ORIGINAL ARTICLE
Malignant Peripheral Nerve Sheath Tumor (MPNST) Arising in Diffuse-type Neurofibroma Clinicopathologic Characterization in a Series of 9 Cases Inga-Marie Schaefer, MD and Christopher D.M. Fletcher, MD, FRCPath
Abstract: Diffuse-type neurofibroma, an uncommon variant of neurofibroma, is associated with neurofibromatosis type 1 in B60% of cases. Typically presenting in young adults as ill-defined plaque-like dermal/subcutaneous thickening, most cases are located on the trunk or the head and neck region. Malignant transformation is extremely rare. Nine cases of malignant peripheral nerve sheath tumor (MPNST) arising in diffuse-type neurofibroma (identified in consult files) are described, including clinicopathologic features and follow-up. Five patients were male and 4 female, aged 31 to 59 years (median 49 y). All diffuse-type neurofibromas contained Meissner corpuscles, with tumor sizes ranging between 3.6 and 45 cm (median, 7.4 cm). Five patients had a clinical history of neurofibromatosis type 1, and 1 had KlippelTre´naunay-Weber syndrome. Six tumors arose on the trunk and 1 each on the leg, arm, and scalp. Increased cellularity, nuclear atypia, and mitoses (range, 1 to 63/50 high-power fields) indicated transition to MPNST, classified as low grade in 5, intermediate to high grade in 1, and high grade in 3 cases, 1 of which exhibited heterologous angiosarcomatous differentiation. S-100 expression was quite strong and diffuse in the neurofibroma components and less extensive or weaker in MPNST. Follow-up, available for all patients (median, 80.5 mo, except 1 recent case), revealed that 1 patient developed local recurrence after 9 months; 1 with metastases at the time of initial diagnosis died 1 month after tumor resection. All other patients were alive without evidence of disease at 15 to 145 months (median, 83 mo). Diffuse-type neurofibroma may show transformation to MPNST in very rare instances. It is important to be aware of possible malignant change, requiring thorough sampling of resection specimens and long-term clinical follow-up of patients with unexcised lesions. Key Words: diffuse-type neurofibroma, Meissner corpuscles, malignant peripheral nerve sheath tumor, neurofibromatosis (Am J Surg Pathol 2015;39:1234–1241)
From the Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Conflicts of Interest and Source of Funding: I.-M.S. is supported by a research grant from the Dr Mildred Scheel Stiftung fu¨r Krebsforschung (No. 110822). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Christopher D.M. Fletcher, MD, FRCPath, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail: cfl[email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
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iffuse-type neurofibroma is a distinct subtype of neurofibroma and most often presents on the trunk or the head and neck region of middle-aged adults (mean 60 y), with an equal sex distribution.1–3 Approximately 60% of these tumors arise in the setting of neurofibromatosis type 1 (NF-1).1,2 On gross examination, diffuse-type neurofibromas appear as ill-defined dermal/ subcutaneous thickening extending into subcutaneous tissue and fascia, with a grayish-white or yellowish firm cut surface. Histologically, these tumors grow along connective tissue septa with infiltration between adjacent subcutaneous adipocytes and entrapment of dermal adnexal structures without destruction. Diffuse-type neurofibromas have a characteristic uniform matrix of fine fibrillary collagen and tumor cells with indistinct cell borders, eosinophilic cytoplasm, and slightly plumper and less elongated nuclei than observed in conventional neurofibroma.2 A characteristic feature, considered a diagnostic requirement for this subtype of neurofibroma, is the presence of eosinophilic, lamellar structures resembling Meissner corpuscles. Furthermore, large ectatic blood vessels2 and focal patchy lymphocytic infiltrates4 have been described in some cases. Immunohistochemically, diffuse-type neurofibromas usually express S-100 protein and neurofilament protein (NFP), which highlights scattered axons in some cases.2 In around 1% of cases scattered melanin-containing pigmented dendritic cells may be encountered.5 This feature is most often observed in diffuse-type neurofibroma but may also occur in tumors with mixed diffuse and plexiform-type features. Malignant transformation in diffuse-type neurofibroma to malignant peripheral nerve sheath tumor (MPNST) is exceptionally rare, with only 7 cases reported to date in the literature.4,6–9 In addition, 1 case included in the present series was reported previously.10 We describe herein a series of 9 cases of MPNST arising in diffuse-type neurofibroma to better define their biological and clinicopathologic characteristics as well as prognostic implications.
MATERIALS AND METHODS Nine cases of MPNST arising in diffuse-type neurofibroma were retrieved from the authors’ consultation files. One case (#6) was reported previously by the referring pathologist and colleagues.10 Diffuse-type Am J Surg Pathol
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MPNST in Diffuse Neurofibroma
TABLE 1. Clinicopathologic Characteristics of 9 Cases of MPNST Arising in Diffuse-type Neurofibroma Case No.
Age (y) Sex
1
41
F
2
31
M
3
51
M
4
41
M
5
50
F
6*
46
7
Site (Side)
No. Size Mitoses/ Lesions (cm) 50 HPF
MPNST Grade
Associated Conditions
S-100 (DTNF/ MPNST)
NFP (DTNF/ MPNST)
Resection Margins
Follow-up Status (mo)
Thoracic spine Flank/ trunk (L) Buttock (R
2
8
2
Low
NF-1
+/(+)
/
R0
ANED (18)
1
21.3
2
Low
NF-1
+/+
/
R1
ANED (145)
1
45
1
Low
NF-1
+/+
/
R1
1
4.5
5
Low
NF-1
+/(+)
/
R1
1
6.7
16
High
NF-1
+/(+)
/
R1
Recent case (6)
M
Chest wall Upper arm (L) Leg (R
Recurrence (9 mo), ANED (117) ANED (78)
1
40
63
High
KlippelTre´naunay-Weber syndrome
+/(+)
/
R0w
DOD (1)
49
F
Back
1
3.6
1
Low
+/+
Scattered axons +/
R1
ANED (92)
8
59
F
Scalp
1
NA
NA
+/+
NA
R1
ANED (15)
9
59
M
Buttock (L)
1
6
22
Intermediate to high High
+/(+)
/
R1
ANED (83)
*Case reported before. wAmputation specimen (+) indicates staining weak or focal; ANED, alive, no evidence of disease; DOD, died of disease; DTNF, diffuse-type neurofibroma; HPF, high-power fields; NA, not available.
