Multisystem Diseases

1. Multisystem Diseases Sharon H. de Kock September 2012

2. LYMPHOID NEOPLASM • Lymphomas arise from the constituent cells of the immune system or from their precursors and are the consequence of genetic aberrations that impair proliferation, differentiation, and ability to undergo apoptosis of lymphatic cells.

3. ORIGIN OF LYMPHOID NEOPLASMS

4. WHO CLASSIFICATION

5. EPIDEMIOLOGY •  Hodgkin disease (HD) and non-Hodgkin lymphomas (NHLs) constitute 10%–15% of all childhood cancers in developed countries and are third in frequency after acute leukemias and brain tumors. • Non-Hodgkin lymphoma (NHL) is the mostcommon type of lymphoma. Although there are more than 50 types of NHL, diffuse large B-cell lymphoma (DLBCL) is the most common type, making up about 30 percent of all lymphomas. • DLBCL affects about 7 out of 100,000 people each year.

6. EPIDEMIOLOGY cont. • HD has a bimodal age distribution: peak in 20-30 yr age grp and the second smaller peak after 50 yrs. • NHDincreases exponentially with age after 20 yrs. • NHLs are twice as frequent in male children as in females. • The subtypes of lymphoma differ in frequency between the adult and paediatric grps, a strong bias towards precursor B- and T- lymphoblastic and Burkitt lymphoma in childhood. • Higher frequencies in whites than blacks or Asians.

7. EPIDEMIOLOGY cont. • Risk is higher with a positive family history. • Oncogeniclymphotrophic DNA and RNA viruses have been implicated in many NHL types. • Most important agent EBV, trigger lymphoma in congenital immuno-defiencies, iatrogenicallyimmuno-suppressed organ transplant recipients, pts receiving maintenance chemotherapy and immuno-suppressive therapy for collagen disorders. • Also the retrovirus human lymphotrophic virus type 1 (HTLV-1) and human herpes virus 8 (HHV-8)

8. EPIDEMIOLOGY cont. • Bacterial overgrowth can also promote lymphomagenesis. Helicobacter pylori has been shown to be necessary for the development of gastric lymphoma.

9. PATHOLOGY • The Reed-Sternberg cell is the malignant cell in HD: Its identification, against the appropriate background of inflammatory cells and fibrosis, is required to make the diagnosis of HD. • Four histologic subtypes of HD are described: lymphocytic predominance (5%), mixed cellularity(20-25%), lymphocytic depletion (<5%) and nodularsclerosis (70%). •  In nodular sclerosis fibroblastic activity results in segmentation of involved LNs into cellular nodules separated by thick bands of collagen.

10. PATHOLOGY cont. • NHLs typically arise from primitive cell lines. • Categorised according to histological distribution of lymphomatous cells- * Nodular form organised in clusters. * Diffuse form distortion of tissue architecture.

11. STAGING Cotswolds staging classification for Hodgkin lymphoma Stage I - Involvement of a single lymph node region (eg, cervical, axillary, inguinal, mediastinal) or lymphoid structure such as the spleen, thymus, or Waldeyer's ring. Stage II - Involvement of two or more lymph node regions or lymph node structures on the same side of the diaphragm. Hilar nodes should be considered to be "lateralized" and when involved on both sides, constitute stage II disease. For the purpose of defining the number of anatomic regions, all nodal disease within the mediastinum is considered to be a single lymph node region, and hilar involvement constitutes an additional site of involvement. The number of anatomic regions should be indicated by a subscript (eg, II-3). Stage III - Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm. This may be subdivided stage III-1 or III-2: stage III-1 is used for patients with involvement of the spleen or splenic-hilar, celiac, or portal nodes; and stage III-2 is used for patients with involvement of the para-aortic, iliac, inguinal, or mesenteric nodes. Stage IV - Diffuse or disseminated involvement of one or more extra-nodalorgans or tissue beyond that designated E, with or without associated lymph node involvement.

