Case Report: Tracheal infiltration with wheezing revealing Hodgkin's disease

Hodgkin's disease with an initial tracheobronchial involvement is not common. The symptoms might be misleading, resulting in a diagnosis delay. We report the case of a 38-year-old woman with a one-month history of wheezing associated with a dry cough. The physical examination revealed a good general state of health, bilateral wheezing and supra-clavicular lymphadenopathy. The adenopathy biopsy's histopathology revealed Hodgkin lymphoma. The whole body FDG-PET scan was an important tool to assess the diagnosis as well as for the staging. The patient was treated with chemotherapy. Another unusual aspect is the tracheobronchial metastasis confirmed by a bronchial biopsy. Thus, our patient was put on a second-line chemotherapy. She died one year after the initial diagnosis. To conclude, it is an atypical clinical presentation of an Hodgkin lymphoma with a tracheobronchial relapse. It should be considered in the differential diagnosis of asthma or a tracheal tumor.


Background
Hodgkin lymphoma is a malignant neoplasia arising typically from lymph nodes.An extranodal lymphoma with an initial tracheobronchial involvement is uncommon in antemortem series.It was reported in about (3.6%) of cases in literature. 1 The symptoms are not specific and may mimic a wide spectrum of diseases like asthma or chronic obstructive pulmonary disease (COPD) … resulting in a diagnosis and a treatment delay. 1,2It is now recognised as a treatable neoplasia.Thus, it is worth mentioning these challenges for clinicians especially after the recent therapeutic progress in order to highlight the atypical manifestations of extranodal lymphoma and to improve the management of these patients.We report the case of a 38-year-old woman with a one-month history of chest wheezing and a dry cough who did not respond to bronchodilators revealing the disease.

Case presentation
A 38-year-old woman presented to our department of Pneumology with a one-month history of dry cough and chest wheezing.She had never smoked.She has not any comorbidities or allergies.She has not a significant family history of neoplasia.She is a house-wife.She is Caucasian.She has often visited the emergency department in the last month for persistent chest wheezing.She had been given beta2-mimetics, without any clinical improvement.The physical examination at admission revealed a good general state.We noticed bilateral diffuse wheezing.Oxygen saturation was (98%) on room air.The examination of the ganglionar areas detected peripheral, bilateral, fixed supra-clavicular lymphadenopathy measuring about (2 cm of diameter).There was not an hepatosplenomegaly.The neurological examination was normal.
The chest X-ray showed a retractile opacity in the right chest with an hilar enlargement (Figure 1).

REVISED Amendments from Version 1
We are delighted to submit this new version of our case report according to the second reviewer's comments.We have made every attempt to fully address his comments in the revised manuscript.As mentioned, we agree that the extraganglionar Hodgkin lymphoma is not rare.However, the initial tracheobronchial involvement is uncommon.It does not exceed (4%) in antemortem series.We highlighted in this revised version that the diagnosis is so challenging giving that the symptoms are not specific and may mimic a wide spectrum of diseases such as (Asthma, COPD …) resulting in a diagnosis delay.In fact, most of the cases are discovered in autopsy series or during the follow up.Moreover, we have included many skilled specialists in clinical Haematology and Histopathology according to the second reviewer's request.We do believe that his insightful suggestions improved our manuscript.Indeed, his advice about a thorough revision of the format, the structure and the style were helpful.As suggested, our case report has been approved by a native speaker.However, we did not change the author list, the content, nor the list of figures and tables.
Below, we have outlined how we handled each of the second reviewer's comments.

