T-cell lymphomas of large cell type. A variety of malignant lymphomas: “Histiocytic” and mixed lymphocytic-“histiocytic”

T-cell Lymphomas of Large Cell Type

A Variety of Malignant Lymphomas: "Histiocytic" and Mixed Lymp ho cytic-' 'His tio cytic "

MARGARITA PALUTKE, MD,' PAMELA TABACZKA, MT(ASCP),§ ROBERT W. WEISE, PHD," ARNOLD AXELROD, MD,t CHRIS PALACAS, MD,t HAROLD MARGOLIS, DO,# PREM KHILANANI, MD,T VORAVIT RATANATHARATHORN MD,8

JOHN PILIGIAN, MD,** RICHARD POLLARD, MD," AND MUJTABA HUSAIN, M D t t

Clinical and morphologic features of seven T-cell lymphomas of the large cell type are described. The tumors were grouped into those with irregular (3 cases) and those with round and regular nuclei (4 cases). In both groups, variation in cell size, numerous histiocytes and vessels, and many mitoses were distinguishing features. In only 1 case in the round and regular nucleus group was there relatively little variation in cell size and a paucity of histiocytes. Abundant polyribosomes, long strands of rough endoplasmic reticulum, and lysosomal granules were prominent electron microscopic features in both groups of tumors. The clinical presentations and courses varied considerably, especially in patients with tumors of the round nucleus type. One patient presented initially with chronic lymphocytic leukemia, 1 with Lennert's lymphoma, another with bone marrow infiltration, and a fourth with subcutaneous tumors. Two patients with the round nucleus type are still alive one and a half and two years after the original diagnosis. Two patients died two years after the onset of symptoms. Each of the 3 patients with tumors of the irregular nucleus type had a rapid clinical course and died within ten months.

Cancer 46:87-101, 1980.

-CELL LYMPHOMAS in adults are rare and not well T defined.' They fall into the category of the diffuse non-Hodgkin's lymphomas. Unlike the nodular B- cell lymphomas, the diffuse lymphomas are hetero- geneous in immunologic cell type and as yet, lack precise morphologic criteria for a useful clinicopathologic classification.'

In this report, we describe the morphologic, immunologic, and clinical characteristics of seven diffuse

From the *Department of Pathology, Section of Hematopathology, Wayne State University School of Medicine, and ?Department of Medicine, Sinai Hospital, Detroit, Michigan, and Veterans Ad- ministration Hospital, Allen Park, Michigan.

5 Chief Technologist, Berman Memorial Laboratories, Wayne State University School of Medicine.

I ' Washington University Medical School, previously at Wayne State University School of Medicine, Department of Pathology.

# Department of Medicine, Martin Place East Hospital, Madison Heights, Michigan.

ll Department of Oncology, Wayne State University School of Medicine.

** Department of Pathology, Harper-Grace Hospitals, Detroit, Michigan.

t+ Department of Pathology, Sinai Hospital, Detroit, Michigan. Address for reprints: Margarita Palutke, MD, Department of

Pathology Wayne State University School of Medicine, 540 E. Canfield Ave., Detroit, Michigan 48201.

The authors thank Richard Rozek, M.S., Linda Forrest and Kathryn Dawson for their assistance.

Accepted for publication July 6,1979.

lymphomas of the T-cell type, in which large cells were either a prominent or predominant component of the tumors (mixed lymphocytic-histiocytic or histiocytic lymphomas according to the Rappaport classification). None of these tumors was associated with mycosis fungoides or Sezary syndrome. This group of cases is part of an ongoing multiparameter study designed to group the lymphocytic lymphomas into distinct clinicopathologic entities. A special effort has been made to describe the light microscopic features of this group of cases in order to facilitate the recognition of the T-cell lymphomas in the routine practice of pathology.

Case Reports

Case I

A 58-year-old black woman experienced a rapidly enlarging right cervical mass producing tracheal deviation and infiltrating the sternocleidomastoid muscle, resulting in respiratory difficulties and dysphagia. Right inguinal lymphadenopathy was also present. Initial histologic diagnosis was poorly differentiated lymphocytic lymphoma. A con- sulting hematopathologist made a diagnosis of lympho- blastic lymphoma of convoluted cell type, most likely T- cell. A tracheostomy was performed. She was treated as an

0008-543X/80/0701/0087 $1.25 0 American Cancer Society

87

88 CANCER July I 1980 Vol. 46

FIG. 1. Case 1. Photomicrograph of lung tumor tissue. Note irregular nuclei, prominent nucleoli and numerous mitoses (H & E, x432).

outpatient with cytoxan, adriamycin, oncovin, and prednisone (CHOP), and irradiation (1000 rad) to the neck. She responded initially, but was readmitted seven and half months later because of progressive shortness of breath and pro-

ductive cough. X-ray examination revealed a right pleural effusion with a diffuse interstitial lung infiltrate. Over 1000 ml of bloody fluid were removed. An open lung biopsy specimen was diagnosed as histiocytic lymphomatous infiltrate of the lung (Fig. 1). Malignant cells were seen in the pleural fluid. The hemogram was unremarkable. Bone marrow was not involved. She died one week later. At autopsy, tumor was found in both lungs, many lymph nodes, liver, adrenal, and kidney.

