Keywords Cough - paraneoplastic syndrome - prostaglandins - renal cell carcinoma
INTRODUCTION
Renal cell carcinomas (RCCs), which originate within the renal cortex, constitute
80–85% of primary renal neoplasms. The classic triad of RCC (flank pain, hematuria,
and a palpable abdominal renal mass) occurs in approximately 9% of patients; when
present, it strongly suggests locally advanced disease. Other symptoms and signs are
related to invasion of adjacent structures or distant metastases.[1 ]
RCC may also be associated with a number of paraneoplastic syndromes. These are typically
due to ectopic production of various hormones (erythropoietin, parathyroid hormone–related
protein, gonadotropins, human chorionic somatomammotropin, renin, glucagon, and insulin).[2 ]
Very few cases have been reported as nonmetastatic RCC presenting with persistent
cough.
CASE REPORT
A 69-year-old male presented to the emergency department with new onset persistent
dry cough. He denied any fever, chills, rhinorrhea, and myalgias. He has no significant
past medical history and takes no chronic medications. He has no known drug or environmental
allergies. Vitals signs showed heart rate of 88 beats per minute, respiratory rate
of 16 breaths per minute, and blood pressure of 135/85mm Hg. His physical exam was
unremarkable except for mild diffuse expiratory wheezes on lung auscultation. A chest
X-ray was clear. Laboratory values including a complete blood count and comprehensive
metabolic panel were also normal. He was given dextromethorphan liquid and inhalational
albuterol with complete resolution of symptoms, and he was discharged home with instructions
to follow-up with his primary care physician. Two weeks later, his cough recurred,
however, associated with left-sided chest pain. He re-presented to the emergency department.
A computed tomography (CT) angiography of the chest was performed to rule out pulmonary
embolism. No pulmonary pathology was found; however, he did have a 4.3-cm left renal
mass most compatible with RCC [Figure 1 ].
Figure 1: Axial lower section of computed tomography scan of the chest with intravenous
contrast showing an incidental left renal mass suggestive of renal cell carcinoma
He was admitted to the hospital and CT of the abdomen and pelvis showed no evidence
of metastasis. An magnetic resonance imaging of the abdomen showed irregular enhancing
5-cm mass on the left kidney [Figure 2 ] and [Figure 3 ] most consistent with RCC.{Figure 2}, {Figure 3}
Figure 2: Coronal section of magnetic resonance imaging of the abdomen demonstrating
an irregular enhancing 5-cm mass on the left kidney most consistent with renal cell
carcinoma
Figure 3: Axial section of magnetic resonance imaging of the abdomen demonstrating
an irregular enhancing mass on the left kidney most consistent with renal cell carcinoma
He was scheduled for laparoscopic nephrectomy. Prior to his nephrectomy, he had several
exacerbations of cough with asthma-like episodes including wheezing and dyspnea. These
responded well to corticosteroids. He underwent left radical nephrectomy. Surgical
pathology confirmed clear cell RCC, Fuhrman nuclear grade 2. The margins of resection
are free of tumor. No lymph node identified. Postoperatively his cough resolved. One
year has passed and he is cough free.
DISCUSSION
This patient had very unusual presentation of nonmetastatic RCC with cough. It has
been suggested that RCC secretes prostaglandins (mainly E2) that can cause cough reflex
through the prostaglandin E receptor 3 pathway.[3 ]
There are a number of reasons why we believe the patient’s cough was directly related
to his RCC. The patient never had asthma or cough previously. His symptoms coincided
with his RCC. Imaging showed no metastasis to lung or extension of tumor to the diaphragm,
which in some cases can cause cough through direct irritation. Symptoms were resolved
after nephrectomy, which supports the theory that RCC induced cough via secretion
of prostaglandins. Cough receptors are situated in the larynx and the tracheobronchial
tree; C-fiber receptors may contribute. Postnasal drip, asthma, and gastroesophageal
reflux disease are the underlying causes of chronic cough in almost 90% of cases.[3 ],[4 ] Angiotensin-converting enzyme inhibitors can cause cough through accumulation of
bradykinin.[5 ]
Okubo et al .[6 ] reported a case where a patient had weight loss and intractable cough, and was found
to have RCC that was surgically removed and cough symptoms were resolved for 7 months.
The patient’s cough recurred and patient was found to have metastatic recurrence of
RCC. Mastectomy was performed with complete removal of the tumor and after 18 months
patient remains cough free.
Benzodiazepines has been suggested to alleviate severe cough symptoms in those patients
as Estfan and Walsh[7 ] reported a case of intractable cough in a patient with metastatic RCC that only
responded to diazepam. Fujikawa et al .[8 ] reported a case of a patient with RCC who developed a refractory cough, which was
immediately resolved after tumor embolization. Similarly, Roberts et al .[9 ] reported a case of chronic cough, fever, and weight loss and incidental discovery
of RCC; his symptoms were completely resolved within 24h after nephrectomy.
