Resident’s Conference

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Residents Conference

• Cynthia Lan, MDJune 21, 2005

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Case presentation

• CC I have a knot under my chin
• HPI 29 AAF who c/o knot under her chin x 1
  week. About 2 weeks ago, she had some upper
  respiratory symptoms (nasal congestion,
  rhinorrhea, sore throat). She went to see her
  doctor and was given amoxicillin. Her respiratory
  symptoms resolved, but the mass under her chin
  remained. The patient does not feel the mass has
  grown in size, but it has not decreased in size
  either so she was concerned.
• She denies fevers, chills, or weight loss. ROS
  otherwise negative.
• PMH 1) Asthma
• 2) C sxn x 2
• 3) Tonsillectomy
• Medications None
• Allergies None
• Soc Hx Married. Has 3 healthy children, ranging
  from ages 9 to 13. Works as store manager at
  Albertsons. Occasional ETOH use. Quit smoking 5
  years ago. Denies IV drug abuse.
• FH Negative for cancer

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• PE afebrile, BP 107/76, P 90, R 18
• General well developed, well nourished African
  American female in NAD
• HEENT PERRL, EOMI, OP clear
• Neck Right sided submandibular mass, firm,
  mobile, non tender, about 3 cm in diameter. No
  other adenopathy appreciated.
• Lungs CTAB
• Breasts no masses
• Abd BS, soft, NT, ND
• Extrem no edema
• Neuro CN 2-12 intact

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Labs

• Chem 8 normal
• CBC WBC 21,000, hgb 10.9, hct 34.1, plt 613.
  (diff 83 neutrophil, 10 lymph, 4 mono, 1 eos)
• LFTs normal, alb 3.8

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CXR
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• Core biopsy of anterior mediastinal mass
  Classical Hodgkins lymphoma, nodular sclerosing
  type. Immunohistochemical studies were positive
  for CD15 and CD30, and are negative for CD45 and
  CD 20.
• Bone marrow biopsy negative for Hodgkins
  lymphoma.

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(No Transcript)
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CD30
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CD15
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CD20 -
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Hodgkins Lymphoma

• The incidence of HL is 2.7 per 100,000.
• Occurs slightly more often in men.
• In North America, there is a higher incidence
  among those of higher socioeconomic status.
• Cumulative lifetime risk of developing Hodgkins
  lymphoma in North America is approximately 1 in
  250 to 1 in 300.
• The highest rates of HL are seen in the US,
  Canada, Switzerland, and northern Europe.
• Intermediate rates are seen in southern and
  eastern Europe
• Low rates are see in Japan, China and other Asian
  countries.

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• Unsure why there is a variation in
• incidence rates
• Postulated reasons include differences
• in incidence, age of onset, or genotype
• of Epstein-Barr virus infection
• crowding during childhood as a result of
• lower socioeconomic status, or intrinsic
• genetic differences in susceptibility.

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• Bimodal age related distribution of incidence of
  HL, with a first peak occurring in the 20s and a
  second after the age of 55.
• Only 5 of cases occur below the age of 15 and 5
  over the age of 70 years.

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Etiology and pathogenesis

• Cause of HL remains unknown
• Epstein-Barr virus likely plays a role in
  etiology but mechanism is not clear.
• No clear association with occupational or
  environmental factors has been found.
• Neoplastic cell is a B-cell that has lost its
  ability to produce antibody but does not undergo
  expected cell death due to defective or blocked
  apoptosis.
• Genetic factor?
• First degree relatives of people with HL have up
  to a five-fold increased risk of developing HL.
• Monozygotic twins are almost 100-fold more likely
  to develop HL compared with dizygotic twins of an
  affected person.
• It is speculated that genetically predisposed
  individuals could react differently to the virus,
  increasing their chances that a lymphoid neoplasm
  be induced.

