Transcript Resident`s Conference

Resident’s Conference
Cynthia Lan, MD
June 21, 2005
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 Albertson’s. Occasional ETOH use. Quit smoking 5 years
ago. Denies IV drug abuse.
FH: Negative for cancer
• PE: afebrile, BP 107/76, P 90, R 18
• General: well developed, well nourished African American female in
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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
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
CXR
• Core biopsy of anterior mediastinal mass: Classical Hodgkin’s
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 Hodgkin’s lymphoma.
CD30 +
CD15 +
CD20 -
Hodgkin’s 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
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socioeconomic status.
Cumulative lifetime risk of developing Hodgkin’s 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.
• Unsure why there is a variation in
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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.
• 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.
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.
• 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.
History of Hodgkin’s Lymphoma
• The first recorded description of Hodgkin’s 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 Hodgkin’s prior work, he named the
condition after Hodgkin.
Sir Thomas Hodgkin (1789-1866)
• 1872 Theodore Langhans (a German pathologist and anatomist)
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publishes the first histopathologic features of Hodgkin’s disease
1878 Greenfield publishes the pathology of lymphomas with
histopathologic features of Hodgkin’s disease.
1894 Sir William Osler’s textbook, The Principles and Practice of
Medicine, was the first publication to mention chemotherapy for
lymphoma (Fowler’s solution—an 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.
Dr. Dorothy Reed Mendenhall 1874-1964
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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 family’s financial decline.
She attended John’s 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.
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.
History (cont)
• WWII Explosion in Bari, Italy exposes servicemen to toxic effects
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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.
• 1980s Several studies comparing ABVD (doxorubicin, bleomycin,
vinblastine, dacarbazine) to MOPP.
• 2001 WHO Classification for Lymphomas Published—term Hodgkin’s
Lymphoma is preferred over Hodgkin’s disease.
Clinical Presentation
• Most patients present with lymphadenopathy, usually in the
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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.
Pathology/Biology
• Diagnosis of Hodgkin’s 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
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 <4,000
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.
• ?Role of staging laparotomy—in 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.
Staging (Ann Arbor classification)
Stage
I
II
Definition
Involvement of single LN region or lymphoid structure (spleen)
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.
Staging (cont)
A
B
X
E
No B symtoms
Unexplained weight loss greater than 10% in the last 6
months, unexplained fever >100.4 F in the past month,
recurrent drenching night sweats in the past month
Bulky disease, mass greater than 10 cm, mediastinal mass
greater than 1/3 the chest diameter at T5-6
Localized solitary involvement of extralymphatic tissue, except
liver and bone marrow
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.
Primary Treatment
• Currently, most pts with Hodgkin’s 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.
Favorable and unfavorable prognosis stage I-II
Hodgkin’s disease
• Among stage I-II pts, retrospective studies have identified a number
of adverse prognostic criteria: large mediastinal adenopathy, age
>50, 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.
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 <
50/h and no B symptoms or ESR < 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)
Randomized Comparison of ABVD Chemotherapy With a Strategy that
includes radiation therapy in patients with limited-stage Hodgkin’s
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 Hodgkin’s lymphoma were stratified
into favorable and unfavorable cohorts. (Unfavorable cohort: age
>40 yr, ESR>50, mixed cellularity or lymphocyte deplete histology,
>4 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.
• Results: Compared to ABVD alone, 5 yr freedom from disease
progression is superior in pts allocated to radiation therapy (93% v
87%, P=0.006), but no differences in event free survival (88% v
86%, P=0.06) 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 ABVD+radiation 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.
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)
Treatment of advanced (stage III-IV) Hodgkin’s 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.
• 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.
Other chemotherapy used for advanced stage Hodgkin’s
lymphoma
• BEACOPP (Bleomycin, etoposide, doxorubicin, cyclophosphamide,
vincristine, procarbazine, and prednisone) was developed by the
German Hodgkin’s 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.
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 >45, 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.
Second malignancies after treatment of Hodgkin’s disease
• Increasing success in the treatment of Hodgkin’s disease has been
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associated with second malignancies.
There is an increased risk of leukemia (10-80 fold), Non-Hodgkin’s
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-Hodgkin’s Lymphoma—incidence 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.
• NEJM 1996 Breast Cancer and other second neoplasms after
childhood Hodgkin’s Disease (Bhatia, et al.)
– Cohort of 1380 children with Hodgkin’s 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.
Issues for the future
• In the past, Hodgkin’s 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.
Follow up on our patient
• Hodgkin’s lymphoma, nodular sclerosing type.
• Stage IIIAX (PET CT showed mediastinal, right supraclavicular,
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infraclavicular and pancreatic hypermetabolic localization consistent
with Hodgkin’s 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.
References
• Abeloff: Clinical Oncology, 3rd ed., 2004. pp 2985–3011.
• Bhatia, et al. Breast cancer and other second neoplasms after childhood
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Hodgkin’s disease. NEJM 1996;334:745-51.
Hasenclever D, Diehl, V, A prognostic score for Advanced Hodgin’s disease.
NEJM 1998;339:1506-1514
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 Hodgkin’s 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 Hodgkin’s disease: results of a multicenter phase II study. Pp
2615-2619.
Tierney, Jr. et al. 2002 Current Medical Diagnosis and Treatment. 549.
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