A 36-year-old man presented with several weeks of night sweats and
enlarged left cervical lymph nodes. Imaging revealed extensive mediastinal
lymphadenopathy with encroachment on the pericardium, enlarged supraclavicular
lymph nodes. A staging bone marrow biopsy was negative. Lymph node biopsy
revealed Hodgkin’s lymphoma, nodular sclerosis type and the patient’s
clinical stage was IIB.
The patient began chemotherapy with doxorubicin, bleomycin, vinblastine
and dacarbazine (ABVD) and completed four cycles, but was changed to
cyclophosphamide, vincristine, procarbazine, prednisone (C-MOPP) for the last
two cycles for fever, pulmonary toxicity and paresthesias of the hands and
feet. Following chemotherapy, he received consolidative radiation to the
mediastinum. Follow-up images were consistent with a complete response. The
patient continued regular follow-up without evidence of recurrent disease.
Five years later, the patient developed abdominal pain that awoke him
from sleep. A PET/CT revealed asymmetric bilateral metabolic activity of the
tonsils, hypermetabolic cervical lymph nodes, and a large retrocaval paraspinal
soft tissue mass. He also had a large hypermetabolic right sided celiac axis
mass and enlarged gastrohepatic, peripancreatic, gastrosplenic, retrocrural,
mesenteric and retroperitoneal lymphadenopathy. The spleen was mildly enlarged
with numerous hypermetabolic hypodense lesions. His bone marrow biopsy was
again negative, but celiac lymph node biopsy via endoscopic ultrasound revealed
a non-Hodgkin’s lymphoma of follicular center origin. Flow cytometry
confirmed these results.
In light of the patient’s bulky disease, he began treatment with
R-CHOP shortly thereafter. A restaging PET/CT after cycle three confirmed a
decrease in hypermetabolism of the tonsils and a decrease in size and
hypermetabolism of the splenic lesions. The abdominal lymphadenopathy was also
decreased in size and standardized uptake value activity. A PET/CT after six
cycles and again four months later did not show evidence of residual
hypermetabolism, and the patient has remained asymptomatic and continues to
work full time.
Figure 1: A focused PET/CT image of the spleen demonstrates a
hypodense lesion in the spleen which is no longer hypermetabolic. In the given
clinical context this is consistent with treated lymphoma.
Figure 2: Selected axial CT image of the upper abdomen
demonstrates retrocaval lymphadenopathy. On the axial PET image, degree of
metabolic activity corresponding to the lymphadenopathy is no higher than
adjacent background. The findings are again consistent with treated lymphoma. A
follow-up PET/CT (not shown) after four months revealed no interval
Figure 3: Axial CT image at the level of mid abdomen
demonstrates "misty" appearance to the mesentery which, when compared to the CT
scan at the baseline (a staging study performed at the time of initial
diagnosis of non-Hodgkin's lymphoma - not shown), revealed interval
Source: M Ghesani
More than 80% of patients with Hodgkin’s disease can be cured
with first-line treatment, depending on their risk factor profile. Long-term
survivors are at risk for second malignancy, which are often fatal. Solid
tumors, leukemia and non-Hodgkin’s lymphoma (NHL) have all been reported.
In a British review of 5,519 Hodgkin’s disease patients treated over a
30-year period, 322 second malignancies occurred and 50 of those were NHL. The
20-year cumulative risk of NHL in those patients was 2.3% (95% CI, 1.6-3.1).
Smaller series have also found the cumulative incidence for NHL after primary
Hodgkin’s disease ranges between 1% and 6%. Some groups have reported that
this risk remained constant during the follow-up period, while others noted
that the greatest risk began 10 years after first-line treatment. The timing
and relationship with previous therapy remains unclear. In a large series by
the German Hodgkin’s Lymphoma Group from 2001, the incidence of secondary
NHL remained constant from zero to eight years. These differences may be due to
differences in observation time, infrequent use of rebiopsy at time of relapse,
the lack of uniform pathologist review, or incorrect original diagnosis in the
The mechanism of the pathogenesis of NHL in patients with
Hodgkin’s disease remains elusive. Historically, some cases of NHL may
have been misdiagnosed as HL. The mutagenic effects of radiation and
chemotherapy may play a role. NHL might represent histologic conversion of
Hodgkin’s disease, especially for the lymphocyte predominant subtype. The
risk might also be related to the immunocommpromised status of a patient with
Hodgkin’s disease, similar to the increased risk of NHL in a transplant
patient. Other factors that may contribute to the development of secondary
malignancy are older age, splenectomy, and splenic irradiation.
