Received: 17 August 2017
Revised: 27 September 2017
Accepted: 19 October 2017
DOI: 10.1111/cup.13068
ORIGINAL ARTICLE
“Chondroblastoma-like” epithelioid fibrous histiocytoma: A previously undescribed and potentially confusing variant Anthony P. Martinez1 | Youran Zou2
| Steven D. Billings2
| Andrew L. Folpe1
1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
Background: Epithelioid benign fibrous histiocytoma has been considered a variant of fibrous
2
Department of Pathology, Cleveland Clinic Foundation, Cleveland, Ohio
histiocytoma, but is now considered a distinct entity, typically showing ALK expression. Most
Correspondence Andrew L. Folpe, MD, Department of Anatomic Pathology, Mayo Clinic, Hilton 11, 200 First Street, SW, Rochester, MN 55905. Email:
[email protected]
oid cells. We have recently encountered 2 examples showing an unusual pattern of pericellular
show typical morphological features, including an epidermal collarette and large, bland, epithelicalcification, a previously unreported finding. Methods: Available slides were reviewed and clinical follow-up was obtained. Results: These lesions occurred on the chins of a 16-year-old and 19-year-old female and showed prominent pericellular calcification in addition to otherwise-typical features of epithelioid fibrous histiocytoma. By immunohistochemistry, both lesions were intensely positive for ALK protein. Clinical follow-up (available for 1 case) showed the patient to be disease-free 5 months after excision. Conclusions: To the best of our knowledge, epithelioid fibrous histiocytomas showing “chondroblastoma-like” calcification have not been previously reported. The chief significance of this finding seems to be in its potential for confusion with other calcifying tumors of the skin and subcutis. Awareness that epithelioid fibrous histiocytomas may show this unusual morphological finding, careful morphological evaluation and ancillary immunohistochemical studies, including ALK protein, should allow for their confident diagnosis in essentially all instances. KEYWORDS
ALK, chondroblastoma, epithelioid fibrous histiocytoma, immunohistochemistry, skin tumors
1 | I N T RO D UC T I O N
polygonal cells with abundant eosinophilic cytoplasm, vesicular nuclei and small nucleoli.1–4 Immunohistochemically, epithelioid
Epithelioid benign fibrous histiocytoma, also known as “epithelioid
fibrous histiocytomas differ from other forms of fibrous histiocy-
cell histiocytoma”,1–3 was first described by Wilson-Jones et al in
toma, often showing epithelial membrane antigen expression2,5,6
19891 and has historically been considered simply an unusual
and lacking myofibroblastic differentiation in the form of smooth
morphological variant of cutaneous fibrous histiocytoma (dermato-
muscle actin and/or desmin expression.7,8 It has very recently
fibroma), defined by the presence of greater than or equal to
been shown that epithelioid fibrous histiocytomas commonly show
50% epithelioid features, and by the absence of “secondary ele-
ALK gene rearrangements and ALK protein expression, strongly
ments” such as foamy macrophages and multinucleated giant
suggesting that they represent a neoplastic entity distinct from
cells.4 Clinically, epithelioid fibrous histiocytomas usually present
ordinary fibrous histiocytomas.2,4,9
as flesh-colored, frequently polypoid nodules on the extremities of
We report 2 examples of epithelioid fibrous histiocytoma show-
young and middle-aged patients, with the thigh being the most
ing a very unusual pattern of “chondroblastoma-like” pericellular cal-
common site.1 Histologically, epithelioid fibrous histiocytomas are
cification, a feature not previously reported in these lesions, and one
usually well-circumscribed and exophytic, with an epidermal collar-
that may result in confusion with other calcifying neoplasms that may
ette and are composed of large, occasionally bi and tri-nucleated
involve the skin.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd J Cutan Pathol. 2018;45:99–103.
wileyonlinelibrary.com/journal/cup
99
100
MARTINEZ ET AL.
1.1 | Methods and materials
immunoreactivity for ALK protein and was CD68-positive; all other
This study was approved by the Mayo Clinic and Cleveland Clinic
tested markers were negative.
