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Dermatopathology
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Case 5 -
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Sarcomatoid (Spindle Cell) Squamous Cell Carcinoma
Steve Billings
University of Indiana School of Medicine
Indianapolis, IN
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Diagnosis:
Sarcomatoid (spindle cell) squamous cell carcinoma.
Clinical Features
Sarcomatoid, or spindle cell, squamous cell carcinoma (SSCC) is an uncommon variant of squamous cell
carcinoma. Typically it occurs in sun damaged or irradiated skin in older individuals. Clinically, the
presentation is rather non-descript. SSCC typically presents as a raised nodule and ulceration is
common.
Case 5 - Slide 1
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Case 5 - Figure 1
Low power examination demonstrated a spindle cell tumor permeating the entire dermis.
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Case 5 - Figure 2
No apparent attachment to the overlying epidermis was apparent.
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Case 5 - Figure 3
The tumor was composed of pleomorphic, hyperchromatic spindled cells.
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Case 5 - Figure 4
There was a prominent desmoplastic response to the invasive tumor.
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Microscopic Features
SSCC is composed of hyperchromatic spindled to pleomorphic giant cells. Typically SSCC has a
fascicular to storiform arrangement. Heterologous mesenchymal elements are rarely present. SSCC are
infiltrative lesions and frequently involve the deep dermis and even subcutis. Some cases have adjacent
actinic keratosis or focal features of conventional squamous cell carcinoma including continuity with an
overlying squamous cell carcinoma in-situ or focal keratin pearl formation. However, not infrequently
there is no evidence of actinic keratosis or conventional squamous cell carcinoma. In these cases the
differential diagnosis may be problematic.
Differential Diagnosis
The differential diagnosis of SSCC includes other malignant spindle cell tumors of the skin. The
primary differential diagnosis includes desmoplastic melanoma, atypical fibroxanthoma and
leiomyosarcoma. Rarely, angiosarcoma may have a predominantly spindled morphology and be considered in
the differential diagnosis of SSCC.
Desmoplastic Melanoma:
Desmoplastic melanoma usually presents on the head and neck in sun-damaged skin in older patients.
Clinically it may be innocuous because of the absence of pigmentation. Therefore patients often present
with locally advanced disease. Microscopically, the tumor cells are usually arranged in short fascicles
in a characteristic packeted arrangement. The tumor cells of desmoplastic melanoma are purely spindled
and lack the bizarre tumor giant cells that may be seen in SSCC or atypical fibroxanthoma. The presence
of infiltrating lymphocytes and lymphoid aggregates are a histologic clue to the diagnosis of
desmoplastic melanoma. Roughly half of cases of desmoplastic melanoma may have an associated atypical
junctional melanocytic proliferation overlying the dermal tumor. When present, this is another helpful
clue to the diagnosis. The tumor cells are strongly S100 protein positive, but usually lack expression
of melanocytic specific markers. Smooth muscle actin immunoreactivity may be seen in the background
myofibroblasts.
Atypical Fibroxanthoma:
Atypical fibroxanthoma usually presents on the head and neck of sun-damaged skin. Microscopically
atypical fibroxanthoma is composed of a fascicular to storiform arrangement of atypical spindled to
pleomorphic tumor cells. It is indistinguishable from pleomorphic undifferentiated sarcoma (malignant
fibrous histiocytoma). Because of this histologic overlap, an unequivocal diagnosis of atypical
fibroxanthoma should only be made on small, superficial lesions. Because of histologic overlap with SSCC
and desmoplastic melanoma, the diagnosis of atypical fibroxanthoma is one of exclusion that ultimately
relies on the absence of immunohphenotypic evidence of keratin or S100 protein expression. To date,
there is no specific positive marker for atypical fibroxanthoma.
Leiomyosarcoma:
Cutaneous leiomyosarcoma may present on any location but is less common on the head and neck.
Leiomyosarcoma is an orderly fascicular growth pattern of fascicles that intersect perpendicularly. The
tumor cells show variable nuclear pleomorphism, but many of the tumor cells have the cigar-shaped nucleus
typical of smooth muscle tumors. Diffuse immunoreactivity for smooth muscle actin with a pattern that
fills the cytoplasm is sarcoma have a more ordered intersecting pattern and have more elongated, blunt
ended nuclei than DM. Immunoreactivity for smooth muscle actin and desmin and the absence of
immunoreactivity for S100 protein are helpful adjuncts in this diagnosis.
Diagnostic Work-up
In the absence of recognizable conventional squamous cell carcinoma or actinic keratosis,
immunohistochemical stains are critical in the diagnosis of SSCC. SSCC is at least focally positive for
cytokeratin and is negative for S100 protein. Focal immunoreactivity for smooth muscle actin may be
seen. However, before approaching selection of appropriate immunohistochemical stains in the diagnosis
of SSCC, it is important to understand the complex nature of cytokeratins in the skin as well as the
nature of antibodies routinely used in the differential diagnosis of malignant spindle cell tumors of the
dermis.
Cytokeratins exist as a family of 20 intermediate filament proteins that are largely but not
exclusively found in epithelial tissue. A wide variety of cytokeratins are found in the skin (Table 1).
Specifically in the epidermis, the basal layer expresses predominantly cytokeratins 5 and 14. The
suprabasal, or spinous layer, predominantly expresses cytokeratins 1 and 10. In certain
hyperproliferative disease states such as psoriasis or squamous cell carcinoma, suprabasal keratinocytes
often express cytokeratins 6, 11, and 16. Follicles have a similar array of cytokeratins to the
epidermis. Adnexae often express low molecular cytokeratins 8 and 18, but myoepithelial cells express
high molecular weight cytokeratins 5 and 14 and often S100 protein and smooth muscle actin.