The majority of secondary NHL are intermediate or aggressive B-cell
lymphomas. In the large series by the GHLG, a large proportion of secondary NHL
in patients with Hodgkin’s disease were of the B-cell type, and the
majority of those were diffuse large B-cell lymphoma (DLBCL). In accord with
prior reports, a larger proportion than primary DLBCL presented with extranodal
sites. Patients with DLBCL had a two-year freedom from treatment failure of 28%
and overall survival of 35%. Patients with secondary T-cell lymphoma had a poor
outcome with six of seven patients dying between three and 28 months after
diagnosis. Thus, the prognosis of secondary DLBCL is worse than for primary
disease, and the prognosis of secondary T-cell lymphoma is dismal.
The outcome was significantly influenced by the time of occurrence
after Hodgkin’s disease and variables of the age-adjusted International
Prognostic Factor Index (IPFI). Although the age adjusted IPFI was validated
for primary NHL, patients in the high/high-intermediate risk group or low/
low-intermediate risk group had a two-year freedom from treatment failure of
<10 % and 40% respectively. These high IPFI, poor-risk patients are
generally not candidates for dose-intensified treatment as primary patients
are, due to their prior therapy and compromised performance status. Therefore,
they may be better candidates for palliative treatment.
Patients developing a secondary NHL within three months of finishing
treatment for Hodgkin’s disease had an overall survival of 20% vs. 42% for
those who developed the disease after 12 months. In terms of prognosis,
patients with an early NHL recurrence are similar to patients with primary
progressive Hodgkin’s disease. This poor prognosis could be due to an
aggressive primary composite lymphoma that was not detected originally or
treatment for Hodgkin’s disease may compromise further treatments. In this
series, patients with DLBCL who were able to receive standard doxorubicin
containing therapy, and were not limited by performance status or prior
treatment, had a better prognosis.
The prognosis for secondary NHL patients who are younger and healthier
with a low IPFI, like the one presented, is potentially good. On the other
hand, patients with unfavorable histologies or high IPFI is quite poor. These
patients might benefit from palliative treatment. The importance of adequate
re-biopsy at the time of recurrence should not be underestimated, to avoid
misdiagnosis and to allow accurate assessment of the incidence secondary
lymphomas in the future. PET/CT may be helpful in selection of the optimal site
for biopsy, with CT imaging generally useful in selecting the sites ideally
suited for image-guided histologic sampling. Among the selected sites for
biopsy based on CT findings, PET imaging can then help determine the site with
higher standardized uptake values to increase the diagnostic yield and provide
the highest histologic grade.
Munir Ghesani, MD, is Associate Clinical Professor of Radiology at
Columbia University College of Physicians and Surgeons and Attending
Radiologist at St. Luke’s-Roosevelt Hospital Center.
Carrie Wasserman, MD, is second year Hematology Oncology Fellow at
St. Luke’s Roosevelt Hospital Center.
For more information:
- Biti G, et al: Second solid tumors and leukemia after treatment for
Hodgkins disease: An analysis of 1121 patients from a single institution.
Int J Radiat Oncol Biol Phys. 1994;29:25-31.
- Enrici RM, et al: The risk of non-hodgkins lymphoma after Hodgkins
disease, with special refernce to splenic treatment.
- Rosenberg SA: The management of Hodgkin’s disease: Half a
century of change. Annals of Oncology. 1996;7:555-560.
- Rueffer U, et al. Non-hodgkins lymphoma after primary hodgkins
disease in the German Hodgkins Lymphoma Study Group: incidence, treatment and
prognosis. J Clin Oncol. 2001;19:2026-2032.
- Swerdlow AJ et al. Risk of Second Malignancy after Hodgkins Disease
in a Collaborative British Cohort: The Relation to Age at Treatment. J
Clin Oncol. 2000;18:498 -509.
- Tura S, et al: Splenectomy and the increasing risk of secondary
acute leukemia in Hodgkins’s disease. J Clin Oncol.