Hodgkin's

Question 1

The presenting signs and symptoms of HL are not distinguishable from NHL, for the most part.

B-symptoms (fever, night sweats, weight loss) are a bit more pronounced in ____ cases.

An occasional HL patient will report pain at the sight of HL following the ingestion of even minimal amounts of ______

Patients typically present with progressive ____________, usually in the neck and/or chest (mediastinum). HL tends to spread in a________ fashion from one lymph node group to its neighbor – in contrast to NHL, which can spread

Answer 1

The presenting signs and symptoms of HL are not distinguishable from NHL, for the most part.

B-symptoms (fever, night sweats, weight loss) are a bit more pronounced in HL cases.

An occasional HL patient will report pain at the sight of HL following the ingestion of even minimal amounts of alcohol.

Patients typically present with progressive lymphadenopathy, usually in the neck and/or chest (mediastinum).

HL tends to spread in a sequential fashion from one lymph node group to its neighbor – in contrast to NHL, which can spread to/from any LN at any time.

Question 2

Hodgkin’s lymphoma makes up ~____% of new hematologic malignancy diagnoses each year, outnumbered 8:1 by __________

Nearly 8200 new cases are expected in the US in 2007, 90% of which occur between the ages of 16 and 65 – as opposed to NHL where probably half of cases occur over age 65.

There is a________distribution in the incidence of HL with one peak in the early 20’s and another in the early 60’s.

Answer 2

Hodgkin’s lymphoma makes up ~6% of new hematologic malignancy diagnoses each year, outnumbered 8:1 by Non-Hodgkin’s Lymphoma.

Nearly 8200 new cases are expected in the US in 2007, 90% of which occur between the ages of 16 and 65 – as opposed to NHL where probably half of cases occur over age 65.

There is a bimodal distribution in the incidence of HL with one peak in the early 20’s and another in the early 60’s.

Question 3

The incidence of HL appears increased with higher/lower socio-economic status.

Answer 3

The incidence of HL appears increased with higher socio-economic status.

The reasons for this are unknown although it is thought that cloistered / sheltered rich kids are not exposed to as many germs as the “other half” and that their immune systems remain over-primed, itching for something to do like transform to lymphoma. Genetics play a role as well (rich parents having rich kids…)

Question 4

The incidence of hodgkin’s is increased in patients who are chronically __________– HIV, organ transplant recipients, etc.

Answer 4

The incidence is increased in patients who are chronically immunosuppressed – HIV, organ transplant recipients, etc.

It is likely that immunosuppression leads to failure to respond to acute viral infection and/or a failure to recognize cells which are chronically infected and displaying viral antigens. These cells would be eliminated in those with normal immune systems and never lead to lymphomagenesis.

Question 5

_____virus has been associated with the development of some cases of HL. Viral DNA sequences are contained in ~1/2 of RS cells. A 3-4 fold increase in risk has been noted in the following infection.

Answer 5

Epstein-Barr virus has been associated with the development of some cases of HL. Viral DNA sequences are contained in ~1/2 of RS cells. A 3-4 fold increase in risk has been noted following EBV infection.

Question 6

Mechanistically, two proteins coded by the _________ genome mimic B-cell cell surface proteins and when expressed on the cell surface provide inappropriate activation and survival signals.

Presumably these proteins can rescue (ie keep alive) a B-cell with a __________Ig gene rearrangement. Once a B-cell rearranges immunglobulin, some of the Ig is expressed on the surface of the cell as a surface receptor and provides survival signals to the cell. If a B-cell can’t make an Ig, it will not get the___________reinforcement from the surface receptor and will undergo__________.

The EBV LMP1&2 affects this mechanism by

Answer 6

Mechanistically, two proteins coded by the EBV genome mimic B-cell cell surface proteins and when expressed on the cell surface provide inappropriate activation and survival signals.

Presumably these proteins can rescue (ie keep alive) a B-cell with a non-productive Ig gene rearrangement. Once a B-cell rearranges immunglobulin, some of the Ig is expressed on the surface of the cell as a surface receptor and provides survival signals to the cell. If a B-cell can’t make an Ig, it will not get the positive reinforcement from the surface receptor and will undergo apoptosis.

The EBV LMP1&2 short circuit this natural weeding out of nonproductive B-cells.

Question 7

The diagnosis of Hodgkin’s Lymphoma requires a substantial piece of tissue because the diagnosis depends in part on the ability to identify the infrequent diagnostic cells _____________and to documentation of the proper cellular background / proper context for the malignant cells.

For this reason, a _________ is preferred when ever possible, a fine needle aspirate is never sufficient.