12. STAGING cont. • All cases are sub-classified to indicate the absence (A) or presence (B) of the systemic symptoms of significant unexplained fever, night sweats, or unexplained weight loss exceeding 10 percent of body weight during the six months prior to diagnosis. • The designation "E" refers to extra-nodal contiguous extension (ie, proximal or contiguous extra-nodal disease) that can be encompassed within an irradiation field appropriate for nodal disease of the same anatomic extent. More extensive extra-nodal disease is designated stage IV. • The subscript "X" is used if bulky disease is present. This is defined as a mediastinal mass with a maximum width that is equal to/ greater than one-third of the internal transverse diameter of the thorax at the level of T5/6 interspace or >10 cm max dimension of a nodal mass. No subscripts are used in the absence of bulk.

13. STAGING cont. Patients can be clinically or pathologically staged. Splenectomy, liver biopsy, lymph node biopsy, and bone marrow biopsy are mandatory for the establishment of pathological stage. The pathologic stage at a given site is denoted by a subscript (eg, M = bone marrow, H = liver, L = lung, O = bone, P = pleura, and D = skin). • The Ann Arbor staging system with Cotswolds modifications. • Data from Lister TA, Crowther D, Sutcliffe SB, et al, J ClinOncol 1989; 7:1630.

14. St Jude staging of NHL in children

15. PET scans illustrate the classification of specific cases of NHL according to the Ann Arbor staging system.

16. CLINICAL • HD usually present with painless cervical or, less frequently, supra-clavicularlymphadenopathy. • More rarely, inguinal or axillarylymphadenopathy is the first presenting sign. • At diagnosis, at least two-thirds of pts have some degree of mediastinal involvement, which may cause compression of the trachea and bronchi.  • Fatigue, weight loss, fever, pruritus and drenching night sweats may be associated.

17. CLINICAL cont. • In children with NHLs, the clinical presentation is much more often extra-nodal than in adults, the most frequently involved sites being intra-abdominal and intra-thoracic. • Acute abdomen with symptoms mimicking those of acute appendicitis is a relatively frequent. • Intussusceptionresulting from the intra-luminal projection of a small tumoral mass is also not unusual.  •  In the abdomen, urinary tract obstruction, obstructive jaundice & pancreatitis, bowel obstruction, IVC compression and GIT bleeding may be observed. 

18. CLINICAL cont. • As lymphomas can involve almost any organ in the body, the differential diagnosis is enormous. • Therefore, lymphoma should be considered in the differential diagnosis of any puzzling lesion.

19. PROGNOSIS • Of HD depends on age (poorer if older); tumour subtype; raised ESR; multiple sites of disease; bulky mediastinal disease; B symptoms. • Of NHD depends on subtype; age >60 yrs; elevated LDH; poor general health status; advanced stages III or IV disease; more than one involved extra-nodal disease site.

20.  International Prognostic Index (IPI) for DLBCL • Gives 1 point for each of the above characteristics, total score ranging from 0-5, representing three risk groups: • Low risk — IPI score of 0 or 1 (91 percent of people in this risk group are still alive at three years) • Low to intermediate risk — IPI score of 2 (81 percent of people in this risk group are still alive at three years) • High to intermediate risk — IPI score of 3 (65 percent of people in this risk group are still alive at three years) • High risk — IPI score of 4 or more (59 percent of people in this risk group are still alive at three years)

21. TREATMENT • The main treatments for Hodgkin lymphoma are chemotherapy and radiation. • Most treatments involve a combination of several chemotherapy drugs. • ABVD includes Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine. ABVD is the most commonly used chemotherapy regimen. • The most common treatment-related side effects include temporary hair loss, nausea, vomiting, fatigue, loss of appetite, increased risk of infections, becoming bruised or bleeding easily.

22. TREATMENT cont. • Long-term side effects of chemotherapy include infertility, lung damage, secondary cancer. • Radiation therapy is directed to the area of affected lymph nodes with a carefully focused beam of radiation. • Side effects include skin changes, fatigue, nausea. • Hematopoietic stem cell transplantation might be offered to people who have recurrent or resistant Hodgkin lymphoma.

