Chemodectoma

* Extracranial meningiomas are rare outside the head and neck region. We report a case of primary pulmonary meningioma, initially detected as a radiographic incidental finding, occurring in an asymptomatic 45-year-old woman. Light microscopic examination of both cytologic and histologic preparations was typical of a classical meningioma and included such features as intranuclear pseudoinclusions, psammoma bodies, and cellular whorls. Immunohistochemistry demonstrated tumor cell positivity for vimentin and epithelial membrane antigen, as is characteristic of meningioma. Ultrastructural analysis showed interdigitating cell membranes and desmosomes, with no evidence of basal lamina, neurosecretory granules, or microvilli. On short-term follow-up, the patient is well and has no evidence of a cranial or spinal meningioma. The previous 10 cases reported in the literature had similar characteristics, including a tendency toward occurrence in middle age to older women, asymptomatic presentation, peripheral lung location, and morphologic features. Finally, other conditions in the differential diagnosis and possible histogenesis are discussed. (Arch Pathol Lab Med. 1997;121:631-636)

Meningioma is one of the most common intracranial neoplasms. These tumors are relatively less common in the intraspinal region and only very rarely occur in extracranial or extraspinal sites.1-3 Most extracranial meningiomas reported have occurred in the head and neck, or paraspinous regions, in sites such as the scalp,4 skull bones,56 eyelid,7 nose and paranasal sinuses,8-12 pharyngeal region,l4 parotid gland,ls l15-16 oral cavity,l7-20 or mediastinum.21 It has been speculated that meningiomas in these sites arise from direct extension of the arachnoid villi or congenitally displaced arachnoid cells.2-24 This hypothesis seems plausible for such locations. However, it is more difficult to explain the origin of the unusual meningiomas that occur outside the head and neck region. The lung is one site of such tumors. Primary pulmonary meningiomas are extremely rare, and to our knowledge only 10 have been documented in eight case reports in the English literature.22-29 We report another such case and provide a comprehensive pathologic description, including

gross, light microscopic, cytologic, ultrastructural, and immunophenotypic findings. Other case reports are also reviewed, and various histogenetic theories are discussed.

REPORT OF A CASE

A 45-year-old woman with a history of hypertension, diabetes mellitus, and uterine leiomyomas presented with symptoms of stress urinary incontinence and persistent suprapubic pain 3 months after a hysterectomy procedure. She was initially evaluated with a computed tomographic (CT) scan of the pelvis and abdomen. The abdominal CT scan extended partially into the thorax, demonstrating enlarged mediastinal nodes, which prompted a focused CT examination of the chest. The chest CT films showed diffuse mild enlargement of the mediastinal nodes, as well as a 1.2-cm nodule in the anteriormost aspect of the lingula. The nodule appeared to be adjacent to the medial aspect of the visceral pleura but did not seem to be arising from it (Fig 1). No other pulmonary parenchymal lesions were present. The nature of the lesion was unclear from the radiographic studies. On further evaluation, the patient gave a history of recent onset of a nonproductive cough, but denied smoking, weight loss, shortness of breath, hemoptysis, or chills. She underwent bronchoscopy, mediastinoscopy, and wedge resection of the lingular mass. An intraoperative diagnosis of benign spindle cell lesion was made, and no additional surgery was undertaken. A final diagnosis of pulmonary meningioma was rendered based on the light microscopic and immunohistochemical findings. Since both benign and malignant intracranial meningiomas have been reported to metastasize to the lung, the patient was evaluated for a possible primary intracranial meningioma. A CT scan of the head was obtained but failed to reveal any mass lesions in the cranium. Furthermore, the patient did not complain of any neurologic signs or symptoms suggestive of an intracranial or intraspinal mass lesion. Laboratory values, including complete blood count with differential and blood chemistries, were all within normal ranges. Although the follow-up interval is short (10 months), the patient is alive and well with no other pulmonary lesions and no signs or symptoms suggestive of an intracranial or intraspinal tumor.