Any further responses from the reviewers can be found at the end of the article
The body computed tomography (CT) scan revealed a bulky mediastino-hilar tumor in the right chest, measuring (90 Â 85 Â 71 mm), invading the right main bronchus, extending to the vena cava and infiltrating the pericardium with a subpleural right node as shown in Figures 2 and 3. Bronchoscopy showed a polypoid mass located in the carina, involving the right main bronchus.Cytology revealed malignant cells.Histopathology of the bronchial biopsy did not show any malignant lesions.Furthermore, we performed a biopsy of the supra-clavicular adenopathy.Histopathology revealed an intense staining for CD15 and CD30 with large multinuclear reed Sternberg cells.Therefore, the diagnosis of an Hodgkin lymphoma was confirmed.The 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed many sites of activity of the disease, with a high metabolic fixation of the FDG in the lymph node stations (1L,3,5,6,7,8,9,10,11R) as well as subphrenic adenopathy.Besides, it revealed an intense endotracheal metabolic fixation (Figures 4, 5).Moreover, the bone marrow biopsy was negative.So, the diagnosis of an advanced stage Hodgkin lymphoma (stage IV) was made.So, the patient received 4 courses of a combined BEACOPP chemotherapy protocol (Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone), as detailed in the table below (Table 1).She was readmitted in our department 2 months because of an acute respiratory failure associated with chest wheezing.Bronchoscopy revealed a bulky stenosing polypoid mass, measuring about 3 cm of diameter, rising from the carina  extending to the trachea and to the main bronchus that remains partially patent.Histopathology revealed large cells associated with an inflammatory granuloma of (lymphocytes, eosinophils, neutrophils …) and a positive staining for CD 15 and CD 30.Thus, we concluded to a tumoral progression with an endotracheobronchial relapse.
The decision of the multidisciplinary medical team was to put the patient on a second-line chemotherapy: IGEV regimen as a salvage therapy (Ifosfamide, Gemcitabine, Vinorelbine and Methylprednisolone).Moreover, injected Chest CT scan revealed a segmental pulmonary embolism.So, she had received a curative anticoagulant treatment.Unfortunately, she died one year after the initial diagnosis.

Discussion
It is well known that Hodgkin lymphoma usually involves the mediastinum.However, pulmonary involvement is less common and can be observed in the lymph nodes, parenchyma, and tracheobronchial tree. 1 It is worth mentioning that Hodgkin lymphoma with a tracheobronchial involvement remains extremely rare. 1 Patients usually present with respiratory symptoms (such as dyspnea, wheezing and cough), fever, and weight loss. 2 The diagnosis may be challenging because the symptoms are not specific.About (30%) of the patients have more than 6-months diagnosis delay. 3We should consider a tracheobronchial tumor in the differential diagnosis when the patient presents to our department with asthma symptoms without any improvement after bronchodilators.In our case, the patient complained of a dry cough and chest wheezing mimicking an asthma attack.She received Beta2-mimetics without any improvement.
Atelectasis is the most frequent radiological finding, occurring in (2/3) of patients.Besides, the chest CT scan may reveal a solitary hilar mass or an obstructive emphysema.Mediastinal or hilar lymphadenopathy are often present. 4doscopy may show ulceration, mucosal infiltrate, or a polypoid mass. 1 Our patient had a polypoid mass rising from the trachea extended to the main bronchus.
Histopathology shows typically large Sternberg cells with positive staining for CD15 and CD30. 3 The diagnosis was made thanks to a biopsy of the supra-clavicular adenopathy in this case.Recent studies suggest that endobronchial ultrasound (EBUS) may be useful in the diagnosis and staging of Hodgkin lymphoma with endobronchial involvement to avoid mediastinoscopy. 5 is worth mentioning that the PET scan is a reliable imaging tool for the diagnosis as well as for the staging of lymphoma especially in this case because mediastinal adenopathy may be due to infectious or inflammatory diseases. 6,7In our case, this exam revealed an intense metabolic fixation FDG in many ganglionar areas as well as an endotracheobronchial fixation.It is also very interesting for the follow-up.Treatment is commonly based on chemotherapy with or without radiotherapy.It depends strongly on the extent of the disease, the general state and the comorbidities. 8Complete resection of the stenotic tracheal tumor may be performed in patients with critical airway obstruction thanks to interventional procedures such as rigid bronchoscopy with a stent placement, photodynamic laser therapy, laser therapy with a neodymium: yttrium-aluminum-garnet laser (Nd-YAG) and photodynamic laser therapy. 9,10lapsed Hodgkin lymphoma is another challenging problem for clinicians especially when it affects the tracheobronchial tree as seen in our case.Prognostic Factors associated to the relapse of the disease have been recently identified including: a poor performance status (PS), an age greater than 50 years old, failure to achieve remission after an initial therapy, anemia and an advanced lymphoma with a clinical staging (III or IV). 11

