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Juan C. Tardío J Cutan Pathol 2008; 35: 1079–1092

As our readers are aware, the excellent review article by Dr. Tardio entitled CD34–reactive tumors of the skin. An updated review of an ever-growing list of lesions was published as the lead article in the December 2008 issue of the Journal. Unfortunately, changes requested by the author during the proofing process had not been made, and we were too late to make those corrections prior to that issue’s going to press. Among these changes was the inclusion of some additional references. We sincerely regret our error, and are therefore publishing the fully corrected version of the article in the January 2009 issue.

Dr James W. Patterson Editor-in-Chief Journal of Cutaneous Pathology

Review Article

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

Over the past few years, a growing number of cutaneous tumors expressing CD34 is being reported. The list contains benign and malignant neoplasms as well as reactive and hamartomatous lesions of diverse lineages of differentiation, including fibroblastic, myofibroblastic, fibrohistiocytic, vascular, neural, adipocytic, smooth muscle, hematopoietic, melanocytic and epithelial. The more frequent diagnostic difficulties are found in spindle cell proliferations, mainly in those of the fibrocytic lineage. In part, this is because of the fact that in this area are, aside to well-defined entities, histologically and clinically diverse, recently reported cutaneous CD34-reactive lesions, whose definitions, limits and relationships are not completely established. The CD34 expression plays a key role in the differential diagnosis of some tumors, such as dermatofibrosarcoma protuberans, epithelioid sarcoma or pleomorphic hyalinizing angiectatic tumor of soft parts, with important therapeutic consequences. In others, as in desmoplastic trichilemmoma, it can help to resolve diagnostic problems in concrete cases. Finally, in many of the CD34-positive lesions, the diagnosis with the hematoxylin and eosin stain is straightforward. However, in all of them, the knowledge of the immunohistochemical profile contributes to our understanding of the cutaneous pathology.

Tardío JC. CD34-reactive tumors of the skin. An updated review of an ever-growing list of lesions. J Cutan Pathol 2008; 35: 1079–1092. © Blackwell Munksgaard 2008.

CD34 is a 115-kDa transmembrane sialomucin encoded on a gene located on chromosome 1q32.1 It is expressed in activated bone marrow progenitor cells, which give rise to the hematopoietic and angioblastic lineages. While CD34 expression is lost during differentiation in the hematopoietic lineage, it is maintained in the angioblastic one.2–4 In addition, evidence exists supporting the idea that a subset of CD34-positive stromal cells derived from bone marrow and muscle represents a type of mesenchymal stem cell.5

The expression of CD34 is known for over 20 years, but its functions remain poorly clarified up-to-date. The following CD34 functions have been proposed5: (i) inhibition of differentiation and promotion of proliferation in hematopoietic stem cells, (ii) adhesion molecule with possible capacity of signaling; CD34 seems to promote the hematopoietic cell adhesion to the stromal microenvironment of the bone marrow, being implicated in the regulation of stem cells;6 it also serves as an l-selectin ligand involved in binding lymphocytes to high endothelial venules in lymph nodes7 and (iii) anti-adhesion molecule. The anti-adhesive role of CD34 might be important in the ability of mobilized precursors to migrate to the bone marrow or to find the appropriate niche.5

In normal skin, CD34 reactivity is found in blood endothelial cells, in interstitial and perivascular spindle-shaped and dendritic cells of the reticular dermis, in elongated cells around the midportion of the hair follicles and in spindle cells around the secretory coils of the eccrine sweat glands (Fig. 1).8,9 Its expression in lymphatic endothelial cells is controversial. A recent report did not find CD34 positivity in resting lymphatic vessels of the skin but detected expression in peritumoral and intratumoral lymphatic vessels of cutaneous malignant melanomas and of human cancers of other locations. The selective expression of CD34 by neoplastic-associated lymphatic vessels would suggest that CD34 is an activation antigen of human lymphatic endothelial cells.10

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Figure 1. Normal skin showing endothelial, dendritic and spindle interstitial, periadnexal and perivascular CD34-positive cells.