Case 2

A 66-year-old black woman was admitted with cervical lymphadenopathy of two weeks’ duration, cough of two months’ duration, and night sweats. Enlarged inguinal nodes were present. A biopsy of one of the inguinal nodes was done and a diagnosis of histiocytic lymphoma was made (Figs. 2A-C). A chest x-ray revealed clear lungs and a widening of the superior mediastinum. There was no hepato- splenomegaly. The hemograms showed mild anemia ( 1 1.6 gidl) and normal numbers of leukocytes and platelets. Although the absolute peripheral blood lymphocyte counts were normal on several occasions, there were numerous

FIG. 2. Case 2. Photomicrographs of inguinal lymph node tissue. A. Note variation in tumor cell size and marked irregularity of nuclei (H & E, x270). B. Higher-power view of same section emphasizes the irregularity of the nuclei. Note numerous mitoses (PAS, ~ 6 8 0 ) . C. Imprint of same lymph node. Note wide variation in size and marked irregularity of the nuclei (Leishman’s stain, ~ 6 8 0 ) . D. Acid phosphatase reaction in cytocentrifuge preparation of E-rosetting tumor cells. Note the diffuse distribution of the granules (x680).

No. 1 LARGE CELL T-CELL LYMPHOMAS . Palutke et al. 89

FIG. 3. Case 3. Photomicrographs ofaxillary lymph node tissue. A. A mixture of cells of varying size, most of them with very irregular nuclei. There are numerous mitoses (H & E, x270). B. Bizarre giant cells and prominent vessels (H & E, ~ 2 7 0 ) . C. Higher-power view showing intimate admixture of histiocytes and tumor cells (H & E, ~ 4 3 2 ) . D. Abnormal lymphocyte in the peripheral blood (Leishman’s stain, X 1080).

immature lymphoid cells with very irregular, convoluted nuclei. The bone marrow was also involved by lymphoma. She was treated with the CHOP regimen. She became pancytopenic, septicemia developed, and she died of dis- seminated intravascular coagulopathy four and a half months after admission.

Case 3

A 74-year-old white man was admitted because o f con- fusion and hypertension. H e had been well until f o u r months prior to admission when he experienced anorexia and weight loss. Because of a positive acid-fast smear of sputum, he was treated with isoniazide and rifampin at another hospital during this period. On the last admission he had generalized lymphadenopathy and hepatomegaly. There were several scattered, tender cutaneous nodules varying from 3 to 10 mm in size, especially on the abdomen. Histologically, a skin nodule was diagnosed as poorly differentiated squamous carcinoma, confirmed by demonstration o f numerous desmo- somes with electron microscopic examination. The lymph node was diagnosed as unclassifiable lymphoma by the surgical pathologist (Figs. 3A-C). The hemogram exhibited

a hemoglobulin of 10.6 gidl and white blood cell count of 24,000/mm3 with an absolute lymphocytosis of 4,800/mm3. The majority of lymphocytes were abnormal. They varied from 7 to 30 p m in diameter and had very irregular and convoluted nuclei (Fig. 3D). Respiratory distress developed and the patient died eight days after admission.

Case 4

A 65-year-old black man had a history of an elevated white blood cell count of several months’ duration when he was hospitalized. On admission, he had generalized lymphadenopathy. The bone marrow was extensively infiltrated by lymphocytes (75% of all cells). His hemogram was normal except for an absolute lymphocytosis of 8550/mm3. A diagnosis of chronic lymphocytic leukemia was made. A biopsy of the left axillary lymph node was done, and diagnosed as diffuse, poorly differentiated lymphocytic lymphoma. The patient was not treated. H e was admitted 20 months later to another hospital because of pulmonary embolism. There was slight hepatomegaly, marked splenomegaly, and massive retroperitoneal lymphadenopathy a s well as peripheral lymphadenopathy. A biopsied axillary lymph node