Conclusion
To conclude, we report a rare case clinical presentation of Hodgkin lymphoma with an endobronchial involvement.It should be considered in the differential diagnosis of asthma or in case of a tracheal tumor.Further studies are required in order to highlight the importance of interventional endoscopy procedures in the diagnosis as well as in the treatment of these cases and to find out the prognostic factors in order to improve the outcomes.

Consent
Written informed consent for publication of their clinical details and/or clinical images was obtained from the family of the patient.
lymphadenopathy.Initial imaging revealed extensive mediastinal disease (up to 90 mm) with infiltration of the pericardium and right mainstem bronchus, the latter of which was also visualized bronchoscopically as a polypoid carinal mass.Diagnosis was based on histopathology of an involved lymph node.PET scan showed extensive foci of hypermetabolism, including the tracheal lesion and lymph nodes above and below the diaphragm.The patient was treated with front-line BEACOPP therapy; however, primary refractory disease was confirmed just two months later.A salvage IGEV regimen was then employed, but the patient expired roughly one year after the initial diagnosis.
I have the following general comments/criticisms of the manuscript.I think it's very misleading to describe or compare this case to primary endobronchial Hodgkin lymphoma, as this patient presented with palpable lymphadenopathy and more widespread disease on imaging.Lung/airway involvement by Hodgkin lymphoma is not particularly uncommon, especially in young adult patients with bulky intrathoracic disease.
The clinical presentation did include airway symptoms, but the diagnosis was readily obtained via conventional lymph node biopsy. 1.
The current WHO & ICC nomenclature for this entity is classic Hodgkin lymphoma, not Hodgkin's disease (antiquated terminology).I strongly recommend the addition of a hematopathologist to the authorship list, with the goal of improving the descriptions of the histopathologic findings.Further, the manuscript would likely benefit from having a microscopic image in support of this diagnosis, as well as formal staging information (presumably stage IIIA/IVA).

2.
The manuscript could use another round of proofreading for language, grammar and punctuation.

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?Partly

Is the case presented with sufficient detail to be useful for other practitioners? Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Diagnostic hematopathology; lymphoma biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.
Author Response 23 Aug 2023 DABOUSSI SELSABIL Dear Dr. Craig, Thanks a lot for your interest!We have included two specialists in clinical Hematology and a specialist in anatomopathology in order to improve the description of the lesions.Moreover, our therapeutic protocol was made according to the recent guidelines.
Extranodal lymphoma is not rare itsself.However, a primary clinical presentation of an extranodal lymphoma with an associated tracheobronchial involvement is so rare in antemortem series.It is often diagnosed in patients followed up for lymphoma during the follow up or in autopsy series.In fact,the diagnosis is so challenging given that the symptoms may mimic a wide spectrum of diseases like asthma or COPD as shown in our case report.Indeed, the bronchial biopsy is often negative.Thus, we aimed to highlight the importance of interventional endoscopy procedures in the initial diagnosis and during the follow up.Moreover, the tracheobronchial relapse is unusual.As you know, the Hodgkin lymphoma invades typically the lymph nodes.
Finally, we aimed to highlight the atypical manifestations of lymphoma in order to increase the awareness of clinicians and improve the prognosis.Since an early diagnosis implies an early treament, it would alleviate the burden of the disease.Besides, we really hope to share this case with other experts in order to find out better therapeutic stratgies.Our patient died despite a combined chemotherapy and a strict follow-up.The treatment of an advanced stage lymphoma is usually aggrssive with a poor prognosis.The median survival does not exceed some months in our developing countries.It would encourage experts to carry on new researchers in this field.

