—  SHORT COURSE #08  —

Cardiovascular and Pulmonary Pathology in Systemic Disease

Case 1 - Tuberous Sclerosis Complex with:
1a - Multiple cardiac rhabdomyomas
1b - Lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia

Henry D. Tazelaar and Marie-Christine Aubry


PDF File (8.2 MB)

Clinical History

Case 1a:
A 29-year-old woman was seen at 34 weeks of gestation for polyhydramnios. The main abnormality identified at fetal echography was a large homogeneous echogenic mass involving the entire left ventricular wall and interventricular septum. At 35 weeks gestation, the patient presented in active labor and gave birth to an infant, pronounced dead thirty minutes after delivery. An autopsy of the infant was performed. The left ventricle of the heart contained multiple masses ranging in size between 0.6 and 5.3cm in diameter.

Slides for Case 1a in the accompanying PDF of the Powerpoint presentation illustrate multiple, well circumscribed, nodules of variable size are replacing the ventricular wall of the heart. The nodules are comprised of enlarged vacuolated cells. The clear vacuoles replace the entire cytoplasm of the majority of the cells. Some cells have mild eosinophilic cytoplasm forming radial projections, around small vacuoles, toward the cytoplasmic membrane, constituting the so-called "spider cell".

Case 1b:
A 38-year-old woman presented with spontaneous pneumothorax. She had a history of subependymal calcification, dermal angiofibromas and bilateral renal tumors. A pulmonary computed tomography scan showed cystic lesions, involving predominantly the lower lobes. Occasional small nodules were also identified. A wedge biopsy of the lung was performed.

Slides for Case 1b are show in the accompanying PDF of the Powerpoint presentation. The first slide shows enlarged cystic airspaces distributed haphazardly within the pulmonary parenchyma. The walls of these cystic lesions contain, at least focally, a proliferation of spindle cells forming ill-defined bundles. The cells contain abundant eosinophilic cytoplasm. The centrally located nuclei are fusiform and cigar-shaped. Some cells are more epithelioid and, the nuclei are oval and vesicular with small prominent nucleoli. Multiple well-circumscribed nodules are identified in the second slide. The nodules are comprised of bland cuboidal cells lining thickened alveolar septa. This pneumocyte proliferation shows a sharp interface with surrounding lung tissue.

Discussion
The systemic disease grouping cardiac rhabdomyomas, pulmonary lymphangioleiomyomatosis (LAM), and micronodular pneumocyte hyperplasia (MNPH), is tuberous sclerosis complex (TSC). TSC is an autosomal dominant disease, with a high spontaneous mutation rate and highly variable expression, characterized by the presence of multiple hamartomas involving different organs, particularly the brain, skin, heart and kidneys. Dr. Bourneville first described the cerebral manifestations of this disease in 1880. Vogt described the classic triad of mental retardation, epilepsy and facial angiofibroma in 1908, but we know now that this triad is only rarely seen in patients with TSC (10-30%). The estimated incidence is thought to be 1 in 6 000 live births and the prevalence 1 per 5 800 to 1 per 15 000, likely representing the most common genetic disease. The criteria permitting the diagnosis of TSC have recently been revised and are detailed in Table 1.

Table 1: Revised diagnostic criteria for TSC (modified from Roach et al, 1998)

Major Features
Facial angiofibromas
Ungual or periungual fibroma
Hypomelanotic macules
Shagreen patch (connective tissue nevus)
Multiple retinal nodular hamartomas
Cortical tuber
Subependymal nodule
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma, single or multiple
Lymphangioleiomyomatosis*
Renal angiomyolipoma*
Minor Features
Pits in dental enamel
Hamartomatous rectal polys
Bone cysts
Cerebral white matter migration lines
Gingival fibromas
Nonrenal hamartomas
Retinal achromic patch
"Confetti" skin lesions
Multiple renal cysts
Definite TSC: either 2 major features (*with the exception of the combination of lymphangioleiomyomatosis and renal angiomyolipoma) or 1 major with 2 minor features
Probable TSC: 1 major and 1 minor feature
Possible TSC: either 1 major or 2 or more minor features

Two genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13, responsible for TSC have been identified. Their respective gene products are hamartin and tuberin. Loss of heterozygosity (LOH) for one of these genes, more commonly TSC2, as expressed by loss of immunoreactivity, is being recognized in the pathogenesis of numerous hamartomas, including rhabdomyoma and LAM, in TSC as well as sporadic cases.

