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 Table of Contents  
Year : 2022  |  Volume : 3  |  Issue : 2  |  Page : 52-57

“Chronic refractory cough with dyspnea” as presenting feature of metastatic renal cell carcinoma: “Beaded Interlobular Septum” on HRTC Thorax Needs Cautious Workup to Rule out Underlying Malignant Pathology

1 Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India
2 Nivaran Scan and Imaging Center, Latur, Maharashtra, India
3 Department of Pathology, MIMSR Medical College, Latur, Maharashtra, India

Date of Submission02-Jan-2022
Date of Decision10-Feb-2022
Date of Acceptance23-Feb-2022
Date of Web Publication15-Jun-2022

Correspondence Address:
Shital Patil
Department of Pulmonary, Medicine, MIMSR Medical College, Latur, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jascp.jascp_2_22

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Cough is the most common respiratory symptoms with infective and noninfective etiological factors involving upper and lower airways. Chronic refractory cough (CRC) has limited etiology and associated symptoms play a crucial role in differentiating it from underlying benign to malignant pathology. Computed tomography (CT) thorax has a vital role in evaluating “CRC with dyspnea” and findings like interlobular septal thickening with nodules will be good answer to etiology. “Beaded interlobular septum with nodules, and enhancing cannonball like nodule” clinching causative factor may be malignant process outside the thoracic cavity. In this case report, a 52-year male presented with CRC and documented lymphangitis with nodule on high-resolution computed tomography thorax and CT abdomen documented right renal mass, ultrasound-guided right renal biopsy documented renal papillary carcinoma. Renal metastasis which predominantly involves both lymphatic and hematogenous route, and propensity of these metastases are hyper-vascular type and presenting with lymphatic interlobular septal dissemination with lymphatic edema resulting in refractory chronic cough with dyspnea which is refractory to steroids and bronchodilators.

Keywords: Beaded interlobular septal thickening, cannonball nodule, refractory cough, renal papillary carcinoma

How to cite this article:
Patil S, Deshmukh A, Gundawar R. “Chronic refractory cough with dyspnea” as presenting feature of metastatic renal cell carcinoma: “Beaded Interlobular Septum” on HRTC Thorax Needs Cautious Workup to Rule out Underlying Malignant Pathology. J Appl Sci Clin Pract 2022;3:52-7

How to cite this URL:
Patil S, Deshmukh A, Gundawar R. “Chronic refractory cough with dyspnea” as presenting feature of metastatic renal cell carcinoma: “Beaded Interlobular Septum” on HRTC Thorax Needs Cautious Workup to Rule out Underlying Malignant Pathology. J Appl Sci Clin Pract [serial online] 2022 [cited 2023 Mar 28];3:52-7. Available from: http://www.jascp.org/text.asp?2022/3/2/52/347595

  Introduction Top

Cough is the most common respiratory symptom, and reason for attendance in majority of outdoor setting ranging from general physicians to specialty clinics here in India. As per the American College of Chest Physicians guidelines cough can be classified according to duration of illness into acute cough lasting for <3 weeks, subacute cough lasting for 3 to 8 weeks, chronic cough lasting for 8 weeks and more.[1],[2] Chronic refractory cough (CRC) is persistent type of cough irrespective of all possible medicines used to treat or partially responding to cough suppressants.

Although cough is a vague respiratory symptom, which is commonly observed in upper and or lower respiratory tract involvement, associated symptoms such as chest pain, dyspnea, hemoptysis, fever, and anorexia will help in localizing the probable origin of cough in respiratory tract. Commonly, chronic cough is caused by upper airway cough syndrome or postnasal drip, bronchitis and bronchial asthma, eosinophilic bronchitis, gastroesophageal reflux, chronic bronchitis, occupational irritants, bronchiectasis, cystic fibrosis, pulmonary neoplasms, and drugs such as angiotensin-converting enzyme inhibitors.[1],[2]

Chest radiology is an important tool in evaluating these cases with CRC, and if initial chest radiograph is normal, high-resolution computed tomography (HRCT) should be done to rule out underlying interstitial or mediastinal pathology.

In this case report, we have documented metastatic malignant lung disease with interstitial involvement secondary to primary renal cell cancer as cause a cause for “CRC with Dyspnea.”

  Case Report Top

A 52-year-male, driver by occupation, tobacco addict, moderately nourished presented with recurrent chronic cough with duration of illness approximately more than 3 months.

He was referred to our center being center for clinical excellence, and his clinical history as:

Cough-dry, persistent for 3 months, no any diurnal or postural variation, increased intensity over 3 months, associated with breathlessness. No hemoptysis, chest tightness, or wheezing.

Breathlessness-initially having SJRQ I and progressed to SJRQ IV score over 3 months' duration, no chest pain, no palpitations, no sweating/perspiration, no fatigability no fever or weight loss over 3 months' period.

