Lymphoma in soft tissue: A clinicopathologic study of 19 cases

Lymphoma in Soft Tissue: A Clinicopathologic Study of 19 Cases DIVA R. SALOMAO, MD, ANTONIO G. NASCIMENTO, MD, RICARDO V. LLOYD, MD, MICHAEL G. CHEN, MD, PHD, THOMAS M, HABERMANN, MD, AND JOHN G. STRICKLER, MD The authors retrospectively reviewed 19 patients who presented with lymphoma as soft tissue masses, without evidence of lymph n o d e or skin involvement. Sites of involvement included lower extremity (seven), upper extremity (six), chest wall (three), gluteal region (two), and frontal subgaleal region (one). Histological and immunophenotypic studies revealed 12 large cell lymphomas (11 B cell and one T cell), two small noncleaved cell lymphomas (B-cell phenotype), and five low grade B-cell lymphomas (two small lymphocytic and three follicular mixed lymphomas). Patients with large cell lymphoma, including seven patients with stages I and II and five patients with stage IV, were treated with anthracycline-based chemotherapy, with or without radiation therapy. One half of these patients are dead of disease, including four of seven with low stage disease. The two patients with small noncleaved cell lymphoma had stage IE disease and

were treated with chemotherapy; one died at 11 months, and the other is alive and disease free at 65 months. Patients with low grade B-cell lymphoma included four stage IE patients who were treated with radiation and one stage IV patient treated with chemotherapy. Two patients are alive and disease free, and three are dead of unrelated causes. The authors conclude that malignant lymphomas initially diagnosed in soft tissues are most commonly large cell lymphomas with a B-cell phenotype. HUM PATrlOL 27:253--257. Copyright © 1996 by W.B. Saunders Company Key words: Epstein-Barr virus, immunohistochemistry, lymphoma, soft tissue. Abbreviations: EBV, Epstein-Barr virus; ISH, in situ hybridization; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; MPO, myeloperoxidase.

Malignant l y m p h o m a occasionally occurs as a soft tissue mass at presentation. Most o f these e x t r a n o d a l l y m p h o m a s " s e c o n d a r i l y " involve soft tissue, either by direct extension f r o m adjacent l y m p h n o d e s or by dissemination. T r u e primary, soft tissue l y m p h o m a is rare, although well-documented cases have b e e n describedJ q Previous clinical studies o f these soft tissue lyrnphomas consist o f a few patients w h o have b e e n staged a n d treated in various ways. F u r t h e r m o r e , s o m e pathological studies do n o t provide clinical information, c u r r e n t l y m p h o m a terminology, o r i m m u n o h i s t o c h e m i c a l characterization. I n this article, the authors describe 19 patients whose l y m p h o m a was initially d i a g n o s e d by biopsy o f a soft tissue mass.

shown. None of the patients had a previous history of lymphoma. Each patient was staged according to the Ann Arbor Staging System. The initial evaluation included the history, physical, complete blood cell count, erythrocyte sedimentation rate, lactate dehydrogenase, liver function tests, serum calcium, chest radiograph, computed tomographic scan of the abdomen with or without the chest, and bilateral bone marrow studies. Patients were not tested for human immunodeficiency virus (H1V). Follow-up information was obtained by review of patient records.

MATERIALS AND METHODS

Clinical Evaluation The initial diagnosis of non-Hodgkin's lymphoma was established by biopsy of a soft tissue mass in 19 patients who were selected from a review of 356 Mayo Clinic patients treated for lymphoma involving soft tissue. None of these patients was included in a previous study9 from this institution. Each of the 19 patients presented with a mass (2.0 to 8.0 cm) in soft tissues (adipose tissue, skeletal muscle, and connective tissue), without clinical or pathological evidence of direct extension from skin or adjacent lymph nodes at the initial evaluation. Lymphomas in areas with numerous lymph nodes (neck, axilla, groin, and retroperitoneum) were excluded, even if direct extension from lymph nodes could not be From the Division of Anatomic Pathology, the Division of Radiation Oncology, and the Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN. Accepted for publication October 12, 1995. Address correspondence and reprint requests to John G. Strickler, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Copyright © 1996 by W.B. Saunders Company 0046-8177/96/2703-001255.00/0

