P&S Medical Review: Oct 1994, Vol.2, No.1
Pulmonary Lymphangiomyomatosis in Tuberous Sclerosis: Association with Chronic Renal Failure

JONATHAN L. BRISMAN, ANDREW J. KIRSCH, JOHN A. TAYLOR, BARRY D. BIRCH, HANINA H. HIBSHOOSH, AND STEVEN A. KAPLAN
Departments of Urology, Squier Urological Clinic, and Pathology

ABSTRACT

Progression to renal failure in tuberous sclerosis patients is a rare phenomenon. Only twenty-nine such cases have been reported in the literature. Similarly, pulmonary lymphangiomyomatosis (honeycomb lung) is an uncommon complication of tuberous sclerosis occurring in less than 1% of patients. In reported cases of tuberous sclerosis and chronic renal failure, there have been no reported cases with known cystic lung disease. We present the first case of tuberous sclerosis with concomitant end-stage renal failure and cystic lung disease consistent with lymphangiomyomatosis as well as a review of the current literature.

CASE REPORT

A 28-year old black woman with tuberous sclerosis was admitted to our medical center with left flank pain and gross hematuria. Medical history was significant for bilateral renal cystic disease and seizures until age eleven. At age 21, she was diagnosed as having bullous lung disease with obstructive and restrictive features. She has had several tube thoracostomies for spontaneous pneumothoraces and requires home oxygen therapy. At age 26, she was begun on hemodialysis for end-stage renal failure. Family history is noteworthy for tuberous sclerosis and polycystic renal disease in her brother and father, who died at age 42. She was of average intelligence while her father and brother were mildly retarded. She was awaiting renal transplantation.

Physical examination revealed a cachectic woman with adenoma sebaceum across her nasal labial folds and malar aspect of her face. She was lethargic, diaphoretic, hypotensive and tachycardic. Her chest was clear to auscultation bilaterally. The abdomen was softly distended with significant left flank and costovertebral angle tenderness. Rectal examination revealed no evidence of blood. A Foley catheter was placed and gross hematuria was noted. Laboratory values included a hematocrit of 17%, blood urea nitrogen (BUN) 76 mg/dl and creatinine 9.9 mg/dl Electrolytes were within normal limits. Microscopic examination of her urine revealed packed red blood cells. There was no evidence of pneumothorax on chest x-ray.

After transfusion of six units of packed red blood cells, her hematocrit rose to 32%. Her hematuria decreased and she remained hemodynamically stable. A renal ultrasound revealed a hyperechoic mass in her left kidney and the presence of bilateral renal cysts. An abdominal and pelvic CT scan revealed a low attenuation 15cm mass in the left retroperitoneum, contiguous with the left kidney, which was consistent with hemorrhage. Bilateral renal cystic disease was also noted. A chest CT scan revealed multiple bilateral pulmonary cystic changes (Figure 1).

Figure 1

Angiography with selective embolization was considered but was felt to be too risky. She was then taken to the operating room where a left radical nephrectomy was performed through a thoracoabdominal incision. The gross pathological specimen was tan-yellow-white in color and measured 20.0 x 11.5 x 15.0 cm (Figure 2). No normal renal parenchyma was identified. The renal pelvis was replaced by approximately 50 unilocular cysts ranging in size between 0.5 - 1.0 cm. Histologic examination revealed a mixture of blood vessels, smooth muscle, and adipose tissue in varying proportions (Figure 3). There was no evidence of extension into the bowel, diaphragm, renal vein, or inferior vena cava. The final pathological diagnosis was angiomyolipoma with concomitant renal cystic disease and retroperitoneal hemorrhage. Her postoperative course was uneventful and she was discharged home in stable condition after one week. She died four months later of undocumented causes. An autopsy was not performed.

DISCUSSION

Tuberous sclerosis, a rare autosomal dominant disorder with variable penetrance, affects approximately 1 in 10,000 people with a point prevalence of 10 per 100,000.13 Classically, the disease is described as a clinical triad of adenoma sebaceum, mental retardation, and seizures. However, due to incomplete penetrance, symptomatology may range from isolated organ involvement, present in mild incomplete disease, or forme fruste, to involvement of multiple organs. The pathophysiology of tuberous sclerosis can include glial tumors of the brain, adenoma sebaceum of the skin, rhabdomyoma of the heart, and hamartomatous tumors of the thyroid, retina, liver, pancreas, lung, kidney, adrenals and ovaries.11,12

Figure 2

The most common renal lesions seen in tuberous sclerosis are angiomyolipomas (AML), affecting approximately 40-80% of patients.11 These hamartomas tend to be multiple and bilateral and consist of varying amounts of smooth muscle, blood vessels and fat. Renal cysts, seen in 25% of patients, are the second most common lesion seen in tuberous sclerosis.1 Although there is no evidence to suggest that AML is a pre-malignant lesion, and in fact malignant transformation has proven to be rare, Hartveit and Halleraker suggest that patients with tuberous sclerosis may be at an increased risk of developing renal cell carcinoma (RCC).5 The increased risk of RCC is thought to stem from a population of hyperplastic epithelial cells which line the renal cysts and are similar in nature to those found in von Hippel-Lindau disease.1