90 CANCER July 1 1980 Vol. 46

FIG. 4. Case 4. Photomicrograph of inguinal lymph node tissue. A. Low-power view showing numerous histiocytes (with light staining cytoplasm) (H & E, x 108). B. Same lymph node showing a predominance of smaller tumor cells. Note histiocyte with abundant cytoplasm (H & E, x270). C. Same lymph node showing more large cells with round nuclei (immunoblasts) and many cells of intermediate size. (H & E, ~ 4 3 2 ) . D. Another area in which the large cells predominate.Note prominent nucleoli (H & E, x432). E. Imprint of same lymph node showing wide range in cell size. Note that some of the smaller cells also have a fine chromatin pattern and prominent nucleoli (Leishman’s stain, ~ 4 3 2 ) . F. Tumor cell in the peripheral blood. Note fine chromatin pattern and visible nucleolus (Leishman’s stain, x 1080).

was considered to be histiocytic lymphoma, evolving from a fourth of the lymphocytes were morphologically abnormal either poorly diEerentiated lymphocytic lymphoma or (Fig. 4F). Most of these had a finer chromatin pattern chronic lymphocytic leukemia (Figs. 4A-E). Although the than that usually seen in cells of chronic lymphocytic leu- peripheral blood lymphocyte count was within normal limits, kemia, a visible nucleolus and dark blue cytoplasm. The


FIG. 4. G. Extensive bone marrow infiltration. Particle section (H & E, x 108). H. Higher-power view of bone marrow infiltrate showing a predominance of smaller cells and a collection of immunoblasts. The distribution of the large cells resembles the pseudo-nodules seen in chronic lymphocytic leukemia (H & E, ~ 4 3 2 ) .

bone marrow was extensively involved by an infiltrate (Figs. 4G, H) interpreted as lymphocytic lymphoma, poorly differentiated. The patient was treated for histiocytic lymphoma with CHOP. The size of the lymph nodes decreased gradually, but no complete remission was achieved. In our opinion, this case represents an unusual form of T- cell chronic lymphocytic leukemia evolving into histiocytic lymphoma. The reason for the conflicting diagnoses of chronic lymphocytic leukemia, poorly differentiated lymphocytic lymphoma, and histiocytic lymphoma was that several examiners were making diagnoses from different tissues which showed marked variation in the proportions of small to transformed lymphocytes and immunoblasts.

Case 5

A 44-year-old white woman had a 2 cm crusted erythematous pruritic area over the left tibia. A biopsy examination revealed that it was “lichenified eczematous dermatitis o r nummular eczema.” It cleared with topical cortisone

therapy. A similar lesion was discovered later on the right shoulder. It disappeared spontaneously. The third lesion appeared three years after the first. This lesion differed in that it was larger and raised, but again, was crusted and erythematous. It was diagnosed as malignant lymphoma, diffuse, mixed lymphocytic and histiocytic type (Figs. 5A, B). There was no peripheral lymphadenopathy, but the lymphangiogram showed enlarged lymph nodes in the inguinal and external iliac chain, bilaterally, and in the right common iliac chain. Blood and bone marrow were not obviously involved. The patient underwent radiotherapy, receiving 3000 rad over the abdomen. This resulted in reduction in size of lymph nodes. Skin lesions recurred on the thorax and responded to treatment with cytoxan, oncovin, and prednisone (COP).

Case 6

A 45-year-old white woman was first seen because of low-grade fever, nausea, vomiting, and weakness. There was

FIG. 5. Case 5. Photomicrograph of skin tumor tissue. A. Note numerous mitoses (H & E, x270). B. Most of the tumor cells have a fairly regular nucleus, prominent nucleoli, and a moderate amount of cytoplasm. A few of the nuclei are slightly irregular (H & E, x680).


mild anemia (10 g/dl) and leukoerythroblastosis. A bone marrow aspiration resulted in a dry tap, but the biopsy imprint and the biopsy specimen itself (Fig. 6A) showed numerous immature cells leading to a diagnosis of acute myeloblastic leukemia. There was splenomegaly (2 cm below the left midcostal margin), but no lymphadenopathy or hepatomegaly. A chest x-ray was normal. She was given antibiotics and chemotherapy (adriamycin, cytosine arabinoside, oncovin, and prednisone). Because of a positive PPD skin test, she also received isoniazid. Four weeks later, her bone marrow was hypocellular and free of tumor and the hemogram was normal. She was maintained on methotrexate, thioguanine, hydroxyurea, cytoxan, and cytosine arabinoside. She did well until ten months later when she presented with fever, generalized peripheral lymphadenopathy, and hepato- splenomegaly. Results of biopsy examination of a lymph node were interpreted as malignant lymphoma, histiocytic type (Fig. 6B). The bone marrow was involved by the same tumor and after review, the initial bone marrow specimen was found to be identical to the later specimen. The patient was treated for histiocytic lymphoma with the CHOP regimen and experienced complete remission.

