Lymphoma



Lymphoma


David K. Gaffney, MD, PhD


































































































ISCL/EORTC Revision to the Classification of Mycosis fungoides and Sézary Syndrome

From Olsen E et al: Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: A proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 110(6):1713-22, 2007.


TNM

Definitions


Skin


T1

Limited patches1, papules, &/or plaques2 covering < 10% of the skin surface; may further stratify into T1a (patch only) vs. T1b (plaque ± patch)


T2

Patches, papules, or plaques covering ≥ 10% of the skin surface; may further stratify into T2a (patch only) vs. T2b (plaque ± patch)


T3

1 or more tumors3 (≥ 1 cm diameter)


T4

Confluence of erythema covering ≥ 80% of body surface area


Node


N0

No clinically abnormal peripheral lymph nodes4; biopsy not required


N1

Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0-2

N1a

Clone negative5

N1b

Clone positive5


N2

Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3

N2a

Clone negative5

N2b

Clone positive5


N3

Clinically abnormal peripheral lymph nodes; histopathology Dutch grades 3-4 or NCI LN4; clone positive or negative


NX

Clinically abnormal peripheral lymph nodes; no histologic confirmation


Viscera


M0

No visceral organ involvement


M1

Visceral involvement (must have pathology confirmation6, and organ involved should be specified)


Peripheral Blood Involvement


B0

Absence of significant blood involvement: ≤ 5% of peripheral blood lymphocytes are atypical (Sézary) cells7

B0a

Clone negative5

B0b

Clone positive5


B1

Low blood tumor burden: > 5% of peripheral blood lymphocytes are atypical (Sézary) cells but does not meet the criteria of B2

B1a

Clone negative5

B1b

Clone positive5


B2

High blood tumor burden: ≥ 1,000/μL Sézary cells7 with positive clone5


1 “Patch” indicates any size skin lesion without significant elevation or induration. Presence/absence of hypo/hyperpigmentation, scale, crusting, &/or poikiloderma should be noted.
2 “Plaque” indicates any skin lesion that is elevated or indurated. Presence or absence of scale, crusting, &/or poikiloderma should be noted. Histologic features such as folliculotropism or large cell transformation (> 25% large cells), CD30(+) or CD30(-), and clinical features such as ulceration are important to document.
3 For skin, “tumor” indicates at least one 1 cm diameter solid or nodular lesion with evidence of depth &/or vertical growth. Note total number of lesions, total volume of lesions, largest size lesion, and region of body involved. Also note if histologic evidence of large cell transformation has occurred. Phenotyping for CD30 is encouraged.
4 For node, “abnormal peripheral lymph node(s)” indicates any palpable peripheral node that on physical examination is firm, irregular, clustered, fixed, or ≥ 1.5 cm in diameter. Node groups palpated include cervical, supraclavicular, epitrochlear, axillary, and inguinal. Central nodes, which are not generally amenable to pathologic assessment, are not currently considered in the nodal classification unless used to establish N3 histopathologically.
5 A T-cell clone is defined by PCR or Southern blot analysis of the T-cell receptor (TCR) gene.
6 For viscera, spleen and liver may be diagnosed by imaging criteria.7 For blood, Sézary cells are defined as lymphocytes with hyperconvoluted cerebriform nuclei. If Sézary cells are not able to be used to determine tumor burden for B2, then 1 of the the following modified ISCL criteria along with a positive clonal rearrangement of the TCR may be used instead: 1) Expanded CD4(+) or CD3(+) cells with CD4/CD8 ratio ≥ 10; 2) expanded CD4(+) cells with abnormal immunophenotype including loss of CD7 or CD26.












































































ISCL/EORTC Revision to the Staging of Mycosis fungoides and Sézary Syndrome

From Olsen E et al: Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: A proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 110(6):1713-22, 2007.


Stage

T

N

M

Peripheral Blood Involvement


IA

T1

N0

M0

B0, B1


IB

T2

N0

M0

B0, B1


IIA

T1, T2

N1, N2

M0

B0, B1


IIB

T3

N0-2

M0

B0, B1


III

T4

N0-2

M0

B0, B1

IIIA

T4

N0-2

M0

B0

IIIB

T4

N0-2

M0

B1


IVA1

T1-4

N0-2

M0

B2


IVA2

T1-4

N3

M0

B0-2


IVB

T1-4

N0-3

M1

B0-2



































Histopathologic Staging of Lymph Nodes in Mycosis fungoides and Sézary Syndrome

From Olsen E et al: Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: A proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 110(6):1713-22, 2007.