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There is a growing number of CD34-reactive cutaneous tumors reported. They include benign and malignant neoplasms as well as reactive and hamartomatous lesions of diverse lineages of differentiation, including fibroblastic, myofibroblastic, fibrohistiocytic, vascular, neural, adipocytic, smooth muscle, hematopoietic, melanocytic and epithelial tumors. CD34 reactivity is usually observed in spindle cells, but expression in epithelioid and pleomorphic cells can be found in some entities. Although several antibodies recognizing specific epitopes on the CD34 antigen are available, most of the studies evaluating CD34 expression have used the MY 10 or the QBEND/10 monoclonal antibodies.11

Here, an updated review of primary CD34-reactive cutaneous proliferations is presented in order to provide the current summarized knowledge of this topic to the reader.

Fibroblastic, fibrohistiocytic and myofibroblastic lesions

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

In CD34-positive lesions, the more frequent diagnostic difficulties are found in spindle cell proliferations, mainly in those of the fibrocytic lineage. In part, this is because of the fact that in this area are, aside to well-defined entities, histologically and clinically diverse dermal CD34-reactive spindle cell lesions, whose definitions, limits and relationships are not completely established. Most of them have been described in the past few years as isolated case reports or in a single paper containing a short series of such cases.12–14 It has frequently been suggested that dermal dendrocytes are the proliferating cells in this type of lesions, and the term ‘dendrocytoma’ has been used for some of them. The heterogeneity of their histological features and the fact that such dendrocytes proliferate during wound healing allow the speculation that some of these lesions, excluding those with a clear hamartomatous nature, are reactive and, probably, related to trauma. These CD34-positive dermal spindle cell proliferations do not have a common histological structure, making difficult to render an accurate diagnosis.

Dermatofibrosarcoma protuberans (DFSP) shows a nearly consistent expression of CD34.15 This immunoreactivity has been reported to be sometimes lost in the fibrosarcomatous areas.16 CD34 expression has been used as an ancillary help for the differential diagnosis of DFSP with other spindle cell cutaneous lesions, mainly with the benign fibrous histiocytoma. The latter is usually CD34 negative, but some positive cases of almost any of its variants can be found. In these cases, immunoreactivity is generally focal.17 Usefulness of CD34 staining for evaluating the excision margins and for distinguishing between residual tumor and scar tissue in re-excisional specimens of DFSP has also been noted (Fig. 2).18 Recently, coexpression of apolipoprotein D has been described in this tumor.19 Giant cell fibroblastoma (GCF) is a neoplasm closely related to DFSP. Hybrid lesions with areas of DFSP and GCF have been found. Furthermore, both tumors share CD34 expression20,21 and a consistent cytogenetic abnormality involving genes COLIA1 on chromosome 17 and PDGFB on chromosome 22.22 Von Willebrand’s factor and lectin Ulex europaeus have been shown to be absent, both in the stromal cells and in the lining of the vessel-like spaces characteristic of GCF.23

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Figure 2. Dermatofibrosarcoma protuberans. A small residual nodule stained by CD34 at the margin of a scar (on the left) in a re-excisional specimen.

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Myxoinflammatory fibroblastic sarcoma (MFS) is a low-grade sarcoma, preferentially located on the acral part of the extremities in adults. It is composed by spindle, epithelioid and large bizarre cells with vesicular nuclei, inclusion-like macronucleoli and basophilic cytoplasm. The latter cells resemble virocytes or Reed-Sternberg cells and are the most distinctive feature of this neoplasm (Fig. 3). Vimentin is the only consistently expressed antigen by MFS cells. Coexpression of CD68 and CD34 is variably found seeing reactivity for CD34 in approximately 30% of the cases. Smooth muscle actin and cytokeratins are occasionally positive.24,25

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Figure 3. Myxoinflammatory fibroblastic sarcoma. An atypical cell with a large nucleolus in a collagenous stroma with inflammatory cells. Inset: focal CD34 expression in large neoplastic cells.

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Solitary fibrous tumor (SFT) of the skin is a very uncommon lesion. It consists of bland spindle cells, arranged in a combination of fascicular, storiform and hemangiopericytoid patterns, and contains a prominent vascularity and thick hyalinized collagen. Spindle cells show consistent CD34 reactivity (Fig. 4).26,27 Coexpression of bcl-2 and CD99 is common.27 Giant cell angiofibroma (GCA) is a neoplasm closely related to SFT, which has a preference for the orbital region. It is composed by a CD34-reactive fusiform component similar to that of SFT, stromal giant cells and angiectoid spaces in a collagenous or myxoid stroma.28 One case of a cutaneous hybrid tumor with areas of both GCA and DFSP has been reported.29

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Figure 4. Solitary fibrous tumor. Prominent vasculature and short spindle cells focally arranged in a hemangiopericytoid pattern. CD34 positivity is shown in the inset.