Table 1 - Cytokeratins in Skin
| Skin compartment | Cytokeratin Type |
| Basal layer of epidermis | CK5,14 |
| Suprabasal layer of epidermis | CK 1, 10 (6,11,16) |
| Follicle | CK5, 6, 14, 15, 16 |
| Palmoplantar epidermis | CK6, 16, 17 |
| Merkel cells | CK20 |
Because of the complexity of the nature of cytokeratins expressed in the skin, it is crucial to
understand what keratins are recognized by which antibody. In routine dermatopathology practice, some of
the most common antibodies utilized include AE1/3, CAM5.2, pan-keratin cocktails, CK34βE12, CK5/6,
and CK20. While antibodies directed against CK5/6 and CK20 are self-explanatory, the targets recognized
by the other antibodies listed are less clear.
AE1/3: This is a cocktail of two monoclonal antibodies AE1 and AE3. AE1
recognizes cytokeratins 10, 14, 15, 16, and 19. AE3 recognizes the cytokeratins 1, 2, 3, 4, 5, 6, and
8. Therefore this antibody is possibly the single most effective pan-keratin marker for use in the
skin. For unclear reasons, immunoreactivity for cytokeratins 5 and 14 is often less robust with AE1/3.
This may manifest as absence or pale staining of the basal layer in adjacent normal epidermis. SSCC may
only express keratins 5 and 14. Therefore AE1/3 may not be adequately sensitive for routine use in the
diagnosis of SSCC.
CAM5.2: This antibody predominantly recognizes CK8 and 18. It highlights
ductular epithelium, but is frequently negative in the epidermis and squamous cell carcinoma. It is not
an ideal marker for squamous tumors.
CK34βE12: This antibody, also known as cytokeratin 903, recognizes
high molecular weight cytokeratins 1, 5, 10, and 14/15. In my experience it is better than AE1/3 for
highlighting the basal layer cytokeratins and is very useful in the diagnosis of SSCC.
CK5/6: Similar to CK34βE12, this antibody is very effective at
highlighting the tumor cells of SSCC and is more sensitive than AE1/3. In my own experience, our
laboratory has had some trouble with this antibody, and I routinely prefer CK34βE12 for the
diagnosis of SSCC.
Other Immunohistochemistry Pitfalls:
Vimentin: There is a common misconception that vimentin is useful in the
differential diagnosis of pleomorphic spindle cell tumors of the dermis. Unfortunately, vimentin
expression is the expected finding in all of the entities in the
differential diagnosis including SSCC, desmoplastic melanoma, leiomyosarcoma, and angiosarcoma.
Therefore its diagnostic utility is very limited in this setting.
S100 protein: S100 protein is the most sensitive marker of melanocytes.
With regards to desmoplastic melanoma, it is usually the only melanocytic marker positive. Melanocytic
specific markers (e.g. HMB45) are positive in less than 10% of cases.
CD68: CD68 highlights lysosomes. It is not specific for histiocytes;
histiocytes just typically have abundant lysosomes. SSCC, leiomyosarcoma or melanoma may be positive.
Immunoreactivity for CD68 is not sufficient evidence for a presumptive diagnosis of atypical
fibroxanthoma.
Summary
SSCC can be reliably distinguished from other entities in the differential diagnosis of cutaneous
pleomorphic spindle cell tumors. Table 2 summarizes the approach to the diagnosis:
Table 2 - Pleomorphic Spindle Cell Tumor Differential Diagnosis
| Feature | SSCC | DM | AFX | LMS |
| Clinical | Variable | Head and Neck | Head and Neck | Variable |
| Pattern | Fascicular to Storiform | Short fascicles | Fascicular to Storiform | fascicles |
| Cytologic Features | Spindled to Pleomorphic | Spindled | Spindled to Pleomorphic | Spindled |
| Clues | Co-existing AK or SCC | Lymphocytes, Junctional melanocytic proliferation | No epidermal component | Intersecting pattern |
| Immunostains | CK+, S100-, SMA -/+ | CK-, S100+, SMA- | CK-, S100-, SMA-/+ | CK-/+, S100-, SMA+, Des+/- |
SSCC = Sarcomatoid squamous cell carcinoma, DM = desmoplastic melanoma, AFX = atypical fibroxanthoma,
LMS = leiomyosarcoma, AK = actinic keratosis, SCC = (conventional) squamous cell carcinoma, CK =
cytokeratin (with antibodies CK34βE12 or CK5/6), Des = desmin
References
- Folpe AL, Gown AM. Immunohistochemistry for Analysis of Soft Tissue Tumors. In: Goldblum JR, Weiss SW. Soft Tissue Tumors, 4th ed. St. Louis: CV Mosby. 2001.
- Cassarino DS. Derienzo DP. Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification. Part one. Journal of Cutaneous Pathology. 33(3):191-206, 2006 Mar.
- Cassarino DS. Derienzo DP. Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification--part two. Journal of Cutaneous Pathology. 33(4):261-79, 2006 Apr.
- Sigel JE. Skacel M. Bergfeld WF. House NS. Rabkin MS. Goldblum JR. The utility of cytokeratin 5/6 in the recognition of cutaneous spindle cell squamous cell carcinoma. Journal of Cutaneous Pathology. 28(10):520-4, 2001 Nov.
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