Typically renal lesions remain silent and are usually incidental findings at autopsy.2 However, they may present with gross hematuria, flank pain, abdominal pain, nausea, vomiting, fever, abdominal distention or simply as a mass.13 Although chronic renal failure (CRF) had rarely been described in the past it appears that the frequency of case reports is increasing. By 1982, only seven cases of chronic renal failure in tuberous sclerosis had been documented.11 By 1991, twenty-two additional cases were reported.8,9,14,15 One theory for the increased incidence of CRF is that tuberous sclerosis patients are living longer due to better medical management and neurosurgery, thus permitting the development of renal cystic disease.11 This is supported by the fact that twenty years ago mortality was 40% by age five and almost 75% by age twenty, whereas today the average patient with tuberous sclerosis can be expected to live well into their twenties.10 Once fatal, epileptic episodes are now better controlled with anti-convulsive medication and mortality attributed to such neurological complications has fallen dramatically.

The exact mechanism by which AMLs and renal cystic disease cause renal failure is not known. Okada et al. noted the rarity of renal failure in patients with tuberous sclerosis and associated renal cystic disease and hypothesized that the cysts, and not the AMLs, were the cause of renal failure.11 Additionally, they postulated that renal hamartomas may in fact be responsible for cyst formation by obstructing arterioles. This is supported by the observation that hamartomas without accompanying cystic changes are less often associated with renal failure than are hamartomas with concomitant cystic lesions.11 Their research also supported the idea that CRF in tuberous sclerosis patients would become more prevalent as these patients lived longer.

Figure 3

Pulmonary lymphangiomyomatosis (PLM) is a rare disease which results from benign proliferation of smooth muscle in lung and other organs. Patients with advanced disease may demonstrate cystic changes and honeycombing in their lungs, leading to a mixed picture of interstitial and obstructive disease. Common complications include pneumothorax, chylothorax, and hemoptysis. Due to the fact that women of reproductive age are predominantly affected by PLM, it was suggested that there might be a hormonal influence, and in fact estrogen receptors have been found in these lesions.7 Furthermore, the anti-estrogen drug Tamoxifen has proven beneficial in slowing the disease process.7

Cystic lung changes associated with tuberous sclerosis are exceedingly rare occurring in less than 1% of patients.3 These lesions are clinically and histologically similar to PLMs. Although there exists some doubt as to whether PLM is associated with tuberous sclerosis, the findings of estrogen receptors in the pulmonary lesions of tuberous sclerosis patients, the response of these lesions to Tamoxifen, and the association of these lesions with AMLs have led some to designate PLM as a forme fruste of the disease.7,15

There have been twenty-nine cases of tuberous sclerosis progressing to CRF,8,9,12,14 and to our knowledge none of these has been associated with angiomyolipomas and concomitant PLM. Whether there is an association between renal failure and PLM in tuberous sclerosis patients is not known. However, several possible explanations are proposed. First, the two entities progress along independent pathways and are late manifestations of the disease. Tuberous sclerosis is a disease of incomplete penetrance and the diagnosis is based on a constellation of clinical stigmata, some of which may or may not be present. The importance of various signs and symptoms required to make a diagnosis have been debated since the time the disease was first described.12 More specifically, it has been argued that due to the high prevalence of AMLs in tuberous sclerosis, AMLs of the kidney are a forme fruste of the disease.15 Likewise, it has been contended that PLM is a forme fruste of tuberous sclerosis as the lesions found in these patients so closely resemble those of non-tuberous patients.7

Another possibility is that the presence of CRF or cystic changes in the kidneys enhances pulmonary cystic disease. This theory stems from a series of articles written in the mid 1980's that elucidated the effects of estrogen and progesterone on PLMs.7 It had been shown previously that estrogen receptors are present in PLM specimens. Due to the fact that estrogens are excreted by the kidney in the form of sulfate esters, it is plausible that CRF or insufficiency may result in increased estrogen levels and accelerated progression of PLMs.

Patients with tuberous sclerosis can be expected to live longer due to better medical and surgical management. As this is a disease of incomplete penetrance one might expect to see an increase in the number and type of clinical manifestations as these patients age. Indeed, the number of reported cases of AML associated CRF has increased in recent years and we now present the first case with associated cystic lung changes. Whether there exists a direct relation between the two, or they are simply late manifestations of one disease, is a question that is yet to be answered.

College of Physicians and Surgeons, Class of 1995. Address correspondance to Andrew J. Kirsch, M.D., Columbia-Presbyterian Medical Center, Department of Urology, 622 W. 168th Street

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