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Lipofibromatosis is a distinctive pediatric tumor characterized by abundant mature adipose tissue and spindled fibroblastic cells involving mainly the fibrous septa of the fat tissue and the skeletal muscle. Small collections of univacuolated cells can be found in the interface between the fibroblastic component and the mature adipocytes. Spindle cells express CD34, CD99 and smooth muscle actin. Positivity for bcl-2, S-100 protein and epithelial membrane antigen (EMA) can also be found in some cases.30

Fibroblasts in the nuchal-type fibroma (NTF) express CD34 and CD99.31,32 Fibromas in Gardner’s syndrome can be histologically identical to NTF.31,33 In addition, cases with a hybrid morphology exhibiting areas of both desmoid-type fibromatosis and NTF34 or areas of DFSP and NTF35 have been reported.

Sclerotic fibroma (SF), also known as circumscribed storiform collagenoma, and pleomorphic fibroma are related tumors, as shown by their common immunophenotypical profile, with frequent expression of CD34 and CD99,36–38 and the existence of tumors with histological features of both, known as giant cell collagenomas or pleomorphic SFs (Fig. 5).39,40 Fibromas of Cowden’s disease are histologically identical to SF.41 Pacinian collagenoma is probably a morphological variant of SF42 characterized by paucicellular slender eosinophilic collagen bundles arranged in concentric whorls. A single case has been reported to date. Dermal dendrocytes within this lesion expressed CD34.43 A SF-like change has been described in various neoplastic and inflammatory cutaneous lesions. It has been suggested that ‘SF features’ may represent a common reaction pattern of the skin and not a distinct entity.44

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Figure 5. Giant cell collagenoma. Multinucleated giant cells with scalloped cytoplasmic contours expressing CD34 (inset) within a hyalinized stroma.

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Superficial angiomyxoma is composed of CD34-reactive bland fibroblasts and elongated thin-walled vessels within a copious myxoid matrix (Fig. 6).45–47 Coexpression of smooth muscle actin, muscle-specific actin, factor XIIIa and S-100 protein has been reported.46

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Figure 6. Superficial angiomyxoma. Thin-walled vessels and scattered CD34-reactive (inset) spindle cells in a myxoid stroma with focal extravasation of erythrocytes.

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Superficial acral fibromyxomas (SAFM) are located in the dermis and/or subcutis of the fingers, toes and palms, mainly involving the subungual and periungual regions. They are composed of spindled and stellate-shaped cells, arranged in a random, loosely storiform or fascicular growth pattern and embedded in a myxoid and/or collagenous matrix (Fig. 7). SAFM frequently express CD34, CD99 and EMA.48 Cellular digital fibromas (CDF) are CD34-positive dense spindle cell proliferations sited in the dermis of the fingers, toes and palms.14 It has recently been suggested that CDF and SAFM correspond to the same lesion.49 Both SAFM and CDF share some phenotypical and histological features with DFSP, but the latter is rarely located in the acral extremities, usually forms larger masses, has a more infiltrative growth and exhibits a monotonous storiform pattern. In addition, SAFM shows a distinctive vascular component, consisting of numerous elongated thin vessels and, in contrast to DFSP, is apolipoprotein D negative.50

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Figure 7. Acral superficial fibromyxoma. Uniform spindle cells in a fibromyxoid stroma with elongated thin-walled blood vessels. Inset: immunohistochemical staining showing a diffuse CD34 expression.

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Several CD34-positive cutaneous fibroblastic lesions have been described in the past few years in isolated case reports, such as CD34-reactive eruptive fibromas,51 myxoid dermatofibrohistiocytoma12 and CD34-reactive myxoid dermal dendrocytoma.13 In addition, CD34 positivity has been reported in a single case of a fibrous papule of the nose,52 a type of lesion that usually expresses factor XIIIa.53

Mammary-type extramammary myofibroblastoma (MTEM) is an extramammary soft tissue tumor morphologically and immunohistochemically identical to myofibroblastoma of the breast. It is usually located in the subcutis. MTEM expresses desmin and CD34. Coexpression of smooth muscle actin can be found in a minority of the cases.54 This tumor is closely related to spindle cell lipoma (SCL) and cellular angiofibroma (CAF) (see subsequently).