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• HL has a unique cellular composition, containing
  a minority of neoplastic cells (Reed Sternberg
  cells) in an inflammatory background.
• Currently classified (by the REAL classification)
  into two distinct diseases classical HL and
  nodular lymphocyte predominance HL.
• Classical HL are further subclassified according
  to the morphology of the Reed-Sternberg cells and
  the composition of the cellular background
  nodular sclerosis, mixed cellularity,
  lymphocyte-rich, and lymphocyte depletion.

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History of Hodgkins Lymphoma

• The first recorded description of Hodgkins
  disease was published in 1666 by Marcello
  Malpighi, an Italian physiologist. His paper was
  entitled De viscerum structuru excercitatio
  anatomica.
• In 1832, Sir Thomas Hodgkin (a British
  Pathologist) published his paper on lymphatic
  disease On Some Morbid Appearances of the
  Absorbant Glands and Spleen. In this paper, he
  describes a small series of cases of lymph node
  or splenic enlargement.
• 1865 Samuel Wilks (another British Physician)
  describes the same disease, independently of
  Hodgkin and with greater precision. As he later
  became acquainted with Hodgkins prior work, he
  named the condition after Hodgkin.

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Sir Thomas Hodgkin (1789-1866)
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• 1872 Theodore Langhans (a German pathologist and
  anatomist) publishes the first histopathologic
  features of Hodgkins disease
• 1878 Greenfield publishes the pathology of
  lymphomas with histopathologic features of
  Hodgkins disease.
• 1894 Sir William Oslers textbook, The
  Principles and Practice of Medicine, was the
  first publication to mention chemotherapy for
  lymphoma (Fowlers solutionan arsenic containing
  medicinal).
• 1898 Carl von Sternberg (an Austrain
  pathologist) first described the giant cells now
  called Reed-Sternberg cells. However he never
  clearly separated Hodgkin's disease from active
  tuberculosis, since a number of his patients had
  both disorders.
• 1902 Dorothy Reed (an American pathologist)
  independently described Reed-Sternberg cells and
  she first clearly separated TB from HD.

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Dr. Dorothy Reed Mendenhall 1874-1964

• American pathologist
• Born in Columbus, Ohio, to a wealthy family,
• but her father died when she was only
• 6 years old, so she went into medicine
• as a result of her familys financial decline.
• She attended Johns Hopkins school of medicine
• In 1900, she won a prestigious internship with
• Dr. William Osler, and in 1901 she won a
• pathology fellowship with Dr. William Welch.
• Working in the Hopkins laboratories, she
• first clearly separated tuberculosis from
• Hodgkin's disease, and maintained that the
• term Hodgkin disease should be limited to
• histological findings in which "her"
• giant cells were present. She later won
• international recognition for her work.

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Reed-Sternberg Cell

• Measure 20 to 60 micrometers in diameter, display
  a large rim of cytoplasm, have 2 nuclei with
  acidophilic nucleoli that covers more than 50 of
  the nuclear area.

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History (cont)

• WWII Explosion in Bari, Italy exposes
  servicemen to toxic effects of mustard gases.
  Follow-up of the exposed men shows marrow and
  lymphatic system suppression.
• 1943 Nitrogen Mustard (a mustard gas derivative)
  was submitted to Goodman and Gilman at Yale for
  treatment of HD and lymphosarcoma.
• In mid 1940s Gilbert and Craft advocate
  irradiation of nodes and surrounding areas-5 year
  survival reported to be 25-35
• 1963 Development of MOMP first combination
  chemotherapy for HD (cyclophosphamide,
  vincristine, methotrexate, prednisone)
• 1964 MOPP combination chemotherapy derived by
  replacing methotrexate with procarbazine in MOMP.
  

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• 1980s Several studies comparing ABVD
  (doxorubicin, bleomycin, vinblastine,
  dacarbazine) to MOPP.
• 2001 WHO Classification for Lymphomas
  Publishedterm Hodgkins Lymphoma is preferred
  over Hodgkins disease.

