Desmoplastic melanoma of the head and neck: histopathologic and immunohistochemical study of 28 cases

Studies of the immunohistochemical profiles and clinical course of desmoplastic melanoma have produced conflicting results. We identified 28 cases of desmoplastic melanoma after a search of our files for spindle cell neoplasms of the head and neck from 1960 through 1995. The 17 male (61%) and 11 female (39%) patients averaged 65 years of age. The cheek was the most common location (12 cases, 43%). The average length of follow-up was 5 years. Overall 5-year survival rate was 46%. Melan A and tyrosinase positivity (P = 0.0195), smooth muscle actin positivity (P = 0.0328), tumor size (P = 0.0297), and tumor thickness (P = 0.0419) were significantly associated with local progression-free survival. No histologic or immunohistochemical marker was associated with overall or metastasis-free survival.     

Gastrointestinal stromal tumors (GISTs): CD117, DOG-1 and PKCθ expression. Is there any advantage in using several markers?

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Expression of CD117, DOG1 and PKCθ was investigated immunohistochemically in a series of 99 paraffin-embedded GISTs in order to determine the sensitivity and diagnostic value of these markers. KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were amplified by PCR and sequenced. A total of 94/99 (94%) GISTs stained positive for CD117, 81/99 (82%) for PKCθ and 90/99 (91%) for DOG-1. A significant correlation was noted between CD117 and DOG-1 expression (p=0.0001). All three markers were expressed in 74% (73/99) of GISTs. Of the five CD117-negative cases, two were PKCθ-negative/DOG1-negative and had mutations in KIT exon 11. Two were PKCθ-positive/DOG1-positive and had mutations in PDGFRA (one each in exons 12 and 18), and one was DOG1-negative/PKCθ-positive, with a PDGFRA exon 18 mutation. The most sensitive marker was CD117, followed by DOG-1 and PKCθ. Although PKCθ was less sensitive, and its staining is more challenging and difficult to interpret, the use of this marker is highly recommended, particularly in CD117-negative/DOG-1-negative GISTs.     

Cytologic features of metastatic and recurrent melanoma in patients with primary cutaneous desmoplastic melanoma

Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by malignant spindle cells associated with prominent fibrocollagenous stroma. Primary melanomas may be entirely desmoplastic ("pure" DM) or exhibit a desmoplastic component admixed with a nondesmoplastic component ("combined" DM). The cytologic features of only 5 cases of DM have been reported previously. Fine-needle biopsy (FNB) specimens from 20 recurrent or metastatic lesions in patients with cutaneous DM and 20 recurrent or metastatic lesions from patients with primary cutaneous non-DM were examined and compared. FNB specimens of patients with DM were less cellular (P = .009) and less often exhibited intranuclear cytoplasmic invaginations (P = .008) and mitotic figures (P = .006) than specimens from patients with non-DM. "Combined" DMs were more commonly composed of epithelioid cells (P = .017) and less often contained bizarre/giant tumor cells (P = .010) than did "pure" DMs. Recurrent and metastatic DM has a range of cytologic appearances. Awareness of the cytologic features and careful clinicopathologic correlation will assist in accurate FNB diagnosis.     

Lymphoepithelioma-like carcinoma of the urinary tract: a clinicopathological study of 30 pure and mixed cases.

We studied 28 cases of lymphoepithelioma-like carcinoma of the bladder, one case in the renal pelvis, and one in the urethra. The mean age of the patients was 67.6 years with 21 (70%) males. Seventeen cases (56.7%) were pure with the remaining mixed with other patterns of carcinoma, including invasive urothelial carcinoma (n=10), invasive adenocarcinoma (n=3), and squamous cell carcinoma (n=2). The surface demonstrated carcinoma in situ (CIS) in six cases, noninvasive high-grade papillary urothelial carcinoma in three cases, and in situ adenocarcinoma in one case. In 19/30 (66%) cases, there was a heavy lymphocytic infiltrate and in the remaining 11/30 (34%) cases a mixed inflammatory infiltrate. None of the 26 cases labeled for EBV-encoded RNA by in situ hybridization. Tumor stages at presentation were: seven cases T1 (23%); 14 cases T2 (47%); seven cases T3 (23%); and two cases T4 (7%). Treatment consisted of radical cystectomy in 13/30 cases (43%); partial cystectomy in 4/30 cases (13%); nephrectomy in one case (3%), and transurethral resection often followed by radiation or chemotherapy in 12/30 (40%) cases. The mean follow up for patients without progression was 31 months. Eight of 27 cases with follow-up (30%) cases had tumor recurrence, with seven patients having metastases. In cases treated with cystectomy, the 5-year actuarial recurrence-free risk was 59% (62 and 57%, for pure and mixed cases, respectively). Lymphoepithelioma-like carcinoma, whether in pure or mixed form, has a similar prognosis to ordinary urothelial carcinoma when treated by cystectomy. Of the three pure cases treated by chemotherapy, two were free of disease at 4 and 65 months and the third had recurrent disease at 17 months. Given the association of lymphoepithelioma-like carcinoma with urothelial carcinoma in 47% of our cases and its propensity for multifocality, partial cystectomy would typically be ill advised for lymphoepithelioma-like carcinoma.     

