Pulmonary choriostoma in a case of tuberous sclerosis complex.

A 52 years old lady was diagnosed to have Tuberous Sclerosis Complex (TSC) on the basis of 2 major and one minor criterion. She had family history of similar complaints in her sister and two sons. There was involvement of kidney in the form of angiomyolipoma, skin in the form of facial angiofibroma and teeth with a dental pit. She had an unusual lung involvement in the form of multiple small choristomas. Choristoma was diagnosed on transbronchial lung biopsy and was present in the form of disorganised striated muscles. The reported pulmonary manifestations of TCS i.e. lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH) are types of hamartomas. Hamartomas and choristomas are both types of disorganized tissue. 'Choristoma'of lung in TSC however is not reported. Clinopathological correlation of pulmonary hamartoma and choristoma, and treatment in TSC has been discussed.

Case Details

A 52 year old lady, normotensive, non-diabetic and non-smoker was referred to pulmonary medicine department of our institute for the evaluation of pulmonary nodules. She did not have significant respiratory complaints. She did however have a history of multiple admissions in the Medicine department during the past year for year for anaemia, anasarca and hydronephrosis. She also had history of non-progressive facial lesions since early childhood and similar lesions in one of her sons. Her sister died at the age of 40 of a seizure disorder. On examination, her vital parameters were normal. There were non tender, non- progressive, pale brown, papular lesions of about 2 to 8 mm over the cheeks. There was poor orodental hygiene with one dental pit found on oral examination. Systemic examination did not reveal any significant abnormality. Dermatological consultation diagnosed the skin lesions as facial angiofibromas (adenoma sebaceum). She was also detected to have mild mental retardation on psychiatric evaluation. Ophthalmological examination was normal.

Investigations

The routine biochemical and hematological investigations were normal except for iron deficiency anaemia (hemoglobin-9.8gms/dl). The computed tomography of kidney, ureter and bladder showed multiple variable sized focal masses containing macroscopic fats almost completely replacing bilateral renal parenchyma suggestive of bilateral renal angiomyolipoma [Figure 1]. The magnetic resolution imaging (MRI) of brain was normal as was the ECG and 2D ECHO. Endocrine evaluation showed hypothyroidism with thyroid stimulating hormone of 8.3IU/ml. An ultrasonography of the neck showed a 11 mm cystic lesion with thin septation in left lobe of thyroid. Thyroid scan showed mildly increased uptake with cold area in inferior pole of left thyroid. Fine needle aspiration cytology was consistent with a benign follicular nodule. The chest radiograph showed a few calcific lesions in both upper lobes with a few nodular lesions in lower lobes. High resolution computed tomography (HRCT) chest showed multiple randomly distributed nodules of about 4 to 13 mm in size in bilateral lung fields. Some of them showed calcification in the periphery and some of them were calcified completely. In addition there were cystic change in lingular region suggestive of localized lymphangioleomyoma [Figure 4a–d]. Spirometry showed restrictive pattern with forced vital capacity (FVC) 1.56 litre (55% predicted), forced expiratory volume in one second (FEV1) 1.28 litre (53%) and FEV1/FVC-82%.

Figure 1

CT of the kidney, ureter, and bladder showing multiple, variable-sized, focal masses containing fats replacing the bilateral renal parenchyma, suggestive of bilateral angiomyolipoma

Figure 4

HRCT of the chest showing multiple, randomly distributed nodules in the bilateral lung fields with calcification; calcified nodules marked with black arrows and noncalcified nodules marked with red arrows in (a-d) and cystic changes in the lingular lobe marked with an arrow in (b)

Pathological Findings

Lung tissue from the transbronchial biopsy showed largely normal lung tissue with one small bit showing a microcyst lined by cuboidal epithelium containing abnormally formed skeletal muscle with striations in the background of normal alveolar tissue suggestive of choristoma of lung [Figure 5a & b].

