Working Formulation


Peripheral T-cell Subtypes


IPI for Aggressive NHL








Castleman’s Disease



Therapy for Highly Aggressive Lymphomas

Mycosis Fungoides




-Nodular Sclerosis (NS) 60-80%

-Lymphocyte Predominant: Two types -- (1) Nodular - may really be a B-cell NHL. Most likely to relapse or progress to NHL. (2) Diffuse


-  Mixed Cellularity

-  Lymphocyte Depleted (LD) <5%. Often confused with DLCL. If see this diagnosis, suspect DLCL. Must also consider Ki-1 NHL (CD30). Difference is that Ki-1 lymphoma is NOT also CD15 + as HD is.

DLCL is CD15- & CD30-



CD15 = LeuM5 --> usually positive in HD (except LP)

CD45 = LCA --> usually negative in HD (except LP)

Most HD will express CDs 15, 20, 25, 30, and not 45 among a background of T4 helper cells.

In contrast, nodular LP --> CD15- and CD45+ among a background of B lymphocytes.

NS --> lacunar cells

LP --> popcorn cells


(Seminars Onc 22:xv 12/95)


1. Those with < 10% chance of having abdominal disease:

- CS IA females
- CS IA males with lymphocyte predominant histology
- CS IIA females < 27yo and < 4 sites of involvement
- CS I dz in axilla only or high neck only
- Mediastinal only dz

2. Those who will get chemo anyway:

- Bulky mediastinal disease


- B symptoms

- Pts > 60yo or with complicating illnesses

- Pts with 4 or more sites above diaphragm


Those with > 20% chance of upstaging from lap:

-All males with CS II (34% chance)
-Pts with 2-3 sites above diaphragm
-Those with high neck or axillary involvement and a + scalene node biopsy

In males, there is a 20-30% chance of having occult splenic or upper abdominal nodal involvement not detected by lymphangiography, CT, MRI, or gallium scan (Ann Onc 4:41, 92).

CT is 63% sens and 84% specific in HD.

Lymphangiogram is 85% sens.

In a recent study, most sensitive combo for predicting a negative lap was a negative CT plus a negative gallium scan.

Note that doing lap does not improve survival; the reason for doing lap is to reduce risk of under-treatment (ie, with RT) --> increased chance of relapse, thus exposing the pt to toxicities of both RT and chemo.

20-30% of laparotomy-staged pts who are treated with RT still relapse despite pathological staging.

Perioperative complications of splenectomy 3-10%. 10-yr cumulative risk of pneumococcal sepsis is 7% (33% fatal).

EORTC H6F trial: early stage with favorable prognostic features, randomized to splenectomy v none. Results: 93% 6YS in no-lap group compared to those who had lap.

NCI: MOPP x 6 is as effective as RT in early stage disease, suggesting that pts who are clinically staged may be treated w chemo alone, thus avoiding the complications of staging lap. (JCO 9:906, 91) Nevertheless, because toxicity was higher in chemo arm, it is difficult to recommend chemo in early stage HD until find less toxic chemo regimen (such as ABVD?).

Italy: Similar study comparing MOPP to extended field RT in pts with PS IA-IIA. No diff in DFS, but significant diff in OS in favor of RT (93 v 56% p<.001).



INFECTION - Bacterial, Mycobacterial, Fungal, Viral, Parasitic

IMMUNOLOGIC - Rheumatic disorders, Serum sickness, Sarcoidosis, Drug rxs (hydantoins)

MALIGNANCIES - Hematologic, Non-hematologic

MISCELLANEOUS OR UNKNOWN - Angioimmunoblastic lymphadenopathy, Dermatopathic lymphadenopathy, Endocrinopathies (Thyrotoxicosis, Adrenal insufficiency), Lipidoses



B-cell            CD 19, 20, 22

T-cell            CD 2, 3, 7

SLL/CLL: CD5+, CD10- CD23+

Mantle cell: CD5+, CD10- CD23-   t(11;14) BCL-1

Follicular center: CD5-, CD10+   t(14;18) BCL-2

MALT/monocytoid B-cell: CD5-, CD10- CD23- but CD19+ CD20+

Large B-cell              BCL-6 (70%). May also express (14;18)