Table 2: Cardiovascular and Pulmonary Manifestations Described in Tuberous Sclerosis Complex
Cardiovascular Pulmonary
Cardiac rhabdomyoma Lymphangioleiomyomatosis (LAM)
Aortic and peripheral aneurysms Micronodular pneumocyte hyperplasia (MPNH)
Congenital cardiac malformations Clear cell tumor
Vascular dysplasia Angiomyolipoma

Cardiovascular manifestations of TSC
Cardiac rhabdomyomas are by far the most common cardiovascular manifestation. Aortic aneurysms have been reported in a total of 15 cases but can also involve the axillary, carotid and cerebral arteries. Various congenital cardiac malformations, including coarctation of the aorta, congenital aortic stenosis and ventricular septal defects, have been described in patients with TSC.

Cardiac Rhabdomyoma

Clinical presentation:
Although cardiac rhabdomyoma represents less than 15% of primary benign cardiac tumors, it is the most common tumor in infancy and childhood. The reported incidence in patients with TSC varies between 47 to 86 % and conversely, 50 to 90% of infants with cardiac rhabdomyoma will have TSC. Predictors of TSC include family history of TSC and multifocality. Cardiac rhabdomyoma is slightly more prevalent in males with a ratio of up to 2:1. They are diagnosed before the age of 1year, in more than 50% of patients. With the advent of prenatal echocardiography, they are now diagnosed earlier and more frequently. Cardiac rhabdomyoma can cause fetal death secondary to non-immune fetal hydrops. The tumors can be situated anywhere within the heart (intramurally, projecting from the epicardium or endocardium) and are commonly multiple (90%). They are far more common in the ventricles than the atria, and slightly more in the left than the right side. The symptoms vary according to the location and size of the tumors, and result from outflow tract obstruction, interference with valvular function, and cardiac failure or arrhythmias when diffusely involving the ventricles or conduction system. Wolff-Parkinson-White syndrome occurs with a greater incidence in patients with TS compared to normal population, the tumor cells functioning as an abnormal conducting bundle. Strokes secondary to thromboembolic events have also been described. Therefore cardiac rhabdomyomas can create significant morbidity and mortality, however, they are asymptomatic in up to 64% of patients. In approximately 70% of patients, they show a tendency to spontaneously regress, mainly before the age of 4 years. Therefore, treatment, whether medical or surgical, is recommended only for patients with life-threatening complications.

Pathologic description:
Macroscopically, the tumor nodules vary in size and can measure up to several centimeters. The well circumscribed, non-encapsulated nodules are paler than the surrounding myocardium. They have a homogeneous smooth cut surface and usually do not contain necrosis, hemorrhage or calcification. Histologically, well-demarcated nodules from the surrounding myocardium are comprised of enlarged vacuolated cells. The cells are larger than the normal myocytes and pale irregular vacuoles fill the cytoplasm. The vacuoles are separated by thin strands of eosinophilic cytoplasm and push the nuclei at the periphery of the cells. When the nucleus is in the center of the cell, with the strands of cytoplasm projected towards the periphery, the cells are called "spider" cells and represent the diagnostic rhabdomyoma cell. The vacuoles are the result of glycogen accumulation, with strong PAS staining. Rhabdomyoma cells have been shown to share features with myocytes by immunohistochemical studies, expression of myoglobin and desmin, and ultrastructural studies, presence of sarcomeres (Z bands) and specialized intercellular junctions (intercalated discs), and therefore are thought to originate from embryonic/immature myocytes.