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Pathological Evaluation Each soft tissue lymphoma was classified by the Working Formulation for Clinical Usage. a° Immunohistochemical studies were performed with standard techniques,11 using paraffinembedded tissue (19 of 19 cases) and fresh tissue (seven of 19 cases). The panel of antibodies used in paraffin-embedded tissue included antibodies to leukocyte common antigen (CD45), the B-lineage marker CD20 (L26), the T-lineage markers CD3 (polyclonal) and CD45RO (UCHL-1), antibodies to myeloperoxidase (MPO), and antibodies to CD30 (BerH2). The panel of antibodies in fresh (frozen) tissue included B-lineage markers (CD20, CD22), T-lineage markers (CD2, CD3, CD5, and CD7), and antibodies to K and )t light chains. In situ hybridization (ISH) for Epstein-Barr virus (EBV) was performed using the procedure described by Chang et al, I2 with EB-encoded RNA 1 and 2 oligonucleotide probes labeled at the three-prime end with fluorescein isothiocyanate and using the alkaline phosphatase fluorescein isothiocyanate detection kit (both from DAKO, Carpinteria, CA). The hybridization products were visualized after developing in 5bromo-4-chloro-3-indolyl phosphate and nitroblue tetrazolium, and nuclear fast red staining for 1 minute, followed by dehydration and sealing with coverslips. A positive reaction was indicated by an intranuclear blue reaction product with sparing of the nucleoli. Positive controls consisted of tissues with proven EBV infection, and negative controls consisted of omission of the oligonucleotide probes and ribonuclease A digestion in selected cases.

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FIGURE 1. Case no. 12: Large cell lymphoma. (Hematoxylineosin stain; original magnification ×640).

clinical stage increased, based on lyric bone lesions (four), hepatic nodules on computed tomography of the abdomen (one), and jejunal lymphoma (one). Constitutional symptoms were present in three patients. Primary treatment consisted of chemotherapy only (four patients), chemotherapy and radiotherapy (five patients), and radiation therapy only (three patients). Details of the radiation therapy are summarized in Table 2. Most patients received megavoltage photon irradiation to mean doses in the range of 40 to 45 Gy with conventional fractionation. Slightly lower doses of radiation were given as secondary treatment for relapse (three patients) at the sites of original disease or to adjacent areas (mean, 35 Gy). Clinical follow-up (Table 1) indicated that five patients were alive and free of disease (15, 28, 30, 100, and 115 months), six patients died of disease (1.5 to 28 months), and one patient was lost to follow-up (12 months). Low stage did not suggest a better survival; four of seven patients with stages I and II disease were dead of disease (11, 11, 21, and 28 months). Small N o n c l e a v e d Cell L y m p h o m a

RESULTS Large Cell L y m p h o m a

The biopsy specimens from 12 patients showed histological and immunophenotypic features of large cell lymphoma (Fig 1). The nuclei of the lymphoma cells were larger than the nuclei of the accompanying macrophages. The lymphoma cells showed rounded nuclear contours, dispersed chromatin, multiple prominent nucleoli apposed to nuclear membranes, and moderately abundant amphophilic cytoplasm. Each lymphoma showed features similar to those observed in large noncleaved cell lymphomas of lymph nodes. The lymphoma cells were CD45 positive, and 11 of 12 cases had a B-cell phenotype (CD20 positive, CD3 negative, CD45RO negative). Immunohistochemical studies on frozen sections (two specimens) confirmed the B-cell phenotype (CD20 and CD22 positive), with immunoglobulin light chain restriction (K, patient no. 5; ~, patient no. 4). Two of the 11 B-cell large cell lymphomas (patient nos. 3 and 4) contained large numbers (>50%) of reactive (small) T cells and were examples of T-cell-rich B-cell lymphomas. One (of 12) large cell lymphoma had a T-ceU phenotype, with expression of CD3 and CD45RO in paraffin-embedded tissue. None of the 12 large cell lymphomas had morphological features of anaplastic large cell lymphoma, and each case was CD30 (Ber-H2) and MPO negative. None of the lymphomas was classified as immunoblastic lymphomas by the Working Formulation. ISH revealed no evidence of EBV mRNA in the neoplastic (large) cells. The 12 patients (seven men; five women) had a median age of 68 years (range, 30 to 81 years), and eight patients were aged 60 years or older (Table 1). Sites of involvement included upper extremity (five), lower extremity (four), chest wall (two), and gluteal region (one). Six patients had stage IE disease with tumor localized in lower extremity (two), upper extremity (three), and buttock (one). Six patients had their

