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CASE REPORT
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Advanced penile lymphoma: Case report and review of the literature


1 Department of Medical Oncology, Hospital María Auxiliadora, Lima, Peru
2 Department of Medical Oncology, Hospital María Auxiliadora; Aliada Oncological Center, Lima, Peru
3 Department of Medical Oncology, Hospital María Auxiliadora; Aliada Oncological Center; Oncological Research Unit, Clínica San Gabriel, Lima, Peru

Date of Submission11-Apr-2021
Date of Acceptance30-Apr-2021
Date of Web Publication28-Jan-2022

Correspondence Address:
Stella Arambulo,
Department of Medical Oncology, Hospital María Auxiliadora, Avda. Miguel Iglesias 968, San Juan de Miraflores, Lima
Peru
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_593_21

 > Abstract 


Primary penile lymphomas are extremely rare. They are aggressive neoplasms that can present as double-or triple-hit lymphomas, and because the associate with a high risk of central nervous system dissemination, treatment consists of high-dose chemotherapy regimens plus intrathecal prophylaxis. Pathology can be confused with squamous cell carcinoma of the penis, leading to inappropriate treatments and unnecessary amputations. We report the case of a patient diagnosed with clinical Stage IV penile non-Hodgkin lymphoma that was treated with a complete and durable response. In addition, we review the available literature on penile lymphoma.

Keywords: Aggressive disease, non-Hodgkin lymphoma, organ preservation, penile lymphoma, rituximab



How to cite this URL:
Arambulo S, Calle A, Vela JM, Sotelo MJ. Advanced penile lymphoma: Case report and review of the literature. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 8]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=336700




 > Introduction Top


Malignant neoplasms of the penis are rare, the most common being squamous cell carcinoma, accounting for <1% of all malignancies in men in the US.[1] While non-Hodgkin lymphoma occurs in extranodal sites in up to 48% of patients, lymphoma of the penis is extremely rare, with only fifty cases reported to date.[2]

Penile lymphomas are aggressive neoplasms, which usually present with MYC and BCL2 and/or BCL6 translocations, also known as double- or triple-hit lymphomas. These types of lymphomas represent approximately 5% of all large B-cell lymphomas and have a poor prognosis with a median overall survival of <2 years.[3]

Central nervous system (CNS) involvement in this type of lymphoma is common both at diagnosis and at relapse and has been reported in up to 50% of affected patients. For this reason, it is recommended that all patients with double- or triple-hit lymphoma undergo a diagnostic lumbar puncture as a part of their initial staging and receive prophylactic CNS therapy, since it has been shown to decrease the incidence of involvement of the CNS.[4]

We present the case of a patient with lymphoma of the penis that received two cycles of the R-EPOCH, and due to the COVID-19 pandemic, was switched to R-CHOP, an easy-to-administer outpatient regimen, and achieving a complete response. Finally, an in-deep review of the available literature on penile lymphoma was conducted.


 > Case Report Top


A 78-year-old male with a history of arterial hypertension and metastatic prostate cancer under androgen blockade, presented with a 1-year history of a growing lesion in the glans and shaft of the penis with a yellowish foul-smelling discharge, with no B symptoms. Physical examination revealed an ulcerative lesion covering the glans and shaft of the penis that measured 5 cm × 4 cm [Figure 1], and a nodular lesion of 1.5 cm × 1.5 cm in the left thigh.
Figure 1: (a) Ulcerative lesion involving the glans and shaft of the penis. (b) Complete clinical response with preservation of normal penile structure and function after systemic treatment

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Due to the suspicion of squamous cell carcinoma of the penis, a partial penectomy had been considered. However, biopsy of the lesion on the penis in January 2020 revealed a diffuse nongerminal center triple expressing non-Hodgkin large B-cell lymphoma, with the following immunohistochemical studies: CD20 (+), CD45 (+), CD3 (−), BCL2 (+), CYCLINE D1 (−), CD10 (−), MUM1 (+), BCL6 (+), CMYC (+), S 100 (−), PANKERATIN (−), and Ki 67 proliferative index of 80% [Figure 2]. Biopsy of the lesion in the left thigh performed in early April 2020 reportedly showed a diffuse large B-cell lymphoma, nongerminal center type with immunohistochemistry: CD20 (+), CD3 (−), BCL2 (+), CD10 (−), BCL6 (−), MUM1 (+), CMYC (−), CD5 (−), and Ki67: 80% [Figure 2].
Figure 2: (a) Penile tumor biopsy. (b) Biopsy of the metastasis in left thigh