Unlike other reported cases, our patient did not have other signs or symptoms suggestive
of malignancy or RCC, such as weight loss, fever, anemia, or hematuria that warrants
further workup. He solely presented with cough prior to RCC diagnosis contrary to
other cases that had a diagnosis of RCC prior to presenting with cough.
Unfortunately neither our case, nor other reported cases demonstrated an increase
in the levels of serum prostaglandins or bradykinins. However, all developed persistent
cough, which was refractory to usual treatment, and a diagnosis of RCC was made. Following
nephrectomy a complete resolution of cough was noted.
This case report details the importance of thorough evaluation of refractory cough
and physician should consider occult RCC as a possible etiology, in the absence of
more common suggestive signs or symptoms such as anemia. RCC can present in various
ways; some are common and some are extremely rare. All are linked to paraneoplastic
etiology. We searched literature and summarized all of those presentations [Table 1 ]
[16 ].
Table 1
Drugs
Paraneoplastic Syndrome
Incidence
Prognostic or treatment monitoring significance
Highest level of Evidence
Pathogenesis
ACTH: Adrenocorticotropic hormone, HCG: Human chorionic gonadotropin, AA: Amyloid
type A, N/A: Not Available, PTHrP: Parathyroid hormone-related protein. aAnemia can
be a paraneoplastic syndrome due to Lactoferrin secretion or due to hematuria. bHypercalcemia
can be a paraneoplastic syndrome secondary to PTHrP and Prostaglandins secretion or
due to bony metastasis. cPotential mechanisms of hypertension in these patients include
increased renin secretion, ureteral or parenchymal compression, presence of an arteriovenous
fistula, and polycythemia. dNephrectomy may result in the amelioration of hepatic
dysfunction. Recurrent elevations of liver enzymes after nephrectomy may herald local
recurrence or distant metastatic disease. It is crucial for all medical practitioners
to be aware of different presentations of RCC which can lead to early diagnosis and
treatment. In essence, decreasing morbidity and mortality associated with such devastating
disease. Abbreviations: Adrenocorticotropic hormone (ACTH), Human chorionic gonadotropin
(HCG), Amyloid type A (AA), Not Available (N/A), Parathyroid hormone-related protein
(PTHrP).
Anemia[2 ]
29-88%
N/A
Prospective studies
Lactoferrin secretion by tumora
Hypercalcemia[2 ]
[10 ]
13-20%
Correlates with higher stage and decrease survival
Prospective studies
PTHrP secretion by tumorb
Constitutional (fever weight loss and fatigue)[2 ]
[11 ]
20 - 30%, fever being most common
N/A
Prospective studies
Prostaglandins secretion by tumor
Hypertension[2 ]
[11 ]
Hypertension among age- matched controls is close to 20%, almost 40% of those with
RCC experience hypertension.
N/A
Prospective studies
Renin secretion by tumor Elevated levels in 37% in RCC and 87% in Wilms' tumor.
Non metastatic Hepatic Dysfunction[12 ] (Stauffer's Syndrome)
3 - 20%
Poor prognosisd
Prospective studies
Hepatotoxins or lysosomal enzymes secreted by RCC that stimulate hepatic cathepsins
or phosphatases, which leads to hepato-cellular injury.
Polycythemia[2 ]
[11 ]
1 - 8%
No prognostic significance Erythropoietin levels may have a role as marker of therapeutic
response.
Prospective studies
Erythropoietin secretion by tumor
Secondary AA Amylodosis[13 ]
4 %
N/A
Case Reports
Mechanism of amyloid production in RCC is not well understood but may involve prolonged
stimulation of the immune system by growth of the malignancy or tumor necrosis.
Thrombocytosis[14 ]
Not reported
Poor prognosis
Retrospective Cohort
Mechanism is not firmly established but could be related to IL-6 production by the
tumor
Polymyalgia Rheumatica[15 ]
Few Cases
N/A; resolved after nephrectomy
Case Reports
Unknown. Did not respond to Prednisone.
Amyotrophic lateral sclerosis[16 ]
Few Cases
N/A; resolved after nephrectomy
Case Report
Unknown
Endocrinopathies (elevated ACTH, HCG, Prolactin, Insulin, Glucagon; resulting in Cushing,
Galactorrhea, Hypoglycemia and Hyperglycemia)[11 ]
Not reported
N/A
Case Reports
Secretion of these hormones by tumor
Others (Light chain nephropathy, vasculitis and coagulopathies)[11 ]
Not reported
N/A
Case Reports
Unknown