Figure 5

Transbronchial lung biopsy with (a) Hematoxylin and eosin (H&E) stain 100× magnification and (b) H&E stain 400× magnification showing abnormally formed skeletal muscle with striations (marked with an arrow) in the background of normal alveolar tissue

Clinical Diagnosis and Discussion

She was diagnosed to have tuberous sclerosis on the basis of two major criteria i.e. facial angiofibroma and angiomyolipoma of kidney. On family screening, one of her sons had mild mental retardation with multiple signal alteration seen in bilateral cerebral parenchyma in a nodular pattern, predominently located in the cortical region of bilateral high frontoparietal region on MRI of brain [Figure 2]. The other son had facial angiofibromas [Figure 3], renal angiomyolipoma and mild mental retardation.

Figure 2

One of the sons’ MRI of the brain showing cortical tuber

Figure 3

Another son's facial angiofibroma

Management

The Choristoma of lung and localized lymphangiomyoma did not require treatment. The patient refused surgical removal of angiomyolipoma. She was treated with sirolimus 2 mg per day for angiomyolipoma. The patient discontinued it after 2 months due to stomatitis and vomiting. She was also given levothyroxine and iron supplements for hypothyroidism and iron deficiency anaemia respectively. Patient is now on regular follow up for the last two years without disease progression. A comparative HRCT is given in Figure 6a & b.

Figure 6

(a and b) Comparative HRCT done 1.5 years apart showing no disease progression

Differential Diagnosis

TSC is diagnosed on the basis of diagnostic criterion consisting of 11 major and 9 minor features [Table 1]. A definitive diagnosis of TCS either needs two major or one major plus 2 minor features.[1] Our patient had two major and one minor features as highlighted in bold text in Table 1 confirming the diagnosis of TSC. The family history further supported the diagnosis.

Table 1

Diagnostic criteria for tuberous sclerosis

Major features	Minor features
Facial angiofibromas (adenoma sebaceum) or forehead plaque	Hamartomatous rectal polyps
Non traumatic ungula or periungual fibroma	Multiple randomly distributed pits in dental enamel
Hypomelanotic macules (>3)	Bone cyst
Shagreen patch	Cerebral white matter migration line
Multiple retinal nodular hamartomas	Gingival fibroma
Cortical tuber	Non renal hamartoma
Subependymal nodule	Retinal achromic patch
Subependymal gaint cell astrocytoma	Confetti skin lesions
Cardiac rhabdomyoma	Multiple renal cyst
Lymphangiomyomatosis
Renal angiomyolipoma

Bold texts are the lesions seen in our patient and italic texts are hamartomas seen in TCS

The reported lung manifestation of TCS are lymphangioleiomyomatosis (LAM), multifocal micronodular pneumocyte hyperplasia (MMPH), and clear cell tumour, of which LAM and MMPH are hamartomas.[2] Radiologically, MMPH presents as small, multiple randomly distributed nodules, LAM has cysts and clear cell tumour is a small solitary pulmonary nodule.[234] Our case on HRCT had multiple, randomly scattered nodules suggestive of MMPH. The nodules of MMPH are however less than 10 mm. These nodules do not have calcification and usually there is ground glass opacification.[4] The nodules in our patient were >10 mm. There was calcification and absence of ground glass opacity. The unusual features suggested either these lesions were precursor of LAM similar to histeocytosis X which is known to evolve from nodules, or variant of MMPH with calcification or a new manifestation of TSC. Transbronchial lung biopsy showed disorganised skeletal muscle suggesting the diagnosis of choristoma. The commonly seen lesions in TSC are hamartomas. Pathologically, pulmonary hamartoma is a benign neoplasm composed of cartilage, connective tissue, smooth muscle, fat, and bone.[5] All these are native to lung. ‘Choristoma’ is an entity similar to hamartoma but having non-native heterotopic tissue. Choristomahas not been reported in TSC. The other lesions seen in our patient on HRCT were cysts in lingular lobe. Characteristic features of pulmonary LAM are round, thin-walled cysts of variable size and contour distributed uniformly throughout the lungs with normal intervening parenchyma. They can involve the juxtaphrenic recesses and medial tips of the middle lobe and lingual but spare the extreme apices.[6] Thus, the cystic lesions involving lingular lobe suggested the diagnosis of localized LAM.