Institutional Review Boards. Case 1 was submitted in consultation to one of us (A.L.F.) and was during its initial evaluation identified as an epithelioid fibrous histiocytoma showing “chondroblastoma-like” cal-
3 | DI SCU SSION
cification during its initial evaluation. Case 2 was submitted in consultation to the Soft Tissue Consultation Service of the Cleveland Clinic
To the best of our knowledge, epithelioid fibrous histiocytomas
Department of Pathology, and was initially regarded as representing
showing “chondroblastoma-like” calcification have not been previ-
a “chondroblastoma-like” soft tissue neoplasm of the skin. Subse-
ously reported, and it is likely that similar cases have historically been
quent evaluation showed this lesion also to represent an epithelioid
diagnosed as representing other entities. Indeed, we were able to
fibrous histiocytoma. A search of the pathology consultation archives
confidently recognize these very unusual calcifying dermal tumors as
of Mayo Clinic and Cleveland Clinic did not reveal additional similar
variants of epithelioid fibrous histiocytoma only with the assistance
cases.
of ALK immunohistochemistry, an ancillary test which we would not
Immunohistochemical studies were performed on formalin-fixed,
have thought to use in the past. Similarly, application of ALK immu-
paraffin-embedded tissue sections at Mayo Clinic and at Cleveland
nohistochemistry has recently allowed for the recognition of “peri-
Clinic for ALK (1:100, D5F3; Cell Signaling, Danvers, Massachusetts),
neurioma-like” epithelioid fibrous histiocytomas.10 Calcification also
OSCAR keratin (1:100, OSCAR; Covance, Princeton, New Jersey),
appears to be an exceedingly rare phenomenon in fibrous histiocy-
high molecular weight keratins (1:50, 34βE12, Dako Corp, Carpen-
toma more generally.11,12
taria, California), smooth muscle actin (1:3000, 1A4, Dako Corp.), and desmin (1:100, DER11, Leica Biosystems, Wetzlar, Germany) using routine laboratory protocols. Clinical information, including follow-up (when available) was obtained from the submitting pathologists.
The differential for “chondroblastoma-like” epithelioid fibrous histiocytomas includes a variety of dermal and subcutaneous epithelioid lesions that can show calcifications and/or chondro-osseous matrix. These include epithelioid sarcoma, cutaneous syncytial myoepithelioma, “chondroblastoma-like” soft tissue chondromas malignant melanoma with osteo/chondrosarcomatous differentiation, extraskeletal osteosarcoma and ossifying fibromyxoid tumor of soft parts.
2 | RESULTS
Epithelioid sarcoma, like epithelioid fibrous histiocytoma, commonly involves the extremities of young adults, and may be com-
2.1 | Clinical histories
posed
Case 1 presented as a long-standing, small nodule on the chin of a 16-year-old female. A shave biopsy was performed for diagnosis. Additional surgery has not been performed, and the patient is reportedly free of disease 5 months after diagnosis. Case 2 also presented as a small mass on the chin of a 19-year-old female, and was clinically regarded as representing a “cyst”. Follow-up information is not available for this patient.