She was kept on a COP maintenance program until relapse occurred 11 months later. Several different chemotherapeutic regimens were tried without response. Progressive pancyto- penia arid multiple lung infiltrates of undetermined origin

FIG. 6A. Case 6 . Photomicrograph of bone marrow biopsy specimen showing replacement by tumor (H & E, ~ 1 0 8 ) . B. Photomicrograph of lymph node tissue. Note intimate relationship of tumor cells and histiocytes. Tumor cells have round nuclei and very large nucleoli (H & E, ~ 4 3 2 ) . C. Photomicrograph of lymph node tissue. Cytocentrifuge preparation of E-rosetting tumor cells of varying size (Leishman’s stain, x680).

developed and she died five months later of intracranial hemorrhage. During her last admission, a false-positive VDRL ( 1 : lOOO), antinuclear antibody (1:600), and hypo- gammaglobulinemia developed with a small peak in the alpha region on electrophoresis.

Case 7

A 49-year-old white woman was admitted because of gradually enlarging cervical and axillary lymph nodes of 16 months’ duration. There were no constitutional symptoms. A biopsy examination of a lymph node was done, but diag- nostic opinions ranged from Lennert’s lymphoma or atypical Hodgkin’s disease, to an abnormal immune response. She received one course of vincristine (2 mg) and prednisone (80 mg). Two months later, there was generalized lymphadenopathy and splenomegaly . She was given another course of chemotherapy, but constitutional symptoms of fever and night sweats developed one month later. The liver and bone marrow were found to be involved by the same lesion. There was a pleural effusion. Lymph nodes and spleen continued to enlarge. Another lymph node biopsy specimen (submental) was interpreted as Lennert’s 1ymph0ma.l~ She was treated with cytoxan, vincristine, and prednisone, but the fever continued. Chest x-rays revealed alveolar infiltrate, but a biopsy examination of the lung showed no evidence of

No. 1 LARGE CELL T-CELL LYMPHOMAS . Paliitke et al.

FIG. 7. Case 7. A Photomicrograph of lymph node section, large areas of which consist of irnmunoblasts and a few small cells. Note numerous mitoses (H & E, x432). B. Imprint of same lymph node showing T cells of varying size (Leishman’s stain, ~ 6 8 0 ) .

lymphoma. Another lymph node biopsy examination showed an increase in the large, immature lymphoid cell component (Figs. 7A, B). The patient did not respond to chemotherapy or antibiotics and died three months later.

Materials and Methods

General

Material is referred to our laboratory from ten area hospitals. The lymph nodes are examined by means of light and electron microscopy and by histochemical, cytochemical, and immunologic methods. Blood and bone marrow samples, whenever available, are similarly studied.

Light Microscopic Studies

The freshly cut surface of the lymph node is gently touched to clean microscope slides. These imprints are air dried and stained with Leishman’s stain. Trans- verse sections of the lymph node (2-3 mm in thick-

93

ness) are fixed in B5 fixative for routine histologic processing. Four to five micron sections are stained with hematoxylin-eosin, periodic acid-Schiff (PAS) and methyl green pyronine (MGP). For the present study, special attention was paid to the ratio of large to small lymphocytes, nuclear shape, number of histiocytes, vascularity, compartmentalization, and number of mitoses per 20 high-power fields.

Electron Microscopic Studies

The methods used for the preparation of tissue for electron microscopic examination have previously been described.” The tissues from Cases 2-7 were examined with a Zeiss EMIOA.

Immunologic Studies

The methods for preparing mononuclear cell suspensions and evaluation of surface immunoglobulin markers and receptors for unsensitized sheep red


cells, complement and immunoglobulin (Fc) have previously been d e s ~ r i b e d . ' ~ ~ ' ~ Cytocentrifuge preparations of all the rosette tests are made using a Shandon- Elliot cytospin and are stained with Leishman's stain.

Intracytoplasmic immunoglobulins (heavy chains of IgG, IgM, IgA, IgD, and kappa and lambda light chains) as well as cytoplasmic muramidase are evalu- ated in BS-fixed, paraffin-embedded tissue sections, using the immunoperoxidase method of Sternberger et al. l7 Antisera are obtained from DAKO-Immuno- globulins (Accurate Chemical and Scientific Company, Hicksville, New York).