Vemurafenib

Vemurafenib is a first-in-class, small molecule BRAFV600E inhibitor. It is indicated in the US for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation, and in the EU as monotherapy in adults with BRAFV600 mutation-positive unresectable or metastatic melanoma. Oral vemurafenib improved overall survival (OS) [co-primary endpoint] in patients with unresectable, previously untreated, BRAFV600E mutation-positive, stage IIIC or IV melanoma, according to the results of a randomized, open-label, multicenter, phase III trial (BRIM-3). With vemurafenib versus dacarbazine, the risk of death was significantly reduced by 63% in the interim OS analysis, and by 56%, 38%, and 30% in subsequent updated OS analyses. The median OS duration was 13.6 months in vemurafenib recipients and 9.7 months in dacarbazine recipients in the most recent OS analysis. In the phase III trial, progression-free survival (PFS) [co-primary endpoint] was also significantly improved in vemurafenib versus dacarbazine recipients (median PFS of 5.3 vs 1.6 months), with a significant reduction in the risk of death or disease progression of 74% in the final PFS analysis. Vemurafenib was also associated with a high overall response rate in patients with previously treated, BRAFV600 mutation-positive, stage IV melanoma, according to the results of a noncomparative, multicenter, phase II trial. Patients had received at least one prior systemic treatment for advanced disease (excluding BRAF inhibitors other than sorafenib or MEK inhibitors). The overall response rate (primary endpoint) was 53% (complete response rate of 6% and partial response rate of 47%), with a median duration of response of 6.7 months, and a median OS duration of 15.9 months. Oral vemurafenib was generally well tolerated in patients with metastatic melanoma, with cutaneous adverse events among the most commonly occurring adverse events. Cutaneous squamous cell carcinoma and/or keratoacanthoma were reported in 18% of vemurafenib recipients in the BRIM-3 trial.     

Immunohistochemical characterization of atypical fibroxanthoma and dermatofibrosarcoma protuberans.

Atypical fibroxanthoma (AFX) and dermatofibrosarcoma protuberans (DFSP) have generated undue interest regarding their histogenesis, biological behavior, and differentiation from other forms of spindle cell tumors of the skin, including spindle cell squamous carcinomas and desmoplastic melanomas. To identify characteristic immunophenotypes, 12 AFXs and 15 DFSPs were examined with a panel of antibodies against cytokeratin; vimentin; desmin; proteolytic enzymes (alpha-1-antitrypsin and alpha-1-antichymotrypsin); melanoma-associated antigens defined by HMB-45, HMB-50, and NKI/C3; muscle-specific actin (HHF-35); and S-100 protein. The staining patterns of these two tumors were nearly identical. All cases tested negative for cytokeratin, desmin, and S-100 protein and strongly positive for vimentin. Six (50%) AFXs and 12 (80%) DFSPs tested focally positive for muscle-specific actin. None of the cases were reactive with melanoma antibodies HMB-45 and HMB-50; NKI/C3 strongly stained 26 of 27 tumors. Compared to HMB-45 and HMB-50, NKI/C3 cross-reacted with nonmelanocytic neoplasms. Two AFXs stained for alpha-1-antitrypsin and alpha-1-antichymotrypsin. This study confirms (1) the immunophenotypic similarity of AFX and DFSP, (2) the presence of myofibroblastic differentiation in both tumors, as reflected by HHF-35 staining, and (3) that AFX and DFSP are easily distinguished from spindle cell squamous carcinoma and desmoplastic melanoma by the absence of cytokeratin, HMB-45, and HMB-50 staining.     