of
deceptively
bland
epithelioid
cells.13
Calcification,
sometimes in a pericellular pattern, may be seen in a subset of epithelioid sarcomas, as may formation of bone and chondroid matrix.14,15 In contrast to “chondroblastoma-like” epithelioid fibrous histiocytoma, however, calcifying epithelioid sarcomas generally lack an epidermal collarette, grow in an infiltrative fashion, contain cells with hyperchromatic, irregular nuclei, express keratins, and show absence of SMARCB1 expression.16,17 Epithelial membrane antigen expression may be seen in both tumors, a potential pitfall. Cutaneous syncytial myoepithelioma is a very rare dermal tumor first reported in 199818 and recently much more completely
2.2 | Pathologic findings
described, in particular by Jo et al.19–21 Like epithelioid fibrous his-
Figure 1 and 2 illustrate the morphological and immunohistochemical
tiocytoma, cutaneous syncytial myoepithelioma typically presents as
features of the 2 cases. The morphological features of the 2 lesions
a dermal nodule and may on occasion show a well-formed epider-
were identical. Both consisted of well-circumscribed, dermally based
mal collarette.20 Additionally, rare cases of syncytial myoepithelioma
nodules with a well-formed epidermal collarette (Figure 1A). Cytologi-
have been reported to show chondro-osseous differentiation21,22
cally, both showed classical features of epithelioid fibrous histiocytoma,
and a single case (illustrated by Jo et al.21) showed a “chicken-wire”
with plump epithelioid cells having abundant eosinophilic cytoplasm,
pattern of pericellular calcification. However, the cells of cutaneous
normochromatic nuclei and small nucleoli (Figures 1C and 2C). Mitotic
syncytial myoepithelioma tend to show a greater degree of spin-
activity was absent. The most striking morphologic feature of both
dling than do those of epithelioid fibrous histiocytoma, grow in a
lesions was the presence of prominent pericellular calcification in a
distinctive syncytial pattern, lack ALK rearrangements or ALK
reticular, lace-like or “chicken-wire” pattern, reminiscent of that seen in
expression, and frequently show EWSR1 rearrangements, features
chondroblastoma of bone (Figures 1B–C and 2A–B). Osteoclast-like
that should allow their confident distinction from epithelioid fibrous
giant cells were focally present adjacent to this calcification (Figure 2D). By immunohistochemistry, both lesions were intensely positive
histiocytoma.22 Chondromas of soft parts usually occur in the hands and feet,
for ALK protein in a cytoplasmic pattern (Figures 1D and 2E). Case
and may ulcerate or involve the overlying epidermis.23,24 Histologi-
1 was negative for low and high molecular weight keratins, smooth
cally, most are composed of well-circumscribed lobules of mature
muscle
hyaline cartilage, but a chondroblastoma-like variant with “lace-like”
actin
and
desmin.
Case
2
also
showed
strong
101
MARTINEZ ET AL.
FIGURE 1
A, Epithelioid fibrous histiocytoma, presenting as a small nodule with an epidermal collarette on the chin of a 16-year-old female (H&E, ×40). B, At medium power magnification, areas of typical epithelioid fibrous histiocytoma, characterized by bland, plump cells with abundant eosinophilic cytoplasm, are seen as are foci showing an unusual pattern of pericellular calcification (H&E, ×100). C, Higher power magnification, showing the “chondroblastoma-like” pattern of pericellular calcification, and occasional reactive osteoclast-like giant cells (H&E, ×200). D, ALK immunohistochemistry was diffusely positive, confirming the diagnosis of epithelioid fibrous histiocytoma (H&E, ×200)
or “chicken-wire calcification” has been described.23–25 In general,
showing osteosarcomatous differentiation28 and cutaneous extraske-
recognition of areas of true cartilaginous differentiation should allow
letal osteosarcoma.29–31 Both osteogenic melanoma and extraskeletal
for the ready distinction of these 2 entities, although in more chal-
osteosarcoma would be expected to contain cells showing much
lenging cases ALK immunohistochemistry may also be of value.
higher nuclear grade than is seen in epithelioid fibrous histiocytoma,
Ossifying fibromyxoid tumor is composed of small, bland, round
as well as a “lace-like” pattern of malignant osteoid production.
to ovoid cells embedded in a fibromyxoid matrix, and sometimes sur-
Immunohistochemistry for melanoma-associated markers (eg, S100
rounded by a partial shell of woven bone.26 Very rarely, ossifying
protein, SOX10, HMB45) would also be expected to be positive in
fibromyxoid tumors may show a somewhat chondroid-appearing
more conventional-appearing areas of osteogenic melanoma.
matrix, but pericellular calcification is not seen. Additionally, ossifying
In summary, we have reported 2 unusual examples of ALK-
fibromyxoid tumors tend to be centered in the subcutis, with only
positive epithelioid fibrous histiocytoma showing pericellular calcifica-
secondary dermal involvement. Immunohistochemistry will also assist
tion, reminiscent of that seen in chondroblastoma of bone. The chief
in the distinction of ossifying fibromyxoid tumor from “chondroblas-
significance of this finding seems to be in its potential for confusion
toma-like” epithelioid fibrous histiocytoma, as the former tumor tends
with other calcifying tumors of the skin and subcutis. Awareness that
to show some combination of S100 protein, desmin, CD56 and neu-
epithelioid fibrous histiocytomas may show this unusual morphologi-
rofilament protein expression27 and lacks ALK expression.
cal finding, careful morphological evaluation and ancillary immunohis-
Finally, “chondroblastoma-like” epithelioid fibrous histiocytomas should be distinguished from extremely rare examples of melanoma
tochemical studies to include ALK protein should allow for their confident diagnosis in essentially all instances.