23. TREATMENT cont. • The standard treatment of advanced DLBCL is combination chemotherapy plus immunotherapy. • The most common chemotherapy regimen for advanced DLBCL is called R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. • Side effects of chemotherapy- fever, low blood count, nausea & vomiting, hypersensitivity reaction, tumorlysis syndrome, also cardio- & neurotoxicity, infertility.

24. TREATMENT cont. • Patients with localized disease may be treated with fewer cycles (usually three cycles) of R-CHOP chemotherapy in combination with radiation therapy to the involved area. • Radiologic imaging test is recommended, six to eight weeks after finishing chemotherapy or 12 weeks after finishing radiation therapy. • The number of CT scans should be limited, particularly in younger individuals, to limit radiation exposure and the risk for second cancers.

25. IMAGING: NODAL DISEASE • Size is the criterion by which LNs demonstrated on CT & MRI are considered to be involved. • Clustering of multiple small LNs in mediastinum or mesentery is suggestive. • Max short-axis diameter of 10mm is upper limit of normal, depending of the exact site. • Portahepatis & pelvis LNs >8mm, retro-crural LNs >6mm & jaw angle LNs >13mm are regarded as abnormal. • When LNs are present in splenichilum, pre-sacral & peri-rectal, abnormal whatever the size.

26. IMAGING: NODAL DISEASE cont. • Enlarged LNs in HD & NHL are usually homogenous & of soft tissue density on CT, may show uniformenhancement post IV contrast administration. • Calcifications uncommon, usually post-treatment. • Necrosis rarely seen, more frequently post-treatment. • On MRI LNs are low – intermediate signal intensity on T1WI, intermediate to high signal intensity on T2WI & very high signal intensity on STIR images. • Heterogeneous signal intensity on MRI & - enhancement on CT, associated with worse outcome.

27. CHOICE OF IMAGING TECHNIQUE • CT is imaging of choice for staging and f/u. Demonstrate enlarge LNs throughout the body & detect associated lesions in soft tissue structures. • Main value of u/s is in confirming that a palpable mass is nodal. • MRI is equal in accuracy to CT in detecting LN involvement, no particular advantage over CT.

28. CHOICE OF IMAGING TECHNIQUE •  PET with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) is helpful in the evaluation of tumour metabolism, also of cellular biochemical processes through molecular imaging. • FDG PET is important in both the primary diagnosis and the evaluation of therapy in lymphoma. •  FDG PET is highly sensitive and specific for the common types of lymphoma (eg, DLBCL). • FDG-PET is accurate in depiction of nodal & extra-nodal disease, more sensitive than Ga-67. Results in clinically significant upstaging in 10-20% of pts.

29. CHOICE OF IMAGING TECHNIQUE •  After the completion of chemo– & radiation therapy, to distinguish between residual tumor or fibrotic tissue may be difficult, but PET/CT allow more accurate diagnosis than MR imaging or CT in these pts. • Some diagnostic pitfalls are encountered at FDG PET. However, anatomic CT helps localize and define disease and avoid these potential pitfalls-

30. PITFALLS OF FDG PET • Lesions in gastric and cerebral lymphoma due to physiologic gastric & cortical accumulation of FDG.  • FDG uptake in the mediastinum may lead to false-positive PET findings. • FDG uptake is observed in lymph nodes with sarcoid involvement.  • Physiologic colonic uptake may be mistaken for lymphoma. • Small-volume lesions may be undetectable.

31. DIAGNOSTIC STEPS OF LYMPHOMA IN CHILDREN

32. LN IMAGING OF THE NECK • 60-80% of pts with HD presents with cervicallymphadenopathy. • Spread most frequently to contiguous nodal grps. • Involvement of internal jugular chain first, than deep lymphatic chains, supra-clavfossa & axillae. • Pts with supra-clav or bilateral neck adenopathy are at increased risk of infra-diaphragmatic dx. • Cervical adenopathy is less common in NHL, although involved LNs may be much larger. • Involved LN-groups tend to be non-contiguous.