Differential diagnosis: (see Table 3)
Cardiac rhabdomyoma should not be confused with other types of rhabdomyoma. Extracardiac rhabdomyomas are rare benign tumors of striated muscle sub-classified as adult, fetal and genital types. Adult rhabdomyoma occurs predominantly in men, with a mean age of approximately 42 years. The histologic features are quite distinct. Although "spider" cells are described in adult rhabdomyoma, they are few and admixed with large, densely eosinophilic polygonal cells. Collectively, these tumors usually do not occur within the heart; however, 4 cases of cardiac adult rhabdomyomas have been described. Two women and two men aged 35-54 years presented mainly with arrhythmias. The tumor arose predominantly within the right atria, with a single case in the right ventricle, and measure between 2 and 9 cm.

Histiocytoid cardiomyopathy, also known as infantile cardiomyopathy, oncocytic cardiomyopathy and Purkinje cell hamartoma,is a rare arrhythmogenic disease, which also affects infants (mean age 12 months), predominantly the female gender (3-4F: 1M). Patients typically present with arrhythmias (65%), often refractory to treatment. Sudden death is the first manifestation of disease in almost a fifth of patients. Unless the disease is recognized and ablation of the arrhythmogenic foci attempted, the outcome is poor with certain death, mostly between the ages of 6 months and 2 years. In patients undergoing ablation of the arrhythmogenic foci, long-term survival has been obtained. Cardiac transplantation is another possible therapeutic avenue. Associated cardiac and extracardiac malformations have ben described in approximately 16 and 17% of patients, respectively, however, they are distinct from those describe in TSC. Macroscopically, yellow-tan nodules, ranging in size between 0.1 to 1.5cm, usually less than 0.2cm, are identified They can occur anywhere in the heart but are more commonly seen in the subendocardium of the left ventricle. The nodules are comprised of polygonal cells containing a foamy, finely granular cytoplasm. In contrast to the cardiac rhabdomyoma, the cells do not contain large clear vacuoles and they only stain faintly for PAS. No "spider" cells are identified. The cells express specific muscle actin, myoglobin, and cholinesterase, and faintly stain for desmin and myosin. They lack reactivity for CD68, lysozyme, anti-trypsin. Ultrastructurally, the cells contain numerous, often abnormal, mitochondria, lipid vacuoles, only scattered glycogen, few myofibrils and Z-bands, and rare intercalated discs. The absence of T-tubules is characteristic. The nature of these cells is still debated and the favored hypothesis suggests these cells represent cardiac myocytes with oncocytic changes.

The adipocytes of benign tumors of fatty tissue could potentially be confused with the vacuolated cells of the cardiac rhabdomyomas. Lipomatous hypertrophy of interatrial septum occur in a much older population (mean age 69 years), is limited to the atrial septum and thought to be responsible for atrial arrhythmias. Histologically, mature adipocytes, adipocytes resembling those seen in brown fat and myocytes are admixed together. The cells do not contain glycogen. Lipomas of the heart are exceedingly rare and are mostly epicardial tumors. They are comprised of mature adipocytes, resembling lipomas at other sites.

Granular cell tumor , another rare, mostly epicardial, neoplasm of the heart, is also found in older patients (aged between 24 to 55 years). The histologic features are identical to the granular cell tumor occurring outside the heart, containing no glycogen and expressing S-100 protein and neuron-specific enolase.

Vacuolated myocytes are seen in storage disease, certain types of drug reactions, and with ischemia. This differential diagnosis is detailed in case 7.