He consulted for similar symptoms to multiple general physicians to internal medicine experts and treated with symptomatic treatment approach with oral medicines including bronchodilators and cough expectorants to cough suppressants. He told during interview that he had consumed at least 100 bottles of various cough mixtures without any relief and multiple antibiotics taken without any response.

One internal medicine specialist had done chest X-ray and started on him on inhaled long acting beta agonist (LABA)- Inhaled corticosteroids (ICS) combination by labeling him as case of “cough variant asthma” his chest X-ray (done 2 months before) was showing nodular opacities bilaterally but predominantly left lower zones and these are missed by internal medicine specialist and radiologist working in rural setting [Image 1].

Clinical examination was showing plethoric face with hyperpigmented lips and malar pigmentation, tachypnea, oxygen saturation at room air was 95% resting and 91% other vital parameters like heart rate, blood pressure was normal.

Respiratory system examination revealed breath sounds normal on both lung fields with adventitious sounds as crackles heard bilaterally with wheezing heard on bilateral bases on forceful expiration.

Other systemic examination was normal. Routine blood investigations including biochemistry were performed, documented. Hemoglobin - 17.2 g% platelets - 5.26 lakhs/uL, total white blood cell counts - 13,400/mm3. Blood sugar level, lipid profile was normal. Liver and kidney functions tests were normal. Viral markers including HBsAg, HCV, and HIV were negative. We have asked details of cough to the attending relatives, and his wife told us that he had consumed at least 300 cough suppressant bottles for persistent cough and consulted many general physicians for refractory cough.

We have repeated chest X-ray as initial screening was falsely labeled as normal and documented nodules with ground glass opacifications in bilateral lower lung fields [Image 2] also nodular opacity documented in the left lower zone [Image 3].

We have proceeded to HRCT thorax as chest X-ray were showing bilateral nodular opacities. HRCT thorax [HRCT Thorax [Image 8] and [Image 9]] were showing bilateral peri-lymphatic nodules, with thickened interlobular septa, beaded interlobular septa, bilateral lung parenchymal nodules, cannonball nodule in the left lower lobe [HRCT Thorax [Image 8] and [Image 9]]and incidental findings of the right anterior segment cystic bronchiectasis [Image 4], [Image 5], [Image 6], [Image 7].

As HRCT thorax suggestive of the possibility of underlying metastatic lung pathology (beaded septum plus nodules, enhancing cannonball nodule in left lower lobe), we have advised for computed tomography (CT) abdomen to rule out primary visceral malignancy from liver, colon, kidney.

Contrast-enhanced CT Abdomen [Image 8] and [Image 9] done suggestive of large well defined rounded isodense to hypodense lesion of size 6.5 cm × 4.5 cm size arising from midpole of right kidney with large exophytic component posteromedially with heterogeneous enhancement on contrast study with loss of surrounding fat planes [Image 8] and [Image 9].

We have taken oncology and urology opinion regarding histopathology confirmation of right kidney mass and two different school of thoughts came up with one suggesting for radical nephrectomy with histopathology evaluation of nephrectomy specimen, while second school of thought suggested image ultrasound (USG)-guided right renal biopsy although the risk of intra-abdominal hemorrhage is high being hypervascular renal tumor.

Interventional radiologist performed image-guided renal biopsy and four passes have been taken and sent for histopathology analysis.

Histopathologist reported as:

Gross examination: Received very scanty fragile white tissue bits (tissue could be lost during processing), whole processed.

Microscopy: Section reveals very scanty tissue as lymphocytes and discrete epithelial cells. No any renal parenchymal tissue was included. No any opinion possible.

Impression: Scanty tissue, no opinion possible.

As first USG-guided renal biopsy specimens were inconclusive may be because more fat in these specimens and fatty tissue has been washed or lipolyzed with formaldehyde solution, we have decided with repeat renal biopsy.

This time, we have again performed USG guided renal biopsy but taken 10 passes of biopsy specimens and sent for histopathology analysis [Image 10] and [Image 11].

This time we have finished biopsy procedure after enough passes and biopsy material collected, and possibility of fatty tissue burnout in formalin container is avoided being more heterogeneous material and sent for analysis.

We have documented minimal bleeding during procedure and the patient complaining of moderate to severe abdominal, lumbar pain after biopsy which has been subsided with analgesic infusion. After 1 h, we have repeated USG abdomen to confirm nothing significant intra-abdominal (perirenal) bleeding.

Histopathology analysis [Image 12].

Gross: Received tiny tissue cores, aggregating to 0.7 cm × 0.8 cm, whole processed.

Microscopy: Section reveals a papillary neoplasm as slender papillae, interconnecting glands, elongated tubules with cells displaying low-grade nuclear pleomorphism. No clear cell morphology noted.