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The soft tissue biopsy specimens from two patients showed pathological features of pleomorphic small noncleaved cell lymphoma. The lymphoma cells were characterized by intermediate size, high nuclear to cytoplasmic ratio, round or oval nuclei, finely distributed chromatin, numerous mitotic figures, two to five distinct nucleoli, and moderate amounts of amphophilic cytoplasm (Fig 2). Interspersed macrophages were numerous, imparting a starry sky appearance. Immunohistochemical studies (paraffin-embedded tissue) showed that each lymphoma was CD45 positive with a B-cell phenotype (CD20 positive, CD3 negative, and CD45RO negative). Immunohistochemical study of frozen sections (one case) showed immunoglobulin (k) light chain restriction. Both lymphomas were EBV negative by ISH. The lymphomas involved the thigh in each patient. Treatment consisted of combination chemotherapy CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) without radiation therapy. One patient is alive and free of disease (76 months). The second patient had a recurrence shortly after treatment and did not respond to salvage chemotherapy. Disseminated disease developed, and the patient died 11 months after the initial diagnosis. Low G r a d e B-Cell Lymphomas

The biopsy specimens from five patients showed features of low grade lymphoma (Working Formulation) including small lymphocytic lymphoma (two) and follicular mixed lymphoma (three). The small lymphocytic lymphomas were characterized by diffuse infiltrates of small lymphoma cells with focal proliferation centers (Fig 3). One specimen had plasmacytoid differentiation. The follicular mixed lymphomas consisted of neoplastic follicles with an admixture of small cleaved and large lymphoma cells. The neoplastic cells in each lymphoma expressed CD45 and showed a B-cell phenotype (CD20 positive, CD3 negative, and CD45RO nega-

LYMPHOMA IN SOFT TISSUE (Salomao et al)

TABLE 1. Case No.

Sex/Age

Location

Large cell lymphoma 1 F/72 Elbow 2 F/71 Forearm 3 F/71 Buttock 4 F/57 Elbow 5 M/59 Calf 6 M/60 Thigh 7 M/33 Thigh 8 F/68 Chest 9 M/64 Arm 10 M/81 Chest 11 M/78 Thigh 12 M/30 Shoulder Small noncleaved cell lymphoma 13 M/69 Thigh 14 F/73 Thigh LOW grade B-cell lymphoma 15 M/73 Forearm 16 M/61 Chest 17 F/65 Thigh 18 M/70 Head 19 F/61 Gluteus

Clinicopathologic Correlation

Diagnosis

Stage

Treatment*

DLCL, B type DLCL, B type DLCL, B type DLCL, B type DLCL, B type DLDL, B type DLCL, B type DLCL, B type DLCL, B type DLCL, B type DLCL, B type DLCL, T type

IAE IAE I,E IAE I~E IAE 1V IV IV IV, I1AE IVB

RT; COP RT; CHOP COPA + RT RT; COPA P + RT CHOP + RT CHOP + RT COPA CHOP COPA ProMACE VCR + P + RT

DOD (11) DOD (11) ADF (28) DOD (28) ADF (100) ADF (30) ADF (15) ADF (115) Lost FU (12) DOD (1.5) DOD (21) DOD (5)

PSNC, B type PSNC, B type

IE IE

CHOP CHOP

AFD (76) DOD (11)

DSLL, B type FM, B type FM, B type FM, B type DSLL, B type

I A F"

RT RT RT RT CHOP + RT

IAE IAE IAE IVA

Long-Term FU (too)

DUC (cerebral vascular accident) (70)

ADF (103) ADF (154) DUC (atherosclerotic heart disease) (34) DUC (cause unknown, no evidence of disease 6 wk earlier) (30)

Abbreviations: ADF, alive and disease free; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; COP, cyclophosphamide, Oncovin (vincristine), prednisone; COPA, cyclophosphamide, Oncovin (vincristine), prednisone, Adriamycin (doxorubicin); DLCL, diffuse large cell lymphoma; DOD, dead of disease; DSLL, small lymphocytic lymphoma; DUC, dead of unrelated causes; FM, follicular mixed type; FU, follow-up; P, procarbazine; ProMACE, prednisone, doxorubicin, cyclophosphamide, and etoposide; PSNC, pleomorphic small noncleaved lymphoma; RT, radiotherapy; VCR, vincristine. * Patient nos. 1, 2, and 4 received radiotherapy as primary treatment and chemotherapy later because of failure or relapse.

tive). I m m u n o h i s t o c h e m i c a l studies of frozen sections

tional fractionation) were used than in the patients with large cell lymphoma. Clinical follow-up (Table 1) showed that one patient was alive and free of disease at 103 months. O n e patient had a local recurrence that was treated with local radiation therapy, and this patient is alive at 154 months. Two patients with no evidence of clinically active disease died of unrelated causes at 34 and 70 months. One patient with stage IV disease received three cycles of CHOP, followed (1 year later) by local radiation of a lytic b o n e lesion. This patient died of unrelated cause and without clinical evidence of active disease (30 months).