MATERIALS AND METHODS

Light Microscopy and Cytology

The specimen was routinely fixed in 10% buffered formalin and embedded in paraffin, and 5-(mu)m sections were cut and stained with hematoxylin-eosin. Sections were examined with a light microscope. Tissue scrapes and touch imprints were prepared from the fresh intraoperative specimen; stained with hematoxylin-eosin, Papanicolaou, and Diff-Quick techniques; and examined under a light microscope.

Electron Microscopy

Electron microscopy was performed on the formalin-fixed and paraffin-embedded tissue. Briefly, several 1-mm cubes of tumor tissue were removed from the paraffin block and deparaffinized

in xylene for 24 hours. The tissue was then rehydrated in successive steps using decreasing concentrations of alcohol. The specimen was postfixed in 2% osmium tetroxide and en bloc staining with 3% uranyl acetate was performed. After embedding in epoxy resin, 1-(mu)m-thick sections were cut and stained with toluidine blue; appropriate blocks were selected from these sections, and ultrathin sections were cut using a diamond knife. Sections were then stained with 0.3% lead acetate and examined with a Phillips CM 10 electron microscope. Immunohistochemistry

Immunohistochemistry was performed on formalin-fixed and paraffin-embedded material. Sections were stained using the avidin-biotin-peroxidase method with antibodies directed against the following determinants: cytokeratin, vimentin, S100, epithelial membrane antigen, chromogranin, desmin, smooth muscle actin, CD34, Leu-7, synaptophysin, and neuron-specific enolase. Antigen retrieval using citrate buffer and a 650-W microwave oven for 7 minutes was performed for all antibodies prior to the primary incubation. Diaminobenzidene was used as the chromogen. Tissue blocks known to express the antigens of interest

served as positive control sections. Normal mouse ascites or nonimmune rabbit serum, used in place of the primary antibodies, functioned as the negative controls. The antibodies, dilutions, and sources are listed in Table 1.

RESULTS

Gross Findings

The tumor consisted of a well-circumscribed, but nonencapsulated, gray to tan-white, rubbery, subpleural nodule measuring 1.3 x 1.0 x 0.8 cm. The cut surface was homogeneous and gray-white, and showed no evidence of necrosis or hemorrhage (Fig 2).

Light Microscopic Findings

Histologic sections showed a well-circumscribed tumor with no capsule. The tumor consisted of a moderately dense population of variably plump and spindled cells arranged in curvilinear fascicles and whorls with an occasional central core of collagen (Fig 3). The cells were moderate in size and showed oval nuclei with finely granular, evenly distributed chromatin and inconspicuous nucleoli. The cells contained a moderate amount of light pink filamentous cytoplasm with indistinct cell membranes. No mitoses or nuclear atypia was noted. Rare psammoma bodies were identified (Fig 4).

Cytologic Findings

The intraoperative scrapes and touch imprints showed a cellular specimen consisting of numerous spindle cells displaying oval nuclei with finely granular, evenly distributed chromatin and small inconspicuous nucleoli. Many of the nuclei exhibited longitudinal nuclear grooves, and some contained nuclear pseudoinclusions. The cells showed a moderate amount of light pink filamentous cytoplasm with hematoxylin-eosin staining. In some areas there were groups of oval nuclei enmeshed in tangles of filamentous material (Fig 5). No nuclear pleomorphism or anaplasia was noted. Psammoma bodies were not found in the cytologic preparations.

Ultrastructural Findings

Although formalin-fixed and paraffin-embedded tissue was used for electron microscopy, satisfactory results were obtained. The tumor cells displayed interdigitating cell membranes and several desmosomes, but there was no basal lamina formation. Organelles were sparse and included short strips of rough endoplasmic reticulum and a

few mitochondria. Occasional intracytoplasmic filaments were also seen. Neurosecretory granules and microvilli were not present (Fig 6).