Cytochemistical and Histochemical Studies

Staining for acid phosphatase,8 p glucuronida~e,~ and PAS was performed on imprints and cytocentrifuge preparations in 4 cases (Cases 2, 4, 6 , 7).

Results

Light Microscopic Findings

The morphological observations of the seven tumors are shown in Table 1. Vascular proliferation, a large number of macrophages, and variation in the size of tumor cells were prominent features in the majority of cases. Plasma cells were not conspicuous. Mitoses were numerous in all tumors. There was no necrosis. Blood and/or bone marrow were involved in 5 cases.

Variation in cell size was especially striking in five tumors. In several cases, large cells predominated in some areas and in others, a second biopsy examination of an enlarging tumor revealed a marked increase in the number of large cells as compared to the initial biopsy examination (Cases 1, 7).

Electron Microscopic Findings

The light microscopic findings were confirmed (Figs. 8-11). The chromatin pattern was fine in the large cells and coarser in the smaller cells. The cytoplasm of large and small cells contained numerous polyribosomes and fairly long strands of undilated rough endoplasmic reticulum. Some of these strands appeared circular (Fig. 10). Lysosomal bodies were noted in several cases, primarily in the large cells (Figs. 8, 11). Occasionally, they could be seen arising from the Golgi region (Fig. 11). As many as three prominent nucleoli per nucleus were observed in several cases. They appeared larger in the large round cells (Fig. 11). Some were adjacent to the nuclear membrane and others were centrally placed. Histiocytes were seen in intimate contact with the tumor cells. Some had ingested cellular debris (Fig. 9B).

Histochemical and Cytochemical Findings

MGP: Most of the cells stained positively. The large cells stained more intensely than the smaller ones.

PAS: Only histiocytes were strongly positive. Acid phosphatase: The tumor cells varied in degree

of positivity. Although in many cells the acid phosphatase granules appeared concentrated in the area of the Golgi, many cells also had numerous granules overlying the nucleus and in other portions of the cytoplasm (Fig. 2D).

p-glucuronidase: The larger cells were less frequently positive for p-glucuronidase than the smaller ones.

Immunologic Findings

The percentages of E-rosettes and surface immunoglobulin markers of tumor and other tissues are shown in Table 2. E-rosetting cells constituted 30-88% of lymphoid cells in suspensions prepared from the tumors. Cells of varying sizes formed E-rosettes (Fig. 6C). In Case 1, in which the lymph node was only partially involved by tumor, cytocentrifuge preparations showed convoluted tumor cells forming E-rosettes. E-rosettes were formed at 37" and at 4°C. There were very few cells with immunoglobulin markers.

Immunoperoxidase reactions for immunoglobulins in tumor cells were negative. Plasma cells contained immunoglobulins of multiple classes. Muramidase was seen only in histiocytes and the few granulocytes that were present.

Discussion

Diffuse histiocytic lymphomas of the Rappaport classification have recently been found to be a hetero- geneous group, immunologically'.10 and histochem- ically,' as well as morphologically and clinically.16 Morphologic criteria alone, so far, have not been sufficient for an accurate immunologic classification of these lymphomas," although they have been used in order to establish a clinical correlation."j

Large series describing the morphologic characteristics of histiocytic lymphomas of T-cell type are not yet available. Waldron et have reported 6 cases of what they describe as a "distinctive malignant lymphoma of peripheral T-lymphocyte origin" in which large T cells are one of the prominent cellular com- ponents. Li and Harrison7 mention 12 T-cell diffuse lymphomas, most of which had variable degrees of nuclear convolution. Eight of these patients had mycosis fungoides or Sezary syndrome. Both groups of investigators describe a marked variation in cell size. In Waldron el al's18 series, the large cells predominated in only 2 of the 6 cases. The large cells were

No. 1 LARGE CELL T-CELL LYMPHOMAS . Palutke et ul. 95

TABLE I . Light Microscopic Findings

Number Large cells1 mitoses1 Histiocytes and

Patient Tissue Architecture Tumor cell morphology small cells 20 HPG plasma cells Blood Bone marrow

1 Inguinal lymph Partially replaced by node diffuse tumor,

follicles with reactive centers in some areas.

The cells vary in size; nuclei very irregular: 1-2 t o 3:l inconspicuous nucleoli.

Vane5 from I : I 93 Histiocytes are scattered; occasional small clusters of plasma cells primarily around vessels.

184 Few plasma cells and histiocytes

Not involved Not involved

Lung tumor Diffuse growth (Fig. 1) pattern

Large cells with very irregular nuclei: nucleoli more prominent.