Answer 7

The diagnosis of Hodgkin’s Lymphoma requires a substantial piece of tissue because the diagnosis depends in part on the ability to identify the infrequent diagnostic cells (Reed-Sternberg cells) and to documentation of the proper cellular background / proper context for the malignant cells.

For this reason, a open biopsy is preferred when ever possible, a fine needle aspirate is never sufficient.

Question 8

R-S cells are multinucleated______ cells. They are the malignant cell in _____, but may make up only a very small proportion of the total cells in a biopsy specimen, the remaining cells are reactive.

The cell of origin was long debated until shown to have rearrangement of _______ gene, demonstrating B-cell commitment. Unlike the malignant cells in NHL, R-S cells do not express CD___, rather CD15 and CD30 are characteristic.

Answer 8

R-S cells are multinucleated giant cells. They are the malignant cell in HD, but may make up only a very small proportion of the total cells in a biopsy specimen, the remaining cells are reactive.

The cell of origin was long debated until shown to have rearrangement of IgH gene, demonstrating B-cell commitment. Unlike the malignant cells in NHL, R-S cells do not express CD20, rather CD15 and CD30 are characteristic.

Question 9

Hodgkin’s Lymphoma is divided into 2 types, Classical and Non-classical.

The Classical type is further sub-divided into 4 sub-types.

Treatment for Classical Hodgkin’s is the same/different for all 4 subtypes.

There are no associated genetic mutations.

1) the most common subtype – represents 60 – 80% of cases, presents in younger patients, most commonly women with mediastinal mass, contains predominantly pleomorphic malignant R-S cells.
2) the second most common (15-30%), contains RS cells with large admixture of inflamatory cells - B- and T-cells, plasma cells and eosinophils; patients tend to be older with male predominance.
3) contains high numbers of mature B-lymphocytes – in contrast to NHL, these lymphocytes are polyclonal / reactive.
4) a rare an aggressive clinical course

Answer 9

Hodgkin’s Lymphoma is divided into 2 types, Classical and Non-classical.

The Classical type is further sub-divided into 4 sub-types.

Treatment for Classical Hodgkin’s is the same for all 4 subtypes, differences between subtypes in terms of response to therapy are minimal.

There are no associated genetic mutations.

1) Nodular Sclerosis (NS) which is most common subtype – represents 60 – 80% of cases, presents in younger patients, most commonly women with mediastinal mass, contains predominantly pleomorphic malignant R-S cells.
2) Mixed cellularity is second most common (15-30%), contains RS cells with large admixture of inflamatory cells - B- and T-cells, plasma cells and eosinophils; patients tend to be older with male predominance.
3) Lymphocyte rich which contains high numbers of mature B-lymphocytes – in contrast to NHL, these lymphocytes are polyclonal / reactive.
4) Lymphocyte depleted-a rare an aggressive clinical course

Question 10

Non-classical N: is comprised of a single sub-type, _________ lymphocyte predominant which has a distinct phenotype and clinical behavior.

The malignant cells are CD______ variants of RS cells.

This disease tends to present in young_____ (late teens / early 20;s) with disease in the _________or ______.

Clinically this disease tends to respond to therapy, but _______ This behavior is akin to the indolent forms of NHL.

Answer 10

Non-classical is comprised of a single sub-type, nodular lymphocyte predominant which has a distinct phenotype and clinical behavior.

The malignant cells are CD20+ variants of RS cells.

This disease tends to present in young men (late teens / early 20;s) with disease in the neck or groin.

Clinically this disease tends to respond to therapy, but ultimately recurrs. This behavior is akin to the indolent forms of NHL.

Question 11

Staging of HL is critical to determining prognosis and choosing a treatment strategy. Staging follows the Ann Arbor system and is informed by physical examination (lymphadenopathy, organomegaly), CT scans and bone marrow biopsy. Functional imaging with PET or Gallium can aid in determining whether occult disease lies on the other side of the diaphragm, particularly whether there__________ involvement.

Staging laparotomies to assess for retroperitoneal lymphadenopathy and splenic involvement were de rigueur through the 1980’s, but were replaced by improved CT and functional imaging. Lymphangiograms have similarly gone the way of the dinosaurs.

Answer 11

Staging of HL is critical to determining prognosis and choosing a treatment strategy. Staging follows the Ann Arbor system and is informed by physical examination (lymphadenopathy, organomegaly), CT scans and bone marrow biopsy. Functional imaging with PET or Gallium can aid in determining whether occult disease lies on the other side of the diaphragm, particularly whether there is splenic involvement.