Updated ISCL/EORTC Classification

Dutch System

NCI-VA Classification


N1

Grade 1: Dermatopathic lymphadenopathy (DL)

LN0: No atypical lymphocytes


LN1: Occasional and isolated atypical lymphocytes (not arranged in clusters)


LN2: Many atypical lymphocytes or in 3-6 cell clusters


N2

Grade 2: DL; early involvement by MF (presence of cerebriform nuclei > 7.5 μm)

LN3: Aggregates of atypical lymphocytes; nodal architecture preserved


N3

Grade 3: Partial effacement of LN architecture; many atypical cerebriform mononuclear cells (CMCs)

LN4: Partial/complete effacement of nodal architecture by atypical lymphocytes or frankly neoplastic cells

Grade 4: Complete effacement














































St. Jude Staging System

From Murphy SB et al: Non-Hodgkin’ s lymphomas of childhood: An analysis of the histology, staging, and response to treatment of 338 cases at a single institution. J Clin Oncol. 7(2):186-93, 1989.


Stage

Definitions


I

A single tumor (extranodal) or single anatomic area (nodal), with the exclusion of mediastinum or abdomen


II

A single tumor (extranodal) with regional node involvement

≥ 2 nodal areas on the same side of the diaphragm

2 single (extranodal) tumors with or without regional node involvement on the same side of the diaphragm

A primary gastrointestinal tract tumor, usually in the ileocecal area, with or without involvement of associated mesenteric nodes only1


III

2 single tumors (extranodal) on opposite sides of the diaphragm

≥ 2 nodal areas above and below the diaphragm

All primary intrathoracic tumors (mediastinal, pleural, thymic)

All extensive primary intraabdominal disease1

All paraspinal or epidural tumors, regardless of other tumor site(s)


IV

Any of the above with initial central nervous system &/or bone marrow involvement2


1 A distinction is made between apparently localized gastrointestinal tract lymphoma and more extensive intraabdominal disease because of their quite different patterns of survival after appropriate therapy. Stage II disease typically is limited to 1 segment of the gut ± the associated mesenteric nodes only and the primary tumor can be completely removed grossly by segmental excision. Stage III disease typically exhibits spread to paraaortic and retroperitoneal areas by implants and plaques in mesentery or peritoneum, or by direct infiltration of structures adjacent to the primary tumor. Ascites may be present, and complete resection of all gross tumor is not possible.
2 If the marrow involvement is present initially, the number of abnormal cells must be ≤ 25% in an otherwise normal marrow aspirate with a normal peripheral blood picture.








Typical centroblasts image are large, noncleaved with vesicular chromatin, and have membrane-bound nucleoli. Reactive small lymphocytes are also present image. DLBCL are CD20(+), CD3(-), CD5(-), and CD45(+). (Courtesy F. Vega, MD, PhD.)






The architecture is replaced by neoplastic follicles composed of numerous centroblasts. In this neoplastic follicle, mitotic figures image and tingible body macrophages image are seen. No small centrocytes are noted. FL are CD20(+), CD3(-), CD10(+), and CD5(-). (Courtesy C. C. Yin, MD, PhD.)






Neoplastic monocytoid (pale) cells expand interfollicular areas image. Two residual germinal centers are present image; one is nearly replaced by the neoplasm while the other shows marked follicular colonization by the neoplastic cells. Marginal zone lymphomas are CD20(+), CD3(-), CD10(-), CD5(-), and CD23(-). (Courtesy P. Lin, MD.)






This entity is histologically the same as chronic lymphocytic leukemia. The lymph node proliferation center is composed of small lymphocytes, prolymphocytes image, and paraimmunoblasts image. (Courtesy C. E. Bueso-Ramos, MD.)







The plaque stage of mycosis fungoides (MF) shows the presence of a Pautrier microabscess image containing small atypical tumor cells. MF shows an elevated CD4/CD8 ratio, +/- clonal T cell gene receptor rearrangement, and frequent depletion of CD2, CD3, CD5, and CD7 positive cells. (Courtesy S. A. Wang, MD.)