neurofibroma was characterized by an ill-defined, infiltrative growth pattern, dermal or subcutaneous localization, and the presence of Meissner corpuscles. Hematoxylin and eosin–stained sections and immunohistochemical stains were reexamined, with attention to cytomorphologic features, growth pattern, the presence of malignant change, defined as foci of increased cellularity, nuclear atypia including increased nuclear-cytoplasmic ratio, and nuclear hyperchromasia, as well as mitotic activity (counted in 50 high-power fields [HPF]). Clinical and follow-up data were obtained from referring pathologists and clinicians using a standardized data sheet (see the Acknowledgments section). Immunohistochemical analyses were performed in our laboratory on 4-mm-thick formalinfixed paraffin-embedded tissue sections using antibodies directed against S-100 protein (Dako, Carpinteria, CA; polyclonal, dilution 1:1000, no pretreatment) and NFP (Monosan, Uden, The Netherlands; clone 2F11, dilution 1:300, no pretreatment) using the Envision Plus detection system (Dako). Appropriate positive and negative controls were used throughout. This study was performed with the approval of the Institutional Review Board at the Brigham and Women’s Hospital.
RESULTS Clinical Features Clinicopathologic data are summarized in Table 1. The patient group comprised 5 men and 4 women, with a Copyright
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median age of 49 years at the time of presentation (range, 31 to 59 y). Five patients (#1 to 5) had a clinical history of NF-1, and 1 patient (#6) had Klippel-Tre´naunay-Weber syndrome. The anatomic distribution was as follows: 6 tumors arose on the trunk and 1 case each on the leg, the arm, and the scalp. Case #9 was initially diagnosed on biopsy as malignant fat-forming solitary fibrous tumor, as areas of diffuse-type neurofibroma with Meissner corpuscles were evident only in the subsequent reexcision. All patients for whom data were available were treated by local resection, achieving tumor-free margins in only 2/9 and positive margins in 7/9 cases. Follow-up information was available for 8 patients (median follow-up 80.5 mo). One case (#5) was very recent and not included in followup analyses. This patient underwent repeated excision of recurrent diffuse-type neurofibroma and finally developed MPNST arising in diffuse-type neurofibroma in the same region 6 years after the first excision. Another patient (#3) developed local recurrence after 9 months and was treated with reexcision. Patient #6 had pulmonary metastases at diagnosis and died from the disease 1 month after tumor resection. All other patients were alive without evidence of disease at 15 to 145 months (median, 83 mo) after tumor resection.
Gross and Microscopic Features The tumor size ranged from 3.6 to 45 cm (median 7.4 cm, data available for 8/9 patients) (Table 1). The tumors were located in the dermis or subcutaneous tissue (Fig. 1A). Eight patients (#2 to 9) had 1 lesion, and 1
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FIGURE 1. A, Histologically, diffuse-type neurofibroma typically arises as an ill-defined plaque-like lesion in dermal or subcutaneous tissue (arrow). Diffuse infiltration of subcutaneous adipose tissue (B) by tumor cells with scattered Meissner corpuscles (C). D, Diffuse-type neurofibroma comprises tumor cells with round to fusiform nuclei in a fine fibrillary collagenous matrix.
patient (#1) had 2 separate diffuse neurofibromas, both exhibiting malignant change to low-grade MPNST. Most tumors were ill defined and exhibited a yellow to white, firm and solid cut surface. Histologically, the diffuse-type neurofibromas showed an infiltrative growth pattern, extending from the dermis into the subcutaneous soft tissue with entrapment of adipose tissue and adnexal structures (Fig. 1B). All cases of diffuse-type neurofibroma showed characteristic eosinophilic lamellar structures resembling Meissner tactile corpuscles (Fig. 1C), which were encountered either in closely
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packed clusters or scattered loosely throughout the tumor. Tumor cells had slightly elongated to plump, sometimes wavy, nuclei and ill-defined cell borders and were distributed in a fine, eosinophilic fibrillary collagenous matrix (Fig. 1D). Foci of melanin pigment– containing dendritic cells were observed in 1 case (#2). Furthermore, a patchy lymphocytic inflammatory infiltrate was occasionally observed in some cases. Focal transition of diffuse-type neurofibroma to MPNST was subtle in the majority of cases, with benign-appearing tumor cells with fusiform to oval nuclei scattered in an Copyright
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MPNST in Diffuse Neurofibroma
FIGURE 2. A, Areas of increased cellularity (top left) with spindle cells showing nuclear atypia and mitoses indicate transition to MPNST (case 1; A). B, Some MPNSTs consisted of tumor cells with more plump to ovoid nuclei surrounded by a hyalinized matrix (case 4; B) and scattered mitoses (B, inset), whereas others showed predominantly spindle cell morphology (case 5; C), with occasional entrapped remnants of Meissner corpuscles (case 5; D).
eosinophilic collagenous matrix blending with areas of increased cellularity, nuclear atypia, and mitotic activity, with a median of 3.5/50 HPF (range, 1 to 63/50 HPF, data available for 8/9 patients) (Fig. 2). The MPNSTs usually showed spindle cell differentiation and were classified as low grade in 5 cases (Fig. 3), intermediate to high grade in 1 case, and high grade in 3 cases (Fig. 4). Most malignant components consisted predominantly of spindle cells with a fascicular and whorled architecture (case #1, 2, 5, 6, 9), whereas others showed a discohesive growth pattern with Copyright
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marked nuclear atypia and scattered histiocytes with abundant pale cytoplasm and cytoplasmic inclusions (#3), hyalinized matrix (#4), or more ovoid to plump tumor cells (#7). Positive excision margins in 6 cases consisted only of the neurofibromatous component. Immunohistochemically, the neurofibroma components expressed S-100 quite strongly and diffusely in˜ 80% of the cells, whereas the MPNST component showed comparable diffuse expression in 4 and less extensive or weaker expression in 4 cases (Fig. 5). Staining with NFP
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FIGURE 3. Case 2—Neurofibromatous tissue (A) shows transition to areas of increased cellularity (B) and then to frank MPNST (C), which had a low mitotic count and was classified as low grade.
revealed single scattered axons in the neurofibroma component of case #7. In patient #6, MPNST with heterologous angiosarcomatous differentiation was observed (Fig. 6), with expression of CD31 by malignant endothelial cells. This patient with Klippel-Tre´naunauy-Weber syndrome had previously undergone resection of a longstanding vascular malformation on the same leg 25 years earlier (materials not available for review).