Table 3: Differential Diagnosis of Cardiac Rhabdomyoma

1 - Extra-cardiac rhabdomyoma:
Adult rhabdomyoma
Fetal rhabdomyoma
Genital rhabdomyoma
2 - Histiocytoid cardiomyopathy
3 - Adipose lesions:
Lipoma
Atrial lipomatous hypertrophy
4 - Granular cell tumor
5 - Storage diseases
6 - Drug reaction
7 - Ischemia

Pulmonary manifestations of TSC
LAM is the most common manifestation of TSC. MPNH, a benign proliferation of type II pneumocytes, is a rare lesion mostly described in patients with TSC, often in association with LAM. Clear cell tumor, also known as sugar tumor, are rare benign pulmonary neoplasm that immunoreact with HMB45, similarly to the smooth muscle hamartomatous lesions in TSC (renal angiomyolipoma and LAM). Consequently, this tumor has been proposed to be included amongst the pulmonary TSC-related lesions, even though only two such cases have been reported. Angiomyolipomas are well-recognized lesions of the kidney, sporadic or arising in TSC. A single case of pulmonary angiomyolipoma of the lung has been described in a patient with TSC.

Pulmonary Lymphangioleiomyomatosis (LAM)

LAM is a rare pulmonary disease characterized by a proliferation of modified smooth muscle cells in the pulmonary interstitium, in a lymphatic distribution.

Clinical presentation:
Patients with TSC who develop LAM represent a distinct subset of patients with TSC, in that they are almost exclusively women of child bearing age and according to most series, do not commonly present with the usual neurologic stigmata of TSC (Table 4). Although LAM is more commonly sporadic, the clinical, radiologic and histologic manifestations of the pulmonary disease are similar to those of patients with TSC. The frequency of LAM in the setting of TSC is under debate. It was thought to occur between <1 to 6%. Recently, Costello et al showed a frequency of 26% among women with TSC. The frequency went up to 56% if only asymptomatic women were considered. Other recent studies showed a frequency of 34% and 39% among asymptomatic women with TSC. Even though not all patients had tissue diagnosis, it is likely that LAM in TSC is greatly underestimated. Sporadic LAM has only been described in women and until recently reported exclusively in women with TSC. The mean age at presentation varies between 33-36 years but post-menopausal women with LAM have been described.

The pulmonary symptoms, in order of frequency, consist of progressive dyspnea on exertion, pneumothorax (two-thirds of which are recurrent), cough, hemoptysis and chylous pleural effusions. Chylothorax appears to be a less common manifestation of LAM associated with TSC and a significant percentage of asymptomatic patients have also been described. Although a restrictive pattern can be observed in patients with LAM (usually less than a third), severe obstruction with hypoxemia and reduced capacity diffusion are most common. The chest radiograph can be normal in the early stage of the disease but eventually will reveal diffuse reticular infiltrates commonly accompanied by hyperinflation, evolving into cystic/bullous changes in advanced stages. Cystic lesions varying between 2 and 20mm, distributed uniformly through both lungs, are characteristic findings on computed tomography (CT) Scan. Non-pulmonary findings in patients with TSC include facial angiofibromas (80-100%), renal angiomyolipomas (60%) and retinal phakomas (25%). Reported neurological manifestations (mental retardation and epilepsy) vary between 11 to 80%, and when present appear to be less severe than in patients with TSC without LAM. Interestingly, angiomyolipoma arises in nearly 50% of patients with LAM who have no other stigmata of TSC. Although this association has raised much speculation about a forme fruste of TSC with LOH of TSC2 found in both sporadic forms of renal angiomyolipoma and LAM, the National Institutes of Health Consensus Conference on TSC requires the presence of other features of TSC to make a definitive diagnosis of TSC in patients who only have a renal angiomyolipoma and LAM.

