**4. Meningothelial proliferations**

I suppose a general definition of "meningothelial proliferation" would likely be in order. It was alluded to earlier in this review. I say "general" because as noted in the case of PPMs the distinction between what is a meningothelial nodule/proliferation and what is termed a meningioma may be a bit arbitrary and certainly subjective. In this review of PPM, for instance, 6/31 "meningiomas" were less than 1 cm in greatest dimension. In pathology, the distinction between what determines a proliferation and what determines a "tumor" is sometimes based on size with 1 cm being a threshold size for specific tumor designations. For instance, the distinction of papillary thyroid microcarcinoma and papillary thyroid carcinoma is based on the former being less than 1 cm in greatest dimension. In radiology, the standard threshold for detecting tumors has traditionally (although not as much now with improvements in imaging modalities) been less than or greater than 1 cm. In the practice of pathology, these distinctions are not always clear and other features in addition to size are considered in the diagnostic algorithm. An important feature is what the tumor is doing to the surrounding tissue. Is it "blending" in as in the cases, for example, of dominant hyperplastic nodules in the thyroid or nephroblastomatosis in the spectrum of Wilms tumor or it is replacing/pushing normal tissue.

With regards to meningothelial proliferations that occur outside the CNS, that is the presence of meningothelial or meningeal tissue that is not a tumor of meninges, these have been described in a few general settings (although not an exhaustive list) including heterotopic neuroglial proliferations, pulmonary meningothelial nodules (to include diffuse pulmonary meningotheliomatosis), teratomas, and rarely in choristomatous lesions particularly in the head and neck.

One of the reasons to include a review of PPM as cited above was that meningothelial proliferations are well-described in the lungs. In the older pathological literature, MPMNs were originally termed "minute pulmonary paragangliomas" or "chemodectomas" since their ontogeny was thought to be distal airway chemoreceptors [70]. However, subsequently, these have been shown not only morphologically but immunohistochemically and ultrastructurally to be meningothelial in origin. They present as a nested proliferation of spindled and epithelioid cells with bland nuclei around small veins in the lung and exhibit the characteristic EMA+, vimentin+, and PR+ immunophenotype. The incidence of MPMN is reported up to 5% in autopsy studies and in up to approximately 14% of surgical biopsy specimens and in nearly half of lobectomy specimens [70]. Interestingly, in the large series by Mukhopadhyay that included resections from patients in the pediatric age range and over 90 pediatric autopsies, no MPMN were seen in the pediatric population [71]. Radiographically, by CT, MPMN are round solid or partially solid nodules and can be multiple and have a "ground glass" appearance. They typically show low SUV (benign) values for FDG-avidity on 18F-FDG PET-CT imaging [13]. Depending on the clinical scenarios (concurrent other lung lesions, history or concurrence of other tumors), metastases or synchronous tumors cannot be entirely excluded thus necessitating removal and pathological examination. Rarely, MPMN can occur in the setting of PPM; some of these cases being diagnosed as intrapulmonary metastases [14, 25].

Diffuse pulmonary meningotheliomatosis (DPM) is an interesting if not quite rare entity. These patients can present with symptoms of restrictive pulmonary disease with diffuse bilateral reticulonodular infiltrates that have the differential diagnoses including a variety of interstitial lung diseases, carcinomatosis, neuroendocrine tumorlets, metastatic meningioma, and pulmonary lymphangioleiomyomatosis (PLAM). The separation of these entities is relatively straightforward based on morphology and immunophenotyping. Metastatic meningiomas should

#### *Meninges Outside the Meninges: Ectopic Meningiomas and Meningothlelial Proliferations DOI: http://dx.doi.org/10.5772/intechopen.100206*