DISCUSSION MPNST arises in around 5% to 10% of NF-1 patients, mostly in the plexiform or localized intraneural variant of neurofibroma, and is thought usually to take years to develop.1,11,12 Most MPNSTs (˜60%) are believed to arise from benign precursor lesions and up to half of all MPNSTs occur in the setting of NF-1.1,11,13 There is undoubtedly a morphologic continuum between neurofibroma, “atypical” neurofibroma, and MPNST, and sharply defined cutoffs for malignant change have not been defined as yet, in part because features of all 3 may be evident in a single specimen. Criteria for malignant
change in neurofibroma include nuclear atypia, that is, nuclear enlargement and hyperchromasia, hypercellularity, and mitotic activity, even though it remains controversial as to whether mitoses always indicate malignant change or whether very few may still be acceptable in neurofibromas if other features of malignancy are not present.1,14 The majority of MPNSTs are deep-seated, highgrade tumors with an unfavorable prognosis and an estimated 5-year survival rate of 40% to 50%, although whether the prognosis is worse in patients with NF-1 remains uncertain.11 However, MPNSTs arising in diffusetype neurofibromas, which appear to be extremely rare, most often present as superficial tumors, and, in the present series, 5/9 cases were classified as low-grade MPNST. Histologically, in general, most MPNSTs show predominantly spindle cell morphology, with epithelioid MPNST accounting for only 5% of cases.15 Immunohistochemically, no more than 40% to 50% of MPNSTs with spindle cell morphology express S-100 protein,16 often in only up to 10% to 20% of cells, as opposed to diffuse-type neurofibroma with stronger expression in at least 50% of cells.
FIGURE 4. Case 6—Neurofibromatous tissue with Meissner corpuscles (A), elsewhere showing subtly increased cellularity and then transition to frank MPNST (C), which was classified as high grade (and showed angiosarcoma elsewhere; see Fig. 6).
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MPNST in Diffuse Neurofibroma
FIGURE 5. Immunohistochemical staining with S-100 protein demonstrated quite strong and diffuse expression in the diffusetype neurofibroma component (case 7; A), and weaker or more focal expression in the MPNST component (case 7; B).
On a molecular basis, dysregulation of cell cycle progression, in particular G1 transition, has been implicated to play a role in the progression of neurofibromas to MPNST.17 A change of expression of the cell cycle regulators p53, p16, and p27 has been observed to occur during tumor progression; however, these markers do not
seem to distinguish reliably between low-grade MPNST and neurofibromas.18,19 Recent evidence suggests a stepwise progression of neurofibroma, first to atypical neurofibroma and then to MPNST, as copy number loss of the CDKN2A locus at 9p21.3 was detected not only in the majority of MPNST but also in atypical neurofibromas
FIGURE 6. A, Patient #6 with MPNST (not shown) arising in diffuse-type neurofibroma (left) showed transition to angiosarcoma, morphologically high grade (right) (A). This patient had a diagnosis of Klippel-Tre´naunay-Weber syndrome. B, At higher magnification, scattered Meissner corpuscles were observed within areas of angiosarcoma consisting of ill-defined vascular channels lined by poorly differentiated, atypical endothelial cells. Copyright
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(94% of cases). These findings suggest that atypical neurofibromas represent premalignant tumors, with CDKN2A loss being an early event in tumor progression.20 However, MPNSTs arising in diffuse-type neurofibromas were not included in these studies. The 7 previously reported cases of MPNST arising in diffuse-type neurofibroma included 5 female and 2 male patients with a median age of 53 years (range, 28 to 88 y).4,6–9 The majority of tumors were located on the extremities (4/7), followed by scalp (2/7) and trunk (1/7). Follow-up, available for 5 patients (median, 3 y), revealed that 3 patients had several local recurrences (up to 14 in 1 patient), altogether over a period of 36 to 44 years. Two of these 3 patients with recurrence died of an unknown cause, but none of them developed metastases or died from MPNST.4 In another study, 1 patient died after 1 year from lung metastases.8 Only 1 of these 7 patients was reported to have a history of NF-1.6 In our series, the tumors showed similar epidemiologic and clinical characteristics as have been reported previously for diffuse-type neurofibromas without malignant change: the median age was 49 years without sex predilection, and 5 of the 9 tumors developed in the setting of NF-1. The diffuse-type neurofibroma components exhibited typical histologic features, such as ill-defined margins, diffuse infiltration between adnexal structures, a uniform matrix of fine fibrillary collagen, Meissner corpuscles, and, in 1 case, foci of melanin pigment–containing dendritic cells. The tumor cells showed indistinct cell borders and slightly plump nuclei, with focal transition to cellular areas with nuclear atypia and mitoses, indicating progression to MPNST. In the present series, the majority of cases (7/9) were excised with positive resection margins, likely attributable to the growth pattern of this type of neurofibroma and difficulties in resectability, but only benign lesional tissue was present at the margins. The MPNSTs arising in diffuse-type neurofibroma in the present series followed a rather favorable clinical course. Except for 1 patient with the unusual constellation of Klippel-Tre´naunay-Weber syndrome and additional heterologous angiosarcomatous differentiation, all patients studied in our series were alive with no evidence of disease after a considerable follow-up time. This somewhat surprising outcome is comparable to that described by Evans in 3 cases, which had a remarkably indolent and protracted course after the development of MPNST.4 Whether or not this reflects an intrinsically different biology remains undetermined, and the case numbers are very small. The diagnosis of diffuse-type neurofibroma is usually straightforward; however, in cases that fail to show Meissner corpuscles on limited biopsy material, localized neurofibroma and dermatofibrosarcoma protuberans (DFSP) enter the differential diagnosis. Like diffuse-type neurofibroma, DFSP shows dermal and subcutaneous localization and an infiltrative growth pattern. However, in contrast to diffusetype neurofibroma, DFSP is characterized by a storiform growth pattern, immunohistochemical expression of CD34, negativity for S-100 protein, and lack of Meissner corpuscles.