Clinical and pathological features of metastases of primary cutaneous desmoplastic melanoma

Murali R, Zannino D, Synnott M, McCarthy S W, Thompson J F & Scolyer R A
(2011) Histopathology  58 , 886–895
Clinical and pathological features of metastases of primary cutaneous desmoplastic melanoma Aims: Primary cutaneous desmoplastic melanoma (DM) may be entirely desmoplastic [‘pure’ DM (pDM)] or exhibit a desmoplastic component admixed with a non‐desmoplastic component [‘combined’ DM (cDM)]. Our aim was to describe the histological features of metastases of primary DM and to determine whether they were predictive of outcome. Methods: The effect of clinicopathological parameters on overall survival (OS) was analysed, and the correlation between histological features of the primary melanoma and metastases was studied in patients with metastatic DM. Results: Twenty‐six patients (18 males; eight females) developed 50 metastases in sentinel nodes (13; 26.0%), regional nodes (10; 20.0%), skin (14; 28.0%), and distant sites (13; 26.0%). The cellular composition of metastases correlated with that of the corresponding primary tumours. Time to development of first non‐sentinel lymph node metastasis was shorter in cDM than in pDM (median 11.2 versus 24.9 months, P = 0.075). The only independent predictors of poorer OS were cDM type [hazard ratio 6.17, 95% confidence interval (CI) 1.61–23.81, P = 0.008] and male sex (hazard ratio 5.98, 95% CI 1.34–26.66, P = 0.019). Conclusions: The cellular composition of primary DM correlates with that of metastatic DM and with outcome. It is important to consider the possibility of primary or metastatic DM when examining tumours composed of spindle cells.     

Sequence analysis and high-throughput immunhistochemical profiling of KIT (CD 117) expression in uveal melanoma using tissue microarrays

We aimed to immunohistochemically examine the expression of KIT (CD 117) in human posterior uveal melanoma and to analyze KIT-positive tumors for gene mutations. Brought into a tissue microarray (TMA) format were 101 formalin-fixed, paraffin-embedded posterior uveal melanomas. Immunhistochemistry was performed using the polyclonal anti-CD117 antibody from Dako (A4502). In ten selected KIT-positive tumors, exons 2, 8, 9, 11, 13 and 17 were sequenced. Of the 101 cases, 89 (88%) could be evaluated on the TMAs. Immunohistochemistry for CD 117 was weakly positive in 5 cases (6%), moderately positive in 10 cases (12%) and strongly positive in 57 cases (69%). No KIT mutations were detected in the analyzed exons. In conclusion, human posterior uveal melanoma frequently expresses CD117 at high levels. Although KIT mutations could not be found, it appears justified to investigate the utility of imatinib mesylate in the treatment of these patients.     

Desmoplastic tumour-associated stroma versus neural tissue in central nervous system metastasis: effects of different microenvironments on tumour growth

Chang K‐C, Lu Y‐C, Lin M‐J, Chen H‐Y & Jin Y‐T
(2011) Histopathology 59 , 31–39 Desmoplastic tumour‐associated stroma versus neural tissue in central nervous system metastasis: effects of different microenvironments on tumour growth Aims: Interactions between tumour cells and extracellular matrix (ECM) are critical in the metastatic cascade. We compared effects of desmoplastic stroma versus neural tissue on central nervous system (CNS) metastasis. Methods and results: Using integrins (ECM receptors), ECM (fibronectin, laminin and collagen IV) and CD31 and vascular endothelial growth factor (VEGF) for angiogenesis, this study examined immunohistochemically 69 consecutive cases of CNS metastases. In contrast to low‐level expression in tumour‐embedded neural tissue, ECM [fibronectin (71%), laminin γ‐1 (79%) and collagen IV (92%)] and CD31‐positive microvascular densities (33 versus 4 vessels/field) were significantly richer in desmoplastic tumour stroma, which was present in 90% (53 of 59) of carcinomas, 100% (five of five) of malignant melanomas and 100% (two of two) of sarcomas. Collagen IV expression in tumour stroma was correlated with the expression of fibronectin (P = 0.013) and laminin (P = 0.034) and with infiltrative tumour edges (P = 0.005); fibronectin‐positive tumour stroma was correlated with a higher microvascular density (P = 0.015). In addition, tumour cells expressed integrins (～75%) and laminin (84%) more frequently than VEGF (23%), and tumour expression of laminin was correlated with the presence of desmoplastic stroma (P = 0.006). Interestingly, laminin‐positive tumour stroma was a worse prognosticator (P = 0.072). Conclusions: ECM‐ and vascular‐rich stroma is important in tumour growth, which underlies therapeutic strategies targeting tumour‐associated stroma.     