be distinguished by clinical grounds (presence of a CNS tumor), involvement of the bronchovascular tree as opposed to DPM which is usually found centered around small veins, and more atypical appearance. Carcinomatosis, neuroendocrine tumorlets, and PLAM are distinguished by positivity for keratins, neuroendocrine markers (typically synaptophysin and chromogranin), and actins while similarly to MPMN and PPM, DPM lesions are EMA, vimentin, and PR positive [61, 71–73]. Primary pulmonary meningothelial lesions (MPMN, DPM, and PPM) are very interesting from developmental and genetic perspectives as lung meningothelial lesions seem to predominate the epidemiological landscape of meningothelial lesions outside of the CNS and head/neck and seem to have an extremely low prevalence in the pediatric population leading some to speculate that their origins may not be pluripotent mesenchymal cells but more related to environmental and age-related factors. Although, just because they are not found in the pediatric age group, should not totally discount that they arise from resting pluripotent stem cells or other dormant embryological remnants and their recrudescence as meningothelial lesions is stimulated by other factors. The lungs like other organs also have a "stem cell niche" that is triggered when there is bronchial epithelial injury for the purposes of regeneration/repair [74]. As we have also discussed there seems to be a spectrum of increasing mutations in MPMN and DPM raising the possibilities for a mutational spectrum or "hit" hypotheses in their pathogenesis.

Meningothelial tissue can occur as part of other pathological lesions. In this final section we will briefly touch on the presence of meningiomas and meningothelial tissue in teratomas and meningothelial elements as part of heterotopic/choristomatous/hamartomatous lesions. Somewhat surprisingly, very few cases of meningioma or meningothelial tissue in teratomas are described. A search of PubMed for "meningiomas" and "teratomas" yielded 8 results. One case was a posterior fossa tumor mimicking a meningioma and another case was teratoma and meningioma in the temporoparietal region. The remaining 6 cases were all gonadal teratomas with meningioma [75–82]. The clinical and pathological characteristics of these meningiomas is presented in **Table 5**. Two cases were in the pediatric age range (5-year-old male and 15-year-old female and all meningiomas were seen on gross examination to be whitish or brown firm nodular areas within the broader context of the mature


#### **Table 5.**

*Clinicopathological characteristics of meningiomas arising in gonadal teratomas.*

cystic teratoma (MCT). Chen et al. searched for and characterized meningothelial proliferations in 25 consecutive ovarian MCT [83]. They found that 40% of their tumor had meningothelial proliferations that resembled what has been described in hamartoma of the scalp with ectopic meningothelial elements (more on this later). The meningeal nature of the tissue was confirmed morphologically and by EMA positivity. In all cases the meningothelial tissue was in close association with skin and mature glial tissue (ectodermally derived). Eight of 10 cases had pigmented cells and 3 had psammomatous calcifications. In the author's anecdotal experience, having microscopically examined numerous teratomas from children and adults and teratomas derived from the harvested embryonic stem cells from several species, the finding of meningeal tissue seems not that uncommon, although I have not encountered a meningioma tumor. A recent case of mine illustrates this from a 13-year-old girl with MCT. The meningeal tissue is intimately associated with mature neuroglial tissue and resembles arachnoid of the meninges (**Figure 2**).

Meningothelial tissue can be part of lesions described as heterotopias, particularly of the neuroglial flavor, hamartomas, and choristomas (tissues not indigenous to the anatomic location). In 2005, we reported a temporal glioneuronal heterotopia in a 19-month-old child without underlying connection to the CNS or calvarial defect. In our review of similar cases from the medical literature to that time, 11 infants were identified ranging in age from birth to 15-months. Six of 11 cases had no connection to the CNS (true heterotopias) and 2/6 had meningothelial elements as a component histologically [84]. In another review published at approximately

#### **Figure 2.**

*Meningeal/meningothelial tissue within a mature cystic teratoma of the ovary in a 13-year-old girl. A: Low magnification view showing mature neuroglial tissue (upper left corner) adjacent to a proliferation of rarified, wispy anastomosing cords of fibrous tissue lined by bland small indistinct nuclei. In other areas of the teratoma, this pattern was also seen adjacent to skin and adnexal structures. This segregation of the meningothelial elements near skin and mature neuroglial is common. (HE, 40X). B: Weak by definite staining of the meningeal tissue with epithelial membrane antigen (EMA, 200X). C: Variably intense staining with progesterone receptor (PR, 400X). D: Diffuse strong intensity staining with vimentin (vimentin, 200X).*

#### *Meninges Outside the Meninges: Ectopic Meningiomas and Meningothlelial Proliferations DOI: http://dx.doi.org/10.5772/intechopen.100206*

the same time by Rogers et al. from Boston Children's Hospital, they reported 11 patients with 12 tumors of the scalp ranging in age from 1-month to 20-months. Seven of the 12 tumors had no connection to the CNS and 5 of those 7 tumors had meningothelial tissue as a prominent component histologically [85].