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In conclusion, malignant change in diffuse-type neurofibroma is extremely rare. Foci of increased cellularity, nuclear atypia, and mitotic figures indicate the presence of MPNST. Approximately half of the cases in our series were associated with NF-1. Thorough sampling of resection specimens is advisable, particularly in very large diffuse-type neurofibromas, to identify areas of malignant transformation, necessitating long-term clinical follow-up. ACKNOWLEDGMENTS The authors thank the following pathologists and clinicians who kindly submitted the cases and provided clinical follow-up information when available: Dr T. Wieczorek, Boston, MA, Dr C.E. Trask, Bangor, ME, Dr Michelle Perkins, Blue Hill, ME, Dr W.E. Taylor, Dallas, TX, Dr, G.M. Hariz, Mesquite, TX, Dr M. Pruszczynski, Nijmegen, The Netherlands, Dr M.J.M. Ploegmakers, Nijmegen, The Netherlands, Dr J.S. Roy, Rye Brook, NY, Dr P. Abenoza, Pompano Beach, FL, Dr D. Abis, West Palm Beach, FL, Dr N.P. Libbey, Providence, RI, and Dr R.J. Koness, Providence, RI. REFERENCES 1. Woodruff JM. Pathology of tumors of the peripheral nerve sheath in type 1 neurofibromatosis. Am J Med Genet. 1999;89:23–30. 2. Megahed M. Histopathological variants of neurofibroma. A study of 114 lesions. Am J Dermatopathol. 1994;16:486–495. 3. Antonescu CR, Scheithauer BW, Woodruff JM. Neurofibroma. AFIP Atlas of Tumor Pathology: Tumors of the Peripheral Nervous System, Fourth Series, Fascicle 19. Silver Spring, Maryland: American Registry of Pathology; 2013:211–264. 4. Evans HL. Sporadic superficial diffuse neurofibromas with repeated local recurrence over many years and a tendency toward malignant change: a report of 3 cases. Am J Surg Pathol. 2013;37: 987–994. 5. Fetsch JF, Michal M, Miettinen M. Pigmented (melanotic) neurofibroma: a clinicopathologic and immunohistochemical analysis of 19 lesions from 17 patients. Am J Surg Pathol. 2000;24:331–343. 6. Inoue T, Kuwashiro M, Misago N, et al. Superficial malignant peripheral nerve sheath tumor arising from diffuse neurofibroma in a neurofibromatosis type 1 patient. J Dermatol. 2014;41: 631–633. 7. Thomas C, Somani N, Owen LG, et al. Cutaneous malignant peripheral nerve sheath tumors. J Cutan Pathol. 2009;36:896–900. 8. Allison KH, Patel RM, Goldblum JR, et al. Superficial malignant peripheral nerve sheath tumor: a rare and challenging diagnosis. Am J Clin Pathol. 2005;124:685–692. 9. Molenaar WM, Dijkhuizen T, van EJ, et al. Cytogenetic support for early malignant change in a diffuse neurofibroma not associated with neurofibromatosis. Cancer Genet Cytogenet. 1997;97:70–72. 10. Ploegmakers MJ, Pruszczynski M, De RJ, et al. Angiosarcoma with malignant peripheral nerve sheath tumour developing in a patient with Klippel-Tre´naunay-Weber syndrome. Sarcoma. 2005;9:137–140. 11. Antonescu CR, Scheithauer BW, Woodruff JM. Malignant tumors of the peripheral nerves. AFIP Atlas of Tumor Pathology: Tumors of the Peripheral Nervous System, Fourth Series, Fascicle 19. Silver Spring, Maryland: American Registry of Pathology; 2013:381–474. 12. Widemann BC. Current status of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Curr Oncol Rep. 2009;11:322–328. 13. Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer. 1986;57:2006–2021.
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14. Lin BT, Weiss LM, Medeiros LJ. Neurofibroma and cellular neurofibroma with atypia: a report of 14 tumors. Am J Surg Pathol. 1997;21:1443–1449. 15. Laskin WB, Weiss SW, Bratthauer GL. Epithelioid variant of malignant peripheral nerve sheath tumor (malignant epithelioid schwannoma). Am J Surg Pathol. 1991;15:1136–1145. 16. Fletcher CDM. Peripheral neuroectodermal tumors. In: Fletcher CDM, ed. Diagnostic Histopathology of Tumors, 4th edn. Philadelphia, PA: Elsevier Saunders; 2013:2032–2063. 17. Kourea HP, Cordon-Cardo C, Dudas M, et al. Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of
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p27(kip) in malignant transformation of neurofibromas. Am J Pathol. 1999;155:1885–1891. 18. Zhou H, Coffin CM, Perkins SL, et al. Malignant peripheral nerve sheath tumor: a comparison of grade, immunophenotype, and cell cycle/growth activation marker expression in sporadic and neurofibromatosis 1-related lesions. Am J Surg Pathol. 2003;27:1337–1345. 19. Kourea HP, Orlow I, Scheithauer BW, et al. Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. Am J Pathol. 1999;155:1855–1860. 20. Beert E, Brems H, Daniels B, et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer. 2011;50:1021–1032.