Immunophenotypic analysis of myeloperoxidase-negative leukemia cutis and blastic plasmacytoid dendritic cell neoplasm

Myeloid leukemia cutis (LC) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are morphologically indistinguishable malignancies that frequently manifest in the skin. Separating myeloperoxidase-negative LC from BPDCN may be particularly challenging. We identified a panel of immunohistochemical stains to distinguish myeloid LC (23 cases) from BPDCN (12 cases): myeloperoxidase, which stained 7 cases (30%) of LC and 0 cases (0%) of BPDCN; CD56, which stained 12 cases (52%) of LC and all 12 cases (100%) of BPDCN; CD4, which stained 2 cases (9%) of LC and all 12 cases (100%) of BPDCN; CD123, which stained 4 cases (17%) of LC and 10 cases (83%) of BPDCN; and Tcl-1, which stained 2 cases (9%) of LC and 9 (82%) of 11 cases of BPDCN. It is interesting that CD33 was not helpful; it stained 18 (78%) cases of LC and 11 cases (92%) of BPDCN. Our results indicate that a panel that includes CD4, CD56, CD123, and Tcl-1 can appropriately distinguish between these 2 entities.     

中性内肽酶及移动相关蛋白-1在恶性黑色素瘤中的表达及意义

目的探讨中性内肽酶（CD10）及移动相关蛋白-1（CD9）在恶性黑色素瘤中的表达及其临床意义。方法采用免疫组织化学SP法检测48例原发性皮肤恶性黑色素瘤（CMM）及23例转移性恶性黑色素瘤（转移性MM）中CD10、CD9蛋白表达水平,并以23例色素痣作为对照。结果（1）CD10在转移性MM、CMM及色素痣中的表达依次减弱,差异均有统计学意义（P〈0．01）,CD9在转移性MM中的表达较CMM显著降低（P〈0．05）;（2）CD9和CD10在恶性黑色素瘤中的表达水平呈负相关（CMM：r=-0.40,P=0.005;转移性MM：r=-0．44,P=0．034）;（3）CD10和CD9在CMM中的表达与病理学类型、淋巴结转移和浸润深度相关;（4）CD10、CD9在CMM间质成纤维细胞中的表达呈负相关（r=-0．43,P=0．007）,且与肿瘤浸润深度明显相关,与淋巴结转移有一定相关性。结论（1）CD10及CD9与恶性黑色素瘤的浸润、转移密切相关,两者在此过程中可能起相互拮抗作用;（2）肿瘤细胞CD10、CD9的表达对CMM的辅助诊断及预后评估具有重要的临床意义;（3）肿瘤间质成纤维细胞中CD10、CD9的表达在CMM的发展过程中亦可能扮演着重要角色。     

Clusterin is widely expressed in systemic anaplastic large cell lymphoma but fails to differentiate primary from secondary cutaneous anaplastic large cell lymphoma

A recent study by Wellmann et al (Blood. 2000;96:398-404) detected clusterin expression in all 36 systemic anaplastic large cell lymphomas (ALCLs) tested, but not in any of 9 primary cutaneous ALCLs. Our purpose was to confirm the diagnostic usefulness of clusterin in systemic ALCL and to evaluate its efficacy in distinguishing primary cutaneous ALCL from secondary skin involvement by systemic ALCL. We examined clusterin expression by paraffin immunohistochemical analysis in 41 systemic ALCLs (18 ALK-1+ and 23 ALK-1-), 9 primary cutaneous ALCLs, and 4 secondary cutaneous ALCLs. Clusterin was positive in 95% of systemic ALCLs (39/41), including 100% (18/18) of the ALK-1+ cases and 91% (21/23) of the ALK-1- cases. Five (56%) of 9 primary and 3 (75%) of 4 secondary cutaneous ALCLs were positive for clusterin. Our observations confirm the diagnostic usefulness of clusterin in systemic ALCL, especially in the ALK-1- cases. However, our data fail to demonstrate its value in distinguishing primary from secondary cutaneous ALCL.     