Impression: Right renal papillary carcinoma (type I).

The patient was referred to “tumor board” meeting with multidisciplinary team of oncologist, urologist, pathologist, radiation oncologist, and pulmonologist, and decided for radical partial nephrectomy with immunotherapy.

  Discussion Top

CRC needs a battery of investigations to document the source of origin in presence of associated dyspnea, and HRCT thorax is crucial investigation in evaluation these cases; as majority of these cases were having normal chest radiograph. Bronchoscopy is also an important tool in CRC as these cases may have underlying infective, inflammatory, or malignant lung pathology resulting into refractory nature of cough.[3]

Bronchoscopy will help in documenting endoluminal or endobronchial abnormality and HRCT thorax will help in differentiating lung parenchyma, pulmonary vasculature, lung parenchyma, interstitial, pleural, and mediastinal pathology as cause for CRC with dyspnea.

Differential diagnosis of chronic cough

Our center approach for management of chronic cough

Interlobular septum is the supporting framework of lung, composed of lymphatic vessels, interstitial smooth muscles, and vasculature. Pulmonary lymphatic vessels are found along the veins and bronchovascular sheaths, as well as in the interlobular septa and pleura. Interlobular septal thickening (ILST) has been documented in various infective etiologies, inflammatory pathologies such as interstitial lung diseases and malignant lung process. HRCT thorax is “gold standard” investigation to diagnose interstitial lung pathology. CT findings usually differentiated into smooth and nodular or beaded-type on the basis of ILST in Subpleural, Interlobular, and peribronchovascular interstitium.

Lymphangitis carcinomatosis is spread of malignant tumor across lymphatic channels and when it occurs in pulmonary interstitial lymphatics, called as pulmonary lymphangitis crcinomatosis. The term “pulmonary lymphangitis carcinomatosis” (PLCs) was first used by Troisier in 1873 to describe diffuse infiltration of the lymphatics of both lungs by malignant cells.[4] Most PLCs originate from an adenocarcinoma with primaries frequently noted in the breast, stomach, lung, pancreas, and prostate. PLC may develop in a bilateral symmetric fashion following hematogenous emboli initially lodging in smaller pulmonary arteries and subsequently spreading through the vessel walls into the perivascular interstitium and lymphatic vessels.[5]

Many patients with ILST present with dry cough with progressive dyspnea and showing refractory nature of cough to all possible medicines and these cases may have labeled as asthma, pneumonia, and tuberculosis in tropical setting like India. These cases with underlying malignancy are always missed or diagnosis of exclusion and high index of suspicion is must as many cases are having either normal chest radiograph or nondiagnostic in more than half cases, and HRCT has a crucial role. Common findings on HRCT include thickening of inter-lobular septa and bronchovascular interstitium giving a characteristic “dot in box” appearance, sub-pleural nodules, and thickening on the interlobar fissures, pleural effusion (s), pleural carcinomatosis, hilar and mediastinal nodal enlargement (40%–50%) with relatively little destruction of overall lung architecture[6]

We have documented nodular ILST presenting along with peribronchovascualr, subpleural interstitium, and conglomerated nodules with masses randomly distributed in lower lung fields.

Nodular ILST is documented in:

  1. Lymphangitis carcinomatosis (secondary to the lung itself or visceral malignancies of adenocarcinoma histological type)
  2. Pulmonary sarcoidosis
  3. Pulmonary Amyloidosis
  4. Silicosis
  5. Lymphoma and lymphoproliferative diseases, lymphocytic interstitial pneumonia.

In our case report, we have documented visceral malignancy arising kidney and metastasis to lung and presenting as CRC with dyspnea and HRCT was showing nodular ILST with beaded septum appearance. Renal cell carcinoma (RCC) typically metastasizes to the lung, bone, lymph nodes, liver, adrenal glands, and brain. Sixty-one percent of patients with RCC have metastatic disease in a single site, and 39% have metastases in multiple sites; younger patients are more likely to have multiple metastatic sites. Pulmonary metastases account for 45% of all metastases from RCC, thus representing the most common anatomic site of disseminated RCC. Pulmonary metastases are usually asymptomatic (90% of cases). On CT images, they manifest as multiple nodules (75.6% of cases) or solitary nodules (30.5% of cases). Lesions are usually well-circumscribed, round or oval, smaller than 2 cm, and in subpleural locations. However, RCC is one of the well-known causes of “cannonball” metastases (i.e., lesions >5 cm in diameter).[7]

As renal metastasis is hypervascular presenting like pulsatile metastasis as seen with thyroid malignancies, these cases clinically behave like interstitial pulmonary edema and predominant earlier presentation is cough and later on progress to CRC with dyspnea. After antiangiogenic therapy, lung metastases of RCC, especially the larger lesions, may show necrosis and cavitation.[7]