High-power view shows Reed-Sternberg (RS) cells with retraction artifact of cytoplasm as an empty or lacunar space. Hence, these cells are known as lacunar cells. An example of an “owl’s eye” cell image is shown. Hodgkin lymphoma is CD15(+) and CD30(+). (Courtesy C. C. Yin, MD, PhD.)






Reed-Sternberg cells image are numerous and pleomorphic, and small lymphocytes are depleted. (Courtesy C. C. Yin, MD, PhD.)






This H&E of NLPHL shows various morphologic appearances of LP cells, including “popcorn” cells image and one with a prominent nucleolus image, similar to the RS cells of classic Hodgkin lymphoma.







Graphic shows multiple malignant left axillary lymph nodes (LNs) image. Stage I is defined as involvement of a single lymphatic site (i.e., nodal region, Waldeyer ring, thymus, or spleen) (I) or localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE).






Graphic shows nodal disease image above the diaphragm. Stage II is confined to one side of the diaphragm; it may involve 2 or more LN groups or localized involvement of a single extralymphatic organ or site in association with regional LN involvement with or without involvement of other LN regions (IIE).






Graphic shows multiple LN groups above image and below image the diaphragm. Stage III is defined as involvement of the LN regions on both sides of the diaphragm, which may also be accompanied by extralymphatic extension in association with adjacent LN involvement (IIIE) or by involvement of the spleen (IIIS) or both.






Graphic shows liver involvement image and multiple LN groups above image and below image the diaphragm. Stage IV is diffuse involvement of 1 or more extralymphatic organs, ± associated LN involvement, or isolated extralymphatic organ involvement in the absence of adjacent regional LN involvement, but with distant disease.







Coronal graphic shows multiple infiltrative lesions image within the right hemipelvis, compatible with lymphoma. Osseous involvement with lymphoma is considered stage IV disease.






Coronal graphic shows 2 patterns of renal involvement with lymphoma, which may present in a multifocal pattern image or as a single, large, often infiltrating mass image. Diffuse involvement of an extralymphatic organ is considered stage IV disease.



OVERVIEW


General Comments



  • Lymphoma: Neoplastic disease of lymphocytes with heterogeneous characteristics



    • Clonal expansion of lymphocytes



      • B cells


      • T cells


      • NK cells


  • Non-Hodgkin lymphoma (NHL) represents 85% of all malignant lymphomas


  • NHL, compared to Hodgkin lymphoma, is more likely to disseminate extranodally


Classification



  • Lymphoma broadly divided into 2 groups



    • Hodgkin lymphoma (HL)


    • NHL


  • Primary malignant tumors (WHO classification)



    • B-cell neoplasms



      • Peripheral (mature) B-cell neoplasms



        • Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)


        • B-cell prolymphocytic leukemia


        • Lymphoplasmacytic lymphoma


        • Splenic marginal zone lymphoma


        • Hairy cell leukemia


        • Plasmacytoma/multiple myeloma including solitary plasmacytoma of bone and extraosseous plasmacytoma


        • Extranodal marginal zone B-cell lymphoma, also called mucosa-associated lymphoid tissue (MALT) lymphoma (MALToma)


        • Nodal marginal zone B-cell lymphoma


        • Follicular lymphoma, grades 1-3


        • Mantle cell lymphoma


        • Diffuse large B-cell lymphoma (DLBCL)


        • Mediastinal (thymic) large cell lymphoma


        • Intravascular large B-cell lymphoma


        • Primary effusion lymphoma


        • Burkitt lymphoma/leukemia


    • Immunodeficiency-associated lymphoproliferative disorders



      • Associated with a primary disorder, HIV, methotrexate


      • Post transplant


      • Primary CNS lymphoma most often but not exclusively associated with AIDS


    • T-cell and NK-cell neoplasms



      • Precursor T-cell lymphoblastic leukemia/lymphoma


      • Peripheral (mature) T-cell neoplasms



        • T-cell prolymphocytic leukemia


        • T-cell large granular lymphocytic leukemia


        • Aggressive NK-cell leukemia


        • Adult T-cell leukemia/lymphoma


        • Extranodal NK-/T-cell lymphoma, nasal type


        • Enteropathy-type T-cell lymphoma


        • Hepatosplenic T-cell lymphoma


        • Blastic NK lymphoma


        • Subcutaneous panniculitis-like T-cell lymphoma


        • Mycosis fungoides/Sézary syndrome


        • Primary cutaneous anaplastic large cell lymphoma


        • Peripheral T-cell lymphoma, not otherwise specified (NOS)