33. U/S of cervical LN with lymphomatous infiltration .Power Doppler shows distorted vasculature. HD.

34. Hypo-echoic cervical LN mass, tendency to aggregate. HD.

35. Coronal FDG PET scan shows bulky masses with increased uptake in neck & left axillary region. HD.

36. Axial pre-treatment FDG PET/CT image shows masses with increased uptake in the supraclavicular region. Post-treatment FDG PET/CT image. HD.

37. LN IMAGING OF THE THORAX • 60-85% of pts with HD and 25-40% with NHL have LNs in the thorax with presentation. • Frequency of nodal involvement in HD- *pre-vascular & para-tracheal 84%; *hilar 28%; *sub-carinal 22%. • Ao-pulm window; ant diaphragmatic grp; internal mammary & post mediastinalgrp account for about 5% of involved nodal grps. • In NHL involvement of hilar (9%) & sub-carinal (13%) LN grps is rarer, sup mediastinal LNs in 35%.

38. LN IMAGING OF THE THORAX cont. • Post mediastinum is in-frequently involved. • If dx is present in the lower part of the mediastinum, contiguous retro-cruraldx is likely. • In HD & NHL large ant mediastinal masses usually represents thymic infiltration as well as a nodal mass. • Large ant mediastinal mass in HD is an adverse prognostic feature. • 10% of pts with HD, CT will show mediastinal LN enlargement despite a normal CXR, these pts also have a poorer prognosis.

39. LN IMAGING OF THE THORAX cont. • CT of the chest will change stage & alter management in up to 25% of pts with HD, therapeutic impact is less in pts with NHL.

40. CXR shows mediastinallymphadenopathy. NHL.

41. CECT Chest shows mediastinal mass on RT with compression on trachea & displaced vessels. HD.

42. CECT Chest shows ant mediastinal mass originating fron the thymus. NHL.

43. TEACHING POINTS • In children with HD, a residual mediastinal mass may be present in as many as 88% of patients after completion of therapy; it is usually benign and is typically composed of areas of necrosis, fibrosis, and inflammation. • In HD, recurrent enlargement of the thymus—the so-called thymic rebound—is typically observed within 6–12 months after suspension of therapy in 25% of affected children.

44. LN IMAGING OF THE ABDOMEN AND PELVIS • At presentation retro-peritoneal LNs are involved in 25-35% of pts with HD & 45-55% with NHL. • Mesenteric LNs are involved in >50% of pts with NHL, <5% of HD pts. • Portahepatis & splenichilum LNs also less frequent involved in HD than NHL. • In HD nodal spread is from one LN group to the other, nodes are frequently of normal size or minimal enlarged. • Spread from the mediastinum through lymphatic vessels to retro-crural LNs, celiac axis, etc.

45. LN IMAGING OF THE ABDOMEN AND PELVIS cont. • Splenichilar nodal involvement is almost always associated with diffuse splenic infiltration. • In NHL nodal involvement is frequently non-contiguous & bulky & associated with extra-nodal dx. • Discrete mesenteric nodal enlargement or masses. • Hamburger sign- loop of bowel is compressed between two large nodal masses. • In pts with massive pelvic dx, MRI is helpful for delineating the full extend of tumour & effect on adjacent organs.

46. Abdominal U/S shows hypo-echoic LN mass. NHL.

47.  CECT scan shows the large lymphomatous mass encasing the mesenteric vessels. NHL.

48. CECT Abdomen, Rt renal artery passes through a para-aortic LN mass (sandwich sign). NHL.

49. Coronal PET scan shows enlarged para-aortic and supra-clavicular lymph nodes. NHL.

50. RECIST • Response Evaluation Criteria in Solid Tumours. • Need of consistent, reproducible, objective & standardized response criteria. • “Common Language”