( f o u r cases) s h o w e d i m m u n o g l o b u l i n l i g h t c h a i n res t r i c t i o n . I S H r e v e a l e d n o e v i d e n c e o f E B V m R N A in t h e n e o p l a s t i c ( l a r g e ) ceils. T h e five p a t i e n t s ( t h r e e m e n ; two w o m e n ) h a d a m e d i a n a g e o f 65 y e a r s ( r a n g e , 61 to 73 years). Sites of involvement included upper extremity (one), lower e x t r e m i t y ( o n e ) , c h e s t wall ( o n e ) , g l u t e a l r e g i o n ( o n e ) , and frontal subgaleal region (one). Four patients had c l i n i c a l s t a g e IAE d i s e a s e a n d w e r e t r e a t e d w i t h l o c a l r a d i a t i o n t h e r a p y ( T a b l e 2). L o w e r d o s e s o f m e g a v o l t a g e p h o t o n s a n d e l e c t r o n s ( m e a n , 36 to 40 Gy; c o n v e n -

TABLE 2, Case No.

Stage

Prim, Rx

Large cell lyrnphoma 1 IaE RT 2 IAE RT 3 Iv.B Chemo + RT 4 IAE RT 5 IAE RT + Chemo 6 IAE Chemo + RT 7 Iva Chemo + RT 12 1VEB RT + chemo Low grade lymphoma 15 IAE RT 16 IAE RT 17 IAE RT 18 IAE RT 19 IVEA Chemo + RT

Radiotherapy as Part of Primary Treatment (13 Patients)

RT Fields

Dose (Gy)

Fractions

Time (d)

Energy

Elbow/axilla Forearm Buttock Arm/elbow/axilla Thigh Thigh Thigh Shoulder/sternum

50.5/44 24 44 30 30 50.4 50 20/15

24/22 14 22 10 15 28 25 5/3

33/31 21 27 11 18 39 36 6/4

~°Co 6 MV 20 MeV E 6 MV 9 MeV E 6 MV 6 MV 10 MV/9 MeV E

Local relapse at 2 mo CR but on to cheIno NED NED 1.4 yr, then nodal extension Inguinal node extension at 8 mo NED NED Rapid progression to other sites

Forearm Chest wall/neck Inguinal/thigh Scalp Pelvis

36.1 36/35 40 20/25 40

18 18/18 20 10/13 20

23 22/22 31 13/19 34

6 MV 10 MV/9 MeV E ~°Co 6°Co/9 MeV E 6~Co

NED NED NED NED NED

Resuh of Rx

at death, 5.8 yr later 5 yr, then extranodal extension 13.3 yr 2.3 yr, then nodal extension at <2 yr

Abbreviations: Chemo, chemotherapy; ~Co, cobalt-60 radiation; CR, complete remission; MV and MeV E, million electron-volts photon and electron energies, respectively; NED, no evidence of disease; Prim. Rx, primary therapy; RT, radiation therapy.

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FIGURE 2. Case no. 14: Small noncleaved cell lymphoma. (Hematoxylin-eosin stain; original magnification ×640.)

DISCUSSION Soft tissue involvement by malignant lymphoma characteristically occurs in patients with previously diagnosed lymphoma involving lymph nodes or other sites. Furthermore, soft tissue lymphomas that involve lymph node-rich areas are presumed to originate from lymph nodes rather than soft tissue. However, the initial site of lymphoma in some patients is within soft tissues, and no evidence exists of extension from adjacent skin, lymph nodes, or bone. v9 Lymphomas in soft tissues at presentation are considered to be primary in soft tissues if staging procedures exclude other sites of distant disease. 6 .'"9 Of the 19 patients in this series who initially presented with lymphoma in soft tissues, 13 patients met the criteria for primary soft tissue lymphoma. The primary histological features of soft tissue lymphoma may be difficult to distinguish from other malignant neoplasms including carcinoma, sarcoma, small blue cell tumors (neuroblastoma, extraskeletal Ewing's sarcoma, rhabdomyosarcoma, primitive neuroectodermal tumor), and granulocytic sarcoma. 1~9 However, the histological diagnosis of lymphoma may be confirmed by immunohistochemical studies (paraffin-embedded tissue) including lymphoid markers (CD45, CD20, CD3), myeloid markers (MPO, KP-1), and keratin antibodies (AE1/AE3, Cam5.2). Immunohistochemical studies 13 show that most primary soft tissue lymphomas have a B-cell phenotype, as previously 129 reported. '"'" Although 5% to 10% of B-cell lymphomas • in immunocompetent patients contain EBV, 1 4 all soft tissue lymphomas in this series were EBV negative. Malignant lymphomas initially diagnosed in soft tissues are most often large cell lymphomas with a B-cell phenotype. When these lymphomas contain numerous reactive T cells (T-cell-rich B-cell lymphomas), they are sometimes classified as diffuse mixed cell lymphomas. Large cell lymphomas also may show immunoblastic features. 6'9 Patients with large cell lymphoma are cur-