Anaplastic Lg Cell: Ki-1+ (CD30), EMA+

T-cell Large Granular LC leukemia: CD3+ CD8+ TCR+ CD16+

NK Large Granular LC leukemia: CD3- CD8- TCR- CD16+ (CD16 is NK marker)

            CD10 = CALLA

(JCO 13:2656 10/95)



Small lymphocytic (5-8%) (MS 5-6y)

Lymphoplasmacytic/ lymphoplasmacytoid (3-5%) (MS 4y)

Follicular small cleaved (15-20%) (MS 6-7y)

Follicular mixed small cleaved & large (10-15%) (MS 4-5y)


Follicular large cell (1-5%) (MS 3y)

Diffuse small or mixed (1-2%) (MS 3-4y)

Intermediate/mantle cell (4-8%) (MS 3-5y)


Diffuse large cell (cleaved, non-cleaved) (20-25%) (MS 1-2y)

Immunoblastic (5-8%) (MS 0.5-1.5y)

Small noncleaved (Burkitts & non-Burk) (3-5%) (MS 0.5-1y)



Lymphoblastic lymphoma (3-5) (0.5-2)


Convoluted and nonconvoluted

Peripheral T-cell lymphoma (5-15) (1-2)

Adult T-cell leukemia/lymphoma



Lennert's lymphoma

Anaplastic large cell (Ki-1)

Cutaneous T-cell

Other (pleomorphic, small, medium, large T-cell)


Classified separately by site.

Most are B-cell, many MALT lineage


(Shipp Proc ASCO Abs 1084, 1992)

Risk factors:

Age > 60
Stage III/IV
>1 extranodal site
Poor KPS
High LDH

CR Rates

0-1 --> 87%
2 --> 67%
3 --> 55%
4-5 --> 44%

2 and 5 YR DFS OF CRs

0-1 --> 79 and 70
2 --> 67 and 51
3 --> 59 and 49
4-5 --> 58 and 42


0-1 --> 84 and 73
2 --> 66 and 50
3 --> 54 and 43
4-5 --> 34 and 26



Angioimmunoblastic Lymphadenopathy (AILD)

- Complex disorder that is still being defined

- May present as febrile systemic illness with:

hemolytic anemia

OR as a bland lymphadenopathy.

- Some resolve spontaneously, but most become rapidly fatal.

- Many cases may simply be Tcell lymphomas that have only a minor population of neoplastic cells (or early dz).


Lennert's Lymphoma (Lymphoepithelioid lymphoma)

Aggressive lymphoma in which collections of epithelioid cells overshadow the underlying neoplastic T lymphocytes.


Anaplastic Large-Cell Lymphoma

Another aggressive Tcell lymph. that occurs in cells that can pass for epithelial cells or histiocytes. Often CD30+


Angiocentric Lymphoma

Current term for combination of lethal midline granuloma and lymphomatoid granulomatosis, based upon common angiocentric and angiodestructive growth pattern.

Midline granuloma is a localized destructive lesion of the nasopharynx and upper airway that is frequently curable with RT.

Lymphomatoid granulomatosis is a grave condition that primarily involves the lung, but frequently disseminates to the GI, kidney, and CNS.




Hereditary Hemolytic Anemias: H. spherocytosis, H. elliptocytosis, Thalassemia, Sickle cell (infants)

Autoimmune Cytopenias: ITP, Essential neutropenia, Acquired hemolytic anemia

Infections & Inflammation: Mono, SBE, TB, RA (Felty syndrome), Sarcoid, Brucellosis, Leishmaniasis (kala azar), Schistosomiasis, Malaria


Congestion (Banti Syndrome): Cirrhosis, Portal vein thrombosis, Splenic vein obstruction, Budd-Chiari syndrome, CHF

Infiltrative Diseases: Leukemias [chronic & acute], CML, Hairy cell; Lymphomas; Polycythemia vera; Agnogenic myeloid metaplasia; Gaucher dz; Niemann-Pick dz; Glycogen storage dz; Amyloidosis

Tumors and cysts




Burkitt's lymphoma and Burkitt cell leukemia (BL) are classified as different manifestations of the same disease in the World Health Organization classification of hematologic malignancies; Burkitt-like lymphoma (BLL), is proposed as a morphologic variant of BL. Burkitt's lymphoma is listed in this program as one of the highly aggressive non-Hodgkin's lymphomas (NHLs).