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Clinical Presentation

• Most patients present with lymphadenopathy,
  usually in the cervical, axillary or mediastinal
  areas.
• In only 10 of patients does the nodal disease
  present initially below the diaphram.
• Very large mediastinal masses can develop with
  only modest symptoms.
• Lymph nodes involved are usually painless, but
  occasionally a patient will note discomfort in
  the involved sites right after drinking alcohol.
• The classic B symptoms (weight loss greater than
  10 of baseline, night sweats, persistent fevers)
  only develop in 25 of patients.
• Such sx usually indicate widespread or locally
  extensive disease and the need for at least some
  systemic treatment as part of the plan.
• Pruitus can precede the diagnosis of HL by up to
  several years.
• An occasional patient will present with
  symptomatic anemia or incidentally noticed
  pancytopenia because HL can involve the bone
  marrow.

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Pathology/Biology

• Diagnosis of Hodgkins lymphoma is based on
  seeing Reed-Sternberg cells in an appropriate
  cellular background in tissue from a lymph node
  or extralymphatic organ such as the bone marrow,
  lung or bone.
• Open biopsy is required for diagnosis, to
  determine the histologic subtype. (FNA can be
  suggestive but is not adequate for diagnosis of
  HL.)
• Immunohistochemical studies
• Classical HL is positive for CD30 and CD15,
  negative for CD45 and CD79a
• Nodular lymphocyte predominant HL is negative for
  CD30 and CD15, positive for CD45 and CD79a and
  CD20

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Evaluation

• History Ask for B symptoms (fever, weight loss,
  night sweats)
• PE LAD, organomegaly
• Labs CBC, ESR, liver function, renal function,
  hepatitis B, HIV (if risk factors are present),
  and albumin.
• Bone marrow biopsy for patients with B symptoms
  or WBC lt4,000 or advanced disease.
• CT scan of chest/abd/pelvis
• PET can be useful to asses residual masses during
  or after planned treatment to identify the
  minority who should receive altered or additional
  therapy.

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• ?Role of staging laparotomyin the past, certain
  stage I-II patients without B symptoms and
  nodular sclerosis histology may undergo staging
  laparotomy (a laparotomy with splenectomy and
  liver biopsy) because if negative, patients can
  be treated with mantle field radiation alone.
• However, it is rarely done these days because of
  the associated morbidity and lack of survival
  advantage in patients with favorable prognosis
  disease. Also, most pts with stage I-II disease
  now receive chemo in addition to radiation anyway.

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Staging (Ann Arbor classification)

• Stage Definition
• I Involvement of single LN region or lymphoid
  structure (spleen)
• II Involvement of 2 or more LN regions on the
  same side of the diaphram
• III Involvement of LN regions on both sides of
  the diaphram
• III1 Limited to spleen, splenic hilar nodes,
  celiac nodes, or portal nodes
• III2 Includes para-aortic, iliac, or mesenteric
  nodes plus those in stage III1
• IV Involvement of extranodal sites beyond that
  designated as E (see next slide) more than one
  extranodal deposit at any location, any
  involvement of liver or bone marrow.

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Staging (cont)

• A No B symtoms
• B Unexplained weight loss greater than 10 in
  the last 6 months, unexplained fever gt100.4 F in
  the past month, recurrent drenching night sweats
  in the past month
• X Bulky disease, mass greater than 10 cm,
  mediastinal mass greater than 1/3 the chest
  diameter at T5-6
• E Localized solitary involvement of
  extralymphatic tissue, except liver and bone
  marrow

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Prognosis

• Prognosis of patients with HL has improved over
  the past 50 years.
• Two factors dominate the prognosis Age and
  stage.
• Elderly patients (those older than 65) make up
  only 5 of all pts with HL, but their likelihood
  of being cured is only ½ that of younger pts
  (comorbid conditions, loss of organ reserve with
  aging, and intrinsic resistance of the disease in
  older pts).
• Pts with limited-stage disease have at least a 90
  to 95 likelihood of cure.
• Pts with advanced disease have 65 chance of cure
  with primary treatment.
• Relapsed disease cure in more than 40 to 50
  with high dose chemotherapy.