        • Angioimmunoblastic T-cell lymphoma


        • Anaplastic large cell lymphoma


    • Hodgkin lymphoma, NOS



      • Nodular lymphocyte-predominant Hodgkin disease (NLPHD) (5%)


      • Classical Hodgkin lymphoma (95%)



        • Nodular sclerosis (only type more common in women than men)


        • Lymphocyte rich


        • Lymphocyte depleted


        • Mixed cellularity


NATURAL HISTORY


General Features



  • Comments



    • NHL



      • Diverse neoplasms with differing prognoses



        • B-cell lymphomas (90%)


        • T-cell lymphomas (10%)


      • More often involving extranodal sites than HL


    • Hodgkin lymphoma



      • Reed-Sternberg (RS) cells comprise minority of the tumor mass


      • Contiguous nodal involvement in central sites is most common


  • Location



    • B-cell lymphomas arise from the lymph node follicles


    • T-cell lymphomas arise in the paratrabecular region of lymph nodes


Etiology



  • Risk factors



    • Immunodeficiency states


    • Epstein-Barr virus (EBV) is associated with African Burkitt lymphoma and some AIDS-associated lymphomas


    • Human T-lymphotropic virus type 1 (HTLV-1) associated with aggressive T-cell leukemia/lymphoma


    • H. pylori associated with gastric MALTomas


    • Chlamydia psittaci associated with orbital MALTomas


Epidemiology & Cancer Incidence



  • Number of cases in USA per year



    • NHL



      • 70,130 estimated new cases of NHL with 18,940 deaths in 2012


      • 7th highest incident cancer in men and women


      • 9th cause of cancer death in men and 7th cause of cancer death in women


      • Probability of NHL from birth to death



        • Males: 1 in 43


        • Females: 1 in 51


  • Sex predilection



    • Males > females


  • Age of onset



    • NHL median age 67; HL has bimodal peak at 30 and 70 years of age


Genetics



  • Common translocations




    • t(14;18), t(11;14), and some t(8;14) probably occur in primitive B cells in the marrow


    • Immunoglobulin gene rearrangements occur in B-cell neoplasms


    • T-cell receptor gene rearrangements occur in T-cell neoplasms


    • DLBCL



      • BCL6 mutations, t(14;18), and others


    • Follicular lymphomas



      • t(14;18) causes dysregulation of BCL2 and blocks apoptosis


    • Mantle cell lymphoma



      • BCL1 mutations, t(11;14)


    • Lymphoplasmacytic lymphoma



      • PAX5/IgH mutations, t(9;14)


    • Marginal zone lymphoma



      • AP12/MLT mutations, t(11;18)


    • Burkitt lymphoma



      • c-MYC translocations, t(8;n)


    • Anaplastic large cell lymphoma



      • NPM/ALK mutations, t(2;5)


Associated Diseases, Abnormalities



  • NHL: 8% of patients have an autoimmune disease


  • HL: 9% of patients have or develop an autoimmune disease



    • Most common are Sjögren syndrome, thyroiditis, polymyositis, scleroderma, and glomerulonephritis


    • Paraneoplastic neurologic manifestations in HL include subacute cerebellar degeneration, limbic encephalitis, subacute necrotic myelopathy, and subacute motor neuropathy


Gross Pathology & Surgical Features



  • Heterogeneous gross pathologies vary among subtypes of NHL


  • Hepatosplenomegaly depending on histology


Microscopic Pathology



  • H&E



    • Histological findings are heterogeneous in NHL, with morphology varying among subtypes


    • Both low- and high-power views are important to assess nodal architecture


  • Special stains



    • Immunohistochemistry is essential: B- &/or T-cell markers may be expressed depending on subtype


    • Flow cytometry often valuable


    • Cytogenetics often valuable


    • Molecular studies growing in importance


Routes of Spread



  • Local spread



    • Large mediastinal masses may invade chest wall, pericardium, or other thoracic structures


  • Lymphatic extension



    • NHL typically spreads to noncontiguous lymph nodes, leading to widely disseminated pattern of nodal involvement



      • Stages III and IV more common than stages I and II


      • NHL commonly spreads to extranodal sites


    • Hodgkin lymphoma typically spreads to contiguous lymph nodes, leading to pattern of nodal spread within same region



