Hyalinizing Spitz nevus: spindle and epithelioid cell nevus with paucicellular collagenous stroma.

Abstract: Hyalinizing spindle and epithelioid cell nevus (Spitz nevus) is an uncommon melanocytic lesion. The histologic features of this benign tumor can mimic those of certain benign (dermatofibroma and desmoplastic cellular blue nevus) and malignant (metastatic carcinoma and malignant melanoma) neoplasms. We report a woman with a hyalinizing Spitz nevus and review the clinical characteristics, histologic features, and differential diagnosis of this lesion. The lesion presented as an asymptomatic red firm nodule on her abdomen. Microscopic examination showed a symmetric lesion in the dermis. The neoplastic cells were large and epithelioid-shaped or plump and spindle-shaped. They were present as isolated individual cells, single cells in a linear pattern, small nests, and fascicles in a paucicellular hyalinized stroma. Neoplastic cells with prominent eosinophilic nucleoli were evenly exhibited from the superficial to deep lesion. Diffuse expression of S-100 protein and absence of staining with antibodies to cytokeratin and HMB-45 were observed. The features were diagnostic of a hyalinizing Spitz nevus. Hyalinizing Spitz nevus is a benign lesion whose histologic features may mimic dermatofibroma, desmoplastic cellular blue nevus, metastatic carcinoma, and malignant melanoma. Immunohistochemical studies are helpful to differentiate these lesions.

Key Words: cell, collagenous, epithelioid, hyalinizing, nevus, paucicellular, spindle, Spitz, stroma

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Spitz nevus is a benign and usually acquired melanocytic nevus. It typically consists of spindle and epithelioid cells in a vascular and edematous stroma. Suster, (1) in 1994, described a variant of Spitz nevi characterized by Spitz nevus cells in a paucicellular dermal stroma. These lesions were called hyalinizing spindle and epithelioid cell nevus, thereby adding a new category to the previously described unusual variants of Spitz nevi (Table 1). (1-18) In this paper, we report a woman with a hyalinizing Spitz nevus and review the clinical features and histologic differential diagnosis of this lesion.

Discussion

Hyalinizing spindle and epithelioid cell nevus is a rare variant of Spitz nevus. To the best of our knowledge, only five patients with this lesion have previously been reported in the literature. (1) Including our patient, hyalinizing Spitz nevus has been observed in three men and three women (Table 2). The median age of the patients is 34 years (range, 23-53 years). The lesions occurred on the abdomen (two patients), leg (two patients), and head and neck (two patients). They presented as red/pink to tan, raised, and indurated nodules with a smooth surface, ranging from 0.5 to 1.0 cm in greatest diameter. Five patients had a solitary lesion and one person had multiple lesions. None of these patients had previous history of internal malignancy. Submitted clinical diagnoses were dermatofibroma in four cases, Spitz nevus in two cases, nevus (not otherwise specified) in one case, basal cell carcinoma in one case, and no specific diagnosis in one case; for some of the patients, more than one clinical diagnosis was submitted. Four patients were followed up for a period of 2 months to 7 years after complete excision of the lesions; no recurrence was noted.

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Microscopically, hyalinizing Spitz nevi are characterized by a dermal proliferation of round, epithelioid, or spindle cells in nests, in a single file arrangement, and in a single cell infiltrating pattern. They are separated by an abundant, hyalinized or collagenous, paucicellular stroma. Nuclear atypia is observed in the majority of cells. Macronucleoli and/or intranuclear inclusions of the cytoplasm may be prominent in the cells. No pigment is observed in the cytoplasm. Architectural maturation in depth is observed in all lesions whereas cytologic maturation may be subtle or absent. There are no individual scattered atypical melanocytes in the epidermis, and junctional nests have been absent.

Immunohistochemical staining in hyalinizing Spitz nevi is positive with antibody to S-100 protein. (1) In addition, the neoplastic cells in hyalinizing Spitz nevi do not stain with antibodies to cytokeratin, epithelial membrane antigen, cinoembryonic antigen, actin, and desmin. Our patient's lesion also showed positive staining with antibody to S-100 protein; the lesion was negative after staining with antibodies to HMB-45 and cytokeratin.