Immunohistochemical heterogeneity of breast carcinomas negative for estrogen receptors, progesterone receptors and Her2/neu (basal-like breast carcinomas).

Basal breast carcinomas triple negative for estrogen receptors, progesterone receptors and Her2/neu breast carcinomas are more aggressive than conventional neoplasms. We studied 64 cases with immunohistochemistry, using 23 antibodies, to characterize diverse pathological pathways. A basal cytokeratin was identified in 81% of tumors and vimentin was identified in 55%. The mean Ki67 index was 46% (range, 10-90%). Coincident expression of p50 and p65, which suggests an active nuclear factor-kappaB factor, was present in 13% of neoplasms. Epithelial growth factor receptor (EGFR), insulin-like growth factor-I receptor (IGF-IR) or c-kit (CD117) was identified in 77% of tumors. Loss of protein tyrosine phosphatase was found in 14%, whereas Akt activation was present in 28%. Several differences were identified between two subtypes of basal breast carcinomas: the pure variant (negative S-100 and actin) was more frequently associated with 'in situ carcinoma' (P=0.019) and pBad overexpression (P=0.098), whereas the myoepithelial variant (positive S-100 or actin) showed more frequent tumor necrosis (P=0.048), vimentin expression (P=0.0001), CD117 expression (P=0.001) and activated caspase-3 (P=0.089). IGF-IR could be as important as EGFR for the growth of these neoplasms. Basal cell carcinoma has at least two subtypes with distinct microscopic and immunohistochemical features.     

Immunohistochemical and genetic analysis of Chinese nasal natural killer/T-cell lymphomas

Nasal natural killer/T-cell lymphoma (N-NK/T-L) is prevalent in China. To further characterize this neoplasm, 36 cases of N-NK/T-L from 304 cases of malignant lymphomas in the north China area were investigated by histopathology, immunophenotyping, and genomic analysis of c-kit, in comparison with 11 cases of B-cell lymphoma (BCL) at the same region and 5 cases of nodal peripheral T-cell lymphoma (PTCL) (unspecified). Histopathologically, N-NK/T-L was characterized by coagulative necrosis, inflammatory background, and angiodestructive growth pattern. In 36 cases of N-NK/T-L, 27 cases (75.0%) were stained for CD45RO and 25 (72.2%) for CD3epsilon. Thirty cases (83.3%) were positive for T-cell intracellular antigen-1, 22 (61.1%) for granzyme B, 18 (50.0%) for CD56, and 11 (30.6%) for CD30, whereas none was positive for CD117. All 5 cases of PTCL displayed positive staining for CD45RO and T-cell intracellular antigen-1, 3 cases for CD3epsilon, but only 1 case for granzyme B. All 11 BCLs presented positive staining for CD20 and CD79a but negative for other antibodies. A significant relationship was observed between neoplastic cells pleomorphism and granzyme B expression (P < .05). Despite the fact that all cases were negative for CD117 staining, genomic sequences of c-kit 11 and exon 17 sequencing showed that 8 (26%) of 31 cases N-NK/T-L proved to contain genomic mutations, including 4 cases in exon 11 and 4 in exon 17. For the control group, only 1 (9%) of 11 BCLs and 1 (20%) of 5 cases of PTCL were detected to harbor mutations in exon 11. All mutations detected in 3 groups were missense by base substitution, and codes 571, 572, and 821 were hot spots. The results suggested that, in addition to histological features and routine immunophenotyping, granzyme B expression should be a more reliable marker in correct diagnosis of N-NK/T-L, and genetic analysis of c-kit mutation should be helpful in the diagnosis of this tumor.     

Posttransplant thrombopoiesis predicts survival in patients undergoing autologous hematopoietic progenitor cell transplantation.