Large cells with very irregular nuclei; 1-2 small inconspicuous nucleoli; karrhyorexis prominent in some areas.

Cells vary considerably in size. Nuclei very convoluted; multinucleated giant cells resembling Reed-Sternberg cells; usually 2 prominent nucleoli in larger cells.

Cells vary markedly in Size from small lymphocytes to large immunoblasts. Nucleoli vary from barely visible in small cells to large and prominent in immunoblasts.

Same

Almost all large cells

2 Inguinal lymph Effaced; diffuse Predominantly large cells

198 Numerous scattered histiocytes: few olasma cells.

Involved Y, of lymphocytes convoluted.

Involved

Not examined

node (Figs. pattern 2A-C)

3 Axillary lymph Effaced, but node (Figs. peripheral sinus is 3A-C) patent and

contains foamy histiocytes.

I : I t o predominantly large

120 Histiocytes occur in

large clusters in patchy areas; few plasma cells.

Involved: ‘4 of lymphocytes convoluted and vary in size. (Fig. 3D)

4 Axillary lymph Obliterated node (1976)

Varies from 1:4 to 1:3

67 Hiatiocytes and plasma cells numerous and scattered, predominantly in small cell areas.

90 Same Inguinal lymph Obliterated; in some node (1978) areas collections (Figs. 4A-E) of immunohlasts

resembling pseudonodules of CLL. Other areas composed almost exclusively of immunoblasts.

5 Subcutaneous Diffuse growth tumor (Figs. 5A. B)

Varies from 1:4 to predomin- nantly large

Involved: cells vary from C L L type to nucleolated lymphosar- coma cells. (Fig. 4F)

Extensively involved; Pseudonod- ules present (Fig. 4G, H)

Cells are more uniform in size than those of other cases. Most are slightly smaller than endothelial cells. In suspension, cells resemble transformed lymphocytes rather than larger immunoblasts. Nuclei are round o r oval and generally regular; occasional giant cells.

Cells vary considerably in size from small lymphocytes to large immunohlasts. Nuclei are round o r oval and regular. Occasional multinucleated giant cells; 1-2 large, prominent central nucleoli

2: I

439 Histiocytes, plasma cell?; and eosinophils around edges of tumor primarily.

Not involved Not involved

6 Lymph node Obliterated; diffuse (Figs. 6B. C) growth.

200 Histiocytes are a very prominent component, singly o r in large clusters. In H & E section, lymphocytes and histiocytes are sometimes difficult to differentiate.

44 Epithelioid histiocytes in clusters are prominent component; rare plasma cells.

OcCdSiondl Extensive large involvement; immature morphology cells are seen like lymph

node. (Fig. 6A)

7 Lymph node # 1 Obliterated; capsule Cells vary in size from small (Ref. 12) infiltrated, but lymphocytes to huge

peripheral sinus immunoblasts. Nuclei are patent regular round o r oval. Some

large cells are multinucleated; 1-5 large, prominent nucleoli in large cells.

1:3 Rare immature Involved lymphocytes

Lymph node # 2 Same (Figs. 7A, B)

Same Varies from 1: 1 176 Fewer clusters of to 5:l epithelioid

histiocytes

also described as having a clear cytoplasm. In contrast, the cytoplasm of the large cells in our series was amphophilic with H & E and strongly pyroninophilic with MGP.

The purpose of this report is to show that T-cell lymphomas of the large cell type have a variety of

morphologic features and clinical manifestations. The major criteria for inclusion into this series were: presence of tumor cells forming E-rosettes with unsensitized sheep cells; absence of surface Ig markers or cytoplasmic immunoglobulins in tumor cells; and absence of mycosis fungoides or Sezary syndrome.


Of the lymphoid cells in involved tissue, 33-88% formed E-rosettes. Cytocentrifuge preparations aided in distinguishing tumor cells from normal lymphocytes. Except in Cases 1 and 5 , a large proportion of the E- rosettes were formed at 37" as well as at 4°C. This property of the T cells precluded accurate evaluation of the Ig-GEA and Ig-MEAC rosettes when sheep cells were used. (We have since used ox red cells for these rosette tests to avoid this problem). Normal peripheral human T lymphocytes form E-rosettes optimally at low temperatures and the rosettes dis- sociate at 37°C.' T cells forming E-rosettes at 37°C

FIG. 8. Case 2 . Elec- tron micrograph of lymph n o d e . No te marked irregularity of the nuclei, fine chromatin pattern, and prominent nucleoli in the larger tumor cells. Several tumor cells have many strands of rough endoplasmic reticulum and others have lysosomal granules.