CAF characteristically arises in the subcutaneous tissue of the vulva and of the inguinoscrotal region. CD34 immunostaining is found in about one half of the cases, expression of estrogen and progesterone receptor proteins in a slightly lower percentage and reactivity for actins and/or desmin in a minority of them.55 Recently, a deletion of a region on chromosome 13q14 that overlaps with the common deleted region of SCL and MTEM has been described in two cases of CAF.56 A close relationship between these three tumors is suggested by their common morphological, immunohistochemical and genetic features. Angiomyofibroblastoma is typically located in the superficial tissues of the vulva and vagina. It shows an almost consistent reactivity for desmin.57,58 CD34 expression is observed in a few of these cases, and positivity for actins is rarely found.58 Prepubertal vulval fibroma arises in the subcutaneous tissue or in the submucosa of the vulvar region of prepubertal females as a unilateral, poorly defined mass. It expresses CD34 and is negative for muscle markers, S-100 protein and hormone receptor proteins.59 A morphologically identical case has been reported in a postmenopausal patient.60

Rare cases of elastofibroma are sited in the skin.61 The scarce fibroblastic cellularity of this lesion shows CD34 positivity,62 although immunohistochemical study is not necessary for the diagnosis because the microscopic features in routine histology are characteristic.

Most cases of ischemic fasciitis also known as atypical decubital fibroplasia express muscle-specific actin and CD68. Coexpression of CD34 has been found in more than 50% of them.63

Cerebriform collagenomas of Proteus syndrome present preferentially in the plantar and palmar surfaces as gyriform masses of markedly thickened skin. Histologically, they consist of hypocellular dense fibrosis involving the dermis and subcutis.64 Lesions with more cellular areas containing CD34-positive bland spindle cells arranged in a storiform pattern have also been described.65 Numerous CD34-reactive dermal spindle and dendritic cells can be found surrounding the smooth muscle bundles in smooth muscle hamartoma. These CD34-reactive cells have been reported to be an intrinsic component of the lesion, together with smooth muscle fascicles, nerve fibers and hair follicles.66 CD34 immunostaining has also been reported in other types of connective tissue/mesenchymal hamartomas,67 including dermal dendrocyte hamartoma with stubby white hair,68 congenital cutaneous granular cell tumors,69,70 medallion-like dermal dendrocyte hamartoma71,72 and polypoid dermal dendrocytic hamartoma.73

There are other fibroblastic lesions that show expression of CD34 in a low percentage of cases. Positivity for this antigen has been reported, with a weak intensity, in one fourth of low-grade myofibroblastic sarcomas,74,75 in less than 20% of infantile fibrosarcomas76 and in sporadic cases of low-grade fibromyxoid sarcoma,77–79 adult fibrosarcoma not associated to DFSP or SFT,80,81 myxofibrosarcoma82 and plexiform fibrohistiocytic tumor.83,84 In the latter, some authors interpret the focal CD34 positivity as background staining and not as true tumor reactivity.85

Vascular tumors

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

CD34 is expressed by the endothelial cells lining the vascular channels of the great majority of benign and malignant vascular lesions.86,87 The reactivity of other cellular components is variable. CD34 positivity can be consistently shown in spindle cells of Kaposi’s sarcoma in the nodular stage (Fig. 8).8 Expression of this antigen is also found in a high number of angiosarcomas, both of the common type and of the epithelioid or spindle cell variants.88–91 Lesser CD34 staining in poorly differentiated than in well-differentiated areas of angiosarcomas has been reported.92

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Figure 8. Kaposi’s sarcoma in nodular stage. Fascicles of bland fusiform cells and numerous extravasated erythrocytes. A diffuse CD34 positivity of the spindle cell component can be seen in the inset.

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CD34 positivity is shown by epithelioid and spindle cells in nearly all epitheliod hemangioendotheliomas.93,94 Kaposiform hemangioendothelioma has a diffuse CD34 expression usually restricted to well-formed capillaries and to spindled cells, while the epithelioid and glomeruloid areas are only focally positive. In these areas, smooth muscle actin-reactive pericytes can be found.95,96 CD34 immunoreactivity can generally be shown in different components of composite hemangioendotheliomas.97,98

In spindle cell hemangiomas, CD34 immunostaining is restricted to endothelial cells lining the vascular channels as well as to vacuolated and epithelioid cells. Spindled cells in solid areas are generally negative for CD34 and, in contrast, show expression of muscle markers.99

Neural lesions

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

CD34-reactive cells are present in all types of peripheral nerve sheath tumors (PNST). These cells are S-100 protein, EMA and Glut1 negative and seem to correspond to endoneurial fibroblasts.100,101 The frequency, proportion and distribution of these cells are different for each type of PNST.