The frequency and clinical significance of secondary thrombocytopenia following initial engraftment in autologous hematopoietic progenitor cell transplantation (HPCT) is unknown. An institutional review board approved retrospective study of thrombopoiesis was performed in 359 patients transplanted with autologous blood (97%) or marrow (3%) who achieved platelet engraftment to >50,000/microL. Idiopathic secondary posttransplant thrombocytopenia (ISPT) was defined as >50% decline in blood platelets to <100,000/microL in the absence of relapse or sepsis. ISPT occurred at a median of day +35 posttransplant in 17% of patients. Patients with ISPT had similar initial platelet engraftment (median 17 days) versus non-ISPT patients (18 days; P=NS) and recovered platelet counts (median 123,00 K/microL) by day 110 posttransplant. Four factors were independently associated with post-transplant death in a multivariate model: disease status at transplant; the number of prior chemotherapy regimens, failure to achieve a platelet count of >150,000/microL posttransplant, and the occurrence of ISPT. A prognostic score was developed based upon the occurrence of ISPT and posttransplant platelet counts of <150,000/microL. Survival of patients with both factors (n=25) was poor (15% alive at 5 years); patients with 1 factor (n=145) had 49% 5-year survival; patients with 0 factors (n=189) had 72% 5-year survival. Patients who failed to achieve a platelet count of >150,000/microL received significantly fewer CD34+ cells/kg (P<.001), whereas patients with ISPT received fewer CD34+CD38- cells/kg (P=.0006). The kinetics of posttransplant thrombopoiesis is an independent prognostic factor for long-term survival following autologous HPC. ISPT and lower initial posttransplant platelet counts reflect poor engraftment with long-term and short-term repopulating CD34+ hematopoietic stem cells, respectively, and are associated with an increased risk of death from disease relapse.     

Melanocytic lesions associated with dermatofibromas: a spectrum of lesions ranging from junctional nevus to malignant melanoma in situ.

Dermatofibromas are common lesions that are often associated with epidermal hyperplasia and basal layer hyperpigmentation. A single case of lentiginous melanocytic hyperplasia overlying a dermatofibroma has been reported, however, nevi and melanoma have to the best of our knowledge, not been previously reported. We present 14 cases of melanocytic lesions associated with dermatofibromas. The clinical data and hematoxylin- and eosin- stained sections were obtained and formalin-fixed, paraffin-embedded tissue was immunostained with antibodies against S-100, Mart-1, Factor XIIIa, and CD117. There were nine females and five males ranging in age from 30 to 64 years and anatomic sites included back (five), arm (six), flank (two), and leg (one). The clinical diagnosis ranged from dermatofibroma to desmoplastic melanoma. Histologically, the melanocytic lesions included junctional, compound, and dermal nevi, and malignant melanoma in situ. In four cases the dermal component appeared to merge with the dermatofibroma. In the case of the melanoma in situ, the dermatofibroma abutted the epidermis. Immunohistochemically, the melanocytic lesions were S-100/ Mart-1+, FXIIIa-, and the dermatofibromas were S-100/Mart-1-, FXIIIa+. Melanocytic neoplasia may appear in association with dermatofibromas. The fibrohistiocytic proliferation may be misinterpreted as a spindle or pleomorphic melanocytic process. Awareness of this association will aid in the correct diagnosis, and immunohistochemical studies will help in the differentiation of these two cell populations.     

HMB-45, S-100, NK1/C3, and MART-1 in metastatic melanoma

The diagnosis of melanoma metastatic to lymph node remains a difficult problem given its histological diversity. We examined the staining patterns of S-100, NK1/C3, HMB-45, and MART-1 (DC10) in melanoma metastases to lymph nodes. Immunohistochemical stains were performed on tissue sections of 126 formalin-fixed lymph nodes from 126 patients with an established diagnosis of metastatic melanoma. A total of 98% of cases (123 of 126) stained positive for S-100, 93% (117 of 125) stained positive for NK1/C3, 82% (103 of 126) stained positive for MART-1, and 76% (95 of 125) stained positive for HMB-45. The distribution and intensity of staining varied among these markers. A diffuse staining pattern, defined as >50% of tumor cells stained, was observed in 83% of MART-1-positive cases but in only 56% of S-100-positive cases, 48% of NK1/C3-positive cases, and 34% of HMB-45-positive cases. A maximally intense signal was almost always observed for MART-1 (83% of positive cases) but was rarely observed for NK1/C3 (20%). S-100 and HMB-45 showed maximally intense staining in 50% and 54% of cases, respectively. S-100 and NK1/C3 stained both histiocytes and melanocytes, whereas MART-1 and HMB-45 stained only melanocytes. Seventy-eight cases (63%) stained positive for all 4 markers, 17 cases (14%) stained for all markers except HMB-45, 13 cases (10%) stained for all markers except MART-1, 6 cases (5%) stained only with S-100 and NK1/C3, 4 cases (3%) stained only with S-100 and HMB-45, and 2 cases stained for all markers except S-100. One case each stained for the following: only S-100, only S-100 and HMB-45, and all markers except NK1/C3. One case exhibited absence of staining for any of these markers. We demonstrate that lymph node metastases of melanoma are heterogeneous with regard to tumor marker expression. S-100 and NK1/C3 were the most sensitive stains for detecting metastatic melanoma; however, they both also stain other nontumor cells in lymph nodes. MART-1 did not stain histiocytes and exhibited a more frequently intense and diffuse staining pattern than NK1/C3. HMB-45 was less sensitive and demonstrated less diffuse staining than MART-1.     

