|Year : 2020 | Volume
| Issue : 2 | Page : 307-311
Akhil Rajendra1, Vanita Noronha1, Bhausaheb Bagal1, Devayani Madhav Niyogi2, Tanuja Manjanath Shet3, Nilendu Chandrakant Purandare4, Anil Ramakant Tibdewal5, Kumar Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital; Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Department of Surgical Oncology, Tata Memorial Hospital; Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Department of Pathology, Tata Memorial Hospital; Homi Bhabha National Institute, Mumbai, Maharashtra, India
4 Department of Nuclear Medicine, Tata Memorial Hospital; Homi Bhabha National Institute, Mumbai, Maharashtra, India
5 Department of Radiation Oncology, Tata Memorial Hospital; Homi Bhabha National Institute, Mumbai, Maharashtra, India
|Date of Submission||30-Mar-2020|
|Date of Decision||09-Apr-2020|
|Date of Acceptance||20-Apr-2020|
|Date of Web Publication||19-Jun-2020|
Department of Medical Oncology, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Rajendra A, Noronha V, Bagal B, Niyogi DM, Shet TM, Purandare NC, Tibdewal AR, Prabhash K. Twin trouble. Cancer Res Stat Treat 2020;3:307-11
| Case Presentation|| |
A 39-year-old gentleman who was a smoker with no known comorbidities presented with complaints of left sided chest pain and low-grade fever. On examination, bilateral supraclavicular lymph nodes and level V cervical lymph nodes were palpable. Contrast-enhanced computed tomography (CT) of the thorax showed a pleural-based soft tissue lesion along the left upper lobe with destruction of the left 2nd rib and extension into the adjacent fat planes. Left supraclavicular lymph node biopsy showed large atypical lymphoid tumor cells which expressed CD20, PAX5, CD30, Bcl6, and Mum1, negative for GATA3, ALK1, and CD23. Based on the immunohistochemistry, a diagnosis of T-cell histiocyte-rich B-cell lymphoma (TCR-B NHL) was made [Figure 1]. A staging whole-body fluorodeoxyglucose positron emission tomography (FDG-PET)-CT revealed supra- and infradiaphragmatic adenopathy, splenomegaly, a pleural-based left upper lobe soft tissue mass, liver surface deposits, and extensive marrow and skeletal lesions [Figure 2].
|Figure 1: (a) Lymph node with partial loss of architecture (H and E, 20). (b) Large cells along sinusoids in a node (H and E, 100). (c) CD20 reveals scattered large cells throughout the node (IHC, 40). (d) Higher power of CD20-positive large cells (IHC, 200)|
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|Figure 2: Baseline fluorodeoxyglucose positron emission tomography computed tomography scan. (a) Maximum intensity projection imaging. (b-d) Fused transverse fluorodeoxyglucose positron emission tomography computed tomography images|
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Bone marrow examination also confirmed the involvement by lymphoma, whereas the cerebrospinal fluid analysis was negative for malignancy (both cytology and flow cytometry). With a baseline lactate dehydrogenase of 248 (100–190) U/L, a diagnosis of TCR-B NHL, Stage IVBEX (E-pleural-based soft tissue lesion and liver, X-Right axillary node) was made with a revised international prognostic index(IPI) score of 3/5 and Central Nervous System IPI Score of 3/5. He was started on dose-adjusted rituximab EPOCH-[rituximab– 375 mg/m 2, etoposide 50 mg/m 2 (D1-D4), doxorubicin 10 mg/m 2 (D1-D4), vincristine 0.4 mg/m 2 (D1-D4), cyclophosphamide 750 mg/m 2 D5 alone, prednisolone 100 mg (D1-D5)] along with intrathecal methotrexate (12 mg) on day 1. He received chemotherapy at level 1 for cycle 1, level 2 for cycle 2, and level 3 for cycle 3 and 4 as per the standard protocol.