Malignant PNST are very rarely located in the skin. Many of them are associated to cutaneous neurofibromas. Classical and epithelioid forms have been reported.102 Although CD34 expression can be observed in some malignant PNST, positivity is absent in the majority of them.102–104 Decreased reactivity has been reported in high-grade malignant PNST when compared with low-grade malignant PNST.105

CD34 expression is consistent in neurofibromas. The positive cells are more numerous at the periphery and within the fibrotic and myxoid areas than in other parts of the lesions (Fig. 9).100,101,103 On the contrary, in schwannomas, the CD34 reactivity is restricted to a few slender cells in the peripheral zones close to the capsule and to some spindle and stellate cells in the Antoni B areas. CD34-positive cells are very infrequent or absent in the Antoni A areas.100,101,103 CD34 is expressed in the majority of nerve sheath myxomas in sparsely distributed spindle cells.106 The three types of benign PNST previously mentioned contain, in addition to the CD34-reactive intraneural fibroblasts, a predominant S-100 protein-positive component of Schwann cells.

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Figure 9. Neurofibroma. CD34-reactive endoneurial fibroblasts in (A). The staining is denser in the periphery of the lesion (above) than in the central areas (bottom). Compare with the more homogeneous expression of S-100 protein in (B).

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Perineuriomas are uncommon benign PNST composed of EMA-positive, Glut1-positive and S-100 protein-negative perineurial cells. Sclerosing, soft tissue (extraneural) and intraneural types are usually recognized. The first two have been reported in the skin. Reticular, lipomatous and plexiform histological variants of soft tissue perineuriomas have been described.107–109 Extensive CD34 expression is shown in most soft tissue perineuriomas,110 while lack of reactivity is usually reported in the sclerosing type.111–113

In palisaded encapsulated neuroma114,115 and traumatic neuroma,101 a variably dense CD34 immunostaining has been described.

CD34 expression in a case of glial heterotopia has been published. It presented as a well-demarcated dermal and subcutaneous mass on the back of an infant. The nodule was composed of clusters of glial cells in a fibromucinous stroma. Stromal spindle cells were CD34 positive.116

Adipocytic tumors

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

Atypical lipomatous tumors and a minority of dedifferentiated and pleomorphic liposarcomas express CD34, particularly in the nonlipogenic areas.117,118

The spindle cell component of different benign fat tumors is consistently CD34 reactive. S-100 protein positivity is usually limited to adipocytic cells in these tumors. In spindle cell lipomas (SCL)/pleomorphic lipomas, the spindle and pleomorphic cells strongly express CD34.119 Coexpression of bcl-2 is common120 and positivity for desmin is occasionally found.121 CD34 expression has been reported in the spindle cell component of one hibernoma of the spindle cell variant. This tumor shows hybrid features of SCL and classical hibernoma, and its clinical presentation and anatomic distribution are similar to SCL. The rest of hibernoma variants are negative for CD34.122 Myxolipomas arise preferentially in the head and neck and include a CD34-positive bland spindle cell component. Their clinicopathologic and cytogenetic features support a close relationship of this lipoma variant to myxoid SCL.123 Spindle and dendritic cells in the myxoid areas of angiomyxolipomas show CD34 positivity.124 In dendritic fibromyxolipomas, spindle cells express CD34 and bcl-2.125 Because of the clinical, histopathological and immunohistochemical similarities, it has been speculated that this tumor represents a myxoid variant of SCL.126

In sclerotic lipomas, the presence of scarce mature adipocytes within the dense fibrosclerotic or myxocollagenous stroma allows its differentiation from other cutaneous sclerotic lesions (Fig. 10).127 CD34 reactivity is frequently found in the nonlipogenic component, usually restricted to some spindle and dendritic cells in the periphery of the lesions. Coexpression of CD99 and inconsistent presence of S-100 protein and muscle antigen immunostaining in rare nonfatty cells have been reported.128

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Figure 10. Sclerotic lipoma. Hypocellular lesion composed of bland spindle cells and scattered adipocytes in a fibrosclerotic stroma. Inset: nonfatty spindle and dendritic cells expressing CD34.