DEFINITION — Burkitt's lymphoma/Burkitt cell leukemia (BL) is a B-cell neoplasm composed of monomorphic, medium-sized cells with basophilic cytoplasm and a high proliferation fraction, characterized by translocation and deregulation of the c-myc gene on chromosome 8. This disorder often presents with extranodal disease and occurs most often in children (endemic, sporadic) and immunocompromised hosts.

PATHOLOGY — Burkitt's lymphoma tumor cells are monomorphic, medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm. Cytologically, Burkitt's lymphoma (BL) cells resemble the small non-cleaved cells within normal germinal centers of the secondary lymphoid follicle. These cells differ from lymphoblastic lymphoma cells in two respects; they have intermediate sized non-convoluted nuclei with coarse chromatin, and the cells have more abundant cytoplasm. Although the Burkitt-like lymphoma (BLL) variant is similar to BL, the cells have greater pleomorphism and fewer nucleoli. Cytoplasmic lipid vacuoles are usually evident on imprints or smears.

There is an extremely high rate of proliferation as well as a high rate of spontaneous cell death. This results in two characteristic findings:

  • The growth fraction of these lymphomas is very high, with frequent mitotic figures being seen and the fraction of Ki-67+ cells approaching 100 percent (see below).
  • A "starry-sky" pattern is usually present, imparted by numerous benign macrophages that have ingested apoptotic tumor cells (eg, tingible body macrophages).

Borderline cases and Burkitt-like lymphoma — Although most cases present no problem in diagnosis, some cases may have larger cells or an admixture of centroblast- or immunoblast-like cells; resulting in morphologic overlap between Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). These borderline cases are often called "non-Burkitt" or "Burkitt-like". In children and HIV+ patients these often have a c-myc translocation and behave similarly to typical Burkitt's lymphoma, while in adults, cases classified as non-Burkitt lymphomas have had bcl-2 gene rearrangement and are thought to represent an aggressive variant of DLBCL.

In the international study of the REAL classification, BLL was a non-reproducible category, in which the pathologists agreed on the diagnosis only 50 percent of the time: disagreements were equally split between DLBCL and BL.

The most appropriate way to handle this borderline between BL and DLBCL has been the subject of debate in the WHO classification project: should it continue to be a separate, non-reproducible category, should it be a subtype of DLBCL, or should it be a subtype of BL? From a clinical standpoint, it is important to identify patients who should be treated as though they had BL, since such patients do not do well with treatment that would be effective for DLBCL. On the other hand, treatment for BL is considerably more aggressive than that for DLBCL, and may have significant treatment-related morbidity, so that it should not be used for the usual case of DLBCL. The question is: how to draw the line between DLBCL and BL so that morphologically borderline cases will be assigned to the correct category?

Defining features of Burkitt's lymphomaThe defining biological feature of Burkitt's lymphoma is c-myc deregulation, as a consequence of which the tumor cells remain constantly in cycle. It is this phenomenon that results in both its morphologic homogeneity and its clinical behavior. Unfortunately, detection of c-myc translocation is not practical in all clinical specimens for technical reasons. In addition, some DLBCLs have t(8;14) and c-myc deregulation, and it is not clear if all such cases should be treated like BL. The best practical surrogate for c-myc deregulation is thought to be the proliferation fraction: in a tumor with c-myc deregulation, 100 percent of viable cells should be in cycle, and should express Ki-67. Thus, the WHO committees concluded the following:

  • Diagnosis of BLL should only be made in a tumor with morphologic features intermediate between BL and DLBCL, in which the Ki-67 fraction of viable cells is at least 99 percent. This tumor will be considered a subtype of BL in the WHO classification.
  • Cases with morphologic features of DLBCL with a high proliferation fraction [or t(8;14)], and cases that are morphologically borderline between BL and DLBCL with a lower proliferation fraction, should be classified as DLBCL.

Postulated normal counterpartThe normal B lymphocyte counterpart from which these lymphomas are derived is controversial. Studies of normal lymphoid tissues, including the observation that CD10, several B-cell activation antigens, and the Burkitt lymphoma-associated glycolipid Ag CD77 are detected in the germinal centers of lymph nodes, and that BL have somatic mutations of their normal immunoglobulin genes like normal GC cells, suggest that BL cells may be the neoplastic counterpart of a subset of normal activated germinal center B-cells.