102
MARTINEZ ET AL.
A, This calcifying epithelioid fibrous histiocytoma also occurred on the chin, in a 19-year-old female (H&E, ×100). B, Multiple foci of pericellular calcification were present, in some areas coalescing into nodules of amorphous calcification (H&E, ×100). C, More typical-appearing areas of epithelioid fibrous histiocytoma were also present (H&E, ×200). D, High power view, showing bland epithelioid cells with pericellular calcification, and reactive osteoclast-like giant cells (H&E, ×200). E, Immunohistochemistry for ALK was diffusely positive (H&E, ×400)
FIGURE 2
103
MARTINEZ ET AL.
Conflict of interest The authors declare that they have no conflict of interest. ORCID Youran Zou
http://orcid.org/0000-0003-2428-8072
Steven D. Billings Andrew L. Folpe
http://orcid.org/0000-0002-2278-5908 http://orcid.org/0000-0002-0273-7351
RE FE R ENC E S 1. Jones EW, Cerio R, Smith NP. Epithelioid cell histiocytoma: a new entity. Br J Dermatol. 1989;120(2):185–195. 2. Jedrych J, Nikiforova M, Kennedy TF, Ho J. Epithelioid cell histiocytoma of the skin with clonal ALK gene rearrangement resulting in VCL-ALK and SQSTM1-ALK gene fusions. Br J Dermatol. 2015;172(5): 1427–1429. 3. Mehregan AH, Mehregan DR, Broecker A. Epithelioid cell histiocytoma. A clinicopathologic and immunohistochemical study of eight cases. J Am Acad Dermatol. 1992;26(2 Pt 1):243–246. 4. Doyle LA, Marino-Enriquez A, Fletcher CD, Hornick JL. ALK rearrangement and overexpression in epithelioid fibrous histiocytoma. Mod Pathol. 2015;28(7):904–912. 5. Doyle LA, Fletcher CD. EMA positivity in epithelioid fibrous histiocytoma: a potential diagnostic pitfall. J Cutan Pathol. 2011;38(9): 697–703. 6. Floris C, Di Naro N, Olla L, Puliga G, Altea D, Tolu GA. Epithelioid fibrous histiocytoma EMA positivity: a case report. Pathologica. 2013; 105(3):98–100. 7. Volpicelli ER, Fletcher CD. Desmin and CD34 positivity in cellular fibrous histiocytoma: an immunohistochemical analysis of 100 cases. J Cutan Pathol. 2012;39(8):747–752. 8. Soini Y. Cell differentiation in benign cutaneous fibrous histiocytomas. An immunohistochemical study with antibodies to histiomonocytic cells and intermediate filament proteins. Am J Dermatopathol. 1990; 12(2):134–140. 9. Walther C, Hofvander J, Nilsson J, et al. Gene fusion detection in formalin-fixed paraffin-embedded benign fibrous histiocytomas using fluorescence in situ hybridization and RNA sequencing. Lab Investig. 2015;95(9):1071–1076. 10. Creytens D, Ferdinande L, Van Dorpe JALK. Rearrangement and overexpression in an unusual cutaneous epithelioid tumor with a peculiar whorled "perineurioma-like" growth pattern: epithelioid fibrous histiocytoma. Appl Immunohistochem Mol Morphol. 2016;24: e25–e27. 11. AbdullGaffar B, Abu Salim S. Oral fibrous histiocytoma-associated calcification. J Cutan Pathol. 2014;41(10):806–809. 12. Famenini S, Cassarino DS. Dermatofibroma-associated dystrophic calcification. J Cutan Pathol. 2014;41(1):68–70. 13. Enzinger FM. Epitheloid sarcoma. A sarcoma simulating a granuloma or a carcinoma. Cancer. 1970;26(5):1029–1041. 14. Chetty R, Slavin JL. Epithelioid sarcoma with extensive chondroid differentiation. Histopathology. 1994;24(4):400–401. 15. Koplin SA, Nielsen GP, Hornicek FJ, Rosenberg AE. Epithelioid sarcoma with heterotopic bone: a morphologic review of 4 cases. Int J Surg Pathol. 2010;18(3):207–212.