(stable E-rosettes) have been described previously in normal thymus glands and in acute lymphocytic leukemia.2 We have observed them not only in the present cases, but also in lymph nodes involved by various other malignant and nonmalignant disorders, including Hodgkin's disease and immunoblastic lymphadenopathy. l4 The significance of this finding is not clear. Some workers have suggested that lymphocytes forming these stable E-rosettes belong to func- tionally less mature lymphocytes.' Others have considered them to be activated lymphocytes.s Another possibility is that they represent a specific subclass

FIG. 9A. Case 3 . Electronmicrograph of lymph node t i s sue showing tumor cells with irregular nuclei and large nucleoli. Note intimate contact with histiocytes containing cellulardebris ( ~ 6 , 1 0 8 ) .

FIG. 9B. Tumor cell from lymph node in Fig. 9A, in very close contact with two histiocytes. Histiocytes contain ingested cellular debris (x3,456).


of T lymphocytes. It is of interest that Sezary cells in our hands, did not form such stable 37” E-rosettes. Sezary cells, in some cases, have been shown to have the properties of helper T cells.3

Morphologically, the tumors could be grouped into two major categories: those with irregular, and those with regular, round or oval nuclei. Cases 1-3 fall into the first, and Cases 4-7 into the second category.

Both types of tumors were characterized by marked variation in tumor cell size (Table 1). In addition, the proportion of large cells varied from area to area of the same tissue and in subsequent biopsy specimens (Cases 1 , 4, 7). Case 7 was originally one of Lennert’s lymphoma with a predominance of small lymphocytes and epithelioid histiocytes.15 A biopsy examination of a lymph node shortly before the patient’s death (six months after the original biopsy), showed a predominance of large immunoblasts and a markedly decreased number of epithelioid histiocytes, suggesting an evolu- tion into an immunoblastic sarcoma.6 The percentage of E-rosetting tumor cells remained almost the same. In Case 4, the proportion of large to small cells varied considerably from area to area within the same lymph

FIG. 10. Case 4. Electronmicrograph of lymph node section in which smaller and intermediate cells predominate. Note many ring shaped strands of rough endoplasmic reticulum ( x 3,456).

node from the second biopsy (Figs. 4A, D), making an accurate assessment of the type of lymphoma difficult. Some areas of the lymph node and bone marrow resembled chronic lymphocytic leukemia with pseudo- nodules4 of transformed lymphocytes (Fig. 4H), yet other areas were consistent with histiocytic lymphoma (Fig. 4D). Closer scrutiny revealed that the smaller cells were not as uniform as they are in chronic lymphocytic leukemia, but varied in size and nuclear chromatin pattern (Fig. 4F). Small and large cells in this case were pyroninophilic. The tissue from the first biopsy specimen showed a similar mixture of small and large cells, but the confluent areas of immunoblastic proliferation were not seen.

Case 5 differed slightly from the other tumors in this series in that the nuclei of the majority of the tumor cells were slightly smaller than those of histiocytes. The cells resembled transformed lymphocytes rather than immunoblasts. This tumor may fit into the category of “blastic” type of histiocytic lymphoma described by Strauchen et ~ 1 . ’ ~ Although mitoses were abundant in all the tumors, they were most abundant in this case, in which 439 mitoses per 20 high power

No. 1 LARGE CELL T-CELL LYMPHOMAS * Palutke et al. 99

FIG. 1 IA. Case 6. Electronmicrograph oflymph node tissue showing T immunoblast with very large nucleolus and very fine chromatin pattern. Note abundance of large mitochondria and long strands of rough endoplasmic reticulum. This cell also has many pseudopodia (X5,256).

fields were counted. As a rule, mitoses were more P-glucuronidase were present in tumor cells of the 4 numerous in areas where large tumor cells pre- cases tested. Acid phosphatase was not always lo- dominated. calized to a specific intracellular area, sometimes being

All tumor cells showed varying degrees of MGP present as abundant granules scattered randomly positivity, the large cells more than the smaller ones. throughout the cytoplasm. The cells were PAS-negative. Acid phosphatase and An interesting consistent finding on electron micro-

FIG. 11 B. Another immunoblast with lysosornal granules in the Golgi region. ( ~ 4 , 2 6 1 ) . C. Higher-power of this Golgi region and the lyso- soma1 granules. ( ~ 2 5 , 3 8 1 ) .