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Malignant Peripheral Nerve Sheath Tumor (MPNST) Arising in Diffuse-type Neurofibroma Clinicopathologic Characterization in a Series of 9 Cases Inga-Marie Schaefer, MD and Christopher D.M. Fletcher, MD, FRCPath
Abstract: Diffuse-type neurofibroma, an uncommon variant of neurofibroma, is associated with neurofibromatosis type 1 in B60% of cases. Typically presenting in young adults as ill-defined plaque-like dermal/subcutaneous thickening, most cases are located on the trunk or the head and neck region. Malignant transformation is extremely rare. Nine cases of malignant peripheral nerve sheath tumor (MPNST) arising in diffuse-type neurofibroma (identified in consult files) are described, including clinicopathologic features and follow-up. Five patients were male and 4 female, aged 31 to 59 years (median 49 y). All diffuse-type neurofibromas contained Meissner corpuscles, with tumor sizes ranging between 3.6 and 45 cm (median, 7.4 cm). Five patients had a clinical history of neurofibromatosis type 1, and 1 had KlippelTre´naunay-Weber syndrome. Six tumors arose on the trunk and 1 each on the leg, arm, and scalp. Increased cellularity, nuclear atypia, and mitoses (range, 1 to 63/50 high-power fields) indicated transition to MPNST, classified as low grade in 5, intermediate to high grade in 1, and high grade in 3 cases, 1 of which exhibited heterologous angiosarcomatous differentiation. S-100 expression was quite strong and diffuse in the neurofibroma components and less extensive or weaker in MPNST. Follow-up, available for all patients (median, 80.5 mo, except 1 recent case), revealed that 1 patient developed local recurrence after 9 months; 1 with metastases at the time of initial diagnosis died 1 month after tumor resection. All other patients were alive without evidence of disease at 15 to 145 months (median, 83 mo). Diffuse-type neurofibroma may show transformation to MPNST in very rare instances. It is important to be aware of possible malignant change, requiring thorough sampling of resection specimens and long-term clinical follow-up of patients with unexcised lesions. Key Words: diffuse-type neurofibroma, Meissner corpuscles, malignant peripheral nerve sheath tumor, neurofibromatosis (Am J Surg Pathol 2015;39:1234–1241)
From the Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Conflicts of Interest and Source of Funding: I.-M.S. is supported by a research grant from the Dr Mildred Scheel Stiftung fu¨r Krebsforschung (No. 110822). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Christopher D.M. Fletcher, MD, FRCPath, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail: cfl[email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
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D
iffuse-type neurofibroma is a distinct subtype of neurofibroma and most often presents on the trunk or the head and neck region of middle-aged adults (mean 60 y), with an equal sex distribution.1–3 Approximately 60% of these tumors arise in the setting of neurofibromatosis type 1 (NF-1).1,2 On gross examination, diffuse-type neurofibromas appear as ill-defined dermal/ subcutaneous thickening extending into subcutaneous tissue and fascia, with a grayish-white or yellowish firm cut surface. Histologically, these tumors grow along connective tissue septa with infiltration between adjacent subcutaneous adipocytes and entrapment of dermal adnexal structures without destruction. Diffuse-type neurofibromas have a characteristic uniform matrix of fine fibrillary collagen and tumor cells with indistinct cell borders, eosinophilic cytoplasm, and slightly plumper and less elongated nuclei than observed in conventional neurofibroma.2 A characteristic feature, considered a diagnostic requirement for this subtype of neurofibroma, is the presence of eosinophilic, lamellar structures resembling Meissner corpuscles. Furthermore, large ectatic blood vessels2 and focal patchy lymphocytic infiltrates4 have been described in some cases. Immunohistochemically, diffuse-type neurofibromas usually express S-100 protein and neurofilament protein (NFP), which highlights scattered axons in some cases.2 In around 1% of cases scattered melanin-containing pigmented dendritic cells may be encountered.5 This feature is most often observed in diffuse-type neurofibroma but may also occur in tumors with mixed diffuse and plexiform-type features. Malignant transformation in diffuse-type neurofibroma to malignant peripheral nerve sheath tumor (MPNST) is exceptionally rare, with only 7 cases reported to date in the literature.4,6–9 In addition, 1 case included in the present series was reported previously.10 We describe herein a series of 9 cases of MPNST arising in diffuse-type neurofibroma to better define their biological and clinicopathologic characteristics as well as prognostic implications.
MATERIALS AND METHODS Nine cases of MPNST arising in diffuse-type neurofibroma were retrieved from the authors’ consultation files. One case (#6) was reported previously by the referring pathologist and colleagues.10 Diffuse-type Am J Surg Pathol
Volume 39, Number 9, September 2015
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Am J Surg Pathol
Volume 39, Number 9, September 2015
MPNST in Diffuse Neurofibroma
TABLE 1. Clinicopathologic Characteristics of 9 Cases of MPNST Arising in Diffuse-type Neurofibroma Case No.
Age (y) Sex
1
41
F
2
31
M
3
51
M
4
41
M
5
50
F
6*
46
7
Site (Side)
No. Size Mitoses/ Lesions (cm) 50 HPF
MPNST Grade
Associated Conditions
S-100 (DTNF/ MPNST)
NFP (DTNF/ MPNST)
Resection Margins
Follow-up Status (mo)
Thoracic spine Flank/ trunk (L) Buttock (R
2
8
2
Low
NF-1
+/(+)
/
R0
ANED (18)
1
21.3
2
Low
NF-1
+/+
/
R1
ANED (145)
1
45
1
Low
NF-1
+/+
/
R1
1
4.5
5
Low
NF-1
+/(+)
/
R1
1
6.7
16
High
NF-1
+/(+)
/
R1
Recent case (6)
M
Chest wall Upper arm (L) Leg (R
Recurrence (9 mo), ANED (117) ANED (78)
1
40
63
High
KlippelTre´naunay-Weber syndrome
+/(+)
/
R0w
DOD (1)
49
F
Back
1
3.6
1
Low
+/+
Scattered axons +/
R1
ANED (92)
8
59
F
Scalp
1
NA
NA
+/+
NA
R1
ANED (15)
9
59
M
Buttock (L)
1
6
22
Intermediate to high High
+/(+)
/
R1
ANED (83)
*Case reported before. wAmputation specimen (+) indicates staining weak or focal; ANED, alive, no evidence of disease; DOD, died of disease; DTNF, diffuse-type neurofibroma; HPF, high-power fields; NA, not available.
