A 69-year-old male patient with no history of comorbid illnesses, a history of chronic smoking for 20 years and chronic alcohol use, and an allergy to penicillin, was seen in the outpatient department in August 2020. He was on regular follow-up for hairy cell leukemia treated in 2008 with cladribine and rituximab. He presented to the hospital with a two-month history of dysphagia, more for solids than liquids. An upper gastrointestinal (UGI) endoscopy showed a circumferential nodular growth starting at 22 cm that was friable to touch. Biopsy of the lesion was suggestive of squamous cell carcinoma. After a complete staging work-up, he was diagnosed with locally advanced squamous cell carcinoma of the upper third esophagus Stage IVA (cT3cN3cM0). He was treated with concurrent chemoradiotherapy with 60 Gray Intensity Modulated Radiation Therapy with Image Guided Radiotherapy delivered in 30 fractions and 7 cycles of weekly paclitaxel (50 mg/m2) with carboplatin (area under the curve 2) [AUC], followed by 2 consolidation chemotherapy cycles with 3 weekly paclitaxel (175 mg/m2) with carboplatin (AUC 5), completed on Nov 24, 2020. On his first follow-up in January 2021, the patient reported intermittent grade 2 dysphagia; he was tolerating semisolid foods adequately and had a weight gain of about 4 kg. A positron emission tomography (PET) scan revealed mural thickening involving the upper and middle esophagus with standardized uptake values (SUV) of 5.17 (prior to chemoradiotherapy, the SUV was 7.21) without any suspicious uptake elsewhere in the body. UGI endoscopy revealed an ulcerated circumferential friable lesion with overlying slough starting at 22 cm and causing luminal occlusion at 24 cm. Cytology and biopsy of the esophageal lesion were taken and sent for histopathological examination, both of which were negative for malignant cells. Additionally, the biopsy showed the presence of dense granulation tissue with fibrinous exudates. Few of the endothelial cells showed large, atypical cells with prominent nucleoli as shown in Figure 1.
What is the diagnosis, and what should be done next? Once you have finalized your answer, read on.
DIFFERENTIAL DIAGNOSIS AND FURTHER MANAGEMENT
On UGI endoscopy, the differential diagnoses for the ulcerated circumferential friable lesion with overlying slough included residual disease, radiation necrosis, or an infection due to some fungus like candida or virus like herpes virus. The presence of inclusion bodies on the histopathology of the esophageal lesion ruled out the possibility of radiation necrosis and tilted the diagnostic possibility toward infection. Immunohistochemistry for cytomegalovirus (CMV) was negative. A polymerase chain reaction (PCR) test on blood for CMV was also negative. In view of the above findings, an immunodeficiency workup was performed, and the patient’s total immunoglobulin (Ig) G (IgG) and IgA levels were suboptimal (serum IgG levels- 312 mg/dL [reference level: 751–1560 mg/dL], serum IgA level – 6.67 mg/dL [reference level: 82–453 mg/dL]). IgG and IgM antibodies for CMV were sent and found to be positive. After a discussion in the difficult cases joint clinic meeting, it was decided to treat the patient with CMV-directed antiviral therapy, based on the available evidence. He received two weeks of intravenous ganciclovir at 5 mg/kg. He developed grade 2 peripheral neuropathy and hence further treatment was stopped, and he was put on observation. A repeat endoscopy and biopsy performed three months later revealed a small ulcer persisting at 25 cm with a stricture, but cytology and biopsy were negative for malignant cells or any atypical cells. His repeat serum IgM for CMV was negative, and serum IgG for CMV remained positive. His intermittent dysphagia had improved, and he was able to tolerate a semisolid diet. His PET scan confirmed the absence of metabolically active disease. Currently, two years after the diagnosis of esophageal cancer, he is on a long-term follow-up and is well with no evidence of disease recurrence.
CMV esophagitis in a patient treated with concurrent chemoradiation for locally advanced esophageal squamous cell carcinoma.
CMV is a beta herpes virus. In immunocompetent individuals, CMV infection causes asymptomatic viremia or a self-limited infectious mononucleosis type illness, with a constellation of symptoms consisting of fever, malaise, cytopenias, and body ache. It affects around 50%–70% of the world’s population. In developing countries, this number can go up to 70%–100%. Most of the infections are indolent or latent. Symptomatic CMV infections occur mostly in immunosuppressed populations like those with hematological malignancies, solid organ transplants, and persons on chronic steroids. CMV infection can present as hepatitis, pneumonitis, colitis, encephalitis, esophagitis, or retinitis.
The diagnosis of CMV infection is established by either isolating the virus or detecting the viral antigens or nucleic acid in any bodily fluid or tissue, irrespective of symptoms or signs. Symptomatic CMV infection constitutes CMV disease. For example, CMV gastrointestinal disease indicates that the patient has gastrointestinal symptoms with mucosal lesions in the gastrointestinal tract along with demonstration of CMV antigens/nucleic acid on the tissue biopsy.
The patient was treated with cladribine and rituximab in 2008 for hairy cell leukemia and he had finished treatment with chemoradiotherapy for esophageal cancer three months prior to the diagnosis of CMV esophagitis. Hence, the immunocompromised state that predisposed him to CMV infection was likely to be the chemoradiotherapy for esophageal cancer, rather than the treatment for hairy cell leukemia. There are few case reports of patients with esophageal cancers on chemoradiotherapy who had developed CMV esophagitis. In a retrospective study of 107 patients with cancer and CMV viremia, 70% of patients had solid malignancies and 30% of patients had hematological malignancies. The requirement for mechanical ventilation, the presence of leukocytosis, and a lack of appropriate early treatment were causes of higher mortality rates. In another retrospective study from the same institution of 73 patients with cancer, the median duration of chemotherapy received before CMV reactivation was 1.5 months (range, 1–12), and the median time to CMV reactivation from the diagnosis of cancer was 4 months (range, 1–21). Out of 17 patients in whom the detailed records were available, 10 (59%) recovered completely from the acute infection, while 7 (41%) had clinical worsening and died because of CMV infection or because of other associated infections/conditions.