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rently treated with chemotherapy, using anthracyclinecontaining chemotherapy regimens, or with combined chemotherapy and radiation therapy. The intergroup trial in the United States compared CHOP; m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone); and ProMACECytaBOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, and methotrexate), and found no statistically significant difference in the 3-year disease-free survival in patients with advanced disease. 15Recently, the Eastern Cooperative Oncology Group has undertaken a trial of CHOP versus CHOP and radiation therapy, and the results of this trial are pending at this time. Shipp et a116 developed a predictive model for aggressive non-Hodgkin's lymphomas, the International Index, which correlated clinical pretreatment characteristics with the relative risk of death. Clinical features that were associated with survival included age (<60 vs >60 years), LDH (normal or > normal), performance status (0 to 1 vs 2 to 4), stage (I or II vs III or IV), and extranodal involvement (<--1 site versus >1 site). Patients were divided into different risk groups on the basis of the number of risk factors, and the predicted 5-year survivals were 73% in the low-risk group (zero or one factor), 51% in the low- to intermediate-risk group (two factors), 43% in the intermediateto high-risk group (three factors), and 26% in the highrisk group (four or five factors). In this study, seven patients were older than 60 years, and five patients had stage III or IV disease. Fifty percent of patients in this series have died of progressive lymphoma. From this information, the authors would have anticipated a higher response rate in our seven patients with limited disease• A significant proportion of lymphomas that appear as soft tissue masses at presentation are low grade B-cell lymphomas including small lymphocytic and follicular lymphomas. These patients usually have low stage dis-

FIGURE 3. Case no, 15: Small lymphocytic lymphoma. (Hematoxylin-eosin stain; original magnification ×640).

LYMPHOMA IN SOFT TISSUE(Salomao et al)

ease and an excellent prognosis, similar to low grade B-cell lymphomas in extranodal locations, such as the orbit, breast, and stomach.17 Although some extranodal low grade B-cell lyrnphomas are lymphomas of mucosalassociated lymphoid tissue, there was no evidence of c o n c u r r e n t or subsequent mucosal-associated lymphoid tissue lymphomas in any of these patients. The limited results with radiation therapy alone in stage IAE lowgrade lymphoma suggest that this modality can be effective for long-term control. Similar results have been reported ~8'l° for other more c o m m o n presentations of localized low-grade lymphoma treated with radiation therapy. Small noncleaved cell lymphoma (B-cell phenotype) that occurs in soft tissue at presentation has been reported previously,6'7 and the authors identified two additional cases in this series. However, the natnral history and response to therapy are difficult to assess because of the low frequency of this histological subtype and the small n u m b e r of reported patients with soft tissue involvement.

Acknowledgment. The authors thank Kelly J. Hain, Lisa A. Baethke, and Charlann M. Thompson for their expert secretarial assistance. REFERENCES l. Bennett W, Rosenberg A, Harris N: Extranodal lymphoma presenting as a soft tissue mass of the extremity. Lab Invest 56:6A, 1987 (abstr) 2. Berg AR, Linder J, Anderson RW, et al: The undifferentiated malignant neoplasm. Identification of lymphoma arising in skeletal muscle by immunohistochemical analysis. JAMA 254:2625-2626, 1985 3. Greta JL, Neville AJ, Smith SC, et al: Massive skeletal muscle invasion by lymphoma. Arch Intern Med 145:1818-1820, 1985 4. Hung LK, Cheng JC, McGuire LJ, et al: Primary malignant lymphoma of the deep tissues of the hand. J Hand Surg [Am] 13:683686, 1988

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