neurofibroma was characterized by an ill-defined, infiltrative growth pattern, dermal or subcutaneous localization, and the presence of Meissner corpuscles. Hematoxylin and eosin–stained sections and immunohistochemical stains were reexamined, with attention to cytomorphologic features, growth pattern, the presence of malignant change, defined as foci of increased cellularity, nuclear atypia including increased nuclear-cytoplasmic ratio, and nuclear hyperchromasia, as well as mitotic activity (counted in 50 high-power fields [HPF]). Clinical and follow-up data were obtained from referring pathologists and clinicians using a standardized data sheet (see the Acknowledgments section). Immunohistochemical analyses were performed in our laboratory on 4-mm-thick formalinfixed paraffin-embedded tissue sections using antibodies directed against S-100 protein (Dako, Carpinteria, CA; polyclonal, dilution 1:1000, no pretreatment) and NFP (Monosan, Uden, The Netherlands; clone 2F11, dilution 1:300, no pretreatment) using the Envision Plus detection system (Dako). Appropriate positive and negative controls were used throughout. This study was performed with the approval of the Institutional Review Board at the Brigham and Women’s Hospital.
RESULTS Clinical Features Clinicopathologic data are summarized in Table 1. The patient group comprised 5 men and 4 women, with a Copyright
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median age of 49 years at the time of presentation (range, 31 to 59 y). Five patients (#1 to 5) had a clinical history of NF-1, and 1 patient (#6) had Klippel-Tre´naunay-Weber syndrome. The anatomic distribution was as follows: 6 tumors arose on the trunk and 1 case each on the leg, the arm, and the scalp. Case #9 was initially diagnosed on biopsy as malignant fat-forming solitary fibrous tumor, as areas of diffuse-type neurofibroma with Meissner corpuscles were evident only in the subsequent reexcision. All patients for whom data were available were treated by local resection, achieving tumor-free margins in only 2/9 and positive margins in 7/9 cases. Follow-up information was available for 8 patients (median follow-up 80.5 mo). One case (#5) was very recent and not included in followup analyses. This patient underwent repeated excision of recurrent diffuse-type neurofibroma and finally developed MPNST arising in diffuse-type neurofibroma in the same region 6 years after the first excision. Another patient (#3) developed local recurrence after 9 months and was treated with reexcision. Patient #6 had pulmonary metastases at diagnosis and died from the disease 1 month after tumor resection. All other patients were alive without evidence of disease at 15 to 145 months (median, 83 mo) after tumor resection.
Gross and Microscopic Features The tumor size ranged from 3.6 to 45 cm (median 7.4 cm, data available for 8/9 patients) (Table 1). The tumors were located in the dermis or subcutaneous tissue (Fig. 1A). Eight patients (#2 to 9) had 1 lesion, and 1
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FIGURE 1. A, Histologically, diffuse-type neurofibroma typically arises as an ill-defined plaque-like lesion in dermal or subcutaneous tissue (arrow). Diffuse infiltration of subcutaneous adipose tissue (B) by tumor cells with scattered Meissner corpuscles (C). D, Diffuse-type neurofibroma comprises tumor cells with round to fusiform nuclei in a fine fibrillary collagenous matrix.
patient (#1) had 2 separate diffuse neurofibromas, both exhibiting malignant change to low-grade MPNST. Most tumors were ill defined and exhibited a yellow to white, firm and solid cut surface. Histologically, the diffuse-type neurofibromas showed an infiltrative growth pattern, extending from the dermis into the subcutaneous soft tissue with entrapment of adipose tissue and adnexal structures (Fig. 1B). All cases of diffuse-type neurofibroma showed characteristic eosinophilic lamellar structures resembling Meissner tactile corpuscles (Fig. 1C), which were encountered either in closely
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packed clusters or scattered loosely throughout the tumor. Tumor cells had slightly elongated to plump, sometimes wavy, nuclei and ill-defined cell borders and were distributed in a fine, eosinophilic fibrillary collagenous matrix (Fig. 1D). Foci of melanin pigment– containing dendritic cells were observed in 1 case (#2). Furthermore, a patchy lymphocytic inflammatory infiltrate was occasionally observed in some cases. Focal transition of diffuse-type neurofibroma to MPNST was subtle in the majority of cases, with benign-appearing tumor cells with fusiform to oval nuclei scattered in an Copyright
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MPNST in Diffuse Neurofibroma
FIGURE 2. A, Areas of increased cellularity (top left) with spindle cells showing nuclear atypia and mitoses indicate transition to MPNST (case 1; A). B, Some MPNSTs consisted of tumor cells with more plump to ovoid nuclei surrounded by a hyalinized matrix (case 4; B) and scattered mitoses (B, inset), whereas others showed predominantly spindle cell morphology (case 5; C), with occasional entrapped remnants of Meissner corpuscles (case 5; D).
eosinophilic collagenous matrix blending with areas of increased cellularity, nuclear atypia, and mitotic activity, with a median of 3.5/50 HPF (range, 1 to 63/50 HPF, data available for 8/9 patients) (Fig. 2). The MPNSTs usually showed spindle cell differentiation and were classified as low grade in 5 cases (Fig. 3), intermediate to high grade in 1 case, and high grade in 3 cases (Fig. 4). Most malignant components consisted predominantly of spindle cells with a fascicular and whorled architecture (case #1, 2, 5, 6, 9), whereas others showed a discohesive growth pattern with Copyright
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marked nuclear atypia and scattered histiocytes with abundant pale cytoplasm and cytoplasmic inclusions (#3), hyalinized matrix (#4), or more ovoid to plump tumor cells (#7). Positive excision margins in 6 cases consisted only of the neurofibromatous component. Immunohistochemically, the neurofibroma components expressed S-100 quite strongly and diffusely in˜ 80% of the cells, whereas the MPNST component showed comparable diffuse expression in 4 and less extensive or weaker expression in 4 cases (Fig. 5). Staining with NFP
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FIGURE 3. Case 2—Neurofibromatous tissue (A) shows transition to areas of increased cellularity (B) and then to frank MPNST (C), which had a low mitotic count and was classified as low grade.