The above studies indicate that the exact prevalence of CMV disease is not known, mostly because it presents with coinfection with other bacterial infections. The mortality rate in symptomatic patients can be as high as 40% even with treatment. Hence, in patients receiving active chemotherapy who develop fever with no obvious cause and who have malaise, fatigue, leukopenia and neutropenia, and other comorbid conditions like human immunodeficiency virus (HIV) infection, CMV infection should be considered as one of the differential diagnoses. Biopsy is the current gold standard for the diagnosis of CMV infection. PCR testing for CMV has a sensitivity of 85% and specificity of 95%. Thus, a negative PCR test does not rule out CMV infection. The serology results merely serve as indirect evidence of a recent or prior CMV infection as they reflect the change in the antibody titers at different time points during the clinical illness. A diagnosis of a recent or acute CMV infectious episode is considered probable (though not definite) in cases where CMV-specific IgM antibodies (suggesting recent seroconversion) are detected. The patient had a non-healing ulcer at the stricture site, with intranuclear inclusion bodies that suggested the presence of CMV infection. His serum CMV DNA test was negative, but the presence of CMV-specific IgM antibodies aided in establishing the diagnosis. Multiple options exist for the treatment of CMV, and the most commonly used regimen is ganciclovir administered intravenously at the dose of 5 mg/kg every 12 hours. Other antiviral medications like oral valganciclovir 900 mg every 12 hourly, intravenous foscarnet 90 mg/kg every 12 hourly, and intravenous cidofovir 5 mg/kg/day can be used. For any patient with serious CMV infection, intravenous ganciclovir is the agent of choice, which was used in this patient as well. A minimum of two weeks of antiviral therapy should be administered. Common side effects of intravenous ganciclovir include gastrointestinal side effects like diarrhea, and hematologic side effects like lowering of the platelet and white blood cell counts. Peripheral neuropathy develops in approximately 9% of patients on intravenous ganciclovir, as was seen with our patient.
For monitoring the response to antiviral therapy, the same assay should be performed on the same type of specimen as used to establish the diagnosis (blood/plasma/tissue). The baseline viral load should be checked on the day when antiviral therapy is initiated; this antiviral load should be checked once a week. Monitoring the viral load kinetics allows for the identification of patients at risk for recurrent CMV infections. The treatment with an antiviral agent should continue until the CMV load is negative or until there is no evidence of CMV. Confirmatory testing should be done one week after discontinuing therapy. Since the patient’s baseline CMV DNA titer was negative, the response was assessed with repeat serologic testing after the completion of treatment. Once the symptoms and viremia have resolved, patients are treated with a one- to three-month course of oral valganciclovir at 900 mg once daily to prevent relapse. In a retrospective cohort study, secondary prophylaxis with oral valganciclovir resulted in decreased relapse rates (21.7% versus 26%; HR, 0.19). Our patient had developed peripheral neuropathy related to valganciclovir, hence secondary prophylaxis with valganciclovir was avoided.
Although CMV infection in a patient with a solid malignancy is a diagnosis that is considered relatively infrequently, the astute clinician should always be aware that it is a part of the differential diagnosis in patients with unexplained infectious disorders, as early treatment can improve outcomes and help prevent severe CMV infection.
Declaration of consent
The authors certify that they have obtained all appropriate patient consent forms. The patient has given his consent for the images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published, and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Cannon MJ, Schmid DS, Hyde TB Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection Rev Med Virol 2010 20 202 13
2. Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials Clin Infect Dis 2017 64 87 91
3. Comi G, Cook S, Giovannoni G, Rieckmann P, Sørensen PS, Vermersch P, et al. Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis Mult Scler Relat Disord 2019 29 168 74
4. Aizawa R, Matsumoto S, Uneno Y, Nishikawa Y, Ozaki Y, Mori Y, et al. Severe esophagitis associated with cytomegalovirus during concurrent chemoradiotherapy for esophageal cancer Jpn J Clin Oncol 2017 47 885 8
5. Umemoto K, Kojima Y, Nagata N, Yokoi C, Sakurai T, Kobayakawa M, et al. Cytomegalovirus esophagitis developing during chemoradiotherapy for esophageal cancer:Two case reports J Med Case Rep 2016 10 259
6. Wang YC, Wang NC, Lin JC, Perng CL, Yeh KM, Yang YS, et al. Risk factors and outcomes of cytomegalovirus viremia in cancer patients:A study from a medical center in northern Taiwan J Microbiol Immunol Infect 2011 44 442 8
7. Agrawal AK, Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, et al. Cytomegalovirus infection in solid malignancies Cancer Res Stat Treat 2020 3 19 24
8. Bansal N, Ghafur KA Cytomegalovirus reactivation in solid tumors:Are we missing the bus (bug)?Cancer Res Stat Treat 2020 3 76 7
9. Durand CM, Marr KA, Arnold CA, Tang L, Durand DJ, Avery RK, et al. Detection of cytomegalovirus DNA in plasma as an adjunct diagnostic for gastrointestinal tract disease in kidney and liver transplant recipients Clin Infect Dis 2013 57 1550 9
10. Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, et al. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation Transplantation 2018 102 900 31
11. Razonable RR, Humar A AST Infectious Diseases Community of Practice Cytomegalovirus in solid organ transplantation Am J Transplant 2013 13 (Suppl 4) 93 106