The histologic presentation of hyalinizing Spitz nevus can mimic benign and malignant tumors. Benign skin lesions include dermatofibromas (5), (16) and desmoplastic cellular blue nevi. (5), (19) Malignant neoplasms include metastatic carcinomas and malignant melanomas (Table 3). (1), (20), (21)

Dermatofibromas, similar to hyalinizing Spitz nevi, can show epidermal hyperplasia and dermal hypercellularity. The appearance of the collagen bundles in dermatofibromas is referred to as "keloidal." In contrast to hyalinizing Spitz nevi, dermatofibromas may demonstrate induction of adnexal structures and hyperpigmentation of the epidermis. (22) In contrast to dermatofibromas, multinucleated tumor cells are rarely present in hyalinizing Spitz nevi. Immunoperoxidase staining also helps to differentiate dermatofibromas from hyalinizing Spitz nevi: neoplastic cells of dermatofibromas express factor XIIIa whereas tumor cells of hyalinizing Spitz nevi express S-100 protein. (5), (16), (18)

Common histologic features may be present in hyalinizing Spitz nevi and blue nevi--especially when the latter are cellular, hypopigmented, and sclerotic. However, hyalinizing Spitz nevi usually present as more well-defined melanocytic lesions. Also, the melanocytes of the blue nevus tend to be more slender than the plumper tumor cells of the hyalinizing Spitz nevus. Although the neoplastic cells of both hyalinizing Spitz nevus and hypopigmented desmoplastic cellular blue nevi demonstrate S-100 protein immunoreactivity, only those of the blue nevus show positive staining with HMB-45. (5), (16), (19)

Metastatic carcinomas usually occur in patients with known malignancy. However, cutaneous metastasis may occasionally be the initial manifestation of internal carcinoma. (23) Suster (1) commented that the discohesive growth pattern in a prominently hyalinized stroma might simulate a metastasis from an occult malignancy. Our patient was a middle-aged woman, which is the peak age for breast carcinoma. Breast carcinoma is the most frequent malignancy to spread to the skin in women. (23) In addition, the histologic presentation in this case included irregular nests, single file pattern, single cell infiltration, and uniform cytologic atypia (no cytologic maturation) resembling breast carcinoma metastatic to the skin. However, the absence of cytokeratin reactivity and the presence of strong S-100 protein positivity ruled out metastatic carcinoma in our case.

The histologic differential diagnosis of hyalinizing Spitz nevus also includes primary and metastatic malignant melanomas. Among primary melanomas, desmoplastic variant is a serious consideration. (21) Immunoperoxidase stains may not be helpful because staining with antibody to HMB-45 is usually negative in desmoplastic melanoma. Unlike hyalinizing Spitz nevus, most desmoplastic melanomas have epidermal involvement by the melanocytic lesion. The neoplastic cells have an increased nuclear to cytoplasmic ratio. Mitoses are usually demonstrable, and necrosis may be present. There is usually a highly characteristic host response consisting of nodular clusters of mature small lymphocytes with a few plasma cells.

Because of the presence of architectural maturation and fibrotic surrounding stroma, nevoid melanoma may also resemble hyalinizing Spitz nevus. (24) However, in nevoid melanoma, mitoses in the deep dermis and foci of lymphocytic invasion may be present.

Hyalinizing Spitz nevus may also mimic dermal metastases of malignant melanoma. However, metastatic melanomas often have infiltrative patterns of growth without maturation, extensive areas of necrosis, and frequent mitoses, sometimes exhibit dusty melanin pigment in the cytoplasm of neoplastic cells, and rarely have a desmoplastic stroma.

Conclusion

Hyalinizing spindle and epithelioid nevus with paucicellular collagenous stroma, an uncommon variant of Spitz nevus, has been described in six patients. The histologic presentation of this lesion mimics dermatofibromas, desmoplastic cellular blue nevi, metastatic carcinomas, and malignant melanomas. The lesion's immunohistochemical profile (S-100 protein positive, HMB-45 negative, and cytokeratin negative) may be helpful to differentiate it from other conditions.

