Systemic amyloidosis: unusual presentation mistaken for a recurrent scabies infection.

We report the case of a 63-year-old woman with a history of undifferentiated connective-tissue disease, polyarthritis, and bilateral carpal tunnel syndrome who presented with generalized pruritus and erythematous and excoriated papules on the trunk and extremities. Empiric scabies treatment was unsuccessful. Patch testing and T-cell receptor gene rearrangement studies were unremarkable. The patient was found to have mild interstitial lung disease and hypogammaglobulinemia. Eventually a diagnosis of primary systemic amyloidosis was made after she developed frank lingual hypertrophy despite normal initial serum protein electrophoresis and negative abdominal fat pad aspiration. Diagnosis was confirmed with lingual biopsy. This case demonstrates an unusual presentation of primary systemic amyloidosis consisting of arthritis and intense debilitating pruritus without primary skin lesions for a full year prior to diagnosis of multiple myeloma. The patient responded to treatment with chemotherapy and corticosteroids.

Immunohistochemical expression of estrogen receptors in chondrosarcomas and enchondromas.

Immunohistochemical expression of estrogen receptors alpha and beta was studied in chondrosarcomas and enchondromas and was correlated with chondrosarcoma grade, type, and dedifferentiation. Estrogen receptor alpha was studied in 37 chondrosarcomas, 10 enchondromas, and 2 extraskeletal myxoid chondrosarcomas. Estrogen receptor beta was studied in 23 chondrosarcomas, 6 enchondromas, and 2 extraskeletal myxoid chondrosarcomas. Ventana prediluted monoclonal anti-ER alpha (clone 6F11) and Biogenex prediluted polyclonal anti-ER beta were used on the Ventana ES autostainer and BenchMark XT IHC/ISH, respectively. Percent of cell staining and intensity (+, ++, or +++) was evaluated. Overall, 61% of conventional chondrosarcoma and 60% of enchondroma were positive for estrogen receptor alpha. Low-grade chondrosarcoma expressed estrogen receptor alpha more frequently than high-grade chondrosarcoma (P

Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy.

Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalian target of rapamycin (mTOR), is a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway thought to have a key role in controlling cancer growth and thus is an important target for cancer therapy. Several inhibitors of mTOR are in clinical trials, including AP23573, which is being tested on metastatic sarcomas and other tumors. We hypothesized that a marker for the activity of mTOR, phosphorylated S6 ribosomal protein, would be predictive of clinical response to the drug, that is, high tumor expression would signify better response than low expression. This was a blinded study. Of 26 patients treated, 20 remained on study, with available paraffin blocks. Fourteen patients received AP23573 alone and six patients received AP23573 in combination with adriamycin. An antibody to the phosphorylated S6 ribosomal protein was used to stain the tumors, all high-grade sarcomas. Pretreatment biopsy or resection material was tested: the original tumor (n=6) or tumor recurrence/metastasis (n=14); either of these may have been after treatment with other agents. Staining was scored for both quantity/percentage of tumor cells and intensity. Scoring was performed without knowledge of tumor response. Staining quantity could be categorized into two natural groups: high expressors (> or =20% of tumor cells, 11 cases) and low expressors (0-10% of tumor cells, 9 cases). The high-expression group had eight stable and three progressive cases (73% stable disease); the low-expression group had three stable and six progressive cases (67% progressive disease). Chi-square analysis showed statistical significance (P< or =0.05) at this initial cutoff (10%) selected blindly. The level of phosphorylated S6 ribosomal protein expression was predictive of early tumor response to the mTOR inhibitor, suggesting that this is a promising new predictive sarcoma marker for targeted mTOR inhibitor therapy.

Angiostatin receptor annexin II in vascular tumors including angiosarcoma.

Inhibitors of angiogenesis, such as angiostatin, are increasingly used for targeting the tumor neovasculature and have had mixed success. Annexin II (ANX2), a 36KDa calcium and phospholipid binding protein, is a cell surface receptor for angiostatin. We hypothesized that, like normal vascular endothelium, vascular neoplasms would express ANX2, implying the potential usefulness of angiostatins in the therapy of this family of soft tissue tumors. Thirty-eight (38) vascular tumors tested included: hemangiomas - capillary [4], cavernous [6], lobular capillary [6], intramuscular hemangioma [3], spindle cell [1], and epithelioid hemangioma [4]; epithelioid hemangioendothelioma [3]; angiosarcoma [7], 4 of which were epithelioid; and angiolipomas [4]. ANX2 antibody (Zymed) was used (1/50 dilution, Ventana ES autostainer). Reactivity location (cytoplasmic, nuclear, membrane), intensity (1+/2+/3+), and quantity (focal, diffuse) was recorded. ANX2 was expressed in 97% of cases (37/38); mostly diffuse [35/37] and focal in 2 cases. Staining was strong (2+ or 3+) in 87%, and 1+ in 5/37 (14%), all benign tumors. Location was mostly cytoplasmic and membranous; no nuclear staining was seen. Both endothelium and pericytes were positive. Epithelioid angiosarcomas showed predominantly membranous staining. To our knowledge this is the first demonstration of an angiostatin receptor (ANX2) in vascular endothelial tumors including angiosarcoma. Diffuse and strong reactivity signified the absence of any down-regulation of ANX2 in both benign and malignant tumors. ANX2 reactivity may be the basis of treatment for a variety of benign tumors, especially in pediatric patients, and may offer a new and potentially less toxic therapy for angiosarcoma.

p16 expression in keratoacanthomas and squamous cell carcinomas of the skin: an immunohistochemical study.