IMMUNOPHENOTYPE — Burkitt's lymphoma cells express surface IgM and B-cell-associated antigens (CD19, CD20, CD22, CD79a), as well as CD10, HLA-DR, and CD43. They lack CD5, bcl-2 and typically lack CD23. They show nuclear staining for BCL-6 protein, which is independent of bcl-6 gene rearrangement.

Expression of CD21, the Epstein-Barr virus (EBV)/C3d receptor is dependent upon EBV status of the tumors. The endemic BLs, which are EBV positive, express CD21, whereas the vast majority of non-endemic BL are EBV negative and lack CD21 expression.

BL generally lack the adhesion molecules LFA-1 (CD11a/CD18), p150/95 (CD11c), and CD44 as reported in the literature. The immunophenotype of the BLLs is very similar to BL, although expression of surface immunoglobulin (sIg), CD10 and CD21 is more variable. The immunophenotype of BLL as defined in the WHO classification has not been determined in prospective studies.

GENETIC FEATURES — Immunoglobulin heavy and light chain genes are rearranged. Studies of the immunoglobulin variable region genes show conflicting results: one study reported unmutated genes, while others report somatic mutations and intraclonal heterogeneity, consistent with ongoing mutations.

Mutations in the 5' noncoding region of the Bcl-6 gene, similar to those seen in DLBCL, have been reported in 25 to 50 percent of the cases. Most African cases contain EBV genomes, as do 25 to 40 percent of the cases associated with acquired immune deficiency syndrome.

Translocations involving the c-myc oncogene — In 90 percent of the cases studied, BL involves a translocation between the long arm of chromosome 8, the site of the c-myc oncogene (8q24), and one of three locations:

  • The Ig heavy chain region on chromosome 14 : t(8;14)
  • The kappa light chain locus on chromosome 2: t(2;8)
  • The lambda light chain locus on chromosome 22: t(8;22).

In African (endemic) cases, the breakpoint on chromosome 14 involves the heavy chain joining region, while in non-endemic cases, the translocation involves the heavy chain switch region. In endemic cases, the breakpoint in chromosome 8 lies outside the c-myc gene, while in sporadic cases it lies within the gene. In one study, cases classified as non-Burkitt lymphoma lacked c-myc translocations and had dual translocation of bcl-2 in one-third of cases. Cytogenetic and molecular genetic analysis of cases classified as BLL according to the WHO proposal are not available.

CLINICAL FEATURESThree distinct clinical forms of Burkitt's lymphoma can be recognized: endemic, sporadic, and immunodeficiency-associated. Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the three forms:

  • The endemic (African) form presents as a jaw or facial bone tumor that spreads to extranodal sites including mesentery, ovary, testis, kidney, breast, and especially to the bone marrow and meninges
  • The nonendemic or American form has an abdominal presentation, most often with massive disease and ascites, involving distal ileum, stomach, cecum and/or mesentery, kidney, testis, ovary, breast, bone marrow, or central nervous system
  • Immunodeficiency-related cases more often involve lymph nodes; both these and sporadic cases may present as acute leukemia.

Burkitt's lymphoma comprises 30 percent of non-endemic pediatric lymphomas, but <1 percent of adult non-Hodgkin's lymphomas; in HIV+ patients it typically affects those with a relatively high CD4 count and no opportunistic infections. In all groups, the majority of patients are male (3 or 4:1). Endemic and sporadic Burkitt's lymphomas are both most common in children; the median age is younger in patients with the endemic form. BL is rare in adults, typically seen in patients less than 35 years of age, and is virtually always the non-endemic form.

Patients typically present with rapidly growing tumor masses and often have a very high serum lactate dehydrogenase (LDH) concentration.

Cases previously classified as non-Burkitt's or Burkitt-like lymphoma (BLL) are also rare. Patients have a median age of 55, also with a male predominance. Tumors involve lymph nodes, the nasopharynx, and GI tract. Occasionally BLL presents as a solitary bone tumor. Like BL, these tumors have a high propensity to invade the bone marrow and central nervous system.. Serum LDH concentrations are often elevated and B symptoms are present in about one-third of patients. The clinical features of BLL as defined in the WHO classification have not been defined.