Staging laparotomies to assess for retroperitoneal lymphadenopathy and splenic involvement were de rigueur through the 1980’s, but were replaced by improved CT and functional imaging. Lymphangiograms have similarly gone the way of the dinosaurs.

Question 12

stage: absence of constitutional symtpoms

Answer 12

stage A

Question 13

stage: presence of unexplained fever, night sweats and >10% weight loss

Answer 13

stage B

Question 14

stage: Bulky mediastinal mass > 1/3 thoracic diameter or > 10 cm

Answer 14

stage M

Question 15

stage: involvement of extranodal site

Answer 15

stage E

Question 16

Classical HL is an aggressive form of lymphoma which will take a patients life if not managed. The goal of therapy for most patients is ____;

those with advanced age and/or comorbid conditions may suggest?

Answer 16

Classical HL is an aggressive form of lymphoma which will take a patients life if not managed. The goal of therapy for most patients is cure;

those with advanced age and/or comorbid conditions may not be candidates for aggressive therapy and should receive palliation, instead.

Question 17

Radiation fields when used alone in the management of HL follow one of three patterns designed not only to target the involved lymph nodes, but also the _____________. The extended mantle field adds coverage of para-aortic nodes and the spleen.

Answer 17

Radiation fields when used alone in the management of HL follow one of three patterns designed not only to target the involved lymph nodes, but also the next set of contiguous nodes, anticipating the pattern of spread. The extended mantle field adds coverage of para-aortic nodes and the spleen.

Question 18

Alkylators

Answer 18

add alkyl group to guanine resulting in DNA crosslinking

Question 19

standard chemo

Answer 19

ABVD

1. A
   adriamycin: cardiac toxicity
2. B
   bleomycin: pulmonary toxicity
3. V
   vinblastine: neurologic toxicity
4. D
   dacarbizine: hematologic toxicity

Question 20

treatment options:

Treatment for limited stage disease can follow one of three strategies: (3)

Extensive stage disease is really only amenable to ___________, although XRT can be used to augment / consolidate treatment to particularly large nodes (>5cm is generally accepted as potentially benefiting from addition of XRT).

Answer 20

Treatment for limited stage disease can follow one of three strategies: (1) XRT alone, short course (3-4 months) (2) chemotherapy followed by reduced dose XRT, or (3) chemotherapy alone.

Extensive stage disease is really only amenable to chemotherapy, although XRT can be used to augment / consolidate treatment to particularly large nodes (>5cm is generally accepted as potentially benefiting from addition of XRT).

Question 21

Overall, Hodgkin Lymphoma treatment has met with excellent results, with cure the norm for most patients.

Factors in early stage disease which predict for treatment failure when local (ie XRT) therapy is given include: (4)

The presence of any one of these factors would advocate for the use of chemotherapy as primary therapy.

Answer 21

Overall, Hodgkin Lymphoma treatment has met with excellent results, with cure the norm for most patients.

Factors in early stage disease which predict for treatment failure when local (ie XRT) therapy is given include: B-symptoms, presence of extranodal disease (say, a lesion in the lung or liver), bulky disease (> 10cm or 1/3 of the intrathoracic diameter), >3 sites of nodal involvement and sedimentation rate > 50 mm/hr.

The presence of any one of these factors would advocate for the use of chemotherapy as primary therapy.

Question 22

The price of success, particularly in limited stage patients with >80% cures, has been the consequences of aggressive treatments. Particularly in the 60’s and 70’s many patients received intensive radiotherapy. As a consequence, more than 15 years out from diagnosis, a patient is more likely to die from complications of therapy (solid tumors within the radiation port, secondary leukemias & myelodysplasias, accelerated vascular heart disease) than from relapse of disease.

Answer 22

yep

Question 23

long term complications for radiation include (3)

long term complications from chemo include (2)

Answer 23

Long term complications:
Radiation
1. secondary malignancies: breast, lung
2. cardiac disease
3. pulmonary fibrosis

Chemotherapy

1. secondary leukemia
2. infertility

Question 24

long term morbidity associated with the curative treatment of Hodgkin Lymphoma.

Answer 24

radiation exposure to the spleen and left breast leading an increase in developing a secondary solid tumor

Question 25

the cumulative excess risk of developing secondary solid tumors as a consequence of prior treatment. While lung and colorectal cancer risks are somewhat elevated (the lungs prove relatively radiation insensitive while abdominal involvement is fairly unusual), the risk in women in particular is dominated by _______cancer.

Answer 25

the cumulative excess risk of developing secondary solid tumors as a consequence of prior treatment. While lung and colorectal cancer risks are somewhat elevated (the lungs prove relatively radiation insensitive while abdominal involvement is fairly unusual), the risk in women in particular is dominated by breast cancer.