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Fibrohistiocytic lipomas have a minor component of bland or plump spindle cells, with minimal mitotic activity, in a collagenous stroma. They are arranged in short fascicular and storiform patterns, forming solid foci or adopting a honeycomb-like disposition. Spindle cells express calponin. Coexpression of CD34 is frequently found, and focal positivity for CD68 and lysozyme has been described.129

Smooth muscle tumors

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

In addition to muscle markers, inconsistent CD34 reactivity has been reported in pilar leiomyomas and angioleiomyomas.87 On the contrary, I have not been able to find any published CD34-positive cutaneous leiomyosarcoma, while a minority of classical and epithelioid leiomyosarcomas from other locations have been reported to express CD34.86,130,131

Perivascular cell tumors

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

Coexpression of actins and CD34 has occasionally been reported in glomus tumors, glomangiomas, glomangiomyomas, myopericytomas and atypical and malignant glomus tumors of skin and deep locations.132–134 Interestingly, all six CD34-positive glomus tumors, glomangiomas and glomangiomyomas included in an article showed a prominent myxoid stroma.133

Melanocytic tumors

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

Before 2007, only two examples of CD34-positive cutaneous melanomas could be found in the literature.136,137 Reactivity for CD34 in melanomas of other locations had also rarely been reported.138 Recently, a series of cutaneous melanomas showing CD34 expression in one third of the 30 cases of invasive melanoma studied has been published. In the positive cases, immunostaining was seen only in a minority of the neoplastic cells. This antigen was absent in ‘in situ’ and microinvasive melanomas. CD34-reactive cases coexpressed CD31. CD34/CD31 expression closely parallels tumor progression and parameters related to aggressive behavior.139

CD34 reactivity has also been shown in melanocytic cells of some congenital cellular blue nevi,140 in endoneurial fibroblasts of the nevic corpuscles of neurotized nevi141 and in stromal cells of neurocristic hamartomas.142

Lesions of hair follicle

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

Fibrofolliculomas and trichodiscomas are two closely related entities or, more probably, different developmental stages of one single hamartomatous lesion, which differentiates toward the hair follicle mantle. Both fibrofolliculomas and trichodiscomas may occur sporadically or as multiple lesions in the Birt-Hugg-Dubé syndrome. Sporadic and syndromic forms are clinicopathologically identical, except for the microscopic contiguous multifocality observed in the setting of the Birt-Hugg-Dubé syndrome.143 The spindle cell component of both lesions is CD34-positive. Recently, it has been suggested that the neurofollicular hamartoma is a cellular trichodiscoma with CD34-positive fibrocytic spindle cells arranged in short fascicles and without signs of neural differentiation and not a distinct entity.144

Folliculosebaceous cystic hamartoma is composed of infundibular cystic structures with attached sebaceous glands, surrounded by a spindle cell stroma that often contains mature adipocytes and numerous blood vessels. Spindle cells focally express CD34.145

Tumors completely or partially differentiated toward the external root sheath of the hair follicle, such as trichilemmoma (Fig. 11),146 desmoplastic trichilemmoma,147 trichilemmal keratosis,148 cystic panfolliculoma149 and proliferating trichilemmal tumor,146 have been reported focally or diffusely expressing CD34. Loss of CD34 immunostaining has been found in malignant tumors by other authors.150 CD34 expression has been considered useful in the diagnosis of some of these tumors, particularly in the differentiation of desmoplastic trichilemmoma from other cutaneous tumors with dense collagenous stroma.147

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Figure 11. Trichilemmoma. Lobules of uniform epithelial cells with clear cytoplasm connecting with the epidermis. Inset: CD34 positivity in the tumor cells.

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Hematopoietic neoplasms

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

Primary and secondary precursor lymphoid and myeloid neoplasms affecting the skin can express CD34. In the lymphoid lineage, reactivity is restricted to a relatively low percentage of lymphoblastic lymphomas/leukemias.151–153 In myeloid infiltrates, CD34 is an insensitive marker compared with other antigens, such as CD43, CD68, lysozyme or myeloperoxidase.154–156

Tumors of uncertain differentiation lineage

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

Epithelioid sarcoma (ES) expresses low-molecular-weight cytokeratin, EMA and vimentin in nearly all cases. Coexpression of CD34 is shown in one half of them (Fig. 12). Immunostaining for high-molecular-weight keratin and muscle-specific actin can also frequently be found.157–161 Although CD34 positivity is not consistent in ES, reactivity with this antibody allows the differential diagnosis with its mimickers, mainly carcinomas, with which partially shares the immunophenotype. Carcinomas are almost always CD34 negative.

