 were clinical and/or pathologic Stages I and II, and 30 were Stages III and IV; of the 10 patients presenting with extranodal NHL, 8 were Stages I and II. Histologically, 84% of the cases were of the intermediate and high‐grade groups according to the Working Formulation; diffuse histiocytic was the most frequent histotype (34%) according to the Rappaport classification. The pattern was diffuse in 94% of the cases. Five patients received no treatment; treatments were conservative (monochemotherapy and/or local radiotherapy) in 19 patients and aggressive (polychemotherapy and/or extended‐field radiotherapy) in 26. Four patients of the latter group died of toxicity; 22 patients died of lymphoma and 13 of other causes; the other 11 (22%) patients are still alive. The overall median survival was 2.2 years. A significantly better survival was observed in patients with Stages I and II (P <0.025) and in those with intermediate grade (P <0.05) when compared with patients having Stages III and IV and high‐grade histology, respectively. Apparently, no significant difference both in response and survival was found between the groups of patients which arbitrarily underwent conservative or aggressive treatments on the basis of their general conditions. Randomized clinical trials should be designed in order to draw more significant conclusions on the correct management of elderly patients with NHL.

Heterogeneous in situ immunophenotyping of follicular dendritic reticulum cells in malignant lymphomas of B-cell origin

The phenotype of follicular dendritic reticulum cells (DRC) was analyzed with monoclonal antibodies (DRC‐1, OKB7, BA‐2, Leu‐M3, and antidesmoplakin 1 and 2) in 28 frozen biopsy specimens of both morphologically and phenotypically analyzed B‐cell lymphomas and 21 normal or reactive controls. The former included 15 follicular center cell lymphomas (FCCL), four intermediately differentiated lymphocytic lymphomas (ILL), four mantle zone lymphomas (MZL), and five well‐differentiated lymphocytic lymphomas (WDLL). In controls, DRC‐1+ and OKB7+ DRC were localized in both follicular centers (FC) and mantle zones (MZ), but BA‐2+ and Leu‐M3+ DRC were confined to FC only. FCCL were usually accompanied by DRC‐1+, OKB7+, and BA‐2+ DRC, and either lost or maintained positivity with Leu‐M3 from case to case. By contrast, MZL consistently lacked BA‐2+ and Leu‐M3+ DRC, and was associated with DRC‐1+ and OKB7+ DRC only. Desmoplakin‐positive DRC occurred in variable proportions in both FCCL and MZL. As opposed to FCCL and MZL, all WDLL and all but one of the ILL (associated only with DRC‐1+, OKB7+, and desmoplakin+ DRC) did not show any DRC as identifiable with the antibody panel used. Remarkably, the difference in the distribution of BA‐2+ and Leu‐M3+ DRC in the normal FC and MZ appears to be maintained in their neoplastic counterparts (FCCL and MZL) also. Such a difference represents an example of the possible interactions between lymphoma cells of different phenotype and their microenvironment, as portrayed by phenotypically heterogeneous DRC.

Immunohistochemical, enzyme histochemical, and immunologic features of giant lymph node hyperplasia of the hyaline-vascular type.

A combined histologic, immunohistologic, enzyme histochemical, and immunologic study has been carried out in a 7‐year‐old girl with recurring extramediastinal monocentric giant lymph node hyperplasia of hyaline‐vascular type. A large panel of monoclonal and polyclonal antibodies to lymphoid and nonlymphoid cell markers were tested on frozen and paraffin‐embedded lymph node tissue as well as on cell suspension and peripheral blood. Tissue enzyme histochemical study, including a conventional hematologic panel, was performed on frozen and plastic‐embedded sections. The pattern was dominated by nodular aggregates of round BA‐1+ Leu‐14+ HLA‐DR+ ATPase+ lymphocytes with polyclonal sIgD and sIgM positivity and lacking clg and BA‐2 staining. Leu‐l+/Leu‐4+, OKT6+, OKT10+, Leu‐7+, and CALLA+ cells were few or absent in the nodules, whereas DRC‐1+ BA‐2+ HLA‐DR+ 5′‐Nuc+ cells formed a dendritic network in the outer portion of the nodules. No immunoreactivity for lymphoid and nonlymphoid cell markers, including cytokeratin and keratin, was detected in centrinodular histiocytic‐like cells. Particularly, the Hassalls‐like structures contained a target‐like positivity for laminin, and consisted of flattened acid phosphatase (AP), alpha‐naphthyl acetate esterase (ANAE), 5′‐nucIeotidase (5′‐Nuc), and adenosine tri‐phosphatase (ATPase) positive cells, whose enzyme profile overlapped with that of the histiocytic‐like cells. The extranodular areas were mainly composed of Leu‐1+/Leu‐4+ lymphocytes with Leu‐3a+/ OKT4+ phenotype and, to a lesser extent, of OKT6+ OKT10+ lymphoid cells and scattered cells with markers of histiocytic lineage. The abundant vascular component was generally identified by laminin positivity and, in smaller proportion, it was positive for Factor VIII‐related antigen. Most of the medium‐sized vessels with high endothelium had marked AP, ANAE, and ATPase activities. The process observed resulted from vascularized nodular aggregates of nontransformed B‐cells with the phenotype of primary follicle lymphocytes, associated to centrinodular histiocytic‐like cells with a distinct enzyme profile.