This risk appears to be particularly high for girls and young women treated in the period of breast development which follows puberty with risks that are 30 to 50 TIMES higher than their age-matched peers.

Question 26

Among survivors treated with mantle RT at doses of 35-45 Gy, the risk of significant __________morbidity is increased 2- to 4-fold above the untreated population;

Answer 26

Among survivors treated with mantle RT at doses of 35-45 Gy, the risk of significant cardiac morbidity is increased 2- to 4-fold above the untreated population; the cumulative risks of significant heart disease among survivors of adult HL are approximately 5%-10% at 15 years,16 16% at 20 years,17 and 34% at 30 years. Accelerated atherosclerotic coronary artery disease is the most common manifestation of radiation-induced cardiac injury and accounts for approximately 40%-50% of adverse cardiac events. Valvular disease is less common, typically has a late onset ( 10 years after RT), and is related to higher doses ( 30 Gy) or young age at treatment. Prior radiation presents considerable challenge in the surgical management of cardiac complications as the pericardium becomes sclerotic and fixed to the heart itself; valve replacement surgeries have significant associated morbidity.

Question 27

The recommendations are designed to mitigate the risks associated with curative treatment for Hodgkin Lymphoma.

1) Women who receive mantle radiation should begin ___________screening 8-10 years following radiation or at age 25-30, whichever comes first.
2) For patients receiving abdominal irradiation, _______ cancer screening starting 8-10 years following the exposure or by age 35 has been recommended.
3) Attention should also be paid to reducing / managing standard cardiac risk factors for patients who have had irradiation which included the heart through __________

“Excellent” control of __________should be the goal.

Answer 27

The recommendations above are designed to mitigate the risks associated with curative treatment for Hodgkin Lymphoma.

1) Women who receive mantle radiation should begin mammographic screening 8-10 years following radiation or at age 25-30, whichever comes first. The relative density of the breasts of younger women may complicate interpretation of screening (Xray) mammograms and MRI has been recommended as an alternative where necessary.
2) For patients receiving abdominal irradiation, colorectal cancer screening starting 8-10 years following the exposure or by age 35 has been recommended.
3) Attention should also be paid to reducing / managing standard cardiac risk factors for patients who have had irradiation which included the heart through lifestyle modification . “Excellent” control of cholesterol should be the goal. Improving diet and exercise will impact both second cancer and cardiovascular risk. Wellness programs and long term care focused clinics are now available to support these patients.

Question 28

Given the excellent control of Hodgkin Lymphoma achieved with chemotherapy and radiation, hematologists and oncologists have been focusing on reducing the long-term complications. Strategies currently under investigation include (2)

It appears possible that radiation can be eliminated altogether in some younger patients with favorable risk disease, but this has not yet become standard practice.

Answer 28

Given the excellent control of Hodgkin Lymphoma achieved with chemotherapy and radiation, hematologists and oncologists have been focusing on reducing the long-term complications. Strategies currently under investigation include (1) lowering radiation doses altogether and (2) limiting the extent of radiation fields to reduce exposure to normal tissue.

It appears possible that radiation can be eliminated altogether in some younger patients with favorable risk disease, but this has not yet become standard practice.

Question 29

In order to reduce under-and over-treatment, we want to allocate more treatment to those predicted to do worse, and less treatment to those who won’t need it.

Response adapted therapy uses response to initial therapy as the trigger to escalate (positive/negative? PET) or de-escalate (positive/negative? PET) treatment relative to the standard of care.

Answer 29

Clinical trials allocating treatment on the basis of prognostic score calculated at the time of diagnosis have failed to show benefit, particularly in the treatment of higher risk patients. Positive functional imaging at the end of treatment has high positive predictive value for relapse while the converse is also true. Similarly, overall outcome can be predicted by the response to functional imaging part way through treatment.

Response adapted therapy uses response to initial therapy as the trigger to escalate (positive PET) or de-escalate (negative PET) treatment relative to the standard of care.

Recent studies in limited stage (I and II) patients showed no loss in efficacy to those with negative PET2 (PET after cycle #2 of six planned) relative to standard of care while those with a positive PET2 fared better if they received escalated chemotherapy relative to continuing on the standard treatment

Question 30

Chemo-immunoconjugate targeting CD30

Answer 30

Brentuximab

Question 31

recognizes PD-1 on T cells, blocking anergy-signaling from target R-S cells, allowing the T cells to re-enter an effector state and attack the R-S cell

Answer 31

Nivolumab