After cycle 4, FDG PET-CT showed complete metabolic response in the supra- and infradiaphragmatic adenopathy, marrow, liver, and splenic lesions. However, the lesion in the left lung was persistent and metabolically active. A core biopsy was done from this lesion, which showed inflamed fibromuscular tissue and fragments of bone. Assuming this to be partial response, he received the 5th cycle of R-EPOCH at level 2. However, following this, he developed fever, cough, breathing difficulty, and hypotension, for which he received broad-spectrum antibiotics and antifungals for a total duration of 14 days. Chemotherapy was not administered in the 6th cycle; only rituximab was administered. Post 6 cycles of chemotherapy, FDG PET-CT showed complete metabolic response with persistent uptake in the left lung apical region with the 2nd rib fracture. He received adjuvant external beam radiotherapy (EBRT) 45 Gray (Gy) in 25 fractions to the right axilla and left 2nd rib. He was kept on observation. At the review visit after 3 months, a repeat FDG PET-CT scan showed increase in the pleural-based left apical opacity with contiguous pathological fracture of the left 2nd rib. There were multiple prominent (2.6 cm) non-FDG avid right axillary nodes [Figure 3].
|Figure 3: PET imaging done after 3 months of completion of treatment (5#DA - R-EPOCH + 1#R + external beam radiotherapy). (a) Maximum intensity projection imaging. (b-d) Fused transverse fluorodeoxyglucose positron emission tomography computed tomography scan IMAGES Dose-adjusted Rituximab EPOCH-[Rituximab –375 mg/m2, Etoposide 50 mg/m2 (D1-D4), Adriamycin 10 mg/m2 (D1-D4), Vincristine 0.4 mg/m2 (D1-D4), Cyclophosphamide 750 mg/m2 D5 alone, Prednisolone 100 mg (D1-D5) along with Intrathecal methotrexate (12 mg) on day 1|
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What is the diagnosis? What additional workup should be done and what should be the further line of treatment? Once you have finalized your answer, turn to pg. 308 and read on
A repeat biopsy of the lung lesion was performed which showed adenocarcinoma, TTF1 positive [Figure 4]. FDG PET-CT was done for staging which showed aortopulmonary window nodes and pretracheal nodes. The patient was diagnosed with lung cancer, cT3N2 (Stage IIIB). He underwent a left upper lobectomy with systematic mediastinal lymph node dissection, with chest wall resection and reconstruction using cement and mesh. The histopathology report showed changes suggestive of response to therapy with no residual viable tumor. No adjuvant treatment was planned, and he was kept on 3 monthly follow-up and is doing well. At the follow-up performed at 4 months postsurgery and 1 year after the initial diagnosis of lymphoma, the patient is asymptomatic and locoregionally controlled.
|Figure 4: (a) Pleural biopsy shows adenocarcinoma infiltrating the fibrous tissue (H and E, 300). (b) Strong TTF1 positivity in the adenocarcinoma cells (IHC, 200)|
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| Discussion|| |
Having multiple malignancies in the same patient is rare. If the multiple malignancies present within 6 months of diagnosis of the primary, it is reported as synchronous occurrence. If it is reported after 6 months of diagnosis or treatment, it is reported as a metachronous occurrence. In our case, the diagnosis of lymphoma was made by a biopsy of the supraclavicular node. The lung lesion was assumed to be a part of the same disease process. When the interim scan showed response in all other areas except for the lung, a biopsy was done but was inconclusive. After completion of all planned chemotherapy and adjuvant EBRT, the mass lesion in the lung persisted prompting a repeat biopsy, which clinched the diagnosis.
Could the baseline imaging have identified the dual disease process?
Baseline imaging (FDG PET-CT) showed enlarged neck nodes with standardized uptake value (SUVmax) of 21.44, axillary nodes with SUVmax of 26.46, mediastinal nodes with SUVmax of 9.08, abdominal nodes with SUVmax of 6.85, splenic deposits with SUVmax of 14.61, hepatic surface deposits with SUVmax of 12.08, marrow and skeletal lesions with SUVmax of 20.73, and the pleural-based soft tissue mass with SUVmax of 6.57. There were no imaging features to categorically classify the pleural-based disease as a different disease process altogether. Involvement of the pleura by the lymphomatous process has been well described in the literature.
How common is the synchronous occurrence of lung cancer and lymphoma? Is there any association found in literature?
With the advent of FDG PET-CT in the evaluation of lymphoma, the identification of new unexpected FDG-avid primary tumors has been reported in 1.2% of cases. Multiple case reports have documented these kinds of occurrences.,,, Factors that could contribute to the occurrence of synchronous primaries include genetic predisposition, immunodeficiency, and the presence of infectious agents such as Epstein–Barr virus (EBV). EBV reactivation after cancer-directed therapy for lung cancer leading to the occurrence of malignant lymphoma has been described in the literature and is theoretically possible. However, in our patient, the lung primary and lymphoma were coexistent.
What are the problems in the therapeutic decision-making in patients with synchronous primaries?
