Virchows Archiv

, Volume 445, Issue 4, pp 347–353

A benign neoplasm with histopathological features of both schwannoma and retiform perineurioma (benign schwannoma-perineurioma): a report of six cases of a distinctive soft tissue tumor with a predilection for the fingers

Authors

    • Sikl’s Department of PathologyCharles University, Medical Faculty Hospital
  • Dmitry V. Kazakov
    • Sikl’s Department of PathologyCharles University, Medical Faculty Hospital
  • Irena Belousova
    • Department of DermatologyMedical Military Academy
  • Michele Bisceglia
    • Department of PathologyIRCCS-Ospedale Casa Sollievo della Sofferenza
  • Michal Zamecnik
    • Sikl’s Department of PathologyCharles University, Medical Faculty Hospital
  • Petr Mukensnabl
    • Sikl’s Department of PathologyCharles University, Medical Faculty Hospital
Original Article

DOI: 10.1007/s00428-004-1102-5

Cite this article as:
Michal, M., Kazakov, D.V., Belousova, I. et al. Virchows Arch (2004) 445: 347. doi:10.1007/s00428-004-1102-5

Abstract

We present six cases of a distinctive soft tissue tumor which occurred in five women and one man. None of the patients had signs of neurofibromatosis. All tumors occurred on the fingers (n=5) or the thenar eminence of the hand (n=1). The mean age of the patients was 33 years. The tumors were 1–2.5 cm in diameter (mean size 1.6 cm). Three patients with follow-up were without signs of recurrence or metastasis. Microscopically the lesions were nonencapsulated and featured a multilobular architecture and both myxoid and pseudocystic change. The lobules varied in size and shape and were separated by variably thickened, dense, sclerotic/collagenous septae. The lobules were composed of two components: schwannomatous and perineuriomatous. The schwannomatous component was immunohistochemically S-100 protein positive and CD34 and EMA negative, and the perineuriomatous component had the appearance of retiform perineurioma. The perineurial parts were mostly S-100 protein and CD34 negative and EMA positive. These two components either formed separate nodules or the schwannomatous tissue surrounded the perineurial parts located in the centers of the lobules. We interpreted the lesions as hybrid tumors with features of schwannoma and retiform perineurioma.

Keywords

Retiform perineuriomaReticular perineuriomaBenign schwannoma-perineuriomaNeurothekeoma

Introduction

Peripheral nerve sheath tumors are traditionally divided into schwannomas, neurofibromas, and perineuriomas. Perineuriomas were described relatively recently [26], and with the help of immunohistochemical stains for epithelial membrane antigen (EMA) these tumors were defined in recent years [4, 7, 8, 10, 11, 19, 31, 35, 40, 41, 43]. The last distinctive type of perineurioma [35] was identified in small series in recent years, and it was variously named retiform [28] or reticular perineurioma [30]. We are aware of only a single case of hybrid tumor containing a component of retiform perineurioma and a schwannian component in the literature [42]. Here we report a small series of six neoplasms with retiform perineurioma/schwannoma features. Our report demonstrates that these hybrid tumors are distinctive lesions.

Materials and methods

All lesions coded as “perineurioma,” “schwannoma,” “neurothekeoma,” and “nerve sheath myxoma” were retrieved from our consultation files. We looked for the cases which contained areas typical of perineuriomas and schwannomas. Six cases met the criteria of this unusual neoplasm. Clinical data were obtained from the hospital records and/or from contributing clinicians or pathologists. There were five women and one man (mean age 33 years, range 20–52). None of the patients had signs of neurofibromatosis. All patients presented with a solitary subcutaneous tumor. The main clinical data are summarized in Table 1. In three cases tissue blocks were available, in one case there was a large number of unstained reserve slides available, and in two cases only limited number of unstained reserve slides were obtained for the study. Tissue samples were fixed in 4% formaldehyde and paraffin-embedded. Sections (5 µm thick) were stained with routine methods, and the Bodian histochemical method for detecting neuroaxons was performed.
Table 1

Main clinical data (NED no evidence of disease)

Case no.