Burkitt's lymphoma is highly aggressive but potentially curable with very aggressive therapy. (See Treatment)



Highly aggressive lymphomas as a group represent about 5 percent of the NHLs diagnosed in Western countries, including approximately 3,000 people in the USA in 1999. These diseases are all uncommon, each one constituting <2 percent of all NHLs. The highly aggressive lymphomas can arise from B-cells or T-cells. They include:

·         Burkitt's lymphoma and the Burkitt-like lymphomas

·         Precursor B lymphoblastic leukemia/lymphoma. In the WHO classification, this condition is also called precursor B-cell acute lymphoblastic leukemia (ALL). It was agreed that precursor B-cell ALL and lymphoblastic lymphomas were a single disease with different presentations.

·         Precursor T lymphoblastic leukemia/lymphoma. In the WHO classification, this condition is also called precursor T-cell acute lymphoblastic leukemia (ALL). It was agreed that precursor T-cell ALL and lymphoblastic lymphomas were a single disease with different presentations.

·         Adult T-cell lymphoma/leukemia.

Tumor lysis syndrome — Physicians preparing to treat patients with one of the highly aggressive NHLs need to be aware that there is a significant risk of tumor lysis syndrome. This syndrome is best prevented via appropriate treatment with allopurinol, correction of any prior electrolyte disturbances and elements of reversible renal failure, as well as the provision of sufficient fluids to insure a high urine output. This is most appropriately performed in a continuously monitored inpatient setting.

Lymphoblastic lymphoma — Lymphoblastic lymphoma/acute lymphoblastic leukemia in adults has been treated with some success, using regimens based upon the successful treatment programs used in children, although results are inferior in adults. A 56 percent disease-free survival at three years has been reported in patients treated with CHOP plus high dose methotrexate, L-asparaginase, and intrathecal methotrexate. When treated with regimens initially developed for childhood ALL (eg, the LSA2L2 protocol), about 40 percent of adults are reported to survive at five years. In one randomized study, the use of autologous stem cell transplantation in first remission produced a trend for improved relapse-free survival, but did not improve overall survival when compared with conventional-dose consolidation/maintenance therapy. Hyper-CVAD has been studied at MD Anderson Cancer Center, with very high complete response rates.

Central nervous system (CNS) prophylaxis is critical in treating this disease, since the CNS is a sanctuary site for recurrence in the absence of such prophylaxis. Radiation may be used for CNS prophylaxis, but may not be sufficient, and intrathecal therapy is encouraged. Mediastinal radiation has shown a benefit in some pediatric trials, however its use is controversial.

The distinction between T-cell ALL and T-cell lymphoblastic lymphoma is somewhat arbitrary, and current practice is to treat T-cell lymphoblastic lymphoma like T-cell ALL.

Burkitt's lymphoma and Burkitt-like lymphoma — Burkitt's lymphoma (BL) and Burkitt-like lymphomas (BLL) in HIV-1 negative adults have been similarly treated with regimens designed for the pediatric populations, which involve the use of high doses of cyclophosphamide, cytosine arabinoside, and CNS prophylaxis with methotrexate. Patients who present with limited stage disease have an excellent prognosis, and may require less intensive chemotherapy. Unlike large cell lymphoma, there is no role for radiation therapy, even in localized disease. Although the complete remission rates are very high, the cure rate is generally less than that observed for DLBCL. In selected series, long-term survivals of 50 to 70 percent have been reported, although when bone marrow or CNS disease is present, long term survival ranges from 0 to 30 percent. An analysis of 65 adults treated with the LMB pediatric protocols reported a CR rate of 89 percent, with three year survival of 74 percent.

A series including 39 adults with diffuse small noncleaved cell lymphoma (the Working Formulation name for Burkitt's lymphoma) demonstrated very high response rates when a pediatric intensive chemotherapy regimen was used, particularly when systemic IVAC (ifosfamide, etoposide, high dose cytarabine and intrathecal methotrexate) was incorporated into the therapeutic program. Event-free survival at two years was as high as 92 percent in this series. Toxicity, mainly complications from prolonged neutropenia, was significant, but not fatal.