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Primary Treatment

• Currently, most pts with Hodgkins disease are
  cured so minimizing long-term consequences of
  treatment is important.
• Although the chances of being cured of HL is
  high, overall expectation of survival is not
  normal.
• Challenge in treating pts with HL is not only to
  cure the disease but to do so while holding the
  potential for long term toxicity to a minimum.
• This usually means choosing an initial approach
  to cure the majority of pts and using secondary
  treatment for the minority who relapse.

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Favorable and unfavorable prognosis stage I-II
Hodgkins disease

• Among stage I-II pts, retrospective studies have
  identified a number of adverse prognostic
  criteria large mediastinal adenopathy, age gt50,
  and B symtoms.
• Large mediastinal adenopathy predicts an
  increased risk of relapse, but date is
  conflicting on whether these findings cause a
  lower rate of survival.
• Older age have a lower survival rate than
  younger patients, probably due to less successful
  treatment at relapse and a greater mortality risk
  from other causes (i.e. second tumors and cardiac
  disease)
• Pts with B symptoms have higher relapse rate.

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Treatment of favorable Stage I-II HL

• Favorable prognostic indicators (as defined by
  the European Organization for the Research and
  Treatment of Cancer H7 and H8 trials) age 50 or
  under, no large mediastinal adenopathy, ESR lt
  50/h and no B symptoms or ESR lt 30/h with B
  symptoms, disease limited to one to three regions
  of involvement.
• Currently there are several treatment options,
  and although there are differences in relapse
  rates, there is no difference in overall
  survival.
• ABVD for 3-6 cycles, followed by involved field
  irradiation with 30 Gy with an optional boost of
  6 Gy to individual nodes of concern.
• Mantle field irradiation (neck, chest, axillary
  LN) to 30 Gy with a total dose of 36 to 40 Gy to
  regions of initial involvement followed by
  paraaortic and splenic irradiation to 30 Gy.
  (Risk of second malignancies is increased with
  these larger radiation fields.)
• Full dose chemotherapy alone is under
  investigation in clinical trials.
• (ABVD doxorubicin, bleomycin, vinblastine,
  dacarbazine)

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Randomized Comparison of ABVD Chemotherapy With a
Strategy that includes radiation therapy in
patients with limited-stage Hodgkins lymphoma
National Cancer Institute of Canada Clinical
Trials Group and the Eastern Cooperative Oncology
Group (Meyer, et al. J of Clinical Oncology, vol
23, no 21) Published ahead of print on April 18,
2005 (Original date July 20, 2005)

• Randomized trial comparing ABVD alone to ABVD
  radiation in 399 pts.
• Pts with nonbulky stage I to IIA Hodgkins
  lymphoma were stratified into favorable and
  unfavorable cohorts. (Unfavorable cohort age gt40
  yr, ESRgt50, mixed cellularity or lymphocyte
  deplete histology, gt4 sites of disease)
• Randomized to ABVD alone or treatment that
  includes radiation therapy. In the ABVD group,
  both cohorts (favorable and unfavorable) received
  ABVD as a single modality x 4-6 cycles. In the
  treatment with radiotherapy group, the favorable
  cohort received sub total nodal radiation therapy
  only, while the unfavorable cohort received
  combined modality therapy with ABVD x 2 cycles
  plus sub total nodal irradiation therapy.
• Median follow up is 4.2 years.