CONTEXT: Distinguishing between keratoacanthoma (KA) and squamous cell carcinoma (SCC) is not an uncommon histologic diagnostic dilemma. OBJECTIVE: To determine if p16 expression is useful in the differential diagnosis of SCC and KA. DESIGN: We studied the expression of p16 by immunohistochemistry in 24 KAs, 24 infiltrating SCCs of the skin, 4 histologically indeterminate lesions, and 8 nonmalignant keratoses. RESULTS: A range of immunohistochemical p16 expression was seen in KAs and SCCs in terms of the thickness of lesional staining and the percentage of cells staining. No significant difference in measures of p16 expression was identified among the KAs, the SCCs, the indeterminate lesions, or the benign keratoses. CONCLUSIONS: These findings suggest that p16 is not a useful marker to distinguish between KA and SCC, supporting the similarity between the 2 lesions; p16 alterations appear to play a role in the pathogenesis of both KA and SCC.

Giant cell tumors: inquiry into immunohistochemical expression of CD117 (c-Kit), microphthalmia transcription factor, tartrate-resistant acid phosphatase, and HAM-56.

CONTEXT: Osteoclast-like giant cells (GCs) in giant cell tumors (GCTs) are thought to derive from a monocyte-macrophage lineage. Microphthalmia transcription factor (MITF) is necessary for osteoclast gene expression and tartrate-resistant acid phosphatase (TRAP) activation; c-Kit plays a role in regulation of MITF. OBJECTIVE: To gain insight into the differentiation of GCTs of bone (GCTBs) and GCTs tendon sheath (GCTTSs) by investigating immunohistochemical staining for c-Kit, MITF, TRAP, and HAM-56 in the GCs and stroma. DESIGN: Immunoreactivity for CD117 (c-Kit), MITF, TRAP, and HAM-56 was studied in 35 GCTBs, 15 GCTTSs, and 5 foreign-body GC controls. RESULTS: Across tumors, MITF and TRAP but not c-Kit were generally expressed in GCs; TRAP was variably expressed in stromal cells. The MITF was expressed more consistently in stromal cells of GCTTSs than GCTBs (P < .001). The GCTBs showed more intense MITF stromal (P < .001) and TRAP GC staining (P = .04) than GCTTSs. HAM-56 staining by stromal cells was associated with MITF stromal staining (r2 = 0.6, P < .001). CONCLUSIONS: Results suggest that MITF and TRAP are expressed during osteoclast differentiation and that a proportion of mononuclear cells in GCTs express the macrophage marker HAM-56. Both GCTBs and GCTTSs show similar patterns of immunohistochemical expression.

Tyrosinase expression in malignant melanoma, desmoplastic melanoma, and peripheral nerve tumors.

CONTEXT: Pathologists may encounter problems in the differential diagnosis of malignant melanoma, spindle and epithelioid neoplasms of peripheral nerves, and fibrohistiocytic tumors. Tyrosinase has been demonstrated to be a sensitive marker for melanoma. OBJECTIVE: To determine the specificity of tyrosinase expression in the differential diagnosis of melanoma, desmoplastic melanoma, and peripheral nerve sheath tumors. DESIGN: Immunoreactivity for tyrosinase, HMB-45 (anti-gp100 protein), S100 protein, CD34, and vimentin was studied in 70 tumors, including 15 melanomas (5 desmoplastic, 4 amelanotic, 6 melanotic), 13 malignant peripheral nerve sheath tumors; 10 schwannomas (1 pigmented), 12 neurofibromas (4 pigmented), and 20 fibrohistiocytic tumors (10 dermatofibrosarcoma protuberans and 10 dermatofibromas). Microwave-based antigen retrieval was performed in 10mM citrate buffer, pH 6.0, for 20 minutes at 121 degrees C. RESULTS: All melanomas demonstrated positive immunostaining for tyrosinase, HMB-45, and S100 protein. Immunoreactivity for HMB-45 was generally stronger than that for tyrosinase in amelanotic lesions and significantly stronger in 1 of the desmoplastic lesions. The 4 pigmented neurofibromas were focally positive for tyrosinase, but did not stain for HMB-45. The pigmented schwannoma was focally positive for both tyrosinase and HMB-45. The malignant peripheral nerve sheath tumors, dermatofibrosarcoma protuberans, and dermatofibromas were nonreactive for tyrosinase and HMB-45. CONCLUSIONS: Our results support the sensitivity of tyrosinase expression and demonstrate the relative specificity of tyrosinase as a marker for melanocytic lesions, including desmoplastic melanoma, although pigmented peripheral nerve tumors may demonstrate focal positive staining. Immunoreactivity for tyrosinase and HMB-45 may have been enhanced by the microwave-based antigen-retrieval technique used in this study.