Inflammatory aortic aneurysm: possible manifestation of IgG4-related sclerosing disease

In this study, we investigate the hypothesis that IgG4-related autoimmune reaction is involved in the formation of inflammatory aortic aneurysms (IAA). We obtained 23 cases of IAA and 11 cases of atherosclerotic aortic aneurysms (AAA) as control group. We evaluated the expression of IgG4 in both IAA study cases and AAA control cases. In addition, immunohistochemical expression of C-Kit, CD21, CD34, S-100 protein, SMA, vimentin, p53, beta-catenin, and ALK-1, and EBV-LMP1 expression by in situ hybridization were performed only in IAA cases. Of the 23 patients, 20 were males and 3 were females (M: F ratio 6.7:1); age ranged from 43 to 81 years (average 64.3 years). Histologically, all 23 cases of IAA formed a mass that displayed inflammatory myofibroblastic tumor-like features. All lesions stained strongly and diffusely for vimentin and SMA (100%); 17 stained strongly and focally for CD34 (74%); and all were negative for C-Kit, CD21, S-100 protein, p53, beta-catenin, EBV-LMP1, and ALK-1. The numbers of infiltrating IgG4-positive plasma cells in IAA cases exceed that of AAA cases. Score 3 (>50 plasma cells/one 40X field) of IgG4-positive plasma cells was only seen in IAA cases (13/23, 57%), whereas none of the 11 cases of AAA showed score 3 IgG4-positive plasma cells (P=0.0018, Fischer‘s exact test). Our findings suggest that IAA may be an aortic manifestation of the IgG4-related sclerosing disease. The high number of positive plasma cells, >50 plasma cells/one 40X field is more specific for the IAA than for AAA; however, lesser number can be seen in both IAA and AAA patients.     

Immunophenotyping of non-Hodgkin's lymphoma. Correlation with relapse-free survival

In a retrospective analysis the authors studied the relation between the immunologic phenotype of B-cell non-Hodgkin's lymphoma (NHL) and disease-free survival. The phenotype included immunoglobulin isotypes; B-cell maturation/differentiation antigens of clusters of differentiation CD9, CD10, CD19-24, CD37, CD38; T-lymphocyte antigens in CD5-7; HLA-DR; peanut agglutinin binding capacity; terminal deoxynucleotidyl transferase; the activation marker CD25 (interleukin-2 receptor); and the proliferation marker transferrin receptor. The phenotype and clinical data were available for 109 patients. Two patients underwent bone marrow transplantation, and 15 patients (with low or intermediate grade NHL) did not receive treatment intended to achieve complete remission. These 17 cases were excluded from the analysis. For individual markers, CD23 expression was associated with a longer actuarial disease-free survival (50% survival in CD23-positive cases was 40 months; and in CD23-negative cases, 16 months; P = 0.01). Among the total study population of 92 patients, this finding applied in particular to those with a low-grade malignancy according to the Kiel classification (P = 0.03). In high-grade NHL (Kiel classification) the absence of CD38 or presence of CD24 on tumor cells correlated with a higher degree of disease-free survival (P values 0.009 and 0.04, respectively). For a combination of five CD markers associated with stages in physiologic B-lymphocyte maturation/differentiation (CD9, CD10, CD21-23), the lowest measure of disease-free survival was observed where NHLs were at an immature stage, and the greatest extent of survival where NHLs were associated with a resting B-cell stage (P = 0.006). These statistical significances aside, the detailed immunologic phenotyping has relatively little prognostic value when compared with that of the malignancy grade assessed by conventional histopathology.