The natural history of LAM is characterized by progressive respiratory insufficiency with cor pulmonale. The reported rate of progression is quite variable and, although earlier studies stated average survivals of 3 to 5 years, more recent series suggest longer survival, up to 80% at 10 years. In patients with TSC, death results generally from pulmonary complications. Since LAM occurs mostly in pre-menopausal women, sex hormones have been assumed to play an important role in the pathogenesis of LAM. Therefore, the therapeutical strategy has mainly relied on hormonal manipulation, mostly progesterone therapy, but also Tamoxifen, or oophorectomy, with questionable benefit. Occasionally, pulmonary transplant is the only therapeutic option, although recurrence in the transplanted lung has been described.

Table 4: Contrasting Features Between Tuberous Sclerosis with and Without Lymphangioleiomyomatosis and Lymphangioleiomyomatosis Without TSC

  TSC no LAMTSC with LAM LAM no TSC
Gender M ≈ W All W except one M All W
Age at dx Infancy/childhood 25-36 yo (mean 30) 33-39 yo (mean 36)
TSC features:

Facial angiofibroma

Seizures

Cognitive impairment/mental retardation

CNS

Renal angiolipoma

Cardiac rhabdomyoma
Retinal involvement 		 
75-89%
78-96%
53-75%
68-100%
54-80%
47-86%
75%
80%
11-86%
29-45%
88%
60%
0%
25%




15-60%

Pulmonary symptoms NA Asymptomatic 0-40%
SOB 25-70%
Pneumothorax 30-60%
Chylothorax 0-10%
SOB 59-91%
Pneumothorax 49-81%
Chylothorax 2-33%
Causes of death Cerebral or renal complications
Early cardiac failure 		Pulmonary complications (86%) Pulmonary complications

Pathologic description:
Macroscopic examination shows multiple thin-walled cysts of variable size distributed throughout the lungs. The main histologic abnormality is the proliferation of smooth muscle cells around small airways, blood vessels, lymphatics, and subpleural space. The smooth muscle cells are modified in that they express a melanogenesis-associated antigen recognized by HMB45 as well as frequently expressing estrogen (ER) and progesterone (PR) receptor proteins. They form a heterogeneous population of cells. Phenotypically, the majority of calls are spindled shape, some with little cytoplasm and an elongated or oval dark nucleus, others with moderately abundant cytoplasm and an oval nucleus. Some are epithelioid with a round nucleus, vesicular chromatin pattern and small nucleolus. The immunophenotype also varies with the cell type. Although all the cells express smooth muscle markers, expression of HMB45 and ER/PR appears to be limited mostly to the epithelioid and larger spindle-shaped cells, and therefore, can be focal. The proliferation of smooth muscle around the small airways leads to their compression with air trapping. Air trapping only partly explains the cystic lesion. Degradation of elastic fibers in the areas of smooth muscle proliferation has been demonstrated and thought to result from a mechanism similar to emphysema i.e. imbalance of the metalloproteinases / inhibitor of proteinases system. These cysts are the clue to the diagnosis, since the walls always contain a smooth muscle proliferation, however focal and small. Rupture of the cystic lesions is responsible for the pneumothoraces. Obstruction of vessels by the proliferating smooth muscle cells results in pulmonary hemorrhage, which translates clinically in hemoptysis and histologically, in hemosiderin-laden macrophage accumulation within alveoli. The findings of LAM are distinctive enough to confirm the diagnosis on transbronchial biopsy and prevent the necessity for a wedge biopsy. HMB45 staining becomes a very useful tool in that setting. Matsui et al have recently published a study describing an histologic score with prognostic significance. The score consists of evaluating the percentage of the biopsy specimen involved by the cystic lesions and smooth muscle proliferation and is classified as 1 when 1-25% of specimen is involved, 2 with 26-50%, and 3 with >50%. Group 3 had the worse prognosis. The smooth muscle proliferation is not always confined to the lung and can occur in other sites, particularly in mediastinal lymph nodes and in the retroperitoneum.