Clinicopathological correlation

Tuberous Sclerosis Complex (TCS) is an autosomal dominant multisystem disorder characterised by the development of multiple hamartomas in numerous organs including central nervous system, skin, heart, kidney, eye and the lungs affecting 1 in 6000 people.[7] The classical combination of seizures, mental retardation, and adenoma sebaceum also known as Vogt's triad is seen in only one-third of patients. Many of the TSC manifestations are hamartomasas shown in Table 1 in italics. Of these, the skin, kidneys, brain, and heart hamartomas are very common. Hamartomas involving the retina, gingiva, bones, gastrointestinal tract, and lungs are rare.[8]

The pulmonary manifestations of TSC are primarily hamartomas. Hamartomas consists of tumorous native tissue whereas choristomas consists of of non-native abbarant rest. Hamartoma and choristoma, both are types of heteroplasias. Heteroplasia is defined as the development of cytological and histological elements that are not normal for the organ or part, in which they occur, or malposition of tissue/part that is otherwise normal. The former is choristoma, while the latter is hamartoma. Both are disorganized normal tissues of the body.[5] Choristoma (aberrant rest, heterotopic tissue) is histologically non-neoplastic tissue proliferationor nodule formation seldom reaching size greater than 1.5 cm.[910] It may be single or multiple and may calcify.[10] Some of the choristomas had calcified in our case. The biopsy had picked up a non-calcified lesion hence calcification was not seen on biopsy but calcification was seen on HRCT. Skeletal muscle choristomas have been reported as an incidental finding associated with congenital anomalies of lung[11] but not with TCS.

Renal angiomyolipoma in our patient was diagnosed on the basis of macroscopic fat on CT scan, which is a characteristic feature of angiomyolipoma.[12] Angiomyolipoma usually presents with Wunderlich syndrome, retroperitoneal hemorrhage, shock, or hyodronephrosis. Wunderlich syndrome is a rare condition, where spontaneous renal haemorrhage occurs into the subcapsular and perirenal spaces. Retroperitoneal hemorrhage is the commonest manifestation whereas hydronephrosis, the manifestation observed in our patient is seen rarely.[13]

Follicular thyroid lesion seen in our patient could be incidental or a manifestation of TSC. It is difficult to prove or disprove one or the other. This is because small series and case reports have documented that tuberous sclerosis patients may have endocrine system alterations leading to dysfunction of the pituitary, parathyroid and other neuroendocrine tissue.[14] Pituitary adenomas, parathyroid adenomas and gastroenteropancreatic and adrenomedullary neuroendocrine tumours have been suggested as a feature of TSC.[14] Benign thyroid nodules have not yet been reported in patients with TSC. Hence it is either a possible association or an incidental finding.

There is no definite treatment for TSC. Surgical treatment is indicated for subependymal giant cell astrocytomas and symptomatic angiomyolipoma of more than 4 cm. Embolization of angiomyolipoma may also be performed if the size is more than 5cm.[2] Sirolimus is the only drug approved for the treatment of TSC. The indication for sirolimus in TSC is subependymal giant cell astrocytomas that cannot be removed surgically. Sirolimus has been also been studied in multiple randomized controlled trials for the management of kidney angiomyolipomas. Studies have shown that renal angiomyolipoma shrink during sirolimus therapy but tend to regrow after the therapy is stopped.[15]

The most commonly reported sirolimus related adverse reactions are stomatitis, respiratory infection, skin lesions and hyperlipidemia. Our patient denied surgical management hence medical management was given, but it had to be stopped due to intolerable side effects.

Conclusion

In conclusion, Tuberous sclerosis complex is a multisystem disorder with formation of hamartoma in various organs. In addition to hamartoma of lung, choristoma, which is also a disorganized tissue, may be seen in TSC. Endocrine involvement may also be a feature of TSC. Medical treatment of TCS primarily consists of use of sirolimus.

Declaration of Patient Consent

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

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Conflict of interest

There are no conflicts of interest