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Staging included bone biopsy and bone marrow aspiration, lumbar puncture, and whole-body CT scan that showed no new findings. Therefore, a final diagnosis of non-Hodgkin lymphoma of diffuse large B-cells of the penis, nongerminal center type, triple-expressor (BCL2 (+), BCL6 (+), CMYC (+), and stage IV due to soft-tissue metastasis in the left thigh was established.

Six cycles of the R-EPOCH scheme plus prophylactic intrathecal chemotherapy were proposed. However, the patient received only two cycles of R-EPOCH, to reduce the risk of contagion associated with hospitalization due to the COVID-19 pandemic, and treatment was switched to an outpatient chemotherapy scheme (R-CHOP), receiving two cycles of this regimen. However, the patient decided to discontinue systemic chemotherapy and refused intrathecal chemotherapy.

Despite having received an incomplete and suboptimal treatment, the patient achieved a complete clinical [Figure 1] and radiological response. Unfortunately, despite all efforts to avoid contagion, the patient finally acquired the SARS-CoV-2 infection, suffering from a severe disease that led to death.


 > Discussion Top


Lymphoproliferative diseases generally originate in the lymphatic system. However, up to 5% of cases affect the urinary tract; being located on the penis in <0.1%.[5]

Primary penile lymphoma is frequently related to MYC and BCL2 and/or BCL6 rearrangements, and therefore, and according to the 2016 World Health Organization, classified as double- or triple-hit high-grade, B-cell lymphomas.[6] Our patient was as a triple-expressor which portends a poor prognosis and thereby justifies treatment with more intense chemotherapy regimens.[7],[8]

Double- or triple-hit lymphomas or immunohistochemically detectable co-expression of MYC and BCL2, in the absence of translocations, constitute a high-risk factor for CNS involvement, observed in 4%–7% of cases. Testicular involvement has been associated with CNS relapse rates of 12%–25%, even in clinical Stage I disease.[9] Our patient had associated risk factors for CNS infiltration, an important point to take into account in our clinical practice since relapse to the CNS leads to universally poor results with a median survival after diagnosis of CNS involvement of only 2–5 months. [4,10] Most studies have found a slight decrease in the incidence of CNS relapse with the use of rituximab, with rates of 2%–4%. This decrease is likely due to a better control of systemic disease, as well as benefit from a minimal penetration of the antibody into the cerebrospinal fluid (CSF). In our patient, three serially obtained CSF samples after R-CHOP were negative for biochemical alterations or tumor cells making meningeal involvement unlikely, highlighting the hypothesis that chemotherapy combined with rituximab may have decreased the risk of CNS involvement.[11],[12]

On the other hand, in our patient, biopsy of the primary tumor provided a different immunohistochemical result from that of the thigh biopsy. This molecular difference between the primary tumor and the metastasis could be explained by the tumor heterogeneity, which, as is already known, is present in both hematological and solid neoplasms.[13]

Non-Hodgkin lymphoma can be difficult to diagnose, depending on the presenting symptoms and the site of the primary. In our patient, the differential diagnosis between this entity and squamous cell carcinoma of the penis was challenging. Indeed, not recognizing lymphoma can lead to unnecessary penile amputation, since this is the standard practice for squamous cell carcinoma and other malignant primary tumors of the penis, especially when the tumor affects the entire shaft.[14]

Finally, the management of lymphoma of the penis will depend mainly on the clinical stage of the disease, age, and the performance status of the patient. Because malignant lymphoma is considered a systemic disease, but with high response rates to chemotherapy and radiation therapy, these therapies should be considered to try to preserve penile function, and radical surgery should only be used after failure of these therapeutic options. While radiation therapy alone offers a 65% cure rate in advanced lymphoma, it can cause disfigurement or loss of erectile function. Therefore, chemotherapy should be considered as the virtual potentially curative treatment standard, in addition to providing preservation of the normal structure and function of the penis as demonstrated in our patient [Figure 2].[15],[16],[17]