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Figure 12. Epithelioid sarcoma. Epithelioid cells with a membranous immunoreactivity for CD34 (inset), within a hyalinized collagen stroma.

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Pleomorphic hyalinizing angiectatic tumor of soft parts (PHATSP) arises in subcutaneous or intramuscular location. Dermal involvement has also been described.162 It is composed of sheets and fascicles of plump spindle and pleomorphic cells with hyperchromatic nuclei, easily identifiable intranuclear inclusions and very scarce mitotic figures. Clusters of ectatic blood vessels of varied size can be found in between the sheets of pleomorphic cells. The vessels are typically surrounded by a hyaline material. The cells adjacent to the vessels frequently contain hemosiderin. CD34 expression has been reported in 50% of the cases. PHATSP differs from schwannoma in the absence of encapsulation and in the lack of S-100 protein expression. Its low mitotic index and the CD34 expression allow the distinction from undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma), a usually CD34-negative neoplasm.163 The so-called hemosiderotic fibrohistiocytic lipomatous lesion is a subcutaneous mass compound of an admixture of fat and hemosiderin-laden CD34-positive plump spindle cells growing in a perivascular, periadipocytic and septal pattern.164 It is considered by some authors as an early form of PHATSP.165

One case of a ‘CD34-reactive spindle cell sarcoma arising in cutaneous hyaline-vascular Castleman disease’ has been reported. Neoplastic cells expressed CD34, fascin, nerve growth factor receptor and, focally and weakly, CD21 and CNA42. They were negative for CD23, CD35, CD31, Von Willebrand’s factor, CD99, bcl-2, factor XIIIa, CD246 and muscle, melanocytic and epithelial markers. Based on the histological and ultrastructural features, the authors propose the diagnosis of poorly differentiated follicular dendritic cell sarcoma; although the immunophenotype is not typical, CD34 has not previously been reported in this type of tumor and follicular dendritic cell sarcoma has not been described before in the skin.166

Ectopic hamartomatous thymoma arises in the subcutaneous or deep soft tissue of the supraclavicular, suprasternal or presternal regions. It presents as a well-circumscribed mass and is microscopically characterized by an admixture of plump and small delicate spindle cells, squamous and glandular epithelial structures and mature adipocytes. Both epithelial and spindle cells express cytokeratins. Coexpression of actin, calponin and CD10 by the spindle cells has been reported. The smaller spindle cells stain for CD34.167

CD34 expression has also been reported in sporadic cases of angiomatoid fibrous histiocytoma 168 and in one case of cellular neurothekeoma,169 two neoplasms commonly considered CD34-negative.170,171

Conclusions

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

Over the past few years, a growing number of cutaneous entities expressing CD34 is being reported. In the list, benign and malignant neoplastic, reactive and hamartomatous lesions of diverse differentiation lineages co-exist. The CD34 reactivity plays a key role in the differential diagnosis of some tumors, such as DFSP, ES or PHATSP. In others, as in desmoplastic trichilemmoma, it can help to resolve diagnostic problems in concrete cases. Finally, in many of the CD34-positive lesions, the diagnosis with hematoxylin and eosin staining is straightforward. However, in all of them, the knowledge of the immunohistochemical profile contributes to our understanding of the cutaneous pathology.

Acknowledgement

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References

I wish to thank Drs Rosario Granados and José A. Aramburu (Hospital Universitario de Getafe, Madrid, Spain), Clara Salas (Hospital Universitario Clínica Puerta de Hierro, Madrid, Spain) and Margarita Elices (Hospital El Escorial, Madrid, Spain) for their contribution to this article.

References

  1. Top of page
  2. Review Article
  3. Fibroblastic, fibrohistiocytic and myofibroblastic lesions
  4. Vascular tumors
  5. Neural lesions
  6. Adipocytic tumors
  7. Smooth muscle tumors
  8. Perivascular cell tumors
  9. Histiocytic lesions
  10. Melanocytic tumors
  11. Lesions of hair follicle
  12. Hematopoietic neoplasms
  13. Tumors of uncertain differentiation lineage
  14. Conclusions
  15. Acknowledgement
  16. References