Sex

Age (years)

Size (cm)

Location

Treatment

Follow-up

1

F

28

1.5

Thumb, left hand

Excision

4 years NED

2

F

50

2.5

Thenar eminence

Excision

Unknown

3

M

26

2.0

2nd finger, left hand

Excision

Recent case

4

F

24

1.5

5th finger, left hand

Excision

Recent case

5

F

20

2.5×2.0

2nd finger, left hand

Excision

1 year NED

6

F

52

1.0×0.5

2nd finger

Excision

7 years NED

In all cases examined by immunohistochemistry either newly cut sections from formaldehyde-fixed, paraffin-embedded material or unstained reserve slides were used. As a detection system we employed the avidin-biotin complex or streptavidin-biotin complex labeled with peroxidase or alkaline phosphatase. Microwave antigen pretreatment was performed prior to applying the primary antibodies. Automated immunostaining employing the Lab Vision autostainer was used. Table 2 lists primary antibodies used in the study. Appropriate positive and negative controls were applied.
Table 2

Antibodies used for immunohistochemical study (EMA epithelial membrane antigen, ASMA α-smooth muscle actin, MSA muscle-specific actin, NFP neurofilament protein)

Antibody specificity

Clone

Dilution

Source

EMA

E29

1:700

DakoCytomation

S-100 protein

Poly

1:4000

DakoCytomation

NFP

2F11

1:1000

DakoCytomation

CD34

QBEnd/10

1:25

Novocastra

Desmin

D33

1:3000

DakoCytomation

ASMA

1A4

1:200

DakoCytomation

MSA

HHF-35

1:4000

DakoCytomation

Melanosome

HMB45

1:200

DakoCytomation

For electron microscopic investigations wet formol-fixed tissue was available in one case. It was postfixed in 4% paraformaldehyde, contrasted in 1% osmium tetroxide, and embedded in epoxy resin (Durcupan-Epon). Sections were cut 1 µm thick, stained with toluidine blue, and examined by light microscopy. Appropriate areas were selected, and thin sections were cut and stained with uranyl acetate and lead citrate, and examined with a Philips (Eindhoven, Holland) EM 208S electron microscope.

Results

Clinical data

The lesions ranged in size from 1.0 to 2.5 cm (mean 1.6). In five patients the neoplasm was located on a finger. The thenar eminence was involved in one patient. Duration was indicated in one case (no. 6); the lesion was present for 15 years before the patient sought medical advice. All lesions were surgically excised. Three patients had a disease free follow-up 1, 4, and 7 years postoperatively. Two patients underwent the excision recently, and in one patient the follow-up was unknown.

Histopathological findings

In all cases the lesions were nonencapsulated and featured a multilobular architecture and both myxoid and pseudocystic change. The latter three features seemed to correlate with the size of the lesions, being more prominent in larger ones. The lobules varied in size and shape and were separated by variably thickened dense, sclerotic/collagenous septae (Fig. 1). The lobules mainly presented perineuriomalike tissue that for the most part demonstrated elongated, spindled cells which often formed loops set in a myxoid matrix typical of retiform perineuriomas (Fig. 2). Occasional cells had multivacuolated cytoplasm and thus vaguely resembled lipoblasts. When myxoid degeneration was prominent, the retiform pattern of perineurioma in lobules was less apparent (Fig. 3). Such lobules contained spindled and occasional epithelioid cells disposed in a loose network in a mucin-rich matrix. Prominent myxoid change was also associated with the formation of peculiar “fibrohyaline balls” lying free in an abundant myxoid matrix in a destroyed lobule (Fig. 4). These balls were composed of a peripheral rim of spindled neoplastic cells and a central collagenous core with radiating delicate collagen fibrils that resembled a spider or a jellyfish. Rare fibrohyaline balls had undergone calcification.
Fig. 1

The lobules vary in size and shape and are separated by variably thickened dense, sclerotic/collagenous septae

Fig. 2

The spindled cells, which often form loops set in a myxoid matrix typical of retiform perineuriomas are seen on the left side and the schwannomatous differentiation on the right

Fig. 3

The retiform pattern of perineurioma in lobules is less apparent when myxoid degeneration is prominent

Fig. 4

Prominent myxoid change leading to the formation of peculiar “fibrohyaline balls” lying free in an abundant myxoid matrix in a destroyed lobule

The schwannomatous areas consisted of elongated cells with tapered, spindled nuclei, mostly arranged in a compact Antoni A pattern, but occasionally also formed arrangement vaguely resembling Verocay bodies. The cells of the schwannomatous component had deeply eosinophilic cytoplasm, by which they differed from the cells constituting the perineuriomatous component. The schwannoma cells were uniform, with only occasional cells possessing a large hyperchromatic nucleus probably representing degenerative atypia. Variously dense deposits of hemosiderin were frequently seen in the schwannomatous areas. These hemosiderin deposits were never seen in the perineuriomatous component of the tumors. Parent nerves were identified in one case. The schwannomatous areas tended to be located at the periphery of a lobule that otherwise represented perineurioma (Fig. 5). In some lobules schwannomatous tissue completely encircled the perineuriomatous tissue (Fig. 6). In three cases the perineuriomatous and schwannomatous lobules were sharply demarcated from each other (Fig. 7). Perineuriomatous areas usually dominated over schwannomatous areas. All tumors lacked mitoses, necroses, and signs of infiltrative growth pointing to the benign nature of the neoplasms.
Fig. 5