Ectopic meningothelial tissues have been described that appear to arise entirely within the skin and often present in the neonate or infant (so called Type I cutaneous meningioma; defined in the beginning of this chapter). These have been previously termed "acoelic meningeal hamartoma" "cutaneous heterotopic meningeal nodules" and "rudimentary meningocele". In the series published in 1989 by Sibley and Cooper referenced earlier, they described 5 cases of what they termed "primary cutaneous meningioma". What they describe histologically is what is expected in meninges both morphologically and immunophenotypically including collagenous bodies and psammomatous calcifications. Some areas in the superficial dermis had a more rarified and lacy appearance with meningocytes wrapping around vessels and adnexa in intimate association similar to that described shortly thereafter by Suster and Rosai [86]. Their series described 5 patients who had pseudoinfiltrative lesions of the skin and subcutis by meningothelial elements that were in intimate association with the surrounding tissue elements (vessels, fat, connective tissue). In fact, they designated that the meningothelial elements were an interspersed component between a proliferation of connective tissue elements. Their designation for these lesions was "hamartoma of the scalp with ectopic meningothelial elements" and this has become the diagnostic term for such lesions. More recent reports in some cases have shortened the nomenclature to "meningothelial hamartoma". Suster and Rosai give the poignant perspective that the designation of these hamartomatous lesions with meningothelial elements are distinguished from primary cutaneous meningiomas by the association with other poorly arranged elements constituting a hamartoma. We have encountered similar tumors in the scalp (**Figure 3A** and **B**) and have published two cases in young children of tongue lesions with meningothelial elements (**Figure 3C** and **D**). Both tongue lesions were entirely composed of the typical anastomosing slit-like channels lined by bland flat-to-cuboidal cells expressing progesterone receptor and epithelial membrane antigen. Interestingly, but not surprisingly, meningothelial elements have been described occurring in the rare "teratoid" lesion of the palate known as hairy polyp [6]. These are pedunculated growths that can be composed of a variety of tissues derived predominantly from ectodermal and mesodermal (mesenchymal) germ layers. In the reported case, the presence of meningothelial tissue was confirmed by immunohistochemistry and ultrastructural examination demonstrating the characteristic interdigitating cytoplasmic processes connected by cell junctions, desmosomes, intermediate filaments (hence positive expression of vimentin).

In summary, CNS meningiomas are the most common primary CNS tumor and meningiomas and meningothelial tissue/proliferation occur in a multitude of extra-CNS sites and present in a diverse manner from isolated non-tumor proliferations to part of hamartomatous lesions to diffuse meningotheliomatosis to meningiomas tumors arising in multiple anatomic locations. Morphologically, immunophenotypically, ultrastructurally, and perhaps genetically, the meningeal tumors and proliferations outside the CNS are very similar to their CNS counterparts suggesting a common cellular origin. Because of the possibility of arising in diverse anatomic locations, they join a long list of differential diagnostic considerations for the practicing pathologist and should be entertained as possibilities particularly when the morphology could significantly overlap other tumors. In most cases, the immunohistochemical profile of EMA, vimentin, progesterone receptor, and SSTR2a (if available) is diagnostic in the proper morphological context. This panel should be included in diagnostically challenging cases.

#### **Figure 3.**

*Examples of ectopic meningothelial proliferations in the head and neck. A and B represent "hamartoma of the scalp with ectopic meningothelial elements" in a young child. 3A: Low magnification view of loose proliferation of anastomosing wispy fibrous cords lined by bland nuclei interdigitating around adnexal structures (HE, 40X). 3B: High magnification view of the microarchitecture of meningothelial proliferations. This pattern closely resembles vascular proliferations, particularly lymphatic malformations in children and must be excluded in the differential diagnosis (HE, 400X). C and D are from a nearly 2-year-old boy with a tongue mass. 3C: Less obvious than the previous case shown here yet the same microarchitectural pattern is appreciated below the surface epithelium of the tongue. This rarified pattern might be considered a "hemangiopericytomatous" pattern but in any case, is abnormal for the submucosa of the tongue (HE, 40X). 3D: This meningothelial proliferation show strong nuclear staining for progesterone receptor (PR, 400X).*