Immunohistochemical Findings

The tumor displayed strong and diffuse positivity for vimentin, but no reactivity for cytokeratin. Epithelial membrane antigen was also detected in most of the tumor cells; the reactivity observed was both membrane-bound and cytoplasmic. Stains for all other determinants, including S100, chromogranin, Leu-7, neuron-specific enolase, synaptophysin, desmin, smooth muscle actin, and CD34, were negative. All negative and positive controls reacted appropriately.

COMMENT

Classical intracranial meningiomas, also designated as syncytial or transitional types, are usually diagnosed based on characteristic light microscopic features. These include a syncytial growth of bland-appearing cells with oval nuclei, a focal whorling architecture, and psammoma bodies. Meningiomas typically show membrane staining for epithelial membrane antigen, diffuse reactivity for vimentin, and little or no reactivity for other markers. Electron microscopy generally demonstrates well-formed desmosomes, interdigitating cell processes, and intermediate filaments in the cytoplasm.

Ten other cases of primary pulmonary meningiomas have been reported (Table 2). Based on the data from these few cases, pulmonary meningiomas occur as solitary, peripheral, small, and circumscribed lung nodules, which have a tendency to occur more commonly in women (nine women, two men). All have behaved in a benign fashion. The tumor we present here meets all of the diagnostic requirements for meningioma and also conforms to the clinical features described in the previously documented cases. However, the extreme rarity of this neoplasm in this location warrants a review of the differential diagnosis, focusing on other solitary spindle cell proliferations of the lung and pleura, such as solitary fibrous tumor (SFT) of the pleura, schwannoma, spindle cell carcinoid, solitary large chemodectoma, leiomyoma, and hamartomatous lesions.

The subpleural nature of this tumor might suggest a diagnosis of SFT of the pleura; in fact, that diagnosis figured prominently in the initial considerations for this tumor. The absence of any physical connection between the tumor and the pleura weighed against such a diagnosis, because almost all cases of SFT arise directly from the submesothelial fibrous layer of the pleura.30 These can present as either sessile or pedunculated lesions covered by a thin layer of pleura. Nevertheless, SFT may not be entirely restricted to the pleura, as histologically similar neoplasms have rarely been described in the lung.30 The great majority of SFTs react with CD34 antibody and do not stain for epithelial membrane antigen. The converse was true in our case. Moreover, desmosomes are not a feature of SFT. Although psammoma bodies are not specific for meningiomas, their presence also suggests a diagnosis of meningioma over SFT.

A spindle cell proliferation with finely distributed, even chromatin and the nuclear palisading seen in some areas of the tissue sections raised the possibility of a schwannoma. Like primary pulmonary meningiomas, schwannomas arise extremely rarely in the lungs (in the absence of neurofibromatosis). In this case, the epithelial membrane antigen reactivity coupled with the absence of S100 and Leu-7 staining excluded this diagnosis. In addition, basal lamina formation is a rather consistent ultrastructural feature in schwannomas, but desmosomes are not present in such neoplasms.

This tumor shares many cytologic and histologic features with a peripheral spindle cell carcinoid tumor; however, the absence of chromogranin, neuron-specific enolase, and synaptophysin immunoreactivity and lack of neurosecretory granules by electron microscopy essentially excluded a carcinoid tumor. Another consideration could be the so-called "pulmonary chemodectoma"; these are typically multiple lesions in the range of 1 to 3 mm and show a close relationship to pulmonary vasculature. These microscopic lesions have also been given the name "minute pulmonary meningothelial-like nodules."31 Solitary and larger examples are described.32 However, the immunohistochemical and ultrastructural features of the tumor in the current case were not consistent with such a diagnosis. Leiomyomas, although rare in the lung, are seen most commonly in adult women, as is also true for primary pulmonary meningiomas. However, this tumor did not show any immunohistochemical reactivity for desmin or smooth muscle actin, and there was no ultrastructural evidence of pinocytotic vesicles or dense bodies. Hamartomas are the most common benign lesions in the lung. Most hamartomas contain cartilage, smooth muscle, fat, or nerve bundle elements in various proportions. This tumor did not show any of these elements and, therefore, hamartoma was not a serious consideration in this case. As mentioned above, meningiomas have been reported