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• Results Compared to ABVD alone, 5 yr freedom
  from disease progression is superior in pts
  allocated to radiation therapy (93 v 87,
  P0.006), but no differences in event free
  survival (88 v 86, P0.06) or overall survival
  (94 v 96, p 0.4) were detected. In subset
  analysis comparing pts stratified into the
  unfavorable cohort, FFD progression was superior
  in pts assigned to ABVDradiation group compared
  to ABVD alone (95 v 88, p 0.004), but no
  difference in overall survival was detected (92
  v 95, p 0.3)
• Conclusion In pts with limited stage HL, no
  difference in overall survival was detected
  between pts randomly assigned to receive
  treatment that includes radiation therapy vs ABVD
  alone. Although 5-year FFD progression was
  superior in pts receiving radiation therapy, this
  advantage is offset by deaths due to causes other
  than progressive HL or acute treatment related
  toxicity.

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Treatment of unfavorable Stage I-II disease

• Combined modality therapy (chemo radiation)
• Chemotherapy (ABVD or MOPP/ABVD) is given to
  maximal tumor response (usually 4 to 6 monthly
  cycles), as judged by CT scan and PET, after
  which 2 additional cycles of consolidation
  chemotherapy are given followed by limited
  radiation therapy.
• Radiation fields can be limited to involved
  regions (shown on CT or PET). Restricting fields
  reduces the risk of pulmonary complications
  related to the radiation. Also, in young women,
  the elimination of axillary irradiation reduces
  the risk of subsequent breast cancer.
• MOPP (nitrogen mustard/mechlorethamine,
  vincristine, procarbazine, prednisone)

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Treatment of advanced (stage III-IV) Hodgkins
disease

• The prognosis of stage III varies with the
  absence (A) or presence (B) of B symptoms. Stage
  IIIA actually is a category of intermediate
  malignancy.
• Chemotherapy has become curative for many
  patients with advanced stages of HD.
• Since the 1960s, MOPP has been the main effective
  chemo for advanced stage HD, but toxicity has
  been an important limitation. (Late complications
  include sterility and increased risk of acute
  nonlymphocytic leukemia.)
• ABVD is more effective and less toxic, and is
  currently the standard for advanced HD.

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• With ABVD, 60 to 70 of pts will be alive and
  free of disease at 5 years.
• Recommendation pts be monitored for response
  during treatment (6 cycles minimum) and receive 2
  courses of chemo beyond best response.
• The addition of radiotherapy improves freedom
  from progression, but not survival.
• Randomized trials have not been done, but
  combined modality treatment is currently favored
  for pts with massive mediastinal disease.

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Other chemotherapy used for advanced stage
Hodgkins lymphoma

• BEACOPP (Bleomycin, etoposide, doxorubicin,
  cyclophosphamide, vincristine, procarbazine, and
  prednisone) was developed by the German Hodgkins
  Lymphoma Study Group.
• May be particularly useful in pts with highest
  risk disease
• Higher rates of toxicity, including infertility
  and a higher risk of MDS/AML when compared to
  ABVD.
• Stanford V (doxorubicin, vinblastine,
  mechlorethamine, vincristine, bleomycin,
  etoposide, prednisone), a combined modality
  treatment with the great majority of pts
  receiving radiation.
• Best results are in pts with less than 3 adverse
  risk factors
• Ongoing trials comparing Stanford V with ABVD.

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Patients who relapse

• 20 to 40 of pts with advanced HD who enter
  complete remission with initial chemo will
  relapse.
• Poor prognostic factors for response to first
  line chemo include B symptoms, age gt45, bulky
  mediastinal disease, extranodal involvement, low
  hct, high ESR and high levels of CD 30.
• Pts with resistant disease (those who do not have
  CR after initial treatment with ABVD) should be
  offered high dose chemo, with or without
  radiotherapy followed by bone marrow transplant.

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Second malignancies after treatment of Hodgkins
disease

• Increasing success in the treatment of Hodgkins
  disease has been associated with second
  malignancies.
• There is an increased risk of leukemia (10-80
  fold), Non-Hodgkins lymphoma (3 to 35 fold), and
  solid tumors (lung, breast, bone, stomach, colon,
  thyroid, melanoma, over 2 fold)
• Acute Leukemia--Highest risks and greatest number
  of cases occur between 5 and 10 years after the
  initiation of treatment, usually with alkylating
  agents.
• Non-Hodgkins Lymphomaincidence ranged from 0.9
  at 6.7 years followup to 1.6 at 15 years.
• One-half to two-thirds of second malignancies are
  solid tumors after 15 or more years of follow-up.
• The risk is inversely related to age at initial
  treatment.
• Lung and breast cancer are the two most common
  second malignancies.
• Other malignancies include bone and soft tissue
  cancer, thyroid cancer, melanoma, and GI cancers.