16. Sullivan LM, Folpe AL, Pawel BR, Judkins AR, Biegel JA. Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions. Mod Pathol. 2013;26(3):385–392. 17. Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol. 2009;33(4):542–550. 18. Fernandez-Figueras MT, Puig L, Trias I, Lorenzo JC, NavasPalacios JJ. Benign myoepithelioma of the skin. Am J Dermatopathol. 1998;20(2):208–212. 19. Kutzner H, Mentzel T, Kaddu S, Soares LM, Sangueza OP, Requena L. Cutaneous myoepithelioma: an under-recognized cutaneous neoplasm composed of myoepithelial cells. Am J Surg Pathol. 2001; 25(3):348–355. 20. Hornick JL, Fletcher CD. Cutaneous myoepithelioma: a clinicopathologic and immunohistochemical study of 14 cases. Hum Pathol. 2004;35(1):14–24. 21. Jo VY, Antonescu CR, Zhang L, Dal Cin P, Hornick JL, Fletcher CD. Cutaneous syncytial myoepithelioma: clinicopathologic characterization in a series of 38 cases. Am J Surg Pathol. 2013;37(5):710–718. 22. Flucke U, Palmedo G, Blankenhorn N, Slootweg PJ, Kutzner H, Mentzel T. EWSR1 gene rearrangement occurs in a subset of cutaneous myoepithelial tumors: a study of 18 cases. Mod Pathol. 2011; 24(11):1444–1450. 23. Lichtenstein L, Goldman RL. Cartilage tumors in soft tissues, particularly in the hand and foot. Cancer. 1964;17:1203–1208. 24. Chung EB, Enzinger FM. Chondroma of soft parts. Cancer. 1978; 41(4):1414–1424. 25. Cates JM, Rosenberg AE, O'Connell JX, Nielsen GP. Chondroblastoma-like chondroma of soft tissue: an underrecognized variant and its differential diagnosis. Am J Surg Pathol. 2001;25(5):661–666. 26. Folpe AL, Weiss SW. Ossifying fibromyxoid tumor of soft parts: a clinicopathologic study of 70 cases with emphasis on atypical and malignant variants. Am J Surg Pathol. 2003;27(4):421–431. 27. Graham RP, Dry S, Li X, et al. Ossifying fibromyxoid tumor of soft parts: a clinicopathologic, proteomic, and genomic study. Am J Surg Pathol. 2011;35(11):1615–1625. 28. Lucas DR, Tazelaar HD, Unni KK, et al. Osteogenic melanoma. A rare variant of malignant melanoma. Am J Surg Pathol. 1993;17(4): 400–409. 29. Kuo TT. Primary osteosarcoma of the skin. J Cutan Pathol. 1992; 19(2):151–155. 30. Falconieri G, Cataldi P, Kavalar R, Stitic V, Luzar B. Cutaneous osteoblastic osteosarcoma: report of 2 new cases integrated with SATB2 immunohistochemistry and review of the literature. Am J Dermatopathol. 2016;38(11):824–831. 31. Llamas-Velasco M, Rutten A, Requena L, Mentzel T. Primary cutaneous osteosarcoma of the skin: a report of 2 cases with emphasis on the differential diagnoses. Am J Dermatopathol. 2013;35(6):e106–e113.
How to cite this article: Martinez AP, Zou Y, Billings SD, Folpe AL. “Chondroblastoma-like” epithelioid fibrous histiocytoma: A previously undescribed and potentially confusing variant. J Cutan Pathol. 2018;45:99–103. https://doi.org/10. 1111/cup.13068