A shorter (six cycles) high-intensity treatment protocol, based upon a protocol for the treatment of adult B-cell ALL, has been reported by the Cancer and Acute Leukemia Group B (study 9251) in 75 adults with small noncleaved cell NHL or the L3 ALL variant. Treatment included one cycle of cyclophosphamide (CYT) and prednisone followed by alternating cycles including ifosfamide or CYT, high-dose methotrexate (MTX), vincristine, dexamethasone, either doxorubicin or etoposide/cytarabine, and triple intrathecal therapy (MTX, cytarabine, hydrocortisone) with or without CNS irradiation.

Complete remission was attained in 80 percent, with 52 percent alive and in continuous CR at a median follow-up of 5.1 years. All patients not achieving CR died of the disease, and all recurrences took place within 16 months of the end of treatment. Hematologic toxicity was profound and significant neurologic toxicity was present in 13 percent. The latter appears to have been reduced in frequency and severity by modifying the CNS irradiation and intrathecal therapy portions of the treatment protocol.

Future prospective trials will assess the relative efficacy of these different high-intensity regimens in adult BL and BLL. Currently, standard therapy for these histologies, even for older adults, must be more aggressive than CHOP chemotherapy, and must include adequate CNS prophylaxis.

Adult T-cell lymphoma/leukemiaThe prognosis of patients with adult T-cell lymphoma/leukemia (ATL) is poor, with a median survival of eight months and four-year survival of 12 percent when treated with regimens devised for advanced, aggressive NHL.

A Japan Clinical Oncology Group study enrolled 96 patients with ATL in a program which included seven cycles of treatment with vincristine, cyclophosphamide, doxorubicin, prednisone, ranimustine, vindesine, etoposide, and carboplatin. The overall response rate was 81 percent, with 36 percent complete remissions; median survival was 13 months, with estimated two- and four-year survivals of 31 and 21 percent, respectively. Toxicity was appreciable, with 82 and 53 percent of patients developing grade 4 neutropenia and thrombocytopenia, respectively. Only 24 patients were able to complete the entire protocol treatment program.

In one study, 15 patients with ATL, eight of whom were in partial or complete remission, were treated with interferon alfa and zidovudine. Median survival of the non-responders was six months, while 55 percent of the responders were alive at four years (p = 0.002).



For Stage IB (>10% body surface area) and higher, but not systemic involvement:

IFNa 3-5 million units TIW, given with PUVA therapy until skin lesions gone. Then stop IFN and continue PUVA monthly as maintenance. See UpToDate.


FLIPI (Follicular Lymphoma International Prognostic Index)
(Blood 104:1233)

Risk factors:
Age > 60
Stage 3+
Hb < 12
Nodal areas > 4
Elevated LDH

Low risk = 0-1 => 5YS 91%  10YS 71%
Inter risk = 2  => 5YS 78%  10YS 51%
High risk = 3+  => 5YS 53%  10YS 36%

HODGKIN’S DISEASE – General Comments

·  At ASH 2004 Diehl presented data suggesting that for early stage HD (I or II), it may be possible to reduce the number of chemo cycles and amount of radiation given. Four arm study gave ABVD x 4 + 30 Gy vs ABVD x 4 + 20 Gy vs ABVD x 2 + 30 Gy vs ABVD x 2 + 20 Gy. An interim analysis in Aug 2003 showed no difference in OS or time to treatment failure.

IPI and Age-Adjusted Indices for Aggressive NHL treated with Doxorubicin
(Blood 83:1165, 1998)

Risk factors:
Age > 60
LDH > normal
ECOG > 1
Stage 3-4
More than 1 extranodal site

Low risk = 0-1 -> 87% CR, 73% 5YS
Low-Int = 2  -> 67% CR, 51% 5YS
Hi-Int = 3 -> 55% CR, 43% 5YS
High = 4-5 -> 44% CR, 26% 5YS

Age-Adjusted IPI for age < 60 years:

LDH > normal
ECOG > 1
Stage 3-4

Low = 0 -> 92% CR, 83% 5YS
Low-int = 1 -> 78% CR, 69% 5YS
Hi-int = 2 -> 57% CR, 46% 5YS
High = 3 -> 46% CR, 32% 5YS