The schwannomatous areas tend to be located at the periphery of a lobule that otherwise resembles perineurioma. The schwannomatous peripheral rim consists of cells with much more eosinophilic cytoplasm

Fig. 6

In some lobules schwannomatous tissue completely encircles the perineuriomatous tissue

Fig. 7

In this case the schwannomatous (left) and perineuriomatous lobules (right) are sharply demarcated from each other

Immunohistochemical findings

The neoplastic cells in the perineuriomatous areas were variously strongly positive for EMA and most of them were negative for S-100 protein (Fig. 8). The neoplastic cells in the schwannomatous areas stained positively with S-100 protein antibody (Fig. 9) and reacted negatively with EMA. In the areas where a cuff of schwannomatous cells encircled a perineuriomatous component located in the centers of the lobules S-100 protein stained exclusively the peripheral rim of the lobules (Fig. 10). In three cases there were areas with cellular populations which revealed both S-100 protein and EMA immunoreactivity. These cells with both S-100 protein and EMA positivity are probably cells with dual schwannoma/perineurioma features. There were no neurofilament protein positive axons. Absence of axons was also confirmed by the negativity of the tumors with Bodian staining. CD34 highlighted small blood vessels. The tumorous cells were CD34 negative. Smooth muscle actin and α-smooth muscle actin decorated pericytes around blood vessels. All the rest of the antibodies were negative in the tumors.
Fig. 8

The neoplastic cells in the perineuriomatous areas were variously strongly positive for EMA and most of them were negative for S-100 protein

Fig. 9

The neoplastic cells in the schwannomatous areas tested positively with S-100 protein

Fig. 10

In the areas where a cuff of schwannomatous cells encircles a perineuriomatous component located in the centers of the lobules, S-100 protein stained exclusively the peripheral rim of the lobules

Ultrastructural findings

Six blocks were available from one case for ultrastructural examination. Unfortunately only a myxoid retiform perineurioma component was found in these six blocks. The schwannomatous component of the tumor was not sampled. Most of the cells examined ultrastructurally were cells with bipolar or multipolar slender cytoplasmic processes set in a myxoid extracellular matrix. Many nuclei were convoluted or deeply indented, with a thin rim of heterochromatin and occasional nucleoli. The cytoplasm contained a various amount of rough endoplasmic reticulum, a few mitochondria, some glycogen particles, and numerous intermediate filaments. The cell membranes showed occasional pinocytotic vesicles. The tumor cells formed many well developed attachment sites with numerous cytoplasmic processes of the neighboring cells. The cells were invested with external lamina (Fig. 11).
Fig. 11

The tumor cells were invested with external lamina, and they formed numerous attachment sites

Discussion

The connective tissue sheath of a peripheral nerve is composed of Schwann cells, perineurial cells, and fibroblasts. Tumors arising from a peripheral nerve sheath can contain these cells in various proportions, as found in many ultrastructural studies [9, 15, 18, 25, 32, 36, 37]. Moreover, some authors [9, 15] have also observed additional cells that had ultrastructural features interpretable as transitional stages among the three main cell types. Erlandson [9] has described the following cells in neurofibromas: (a) Schwann cells, (b) perineurial cells, (c) cells having features of Schwann cell and fibroblast, (d) fibroblasts, and (e) transitional Schwann-perineurial cells. Although ultrastructural studies of neurofibromas clearly showed that the perineurial cells are part of a cell population in neurofibromas, immunohistochemical studies using EMA as a marker for perineurial cell differentiation failed to demonstrate convincingly this differentiation [1, 18, 33]. EMA+ cells were rarely found only in peripheral areas of some neurofibromas [1, 29, 34], and these were interpreted as remnants of the nerve sheath of the affected nerve.