Kind regards Saidane Asma Military hospital
Competing Interests: All the authors declare that they don't have any conflict of interest.
Reviewer Report 10 May 2023 https://doi.org/10.5256/f1000research.143726.r171452University of Missouri, Columbia, MO, USA It's an interesting case report that addressed the importance of considering a tracheal tumor in the differential diagnosis of bronchial asthma when the patient presents with asthma symptoms without any improvement after bronchodilators.Although Hodgkin lymphoma with a tracheobronchial involvement remains extremely rare, the clinician should be aware of that and consider it in the differential diagnosis in order to diagnose the tumor in the early stage of the disease and save the patient's life.
I have a number of comments that the authors may find useful: The background of the case's history was very short, I encourage the authors to give more details about Hodgkin's disease.As well as more details about the patient's history in the (case presentation) would be helpful such as nationality, if she is married, occupation/environment, history of passive smoking, alcohol, family history, and other risk factors.Also, if the patient presented with any other symptoms such as unexplained fever or weight loss, fatigue, night sweating, and chest pain? 1.
The authors state that the patient visited the emergency room several times, I am wondering if the ER doctor performed a complete physical examination including the lymph node examination in order to discover the supra-clavicular lymphadenopathy.I am also wondering if the patient does not improve by the Beta agonist treatment, why the ER doctor does not order the chest X-ray during that time to exclude any other diseases? 2.
During respiratory auscultation usually, we used the term bilateral diffuse rhonchi instead of wheezing.Also, I suggest the authors include more details on the physical examination, such as the vital signs during the time of admission, and the general physical examination if the patient was conscious, oriented, dyspneic, tachypneic, anemic, any cyanosis and lower limb edema? 3.
On page #3, the authors mentioned (PET) scan that showed many sites of activity of the disease, with a high metabolic fixation of the FDG in the lymph node stations (1L,3,5,6,7,8,9,10,11R). Are the authors using the International Association for the Study of Lung Cancer (IASLC) to define the stations?Could you explain it in the paper if this is the case?Also, the patient was at which stage when Hodgkin's lymphoma was diagnosed? 4.
For Fig # 3; to be more clear, I think it's better to use the arrow to show the site of the bulky tumor which invades the carina.The same thing with Fig # 4, the CT mediastinal section, please add more description in the legend that would be helpful.

5.
For Fig # 4, looks like a blurry image and is not clear to me with little description in the legend.I encourage the authors to mention more details in each figure and use arrows and landmarks to be easier to understand the regions that are involved with tumors.

6.
I am wondering as I did not see any blood test results or requested such CBC, ESR, CRP, Blood film, etc.? Have physicians requested?I think it's worth mentioning it in the case report by making a table of the blood test results even if it is normal.

7.
I think more details on the BEACOPP chemotherapy protocols would be helpful such as 8. regimens, dosage, and for how long the patient received it.Additionally, if there was any follow-up CT or PET scan done after the patient received chemotherapy.Does the patient receive any radiotherapy or immunotherapy?It appears the patient does not have regular follow-ups with her doctor after receiving the chemotherapy as she developed acute respiratory failure as a result of bulky stenosing polypoid mass which was diagnosed by bronchoscopy and unfortunately she also developed segmental pulmonary embolism.I encourage the authors to address if the patients were on regular follow-ups in the case presentation section or not.Reviewer Expertise: My area of expertise in research is the neuronal control of the Cardiorespiratory system during exposure to hypoxia by using the transgenic animals model.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
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Figure 1 .
Figure 1.Chest X-ray showing a retractile opacity in the right chest with hilar enlargement.

Figure 2 .
Figure 2. Coronal section of the computed tomography chest demonstrating a bulky tumor invading the carina, the right main bronchus, the pericardium with a subpleural right node.

Figure 3 .
Figure 3. CT mediastinal section showing an important mediastino-hilar mass infiltrating the right main bronchus.

Figure 4 .
Figure 4.A PET scan image showing hypermetabolic lymph nodes.

Figure 5 .
Figure 5.A PET scan image showing the subphrenic ganglionar fixation of the FDG.

9 .
Is the background of the case's history and progression described in sufficient detail?PartlyAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?PartlyIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?YesIs the case presented with sufficient detail to be useful for other practitioners?YesCompeting Interests: No competing interests were disclosed.