Table 1. Variants of Spitz nevus

Variants                                   Reference

Angiomatoid Spitz nevus (a)                2, 3

Atypical pigmented spindle cell nevus (b)  4, 5

Atypical Spitz nevus (c)                   4, 5

Desmoplastic Spitz nevus (d)               6, 7

Hyalinizing Spitz nevus (e)                1

Malignant Spitz nevus (f)                  5, 8

Pagetoid Spitz nevus                       5, 9

Pigmented spindle cell nevus               4, 10, 11

Recurrent Spitz nevus                      12

Spitz nevus with florid pseudoepithelial   13
  hyperplasia

Spitz nevus with halo phenomenon           14

Tubular epithelioid cell nevus (g)         15

(a) Several investigators consider angiomatoid Spitz nevus to be a
variant of desmoplastic Spitz nevus. (2), (3)
(b) This variant of Spitz nevus has also been referred to as a pigmented
spindle cell nevus with architectural disorder and cytologic atypia.
(c) This variant of Spitz nevus has also been referred to as a Spitz
nevus with architectural disorder and cytologic atypia.
(d) Some investigators consider "desmoplastic Spitz nevus" to be
synonomous with "desmoplastic nevus." (2), (5), (7) However, other
authors maintain that "desmoplastic nevus," which they also refer
to as "desmoplastic (sclerotic) nevus," is a distinct
entity. (16-18)
(e) Several investigators consider hyalinizing Spitz nevus to be a
distinct variant of Spitz nevus. (1), (2), (16) However, some
researchers consider hyalinizing Spitz nevus to be a variant of
desmoplastic Spitz nevus. (3)
(f) Although these melanocytic lesions resemble Spitz nevi, they tend to
demonstrate atypical features and to be very large and/or extend
unusually deep. Because these lesions spread to regional lymph
nodes, they have also been referred to as metastasizing
Spitz tumors.
(g) Some investigators do not consider this tumor to be a tubular
variant of Spitz nevus because the lack of immunoexpression for
epithelial markers in the tubular and microcystic structures
militates against tubular differentiation. (2)

Table 2. Clinical features of hyalinizing Spitz nevus (a)

Patient no.  Sex/Age (yr)  Size (b) (cm)   Site       Follow-up

1                M/23           0.6       Scalp    2 yr
2                M/28           0.8       Abdomen  7 yr
3                M/36           0.5       Leg      Lost to follow-up
4                F/31           0.6       Thigh    4 yr
5                F/45           0.5       Neck     Lost to follow-up
6                F/53           1.0       Abdomen  2 mo

Patient no.   Reference

1            1, Patient 1
2            1, Patient 5
3            1, Patient 4
4            1, Patient 3
5            1, Patient 2
6            Present report

(a) The submitted clinical diagnoses were dermatofibroma (four cases),
Spitz nevus (two cases), nevus (one case), basal cell carcinoma (one
case), and "lesion" (one case); from cases 1 to 5, seven clinical
diagnoses were submitted, and our patient (case 6) had two
clinical diagnoses.
(b) Measurement of greatest diameter.

Table 3. Hyalinizing Spitz nevus: Malignant neoplasms in the histologic
differential diagnosis (a)

Histologic features            Hyalinizing Spitz nevus

Lesion                       Symmetric

Neoplastic cells             Spindle and epithelioid cells
                               in nests, single file, and
                               single cell arrangement

Architectural maturation     +

Cytoplasmic melanin pigment  -

Mitoses                      -

Necrosis                     -

Stroma                       Markedly hyalinized

Epidermal involvement        -

Host response                -

Cytokeratin                  -

S-100 protein                +

HMB-45                       -

Histologic features          Metastatic carcinoma


Lesion                       Asymmetric

Neoplastic cells             Mimicking primary tumors

Architectural maturation     -

Cytoplasmic melanin pigment  -

Mitoses                      +

Necrosis                     [+ or -]

Stroma                       Variable

Epidermal involvement        [+ or -]

Host response                +

Cytokeratin                  +

S-100 protein                - (c)

HMB-45                       -

Histologic features            Primary melanoma

Lesion                       Asymmetric

Neoplastic cells             Nests and fascicles rather than

                               single cells present at base of

                               the lesion

Architectural maturation     -

Cytoplasmic melanin pigment  [+ or -]

Mitoses                      +

Necrosis                     +

Stroma                       Variable

Epidermal involvement        + +

Host response                + +

Cytokeratin                  - (b)

S-100 protein                +

HMB-45                       [+ or -]

Histologic features          Metastatic melanoma

Lesion                       Asymmetric

Neoplastic cells             Circumscribed or

                               infiltrative nodules

Architectural maturation     -

Cytoplasmic melanin pigment  -

Mitoses                      +

Necrosis                     + +

Stroma                       Variable

Epidermal involvement        [+ or -]

Host response                [+ or -]

Cytokeratin                  - (b)

S-100 protein                +

HMB-45                       [+ or -]

(a) -, absent; [+ or -], present or absent; + present; + +, prominent.
(b) Cytokeratin may be focally positive.
(c) Rare carcinomas are S-100-protein-positive.