revealed single scattered axons in the neurofibroma component of case #7. In patient #6, MPNST with heterologous angiosarcomatous differentiation was observed (Fig. 6), with expression of CD31 by malignant endothelial cells. This patient with Klippel-Tre´naunauy-Weber syndrome had previously undergone resection of a longstanding vascular malformation on the same leg 25 years earlier (materials not available for review).
DISCUSSION MPNST arises in around 5% to 10% of NF-1 patients, mostly in the plexiform or localized intraneural variant of neurofibroma, and is thought usually to take years to develop.1,11,12 Most MPNSTs (˜60%) are believed to arise from benign precursor lesions and up to half of all MPNSTs occur in the setting of NF-1.1,11,13 There is undoubtedly a morphologic continuum between neurofibroma, “atypical” neurofibroma, and MPNST, and sharply defined cutoffs for malignant change have not been defined as yet, in part because features of all 3 may be evident in a single specimen. Criteria for malignant
change in neurofibroma include nuclear atypia, that is, nuclear enlargement and hyperchromasia, hypercellularity, and mitotic activity, even though it remains controversial as to whether mitoses always indicate malignant change or whether very few may still be acceptable in neurofibromas if other features of malignancy are not present.1,14 The majority of MPNSTs are deep-seated, highgrade tumors with an unfavorable prognosis and an estimated 5-year survival rate of 40% to 50%, although whether the prognosis is worse in patients with NF-1 remains uncertain.11 However, MPNSTs arising in diffusetype neurofibromas, which appear to be extremely rare, most often present as superficial tumors, and, in the present series, 5/9 cases were classified as low-grade MPNST. Histologically, in general, most MPNSTs show predominantly spindle cell morphology, with epithelioid MPNST accounting for only 5% of cases.15 Immunohistochemically, no more than 40% to 50% of MPNSTs with spindle cell morphology express S-100 protein,16 often in only up to 10% to 20% of cells, as opposed to diffuse-type neurofibroma with stronger expression in at least 50% of cells.
FIGURE 4. Case 6—Neurofibromatous tissue with Meissner corpuscles (A), elsewhere showing subtly increased cellularity and then transition to frank MPNST (C), which was classified as high grade (and showed angiosarcoma elsewhere; see Fig. 6).
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MPNST in Diffuse Neurofibroma
FIGURE 5. Immunohistochemical staining with S-100 protein demonstrated quite strong and diffuse expression in the diffusetype neurofibroma component (case 7; A), and weaker or more focal expression in the MPNST component (case 7; B).
On a molecular basis, dysregulation of cell cycle progression, in particular G1 transition, has been implicated to play a role in the progression of neurofibromas to MPNST.17 A change of expression of the cell cycle regulators p53, p16, and p27 has been observed to occur during tumor progression; however, these markers do not
seem to distinguish reliably between low-grade MPNST and neurofibromas.18,19 Recent evidence suggests a stepwise progression of neurofibroma, first to atypical neurofibroma and then to MPNST, as copy number loss of the CDKN2A locus at 9p21.3 was detected not only in the majority of MPNST but also in atypical neurofibromas
FIGURE 6. A, Patient #6 with MPNST (not shown) arising in diffuse-type neurofibroma (left) showed transition to angiosarcoma, morphologically high grade (right) (A). This patient had a diagnosis of Klippel-Tre´naunay-Weber syndrome. B, At higher magnification, scattered Meissner corpuscles were observed within areas of angiosarcoma consisting of ill-defined vascular channels lined by poorly differentiated, atypical endothelial cells. Copyright
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(94% of cases). These findings suggest that atypical neurofibromas represent premalignant tumors, with CDKN2A loss being an early event in tumor progression.20 However, MPNSTs arising in diffuse-type neurofibromas were not included in these studies. The 7 previously reported cases of MPNST arising in diffuse-type neurofibroma included 5 female and 2 male patients with a median age of 53 years (range, 28 to 88 y).4,6–9 The majority of tumors were located on the extremities (4/7), followed by scalp (2/7) and trunk (1/7). Follow-up, available for 5 patients (median, 3 y), revealed that 3 patients had several local recurrences (up to 14 in 1 patient), altogether over a period of 36 to 44 years. Two of these 3 patients with recurrence died of an unknown cause, but none of them developed metastases or died from MPNST.4 In another study, 1 patient died after 1 year from lung metastases.8 Only 1 of these 7 patients was reported to have a history of NF-1.6 In our series, the tumors showed similar epidemiologic and clinical characteristics as have been reported previously for diffuse-type neurofibromas without malignant change: the median age was 49 years without sex predilection, and 5 of the 9 tumors developed in the setting of NF-1. The diffuse-type neurofibroma components exhibited typical histologic features, such as ill-defined margins, diffuse infiltration between adnexal structures, a uniform matrix of fine fibrillary collagen, Meissner corpuscles, and, in 1 case, foci of melanin pigment–containing dendritic cells. The tumor cells showed indistinct cell borders and slightly plump nuclei, with focal transition to cellular areas with nuclear atypia and mitoses, indicating progression to MPNST. In the present series, the majority of cases (7/9) were excised with positive resection margins, likely attributable to the growth pattern of this type of neurofibroma and difficulties in resectability, but only benign lesional tissue was present at the margins. The MPNSTs arising in diffuse-type neurofibroma in the present series followed a rather favorable clinical course. Except for 1 patient with the unusual constellation of Klippel-Tre´naunay-Weber syndrome and additional heterologous angiosarcomatous differentiation, all patients studied in our series were alive with no evidence of disease after a considerable follow-up time. This somewhat surprising outcome is comparable to that described by Evans in 3 cases, which had a remarkably indolent and protracted course after the development of MPNST.4 Whether or not this reflects an intrinsically different biology remains undetermined, and the case numbers are very small. The diagnosis of diffuse-type neurofibroma is usually straightforward; however, in cases that fail to show Meissner corpuscles on limited biopsy material, localized neurofibroma and dermatofibrosarcoma protuberans (DFSP) enter the differential diagnosis. Like diffuse-type neurofibroma, DFSP shows dermal and subcutaneous localization and an infiltrative growth pattern. However, in contrast to diffusetype neurofibroma, DFSP is characterized by a storiform growth pattern, immunohistochemical expression of CD34, negativity for S-100 protein, and lack of Meissner corpuscles.