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• NEJM 1996 Breast Cancer and other second
  neoplasms after childhood Hodgkins Disease
  (Bhatia, et al.)
• Cohort of 1380 children with Hodgkins disease
  (age at dx 1-16 yr)
• Estimated incidence of any second neoplasm 15
  years after the diagnosis of HD was 7.0
• The incidence of solid tumors was 3.9
• Breast cancer was the most common solid tumor
  with an incidence that approached 35 by 40 years
  of age.
• The estimated incidence of leukemia was 2.8 at
  14 years after diagnosis.
• Treatment with alkylating agents, recurrence of
  HD, and late stage of disease at diagnosis were
  risk factors for leukemia.

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Issues for the future

• In the past, Hodgkins disease was largely
  incurable, but at present it is often curable.
• With 15 of pts still dying of lymphoma, there
  are new treatments on the horizon
• Currently under investigation for treatment of HL
  is gemcitabine (a pyrimidine antimetabolite that
  inhibits DNA synthesis).
• Small Phase II study done in Italy and Germany
  (Santoro, et al. Journal of Clinical Oncology,
  Vol 18, No 13, 2000)
• 23 pts with refractory or relapsed HD, who had
  more than one previous chemotherapy regimen
• Overall response rate of 39 with gemcitabine
  therapy
• Targeted immunotherapy is a new treatment being
  researched. Rituximab (anti CD20 monoclonal
  antibody) has proven useful for several different
  types of B-cell lymphomas, and the nearly
  universal expression of CD20 on the neoplastic
  cells of lymphocyte predominant HL suggests that
  this lymphoma might be treated successfully with
  rituximab.

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Follow up on our patient

• Hodgkins lymphoma, nodular sclerosing type.
• Stage IIIAX (PET CT showed mediastinal, right
  supraclavicular, infraclavicular and pancreatic
  hypermetabolic localization consistent with
  Hodgkins lymphoma, with the largest lesion in
  the mediastinum measuring 13 cm).
• She has completed 6 cycles of chemotherapy with
  ABVD.
• Her mediastinal mass has decreased in size to
  7.85 x 6.4 cm.
• Her most recent PET scan after 6 cycles shows
  decreased metabolic activity in thoracic mass,
  implying fair response to therapy. The other
  areas of abnormal intensities have resolved and
  no new abnormalities are noted.
• She is scheduled to undergo 2 more cycles of ABVD.

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References

• Abeloff Clinical Oncology, 3rd ed., 2004. pp
  29853011.
• Bhatia, et al. Breast cancer and other second
  neoplasms after childhood Hodgkins disease. NEJM
  1996334745-51.
• Hasenclever D, Diehl, V, A prognostic score for
  Advanced Hodgins disease. NEJM
  19983391506-1514
• Meyer, et al. J of Clin Oncol vol 23, no 21.
  Randomized Comparison of ABVD Chemotherapy with a
  strategy that includes radiation therapy in
  patients with limited stage Hodgkins lymphoma
  National Cancer Institute of Canada Clinical
  Trials group and the Eastern Cooperative Oncology
  Group. Pp1-9.
• Santoro, et al. J of Clin Oncol vol 18, no 13.
  Gemcitabine in the treatment of Refractory
  Hodgkins disease results of a multicenter phase
  II study. Pp 2615-2619.
• Tierney, Jr. et al. 2002 Current Medical
  Diagnosis and Treatment. 549.
• www.lymphomainfo.net
• www.Uptodate.com
• www.whonamedit.com