Mutations in TSC2 have been found in pulmonary tissue of patients with LAM, both sporadic and associated with TSC. The mutations are localized to the LAM cells and not present in the normal lung. In addition, identical mutations have been identified in angiomyolipomas and LAM lesions suggesting that after arising from a single site, LAM cells can migrate or metastasize to other organs. This hypothesis is further supported by two studies of recurrent LAM in transplanted lungs demonstrating that the LAM cells were derived from the patients.

Differential diagnosis: (see Table 5)

For clinicians and radiologists, the differential diagnosis is that of pulmonary cystic lesion and therefore includes idiopathic pulmonary fibrosis, eosinophilic granuloma and emphysema. For pathologists, the differential diagnosis will mainly include pulmonary lesions characterized by smooth muscle proliferations, alveolar hemorrhage and emphysema.

Benign metastasizing leiomyoma (BML) is likely to represent metastatic low-grade leiomyosarcoma and occur in women who commonly have a previous history of uterine smooth muscle neoplasm. Their average age of presentation is older than patients with LAM with a reported mean of approximately 47 years. They are asymptomatic in up to two thirds of cases and pneumothorax is an unusual manifestation of the disease. Histologically, BML is characterized also by a smooth muscle proliferation, however the smooth muscle cells form solid nodules with associated cystic air spaces. Entrapped alveolar epithelium is commonly identified, imparting a biphasic appearance to the nodules. Although the cells can express ER and PR, they are negative for HMB45. In difficult cases, clinical correlation can help resolve the dilemma.

Metastatic endometrial stromal sarcoma (ESS) is well known to mimic LAM. Indeed, metastatic ESS can form cystic lesions containing focal proliferation of spindle cells. However, the spindle cells are uniform, short and with little cytoplasm. These cells can express smooth muscle actin, ER and PR; however, they are negative for HMB45.

Muscular cirrhosis describes the smooth muscle proliferation found in honeycomb lung, mainly seen in usual interstitial pneumonia. It can also refer to the peribronchial smooth muscle proliferation found in patients with severe small airway disease.

Emphysema enters the differential diagnosis when the cystic air spaces of LAM are numerous, very thin walled and large. Even in these cases, foci of the characteristic smooth muscle proliferation can be identified and highlighted by immunoreactivity with smooth muscle actin.

Occasionally, the pulmonary hemosiderosis in LAM can be so striking as to raise the diagnosis of pulmonary hemorrhage syndrome. Again, the identification of smooth muscle proliferation associated to the cystic air spaces will permit the correct diagnosis.

Table 5: Differential Diagnosis of LAM

Clinical Histologic
Eosinophilic granuloma
Idiopathic pulmonary fibrosis
Emphysema 		Benign metastasizing leiomyoma
Metastatic endometrial stromal sarcoma
Muscle cirrhosis
Emphysema
Pulmonary hemorrhage syndrome

Micronodular Pneumocyte Hyperplasia (MPNH)

Popper et al coined the term MPNH for a peculiar pneumocyte hyperplasia first recognized by Spencer in a patient with TSC back in 1962. Corrin et al subsequently described "an acinar atypical adenomatoid proliferation of epithelium which were supported by what appeared to be uniformly and only slightly thickened interalveolar septa" in two patients with LAM not associated with TSC. This lesion, also known as micronodular hyperplasia of type II pneumocytes, acinar atypical adenomatoid proliferations of epithelium and atypical adenomatoid proliferation of cuboidal epithelium, can occur sporadically but mainly associated with LAM, in patients with or without TSC.

Clinical presentation:
Reviewing the most recent cases, since 1991, for which clinical information is easily available, MNPH arises more commonly in women (Figure 1). Age ranges between 16 and 57 years. Although MNPH can be an isolated finding, it is most commonly found in patients with TSC, usually in association with LAM. The only proven man to have LAM also had MNPH (see Figure 1).

Pulmonary symptoms, although common, are likely attributable to the associated LAM. However, three patients without LAM did present with respiratory distress and pneumothorax. Nodular/reticulonodular infiltrates are seen on chest CT Scan. One patient died following lung transplantation for chronic respiratory failure attributed to MNPH. With this exception, MNPH is considered a benign process without attributable deaths.