Gastric resection. A cause of high frequency of gastric carcinoma

On 10,630 autopsies, 480 cases with a gastric resection for benign conditions, performed more than 5 years previously, were found. Pathologic findings revealed 31 (6.5%) cases of gastric stump carcinoma. On the basis of clinical and pathologic data, the authors could demonstrate that gastric carcinoma occurs with significantly higher frequency in resected patients than in unresected ones. Patients having resection before age 45 years are at increased risk (2.46) in developing gastric stump carcinoma, while patients undergoing operation at age 45 years or later are not (0.65). The distribution of gastric carcinoma according to age classes at death in resected and unresected patients is very similar, with an increasing frequency after age 55 years in both groups.

Intermediate lymphocytic lymphoma encompassing diffuse and mantle zone pattern variants: A distinct entity among low-grade lymphomas?☆

Intermediate lymphocytic lymphoma has been operationally included among low-grade lymphomas, but few clinical data appeared to support definitely such an inclusion. The clinicopathologic features of 13 out of 14 cases of intermediate lymphocytic lymphoma either encompassing diffuse or mantle-zone pattern variants (ILL or MZL, respectively), diagnosed by conventional histology according to established criteria, are reported. Frozen section immunophenotypic analysis was also performed in 10 cases and enzyme studies were done in five. The 14 cases formed 6.9% of 203 non-Hodgkins lymphomas (NHL) histologically diagnosed over a 2-year period. Among the 13 cases studied, there were nine males (five with ILL and four with MZL) and four females (one with ILL and three with MZL). Median age was 59 years. Splenomegaly (46%), high stage diseases (100%), involvement of bone marrow (92%) and peripheral blood (38%), and diffusion to and/or involvement of extranodal sites (38%), all were common findings at presentation. The 34 low-grade NHL of the total series classified according to the Working Formulation did not significantly differ from the ILL/MZL group in terms of frequency of involvement of bone marrow (69%) and peripheral blood (56%) as well as diffusion to and/or involvement of extranodal sites (26%). In ILL/MZL, therapy modalities were not uniform and the short follow-up time precluded firm conclusions on prognosis. Immunohistology demonstrated that ILL/MZL diagnosed by adequate morphologic criteria is a fairly homogeneous entity, also sharing most of its consistent immunological features with low-grade NHL. Thus, ILL/MZL is a relatively frequent and consistently recognizable clinical and pathological entity that may deserve a distinct place among NHL according to the Working Formulation. Proper clinical studies are needed to establish on a firmer basis the prognosis and optimal treatment of ILL/MZL.

Dendritic reticulum cell pattern as a microenvironmental indicator for a distinct origin of lymphoma of follicular mantle cells

Follicular dendritic reticulum cells (DRCs) are known to be normally present in primary follicles and both follicular centres and mantle zones of secondary follicles of peripheral lymphoid tissue. Involved frozen biopsy tissue specimens from eight cases of intermediate lymphocytic lymphoma/mantle zone lymphoma (ILL/MZL); eight cases of follicular centre cell lymphomas (FCCL) of the centroblastic/ centrocytic type; and seven cases of well‐differentiated lymphocytic lymphoma (WDLL) consistent with chronic lymphocytic leukaemia (CLL) were analysed immunohistologically with R4/23 (DRC‐1) monoclonal antibody reactive with ‘bystander’ DRCs. As opposed to FCCL and most WDLL/CLL cases, the DRCs consistently formed a loose, ill‐defined meshwork with a radiating or blurred outline in all MZL cases and one ILL. On the basis of the observed findings as well as from those reported in literature, the hypothesis is proposed that ILL/MZL originates from the follicular mantle zone and represents a distinct lymphoma entity owing to its peculiar immunostaining pattern of DRCs that allows it to be separated from both FCCL and WDLL/CLL. Moreover, the absence of DRCs in the microenvironment of other B‐cell malignancies such as prolymphocytic leukaemia and hairy cell leukaemia, analogously with most CLL cases, would speak in favour of their different—possibly extrafollicular— compartment of origin within lymphoid tissue.