The presence of perineurial cells was later confirmed by Zamecnik and Michal [42], who described them as a prominent histological feature in 8% of neurofibromas. The perineurial cells were most often present in pericapsular and perivascular areas. These perineurial cells in pericapsular and perivascular areas are most probably preexisting perineurial cells of the peripheral nerves from which the neurofibromas arose and are not, in contrast to the tumors that we describe, an integral part of the tumors. In addition, the authors presented an interesting tumor which had features of both neurofibroma and retiform perineurioma. This was the first published neoplasm having both perineuriomatous and peripheral nerve sheath differentiation. We again reviewed this case, which is included in our present series, and together with other five similar to identical cases they have now been studied immunohistochemically for the presence of neurofilaments and CD34, which label axons and fibroblasts in neurofibromas respectively [21, 24, 38]. The nonperineuriomatous parts of the tumor were immunohistochemically negative for the antibody to neurofilament proteins and histochemically negative with the Bodian method, findings which confirm that the lesions are devoid of axons. In addition, these parts of the tumors showed an absence of CD34 positive cells. Based upon these findings we think that these nonperineuriomatous parts of the lesions should be interpreted as schwannomatous rather than neurofibromatous component. Interestingly, only the S-100 protein positive schwannomatous parts but not EMA positive perineuriomatous parts of the tumors had sometimes heavy depositions of hemosiderin. The lobular architecture, frequent pseudocystic arrangement of the lobules, myxoid nature of the lesions, the retiform arrangement of the perineuriomatous parts of the lesions, which is identical to the retiform (reticular) perineurioma [28, 30] and predominant occurrence in the fingers highlight the uniqueness of the tumors in this report. We have seen examples of schwannoma-perineurioma hybrid tumors outside the soft tissues of the fingers. These tumors look different from our cases. They can be considerably larger, usually lack the pseudocystic lobular arrangement, the perineuriomatous and schwannomatous components are much more intermingled, and the retiform arrangement of the perineurial component is much less expressed [28, 30].

We reviewed the literature for similar lesions published in the past. Judging purely from a morphological point of view, several reports may have described identical neoplasms under the names of dermal nerve sheath myxoma, cutaneous lobular neuromyxoma, bizarre cutaneous neurofibromas, Pacinian neurofibroma, and neurothekeoma [1, 5, 13, 16, 17, 22, 27]. These lesions had a similar lobular architecture and myxoid areas resembling retiform perineuriomas. In particular, the lesion pictured in Fig. 1 in the report of Argenyi et al. [3] on nerve sheath myxomas seems to show similarities to our cases. Their detailed Fig. 1B is highly suggestive of a retiform perineurioma arrangement. In addition, at least two of the cases in their report revealed both S-100 protein and EMA positivity. The rest of the reports that we reviewed, however, were published either before the era of immunohistochemistry or presented no information on EMA and/or S-100 protein staining. It is therefore impossible to judge these reports critically and objectively and compare them with our cases.

Owing to distinct histopathological features the differential diagnosis of this neoplasm should pose no problem provided a pathologist is familiar with the appearance of retiform perineurioma, a relatively rare neoplasm and that of schwannoma. However, retiform perineurioma is rare and less known lesion, and therefore we ourselves started to recognize these hybrid tumors only after having seen quite a number of retiform perineuriomas. When a myxoid change is prominent, this hybrid tumor may resemble nerve sheath myxoma (neurothekeoma) [24]. The combination of schwannomatous tissue and perineuriomatous tissue enables a clear distinction from any known neoplasm. In addition, staining for both EMA and S-100 protein assists in revealing the biphasic nature of the neoplasm. We have also recently seen an example of benign schwannoma in which peculiar multifocal myxoid degeneration resulted in an appearance simulating a retiform perineurioma. Microscopically this neoplasm was probably the closest mimic of the reported tumor we ever saw; however, immunohistochemistry facilitated the correct diagnosis.

Retiform perineurioma was first described by Ushigome et al. [35] and later defined in small series in recent years, and it was named as retiform perineurioma [28]. We use a descriptive name for the reported tumor: a neoplasm with histopathological features of both schwannoma and retiform perineurioma. Because the term “retiform” has been used in some tumors to connote the resemblance of rete testis other term, namely “reticular” was suggested for this tumor [30]. However, we think that there are other well established anatomical terms in which the word “rete” is used, for example, “rete carpi dorsale” [39], “rete mirabile” [20], and “rete pedis” [12] as well as other terms with histological connotations such as “choroid rete” [23] “rete ridges” in the skin [6], “rete ridges” in esophagus [14], and others [2]. We therefore believe that there is no need to compare the term “retiform” to the rete testis. In the case of perineurioma it was devised to describe the typical netlike arrangement of the tumor [28].

In conclusion, we describe clinicopathological features of distinctive benign hybrid neoplasm composed of schwannoma and retiform perineurioma. In contrast with other nerve sheath tumors, the lesion shows no association with neurofibromatosis or schwannomatosis.

Copyright information

© Springer-Verlag 2004