Figure 1: Distribution of MPNH in Patients with TSC with and Without LAM

Pathologic description:
MNPH are habitually multiple and randomly distributed in the lung parenchyma, ranging between < 1mm to 8mm. These minute nodules are comprised of flat to cuboidal cells lining mildly thickened, fibrotic alveolar septa. They are sharply circumscribed from the adjacent normal pulmonary parenchyma. The cells are usually very bland but can focally show mild atypia, with increased nuclear size and prominent nucleoli. The epithelial cells stain diffusely for keratin, surfactant and TTF-1 and are negative for Clara cell protein. This immunohistochemical profile supports a type II pneumocyte proliferation. In contrast to LAM, the cells are negative for HMB45 and ER/PR. Similarly, no LOH of TSC2 has been identified in MPNH, supporting a different pathogenesis.

Differential diagnosis: (see Table 6)
The differential diagnosis includes mainly lesions comprised of or mimicking type II pneumocytes.

Atypical adenomatous hyperplasia (AAH)/ bronchioloalveolar carcinoma (BAC): AAH, also known as atypical alveolar cell hyperplasia and bronchoalveolar cell adenoma, is presumed a precursor to BAC/ adenocarcinoma. It is usually an incidental finding in surgical specimens, commonly found in association with lung carcinoma. Histologically, AAH is a small lesion (often 5 mm or less) with uniform proliferation of cuboidal cell along alveolar septa. In distinction from MNPH, the cells are slightly more atypical, with increased nuclear cytoplasmic ratio and mainly show peripheral lepidic growth. BAC, a subtype of adenocarcinoma, usually forms larger lesions, shows more significant nuclear atypia with increased cellular density and also shows marked peripheral lepidic growth with progressive tapering into adjacent pulmonary parenchyma.

Papillary adenoma: Rare lesion that presents as a solitary nodule in asymptomatic patients. The tumors range in size between 1-4 cm and are well demarcated. They are comprised of true papilla lined by cytologically bland cuboidal cells. These cells, by immunohistochemical and ultrastructural studies, show mostly type II pneumocyte differentiation but can also show Clara cell differentiation.

Alveolar adenoma: Another rare benign neoplasm of the lung found mostly in older women as an asymptomatic solitary coin lesion. Histologically, these well-circumscribed tumors are multicystic. The cysts, which often contain an eosinophilic granular exudate, are larger in the center and surrounded by thin septa lined by hobnail or cuboidal cell. The cells have ultrastructural features of type II pneumocytes.

Meningothelial-like nodule (pulmonary chemodectoma) is a rare, usually, incidental finding, in adults, predominantly women. The nodules, usually multiple, measure between 1-3mm.The cellular proliferation is typically perivenular, extending into adjacent alveolar septa. The oval shaped cells form small, occasionally swirling nests. The nuclei are uniform and often contain pseudo-inclusions. The immunohistochemical and ultrastructural findings show similarities with meningiomas, hence the name meningothelial-like.

Sclerosing hemangioma: Uncommon neoplasm, which occurs mostly in middle-aged women as a solitary mass. Histologically, four patterns have been described, and more than one is usually identified within the same tumor. They are solid, sclerotic, papillary and hemorrhagic. Two cell populations are present; one lining the papillary structures with a cuboidal shape, the other solid growing polygonal cells. The studies indicate that sclerosing hemangiomas are epithelial neoplasms with immunophenotypic characteristics of type II pneumocytes and/or Clara cell.

Table 6: Differential Diagnosis of MNPH

1- Atypical adenomatous hyperplasia/ bronchioloalveolar carcinoma, non-mucinous type
2- Papillary adenoma
3- Alveolar adenoma
4- Meningothelial-like nodule
5- Sclerosing hemangioma

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