The development of metastatic disease can also be predicted on the basis of histologic subtype of the primary RCC. Patients with clear cell RCC which is the most common subtype, representing 75%–80% of all RCCs, according to the Heidelberg classification have the highest risk of developing metastatic disease. More than 90% of patients with metastatic RCC have clear cell RCC. The remaining 10% of patients with metastatic RCC have a heterogeneous group of nonclear cell RCC subtypes, including papillary, chromophobe, collecting duct, and unclassified RCC.[8]

We have suspected malignant process is a reason for CRC with dyspnea due to poor response to bronchodilators, steroids and diuretics, and beaded nodular septum on HRCT thorax and CT abdomen showing renal mass. As renal biopsy is contraindicated in suspected renal cancer, oncosurgeon and nephrologist denied for renal biopsy due to chance of catastrophic intra-abdominal bleeding postprocedure, due to hypervascular nature of tumor. Interventional radiologist agreed for renal biopsy with proper counseling of patient and relatives.

We have performed renal biopsy without any adverse event documented postprocedure, adequate tissue material obtained and diagnosed as renal papillary cancer is probable cause for lung metastasis and clinical presentation as CRC with dyspnea.

Hypervascular nature of metastasis is the reason of persistent or partially responding lymphatic pulmonary edema secondary to ILST and very poorly responding to bronchodilators, steroids, and diuretics.

Indications for percutaneous renal mass biopsy as per our clinical experience and intuitional protocol are:

  1. Suspected renal mass from extrarenal primary
  2. Inoperable or unresectable renal mass
  3. Renal mass with underlying comorbidities or poor performance status, where the risk of biopsy outweighs risk of surgery
  4. Renal mass-like pathology with underlying suspected infective process.

Clinical pearls learned from this case are:

  1. Although cough is the most common respiratory symptom with various etiological factors, refractory cough with dyspnea needs prompt evaluation to differentiate benign etiology from malignant one
  2. HCRT thorax is “core investigation” while evaluating these cases. Lymphangitis carcinomatosis is vague manifestation of extra-thoracic and thoracic lymphohematogenous dissemination of malignant process, and beaded septum with cannonball nodule is clue toward to rule out thyroid or renal malignant process
  3. Refractory nature of cough with dyspnea which was transiently responding to steroids and bronchodilators may indicate hypervascular nature of metastatic lung pathology
  4. Renal papillary carcinoma has a propensity toward lung metastasis and causing beaded interlobular septum with cannonball nodules on HRCT thorax
  5. USG-guided renal biopsy is easy, relatively safe, and cost-effective tool to diagnose renal cancer than to undergo a conventional treatment approach as “radical nephrectomy”
  6. Nephrectomy is preferred as hypervascular nature of renal cancer and chances of catastrophic intra-abdominal hemorrhage which is unpredicted in image-guided renal biopsy
  7. We documented safety of USG-guided renal biopsy without any adverse events
  8. High index of suspicion and multidisciplinary approach is must while dealing cases with “refractory cough with dyspnea” to categorize from asthma to metastatic lung process.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Irwin RS, French CL, Chang AB, Altman KW; CHEST Expert Cough Panel. Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest 2018;153:196-209.  Back to cited text no. 1
Morice AH, Millqvist E, Bieksiene K, Birring SS, Dicpinigaitis P, Ribas CD, et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J 2020;55:1901136. DOI: 10.1183/13993003.01136-2019.  Back to cited text no. 2
Bruce DM, Heys SD, Eremin O. Lymphangitis carcinomatosa: A literature review. J R Coll Surg Edinb 1996;41:7-13.  Back to cited text no. 3
Yu L, Xu X, Niu S. Should computed tomography and bronchoscopy be routine examinations for chronic cough? J Thorac Dis 2020;12:5238-42.  Back to cited text no. 4
Soares FA, Pinto AP, Landell GA, de Oliveira JA. Pulmonary tumor embolism to arterial vessels and carcinomatous lymphangitis. A comparative clinicopathological study. Arch Pathol Lab Med 1993;117:827-31.  Back to cited text no. 5
Marchiori E, Zanetti G, Hochhegger B. Interlobular septal thickening. J Bras Pneumol 2016;42:161.  Back to cited text no. 6
Motzer RJ, Bacik J, Mariani T, Russo P, Mazumdar M, Reuter V. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 2002;20:2376-81.  Back to cited text no. 7
Jinzaki M, Tanimoto A, Mukai M, Ikeda E, Kobayashi S, Yuasa Y, et al. Double-phase helical CT of small renal parenchymal neoplasms: Correlation with pathologic findings and tumor angiogenesis. J Comput Assist Tomogr 2000;24:835-42.  Back to cited text no. 8


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