TABLE 2. Percentages of E-Rosettes and Surface Immunoglobulin Markers

Sheep red cell rosettes Ig Markers

Patient Tissue E; 4°C E; 37°C A G M D K L

1

2

3

4

5

6

7

Control

Control

Lymph node

Blood Lymph node

Lymph node

Blood (1) Lymph node Bone marrow

Skin nodule

Blood Lymph node Bone marrow

Blood Lymph node 1 Lymph node 2

Blood (45) Mean

Lymph node ( 1 1) Mean

53

56 88

73

59 37 30

42

41 60 33

47 48 54

41-81 61

23-57 36.6

5

26 72

24

7 23 15

0

5 38 0

6 33 47

0-6 1

0-8 1.8

1

0 1

1

0 2

0

3 N D

0 0 0

0- 8 3

2-9 4.5

7

15* 0

2

3 6

7

17* N D

15* 1 1

2-22 11

3- 18 9.5

2 3

2 0 2 0

3 1

Whole Ig 6% 5 2 0 0

0 0

12 1 N D ND

Whole Ig 0

1 0 1 1 0 2

2- 12 0-6 6 1.2

2- 13 2-8 7.5 5.5

4

17* 3

2

1 2

4

20* N D

14* 1 I

3- I6 7

4- 12 8

~~ ~~

6

1 0

2

6 3

0

4 N D

0 1 1

2- I3 5

1-7 4.2

* Due to large numbers of monocytes in mononuclear cell preparation.

N D = not done.

scopic examination (Figs. 8- 11) was the presence of fairly long strands of nondilated, rough endoplasmic reticulum which frequently appeared circular. This was present in both small and large cells and in cells with round or irregular nuclei. In addition, lysosomal granules were present, frequently concentrated in the Golgi region.

Histiocytes were a prominent component of all the tumors except for that in Case 5, in which they were present in appreciable numbers only around the periphery of the subcutaneous tumor. In the first lymph node biopsy specimen of Case 7 (Lennert’s lymphoma), histiocytes were epithelioid and appeared in large, prominent clusters; in the subsequent biopsy specimen they were much less numerous or apparent. In Case 6 , it was difficult to distinguish immunoblasts from histiocytes in some areas of the tumor in H & E stained sections because the histiocytes were so abundant and intimately intermingled with the tumor cells and had large, frequently round nuclei. The PAS and immunoperoxidase stains for muramidase clearly identified the cells, however. The presence of muramidase in histiocytes also helped to quantitate the histiocytes in the other tumors where they appeared much less abundant in H & E sections. A starry sky pattern, denoting marked phagocytosis by histiocytes, was not seen. However, electron microscopic ex-

amination demonstrated that many of the histiocytes contained ingested cellular debris.

Compartmentalization of the tumor into microscopic clusters of 10-30 cells by delicate collagenous bands as described by Waldron et al.‘* was not noted. How- ever, vessels were abundant and endothelial cells were generally large and prominent as described in Waldron rt a l . ’ ~ ’ ~ series.

Peripheral blood smears contained numerous tumor cells in 3 cases, occasional tumor cells in 1. Bone marrow was involved in at least 4 and probably 5 cases. Pulmonary involvement was demonstrated in 1 case only, unlike Waldron et al. ’s series,ls in which a large number of patients had pulmonary involvement. Skin was involved by lymphoma only in Case 5. The skin lesions in Case 3 proved to be squamous cell carcinoma.

The clinical courses of the 7 patients differed considerably, but two distinct subgroups could be identified. All 3 patients with tumors that had very irregular nuclei presented with rapidly enlarging peripheral lymph nodes. All 3 had short clinical courses. The longest survival time in this group was ten months. The clinical courses of the 4 patients with tumors of the round, regular nuclear type varied considerably. Gradually developing lymphadenopathy was a present- ing feature in Cases 4 and 7. Bone marrow involvement


mimicking acute leukemia was initially found in Patient 6, who presented with systemic symptoms. Skin lesions over a period of five years were the major problems in Case 5 . Both patients subsequently developed lymph node involvement.

The survival rate in this second group of patients was longer. Two died approximately two years after the onset of symptoms and 2 are still alive two and a half (Case 4) and one and a half years (Case 5 ) after the original diagnosis. In the latter case, it is conceivable that the malignancy started three years prior to diagnosis.

In summary, we have presented clinical and morphologic findings in 7 patients with T-cell malignancies of the large cell type. Major light microscopic features which should alert a pathologist to the possibility that a lymphoid tumor is of T-cell variety are: diffuse growth pattern, marked variation in tumor cell size, marked irregularity of the nucleus, and a large number of histiocytes in tumors composed of cells with round, regular nuclei as well as those with irregular nuclei.

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Documents

T-cell lymphomas of large cell type. A variety of malignant lymphomas: “Histiocytic” and mixed lymphocytic-“histiocytic”