From the Departments of Pathology and Dermatology, The University of Texas-Houston Medical School, and the University of Houston Health Center, Houston, TX.

Reprint requests to Philip R. Cohen, MD, 805 Anderson Street, Bellaire, TX 77401-2806. Email: [e-mail]

Accepted August 20, 2002.

Copyright [c] 2004 by The Southern Medical Association 0038-4348/04/9701-0102

References

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RELATED ARTICLE: Key Points

* Hyalinizing spindle and epithelioid nevus with paucicellular collagenous stroma is an uncommon variant of Spitz nevus.

* Hyalinizing Spitz nevus usually presents as a solitary, red to tan, raised and indurated, 0.5 to 1.0 cm smooth nodule on either the abdomen, legs, or head and neck.

* Hyalinizing Spitz nevus is characterized by a dermal proliferation of round, epithelioid, or spindle cells in nests, in a single file arrangement, and in a single cell infiltrating pattern, which are separated by an abundant, hyalinized or collagenous, paucicellular stroma.

* The histologic differential diagnosis of hyalinizing Spitz nevus includes dermatofibroma, desmoplastic cellular blue nevus, metastatic carcinoma, and malignant melanoma.

* The immunohistochemical profile of hyalinizing Spitz nevus (S-100 protein positive, HMB-45 negative, and cytokeratin negative) may be helpful to differentiate it from other conditions with similar appearing histology.

RELATED ARTICLE: Case Report

A 53-year-old white woman presented with an asymptomatic 1.0 X 0.7 cm red firm nodule with a smooth surface in the mid-abdomen. She had no history of malignancy. A tangential excision was performed.

The dome-shaped specimen was fixed in 10% buffered formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin. Immunoperoxidase staining was performed on paraffin sections using the three-step avidin-biotin complex method. The following monoclonal antibodies were used: cytokeratin (AE1-AE3 and CAM5.2), S-100 protein, and HMB-45.

Light microscopic examination of the hematoxylin and eosin--stained sections showed a bilaterally symmetric lesion in the dermis (Fig. 1). The neoplastic cells were arranged as either loosely cohesive nests with irregular outlines, or as fascicles of cells, or as single files of individual cells; the cells were separated by a paucicellular collagenous stroma (Fig. 2A). There was architectural maturation demonstrated by the size of the nests or fascicles attenuating toward the base of the lesion where occasional single cells were scattered in the hyalinized stroma (Fig. 2B). The neoplastic cells were large and epithelioid-shaped or plump and spindle-shaped. Transitional forms between these cell shapes were also present. The nuclei were large and vesicular with prominent eosinophilic nucleoli and perinucleolar clearing. The cytoplasm was abundant and eosinophilic; pigment was absent. Cytologic atypia was evenly distributed from the superficial to the deep dermis; thus, cytologic maturation, which is characteristic of typical nevi, was absent (Fig. 2). However, there were no mitoses and no evidence of necrosis. Chronic inflammatory cells, which may indicate a host reactive response, were scant. The overlying squamous epithelial cells showed mild acanthosis. There was no dermal-epidermal junction activity and an absence of spread of neoplastic cells in the epidermis.

Immunoperoxidase staining revealed that the neoplastic cells were strongly positive for S-100 protein (Fig. 3). The S-100-positive cells were negative for both HMB-45 (Fig. 4) and cytokeratin (AE1-AE3 and CAM5.2; Fig. 5). The benign squamous epithelial cells were positive for cytokeratin (AE1-AE3; Fig. 5).

A diagnosis of hyalinizing Spitz nevus was made. Because the deep and lateral margins were involved, reexcision of the residual lesion was performed. Histologic sections showed scar tissue without residual tumor.

Jing Liu, MD, Philip R. Cohen, MD, and Anwar Farhood, MD