in extracranial and extraspinal sites; however, most of these occurred in the head and neck region. In the presence of such spatial proximity, the possibility of direct extension of intracranial meningothelial proliferations must be considered, since histologically benign meningiomas can invade dural sinuses and even skull bones.25 The tumor presented here occurred in a site that is both spatially and embryologically unrelated to cranial or spinal meninges. Various theories can be offered to explain such a phenomenon.

Cranial nerves may acquire meningeal sheaths as they exit the cranial foramina. Such meningeal sheaths along the vagus nerve in the pulmonary parenchyma would seem to represent a plausible explanation for the source of pulmonary meningiomas. Arguing against this idea is reported tumor location; one would expect a central lung location rather than the subpleural site observed in most reported cases, since the meningeal coverings of the nerves become sparse and focal as the nerves ramify.

One can postulate ectopic embryonic rests of arachnoid cells within the lung. Ectopic embryonic rests of various tissues are well known as sites of neoplasms; examples include intrathymic parathyroid adenomas,33,34 germ cell neoplasms of the mediastinum35,36 and retroperitoneum,37 and tumors arising from Muellerian rests in the pelvis and abdomen. However, the ectopic rest theory is difficult to reconcile with the absence of extracranial meningiomas in other visceral organs.

Metastasis to the lung from an intracranial meningioma is uncommon, but is an established fact38,39; for that reason, it is always important to document the lack of a craniospinal source before diagnosing a primary pulmonary meningioma. There are examples of metastatic tumors arising from tiny primary sources in other organs, including metastases from minute tumors of the thyroid, kidney, gonads, and pancreas. However, in all such examples, the tumors are overtly malignant. Histologically benign meningiomas behave in a biologically benign fashion in nearly all cases, although histologically benign tumors have been reported to metastasize to distant sites, including the lungs.? Nonetheless, given the number of cases of pulmonary meningioma in which a cranial primary tumor has not been discovered, even with prolonged follow-up, it is unlikely that undetectable primary lesions in the cranium are a viable explanation.

It could be proposed that Schwann cells of intrapulmonary nerves might give rise to such lesions. Schwann cells are facultative fibroblasts, and it is known that intracranial meningiomas may arise from dural fibroblasts.25 This metaplastic theory is hard to reconcile with the total absence of immunohistochemical or ultrastructural features of Schwann cells in any reported example of pulmonary meningiomas.

Finally, various constituents of organs possess the capacity to regenerate, and thus harbor, multipotential stem cells. Therefore, a tumor such as pulmonary meningioma, which bears little or no resemblance to the organ in which it arose, may simply represent unusual differentiation of a multipotential stem cell.

In summary, primary pulmonary meningiomas are rare neoplasms that demonstrate all of the histologic, immunohistochemical, and ultrastructural characteristics of their intracranial counterparts. The diagnosis requires radiographic and clinical exclusion of a cranial or spinal neoplasm. With the addition of the case presented here, 11 such tumors have behaved in a benign fashion, showing no recurrences after simple excision. Various histogenetic theories for primary pulmonary meningiomas have been suggested, with no definitive proof for any mechanism.

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Accepted for publication January 27, 1997. From the Lauren V. Ackerman Laboratory of Surgical Pathology, Department of Pathology, Barnes Hospital/Washington University School of Medicine, St Louis, Mo.

Reprint requests to Division of Surgical Pathology, Box 8118, Barnes Hospital, One Barnes Hospital Plaza, St Louis, MO 63110 (Dr Ritter).

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