      • Stages I and II more common than stages III and IV


      • Rarely spreads to extranodal sites


  • Metastatic sites



    • Common sites include



      • Spleen


      • Liver


      • Bone


      • Kidney


IMAGING


Detection



  • General



    • Choice of modality often depends on specific factors, such as anatomic location



      • Often palpable abnormality, such as lymphadenopathy, may be initially evaluated with CT


    • Lymphoma is frequently a systemic disease; patients are routinely evaluated with CT or PET/CT



      • Initial evaluation most often includes axial coverage from skull base through pelvis


  • Ultrasound



    • Useful modality in initial evaluation of NHL for directing/guiding interventional diagnostic procedures


    • Evaluation of anatomic sites located superficially (i.e., neck, breast, axilla, extremities)


    • Will often see multiple, bilateral, nonnecrotic enlarged nodes



      • Despite large lymph node size, cystic necrosis is uncommon


    • Can also be used in assessment of spleen and kidneys



      • Right kidney may be imaged better than left kidney


  • Radiograph



    • Fairly limited in overall assessment with some exceptions, such as pulmonary NHL


    • Cavitating lesions may mimic tuberculosis


    • Because radiographic features are nonspecific, can be confused for variety of other processes, particularly infectious etiologies


  • Mammography



    • Can detect primary or metastatic NHL of breast



      • Primary lymphoma of breast is uncommon


    • Breast involvement appears as solitary mass without calcification



      • May also present with multiple masses, which makes differentiation of primary disease from metastatic disease impossible


      • Margins may be distinct or indistinct


  • CT



    • NECT



      • Cannot distinguish etiology of enlarged lymph nodes on NECT and CECT


      • Can detect diffusely enlarged spleen but may miss focal lesions without contrast enhancement


    • CECT



      • Optimal modality for detection in addition to FDG PET (PET/CT)


      • Will more accurately depict lesions that may be missed on NECT, particularly when there is organ involvement


      • Typically, portal venous phase of imaging is sufficient



    • Primary modality for overall evaluation of lymphoma


    • Primary head and neck extranodal lymphoma



      • NHL imaging findings may be identical to squamous cell carcinoma of pharyngeal mucosal space



        • Can arise from tonsils, mandible, hard palate, nasopharynx, parotid glands, nasal cavity, paranasal sinuses, pharynx, larynx, thyroid gland, and ocular adnexa


        • Most common sites of occurrence in pharyngeal mucosal space: Faucial (palatine) tonsil > nasopharyngeal adenoids > lingual tonsil (i.e., Waldeyer ring)


      • Accounts for up to 20% of all NHL cases


    • Thoracic lymphoma



      • CT and radiographs are primary modalities for evaluation of chest involvement


      • Radiologically, appearance of intrathoracic involvement in NHL may be similar to that of HL


      • Unlike HL, NHL is relatively evenly distributed in all mediastinal compartments, and posterior mediastinal lymphadenopathy is relatively common


      • CT can be used to evaluate for possible superior vena cava syndrome


    • CT is also used to evaluate abdomen, pelvis, genitourinary tract, and gastrointestinal tract


  • MR



    • Indicated for CNS imaging


    • Otherwise used as problem-solving tool


  • PET/CT



    • Can be used for initial diagnosis or detection of lymphoma



      • For example, in patients with retroperitoneal adenopathy not easily accessible by percutaneous means


      • PET may be falsely negative for some cell types such as MALT, mantle cell lymphoma, and small lymphocytic lymphoma


    • Optimally performed with contrast-enhanced CT as part of exam


    • Increasingly important as an early response indicator to therapy


  • Nuclear medicine



    • In general, PET/CT has replaced gallium-67 (Ga-67) for evaluating patients with lymphoma


    • Ga-67 sensitivity



      • Higher for more common histologic subtypes of low-grade NHL than for rare types


      • About equivalent for HL and high-grade NHL


  • Image-guided FNA



    • Often CT- or ultrasound (US)-guided



      • With sufficient sample, sensitivity and specificity > 90-95% may be achieved


      • In certain diagnostic settings, core biopsy or open resection may be preferred to evaluate nodal architecture


    • Residual masses



      • Open procedures may be preferred over percutaneous procedure



        • Fibrotic tissue increases likelihood of false negatives


Staging

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Jun 1, 2016 | Posted by in ONCOLOGY | Comments Off on Lymphoma

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