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In conclusion, malignant change in diffuse-type neurofibroma is extremely rare. Foci of increased cellularity, nuclear atypia, and mitotic figures indicate the presence of MPNST. Approximately half of the cases in our series were associated with NF-1. Thorough sampling of resection specimens is advisable, particularly in very large diffuse-type neurofibromas, to identify areas of malignant transformation, necessitating long-term clinical follow-up. ACKNOWLEDGMENTS The authors thank the following pathologists and clinicians who kindly submitted the cases and provided clinical follow-up information when available: Dr T. Wieczorek, Boston, MA, Dr C.E. Trask, Bangor, ME, Dr Michelle Perkins, Blue Hill, ME, Dr W.E. Taylor, Dallas, TX, Dr, G.M. Hariz, Mesquite, TX, Dr M. Pruszczynski, Nijmegen, The Netherlands, Dr M.J.M. Ploegmakers, Nijmegen, The Netherlands, Dr J.S. Roy, Rye Brook, NY, Dr P. Abenoza, Pompano Beach, FL, Dr D. Abis, West Palm Beach, FL, Dr N.P. Libbey, Providence, RI, and Dr R.J. Koness, Providence, RI. REFERENCES 1. Woodruff JM. Pathology of tumors of the peripheral nerve sheath in type 1 neurofibromatosis. Am J Med Genet. 1999;89:23–30. 2. Megahed M. Histopathological variants of neurofibroma. A study of 114 lesions. Am J Dermatopathol. 1994;16:486–495. 3. Antonescu CR, Scheithauer BW, Woodruff JM. Neurofibroma. AFIP Atlas of Tumor Pathology: Tumors of the Peripheral Nervous System, Fourth Series, Fascicle 19. Silver Spring, Maryland: American Registry of Pathology; 2013:211–264. 4. Evans HL. Sporadic superficial diffuse neurofibromas with repeated local recurrence over many years and a tendency toward malignant change: a report of 3 cases. Am J Surg Pathol. 2013;37: 987–994. 5. Fetsch JF, Michal M, Miettinen M. Pigmented (melanotic) neurofibroma: a clinicopathologic and immunohistochemical analysis of 19 lesions from 17 patients. Am J Surg Pathol. 2000;24:331–343. 6. Inoue T, Kuwashiro M, Misago N, et al. Superficial malignant peripheral nerve sheath tumor arising from diffuse neurofibroma in a neurofibromatosis type 1 patient. J Dermatol. 2014;41: 631–633. 7. Thomas C, Somani N, Owen LG, et al. Cutaneous malignant peripheral nerve sheath tumors. J Cutan Pathol. 2009;36:896–900. 8. Allison KH, Patel RM, Goldblum JR, et al. Superficial malignant peripheral nerve sheath tumor: a rare and challenging diagnosis. Am J Clin Pathol. 2005;124:685–692. 9. Molenaar WM, Dijkhuizen T, van EJ, et al. Cytogenetic support for early malignant change in a diffuse neurofibroma not associated with neurofibromatosis. Cancer Genet Cytogenet. 1997;97:70–72. 10. Ploegmakers MJ, Pruszczynski M, De RJ, et al. Angiosarcoma with malignant peripheral nerve sheath tumour developing in a patient with Klippel-Tre´naunay-Weber syndrome. Sarcoma. 2005;9:137–140. 11. Antonescu CR, Scheithauer BW, Woodruff JM. Malignant tumors of the peripheral nerves. AFIP Atlas of Tumor Pathology: Tumors of the Peripheral Nervous System, Fourth Series, Fascicle 19. Silver Spring, Maryland: American Registry of Pathology; 2013:381–474. 12. Widemann BC. Current status of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Curr Oncol Rep. 2009;11:322–328. 13. Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer. 1986;57:2006–2021.
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14. Lin BT, Weiss LM, Medeiros LJ. Neurofibroma and cellular neurofibroma with atypia: a report of 14 tumors. Am J Surg Pathol. 1997;21:1443–1449. 15. Laskin WB, Weiss SW, Bratthauer GL. Epithelioid variant of malignant peripheral nerve sheath tumor (malignant epithelioid schwannoma). Am J Surg Pathol. 1991;15:1136–1145. 16. Fletcher CDM. Peripheral neuroectodermal tumors. In: Fletcher CDM, ed. Diagnostic Histopathology of Tumors, 4th edn. Philadelphia, PA: Elsevier Saunders; 2013:2032–2063. 17. Kourea HP, Cordon-Cardo C, Dudas M, et al. Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of
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p27(kip) in malignant transformation of neurofibromas. Am J Pathol. 1999;155:1885–1891. 18. Zhou H, Coffin CM, Perkins SL, et al. Malignant peripheral nerve sheath tumor: a comparison of grade, immunophenotype, and cell cycle/growth activation marker expression in sporadic and neurofibromatosis 1-related lesions. Am J Surg Pathol. 2003;27:1337–1345. 19. Kourea HP, Orlow I, Scheithauer BW, et al. Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. Am J Pathol. 1999;155:1855–1860. 20. Beert E, Brems H, Daniels B, et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer. 2011;50:1021–1032.
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