• Users Online: 891
  • Print this page
  • Email this page


 
 
Table of Contents
IMAGE CHALLENGE
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 307-311

Twin trouble


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 Submission30-Mar-2020
Date of Decision09-Apr-2020
Date of Acceptance20-Apr-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_103_20

Get Permissions


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

How to cite this URL:
Rajendra A, Noronha V, Bagal B, Niyogi DM, Shet TM, Purandare NC, Tibdewal AR, Prabhash K. Twin trouble. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Sep 19];3:307-11. Available from: http://www.crstonline.com/text.asp?2020/3/2/307/287195




  Case Presentation Top


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)

Click here to view
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

Click here to view


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.[1]

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

Click here to view


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)

Click here to view



  Discussion Top


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.[2] 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.[3]

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.[4] Multiple case reports have documented these kinds of occurrences.[5],[6],[7],[8] 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).[9] 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.[10] 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.[6] 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.[11] 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%.[12],[13] 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.[14]

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%.[15] 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.[16] 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.[17] 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.[18] 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%.[19] 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.[20]


  Conclusion Top


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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N, et al. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: A pharmacodynamic approach with high efficacy. Blood 2002;99:2685-93.  Back to cited text no. 1
    
2.
Available from: https://www.seer.cancer.gov/arch ive/manuals/codeman.pdf. [Last cited on 2020 Apr 01].  Back to cited text no. 2
    
3.
Vega F, Padula A, Valbuena JR, Stancu M, Jones D, Medeiros LJ. Lymphomas involving the pleura: A clinicopathologic study of 34 cases diagnosed by pleural biopsy. Arch Pathol Lab Med 2006;130:1497-502.  Back to cited text no. 3
    
4.
Ishimori T, Patel PV, Wahl RL. Detection of unexpected additional primary malignancies with PET/CT. J Nucl Med 2005;46:752-7.  Back to cited text no. 4
    
5.
Fonseca D, Musthyala B, Ahmed F, Murthy SS, Raju KV. A tale of synchronous lung carcinoma and diffuse large B-cell lymphoma of ileum: A rare combination. Lung India 2015;32:398-401.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Fujii M, Shirai T, Asada K, Saito Y, Hirose M, Suda T. Synchronous diffuse large B-cell lymphoma and squamous cell lung carcinoma. Respirol Case Rep 2014;2:33-5.  Back to cited text no. 6
    
7.
Sen E, Yasar A, Sak SD, Utkan G, Erden E, Saryal S. Lung adenocarcinoma and synchronous B-cell lymphoma of stomach. CHEST 2015;148:601A.  Back to cited text no. 7
    
8.
Samuel G, Simoff M, Chaabaan S, Diaz-Mendoza J. Synchronic diagnosis of non-hodgkin lymphoma and lung adenocarcinoma via EBUS-guided TBNA. J Bronchology Interv Pulmonol 2018;25:e41-42.  Back to cited text no. 8
    
9.
Babu G, Asati V, Lakshmaiah KC, Lokanatha D, Jacob LA, Babu S, et al. Every distant deposit is not a metastasis: Synchronous primaries do exist. Indian J Cancer 2019;56:70.  Back to cited text no. 9
[PUBMED]  [Full text]  
10.
Ohno Z, Tamaki H, Ohsuga T, Iwata H, Yasuda N, Mori Y. Primary lung cancer complicated by malignant lymphoma in two cases of epstein-barr virus infection. Case Rep Oncol 2012;5:367-72.  Back to cited text no. 10
    
11.
Bartlett NL, Wilson WH, Jung SH, Hsi ED, Maurer MJ, Pederson LD, et al. Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: Clinical outcomes of the phase III intergroup trial alliance/CALGB 50303. J Clin Oncol 2019;37:1790-9.  Back to cited text no. 11
    
12.
Zinzani PL, Tani M, Trisolini R, Fanti S, Stefoni V, Alifano M, et al. Histological verification of positive positron emission tomography findings in the follow-up of patients with mediastinal lymphoma. Haematologica 2007;92:771-7.  Back to cited text no. 12
    
13.
Zinzani PL, Fanti S, Battista G, Tani M, Castellucci P, Stefoni V, et al. Predictive role of positron emission tomography (PET) in the outcome of lymphoma patients. Br J Cancer 2004;91:850-4.  Back to cited text no. 13
    
14.
Gisselbrecht C, Van Den Neste E. How I manage patients with relapsed/refractory diffuse large B cell lymphoma. Br J Haematol 2018;182:633-43.  Back to cited text no. 14
    
15.
Manhire A, Charig M, Clelland C, Gleeson F, Miller R, Moss H, et al. Guidelines for radiologically guided lung biopsy. Thorax 2003;58:920-36.  Back to cited text no. 15
    
16.
Slevin ML, Clark PI, Joel SP, Malik S, Osborne RJ, Gregory WM, et al. A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 1989;7:1333-40.  Back to cited text no. 16
    
17.
Thompson DS, Hainsworth JD, Hande KR, Holzmer MC, Greco FA. Prolonged administration of low-dose, infusional etoposide in patients with etoposide-sensitive neoplasms: A phase I/II study. J Clin Oncol 1993;11:1322-8.  Back to cited text no. 17
    
18.
Barone C, Astone A, Cassano A, Noviello MR, Fontana T, Ricevuto E, et al. Advanced non-small-cell lung cancer (NSCLC) treated with folinic acid (F), fluorouracil (FU), vincristine (O), and mitomycin-C (Mi), (F-FOMi). Am J Clin Oncol 1992;15:506-8.  Back to cited text no. 18
    
19.
Roy SF, Louie AV, Liberman M, Wong P, Bahig H. Pathologic response after modern radiotherapy for non-small cell lung cancer. Transl Lung Cancer Res 2019;8:S124-134.  Back to cited text no. 19
    
20.
Tanba K, Chinen Y, Uchiyama H, Uoshima N, Shimura K, Fuchida S, et al. Prognostic impact of a past or synchronous second cancer in diffuse large B cell lymphoma. Blood Cancer J 2018;8:1.  Back to cited text no. 20
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Case Presentation
Discussion
Conclusion
References
Article Figures

 Article Access Statistics
    Viewed223    
    Printed16    
    Emailed0    
    PDF Downloaded30    
    Comments [Add]    

Recommend this journal