 > Conclusion Top


Lymphoma of the penis is an infrequent and aggressive neoplasm, with a high risk of dissemination to the CNS. It is usually a diagnostic and therapeutic challenge, where high-dose chemotherapy regimens with intrathecal prophylaxis constitute the standard approach. As shown in the reported case, less toxic but active regimens, such as R-CHOP, may also be considered for fragile patients or in case of hospitalization limitations derived from the current COVID-19 pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Douglawi A, Masterson TA. Updates on the epidemiology and risk factors for penile cancer. Transl Androl Urol 2017;6:785-90.  Back to cited text no. 1
    
2.
Tanaka Y, Tanaka A, Hashimoto A, Shinzato I. Isolated Pituitary Stalk Relapse of Primary Penile Lymphoma. Intern Med 2017;56:835-9.  Back to cited text no. 2
    
3.
Copie-Bergman C, Cuillière-Dartigues P, Baia M, Briere J, Delarue R, Canioni D, et al. MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study. Blood 2015;126:2466-74.  Back to cited text no. 3
    
4.
Savage KJ, Slack GW, Mottok A, Sehn LH, Villa D, Kansara R, et al. Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL. Blood 2016;127:2182-8.  Back to cited text no. 4
    
5.
Patel A, Muthukrishnan I, Kurian A, Amalchandra J, Sampathirao N, Simon S. Multicentric primary diffuse large B-cell lymphoma in genitourinary tract detected on 18F-F-fluorodeoxyglucose positron emission tomography with computed tomography: An uncommon presentation of a common malignancy. World J Nucl Med 2021;20:117-20.  Back to cited text no. 5
  [Full text]  
6.
Swerdlow SH, Campo E, Pileri SA, Lee Harris N, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375.  Back to cited text no. 6
    
7.
Howlett C, Snedecor SJ, Landsburg DJ, Svoboda J, Chong EA, Schuster SJ, et al. Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol 2015;170:504-14.  Back to cited text no. 7
    
8.
Landsburg DJ, Falkiewicz MK, Maly J, Blum KA, Howlett C, Feldman T, et al. Results of patients with double hit lymphoma achieving first complete remission. J Clin Oncol 2017;35:2260.  Back to cited text no. 8
    
9.
Kridel R, Telio D, Villa D, Sehn LH, Gerrie AS, Shenkier T, et al. Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era. Br J Haematol 2017;176:210-21.  Back to cited text no. 9
    
10.
El-Galaly TC, Cheah CY, Bendtsen MD, Nowakowski GS, Kansara R, Savage KJ, et al. Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large B-cell lymphoma. Eur J Cancer 2018;93:57-68.  Back to cited text no. 10
    
11.
Kansara R. Central nervous system prophylaxis strategies in diffuse large B cell lymphoma. Curr Treat Options Oncol 2018;19:52.  Back to cited text no. 11
    
12.
Mannisto S, Vähämurto P, Pollari M, Clausen MR, Jyrkkiö S, Kellokumpu-Lehtinen PL, et al. Intravenous but not intrathecal central nervous system-directed chemotherapy improves survival in patients with testicular diffuse large B-cell lymphoma. Eur J Cancer 2019; 115:27-36.  Back to cited text no. 12
    
13.
Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol 2018;15:81-94.  Back to cited text no. 13
    
14.
Sun D, Yang P, Zhang L, Jiang L, Yu G. Secondary NK/T cell lymphoma after radiotherapy for non-HPV-related squamous cell carcinoma of the penis: an early warning event and literature review. Int J Clin Exp Pathol 2020;13:2173-80.  Back to cited text no. 14
    
15.
Wang X, Gong Z, Li SX, Yan W, Song Y. Extranodal nasal-type natural killer/T-cell lymphoma with penile involvement: a case report and review of the literature. BMC Urol 2017;17:77.  Back to cited text no. 15
    
16.
Naik N, Lin M, Lin P. Genitourinary involvement of lymphomas on FDG-PET. Br J Radiol 2018;91:20170273.  Back to cited text no. 16
    
17.
Lontos K, Tsagianni A, Msaouel P, Appleman LJ, Nasioudis D. Primary urinary tract lymphoma: Rare but aggressive. Anticancer Res 2017;37:6989-95.  Back to cited text no. 17
    


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