Synchronous primaries always create a therapeutic dilemma in deciding the course of treatment. In this scenario of coexistent lymphoma and lung cancer, it becomes difficult to ascertain the stage of the lung cancer as both the diseases can involve the mediastinal nodes as part of the disease process. The plan of treatment in lung cancer would depend on the final stage, which would depend on the mediastinal nodal status. Case reports have shown that in such a scenario, FDG PET-CT performed after the treatment of the lymphoma would ascertain the stage of lung cancer. In our case, however, the diagnosis of the primary lung cancer was not made initially as all the sites of disease (lung, liver, spleen, nodes, and bone) were assumed to be a part of the lymphomatous disease process.
The role of biopsy in a nonresponding lymphoma patient
In the FDG PET-CT performed after the completion of chemotherapy and EBRT, the patient would have been defined as having progressive disease, based on the Lugano criteria for assessing response. Clinically, the patient would fall in the category of refractory diffuse large B-cell lymphoma (DLBCL). In the Cancer and Leukemia Group B 50303 trial, in patients with DLBCL who were treated with DA-REPOCH, 1.3% of the patients developed progressive disease when on treatment compared to 2.8% with R-CHOP. The treatment for this group of patients would have been salvage chemoimmunotherapy followed by autologous transplantation. However, in our patient, a repeat biopsy was performed which completely changed the treatment plan. The predictive value of FDG PET-CT in identifying residual disease is 57%., Thus, a repeat biopsy is always warranted as it confirms the diagnosis of lymphoma, the presence of discordant histology, the proportion of low-grade component, and possible second primary.
Something to keep in mind is that our patient had undergone a biopsy after 4 cycles of DA-REPOCH, which was negative. The procedure was performed using an 18-gauge needle and 5 full cores and bits were sampled which were adequate as per the standard recommendations. The diagnostic accuracy with this kind of approach ranges from 74 to 95%. The possible reasons for the false negative result of the biopsy could have been due to the heterogeneity of the tumor itself or due to the sampling of the surrounding inflammatory tissue or fibrosis.
How do we explain the pathological complete response in this patient?
The chemotherapy regimen which the patient received contained etoposide which was administered at a dose of 50 mg/m 2 continuous infusion for 4 days for a total of 5 cycles. The cumulative dose of etoposide received by the patient would have been 1256 mg/m 2. Slevin et al. had proven the importance of the scheduling of etoposide for the treatment of lung cancer based on the target of achieving an etoposide drug concentration of >1 mg/l for the longest duration. A dosing of 25 mg/m 2 of etoposide as a continuous infusion results in a drug concentration ranging from 0.2 to 1 mg/L. Thus, etoposide at the administered doses would have had antitumor activity for lung cancer also. Among the other drugs, vincristine has been used in non-small cell cancer in the past which may also have contributed to the antitumor activity. None of the other drugs used including doxorubicin, cyclophosphamide, prednisolone, and rituximab should have had any significant antitumor activity in lung cancer.
The biopsy of the persistent lung lesion was performed 1 month after the completion of chemotherapy and EBRT, which had detected adenocarcinoma lung. However, the surgical excision performed 3 months after EBRT showed a pathological complete response (CR). The radiation therapy (RT) doses administered were 45 Gy in 25 fractions. There is evidence in the literature to show that patients with lung cancer can attain a pathological CR after RT to the lung mass, with rates from 17%–67%. However, in all these studies, RT was either administered along with chemotherapy as concurrent chemoradiotherapy or after a course of neoadjuvant chemotherapy. RT alone contributing to the pathological CR would be rare and there must have been some role of the chemotherapy (DA-REPOCH) administered in attaining the same. Whether DA-REPOCH served the purpose of neoadjuvant chemotherapy is not clear.
Prognostic impact of dual primaries in the case of diffuse large B-cell lymphoma
As the occurrence of this event is less common, not much data are available to exactly characterize the outcomes in such patients. A retrospective analysis performed in 809 patients with DLBCL at multiple institutes in Japan identified 123 patients with synchronous and metachronous cancers. After a median follow-up of 899 days, the overall survival (3-year OS, 56.2% vs. 74.6%, P < 0.001) and progression-free survival (3-year PFS, 49.3% vs. 64.2%, P < 0.01) were significantly shorter in the group with multiple primaries. The OS and PFS were shorter in patients with low IPI and high IPI, but not in the patients with intermediate IPI and the rate of death was higher in the patients with high IPI and multiple primaries. Half of the IPI high-risk patients died due to lymphoma progression.
| Conclusion|| |
In patients with lymphoma, mixed response should always prompt a repeat histopathological examination at the site of nonresponding disease.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]