Anatomic Abstracts
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June 2012 Editors:
Although exanthematous drug eruptions of the macular and papular type are common and often cause diagnostic problems, histopathologic features are not precisely defined in the literature. The authors conducted a prospective histopathologic study of maculopapular drug eruptions in 48 patients in whom the diagnosis had been made on the basis of clinical examination, history of a known offending drug, and followup. More than one biopsy was taken in 11 patients for a total of 60 biopsy specimens. The most consistent epidermal features were mild spongiosis mainly of the lower layers (97 percent of biopsies), some hyperplasia (72 percent), a few lymphocytes (82 percent), and neutrophils (32 percent). The dermoepidermal junction revealed discrete vacuolization (97 percent), scattered lymphocytes (75 percent), and rare necrotic keratinocytes (32 percent). All cases showed a dermal perivascular inflammatory infiltrate that was superficial in 72 percent of biopsies and superficial and deep in 28 percent of biopsies. An interstitial infiltrate in the papillary dermis could be found in 93 percent and was more often patchy than lichenoid. In general, the perivascular infiltrate was mild and composed of lymphocytes (100 percent), eosinophils (60 percent), and neutrophils (50 percent). In the papillary dermis, neutrophils often outnumbered eosinophils. Clusters of neutrophils (38 percent) and eosinophils (20 percent) in the lumina of dilated, otherwise normal blood vessels were another feature. Rashes induced by anticonvulsants and anxiolytics were characterized by predominance of neutrophils and largish lymphocytes. Edema of the papillary dermis was encountered frequently (85 percent), whereas wiry collagen bundles were an exceptional finding. The authors concluded that their study defined a constellation of histopathologic findings highly suggestive of the diagnosis of exanthematous drug eruptions of the macular and papular type. Naim M, Weyers W, Metze D. Histopathologic features of exanthematous drug eruptions of the macular and papular type. Am J Dermatopathol. 2011;33(7):695–704. Correspondence information not provided.
The authors conducted a study to update the American Society of Clinical Oncology’s technology assessment guidelines on chemotherapy sensitivity and resistance assays, published in 2004. A working group reviewed data from Medline and the Cochrane Library published between Dec. 1, 2003 and May 31, 2010. The literature search yielded 11,313 new articles. The limits for “human and English” were used, and then standard American Society of Clinical Oncology search strings for randomized controlled trials, meta-analyses, guidelines, and reviews were added, yielding 1,298 articles for abstract review. Of these, only 21 articles met predefined inclusion criteria and underwent full text review. Five reports of randomized controlled trials were included for data extraction. The authors found that review of the literature did not identify any chemotherapy sensitivity and resistance assays (CSRAs) for which the evidence base is sufficient to support use in oncology practice. Use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations based on published reports of clinical trials and a patient’s health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials to evaluate these technologies remains a priority. Burstein HJ, Mangu PB, Somerfield MR, et al. American Society of Clinical Oncology clinical practice guidelines update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol. 2011;29(24):3328–3330. Reprints: American Society of Clinical Oncology at guidelines@asco.org
Immunohistochemical staining for p53 is used as a surrogate for mutational analysis in the diagnostic workup of carcinomas of multiple sites, including ovarian cancers. Strong and diffuse immunoexpression of p53 is generally interpreted as likely indicating a TP53 gene mutation. However, the immunoprofile that correlates with wild-type TP53 is not as clear. In particular, the significance of completely negative immunostaining is controversial. The authors conducted a study to clarify the relationship of the immunohistochemical expression of p53 with the mutational status of the TP53 gene in ovarian cancer. The authors analyzed 57 ovarian carcinomas (43 high-grade serous ovarian/peritoneal carcinomas, two malignant mesodermal mixed tumors [carcinosarcomas], two low-grade serous carcinomas, four clear-cell carcinomas, one well-differentiated endometrioid carcinoma, and five carcinomas with mixed epithelial differentiation) for TP53 mutations by nucleotide sequencing (exons four through nine) and subjected them to immunohistochemical analysis of p53 expression. Thirty-six tumors contained functional mutations and 13 had wild-type TP53. Five tumors were found to harbor a known TP53 polymorphism, and changes in the intron region were detected in three. Tumors with wild-type TP53 displayed a range of immunolabeling patterns, with the most common pattern showing 10 percent or fewer positive cells in six cases (46 percent). Mutant TP53 was associated with 60 percent to 100 percent positive cells in 23 cases (64 percent of cases). This pattern of staining was also seen in three cases with wild-type TP53. Tumors that were completely negative (no cells staining) had a mutation of TP53 in 65 percent of cases and wild-type TP53 in 11 percent. Combining two immunohistochemical labeling patterns associated with TP53 mutations (zero positive cells and 60 percent to 100 percent positive cells) identified a mutation in 94 percent of cases (P<.001). Immunohistochemical analysis can be used as a robust method for inferring the presence of a TP53 mutation in ovarian carcinomas. In addition to a strong and diffuse pattern of p53 expression (in more than 60 percent of cells), complete absence of p53 immunoexpression is commonly associated with a TP53 mutation. Accordingly, this latter pattern, unlike low-level expression (10 percent to 50 percent cells), should not be construed as indicative of wild-type TP53. Yemelyanova A, Vang R, Kshirsagar M, et al. Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis. Mod Pathol. 2011;4:1248–1253. Correspondence: Dr. A. Yemelyanova at ayemely1@jhmi.edu
The authors conducted a study to identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma and to examine the impact of lymph node assessment on survival. They identified, from an international multi-institutional database, 449 patients who underwent surgery for intrahepatic cholangiocarcinoma (ICC) between 1973 and 2010. They then evaluated clinical and pathologic data using univariate and multivariate analyses. Median tumor size was 6.5 cm. Most patients had a solitary tumor (73 percent) and no vascular invasion (69 percent). Median survival was 27 months, and five-year survival was 31 percent. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P<.001), multiple lesions (HR, 1.80; P=.001), and vascular invasion (HR, 1.59; P=.015). Tumor size was not a prognostic factor (HR, 1.03; P=.23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P<.001). Lymphadenectomy was performed in 248 patients (55 percent), and 74 of those patients (30 percent) had lymph node metastasis, which was associated with worse outcome (median survival: N0, 30 months versus N1, 24 months; P=.03). Although patients without lymph node metastasis could be stratified by tumor number and vascular invasion (N0; P<.001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P=.34). The authors concluded that although tumor size provided no prognostic information, tumor number, vascular invasion, and lymph node metastasis were associated with survival. N1 status adversely affected overall survival and influenced the relative effect of tumor number and vascular invasion on prognosis. Lymph-adenectomy should be strongly considered for ICC because up to 30 percent of patients will have lymph node metastasis. De Jong MC, Nathan H, Sotiropoulos GC, et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011;29(23):3140–3145. Correspondence: Dr. Timothy M. Pawlik at tpawlik1@jhmi.edu
The authors described a clinicopathologically distinct subtype of cholecystitis, the extensively calcific version of which has been presented in the clinical literature as “porcelain” gallbladder. This cholecystitis, referred to herein as hyalinizing cholecystitis (HC), is characterized by dense, paucicellular hyaline fibrosis transforming the gallbladder wall into a relatively thin and uniform band. The process diffusely effaces most of the normal structures of the gallbladder, and some cases show calcifications. To determine the clinicopathologic associations of HC, the authors systematically analyzed 4,231 cholecystectomies (606 of which had carcinoma) histopathologically and conducted a targeted search in their databases. The authors identified 96 cases of HC (1.6 percent of cholecystectomies). Patients with HC were a decade older than “ordinary” cholecystitis patients (56 versus 47; P<.001), suggesting that HC may be a long-term complication of chronic injury in some patients. Calcifications of variable amounts and degrees were identified in two-thirds of the cases. Furthermore, 10 cases showed diffuse marked calcifications and were considered separately as complete porcelain gallbladder. Thirty-eight HC cases had carcinoma with a calculated frequency of 15 percent and an odds ratio of cancer risk of 4.6. Only 42 percent of the invasive cases were associated with calcifications; none of the 10 diffusely calcific cases had carcinoma. HC-related carcinomas were challenging diagnostically. They did not form distinct masses or significant thickening (mean thickness, 2.6 mm versus 4.0 mm in ordinary adenocarcinomas; P<.002). Microscopically, they had widely scattered and bland-appearing glands embedded in the thin band of hyaline stroma of HC, commonly showing a disappearing lining, leaving behind the granular, necrotic intraluminal debris (regression) with or without calcifications, which could be the only sign of cancer in some sections. The morphologic features that allowed these glands to be recognized as malignant included their longitudinal axis parallel to the surface, irregular contours, clear cytoplasm with distinct borders, nuclear irregularities, and washed-off chromatin. Surface epithelium, if preserved (and it was not in most cases), typically showed carcinoma in situ of denuding or micropapillary types. HC-associated carcinomas, with a median survival of seven months, appeared to have a clinical course at least as aggressive as that of regular carcinomas (median survival, 12 months; P=.02). The authors concluded that HC is a distinct clinicopathologic entity that is often associated with carcinoma, and the carcinomas arising from this group are often very subtle and prone to misdiagnosis microscopically. As HC is typically devoid of epithelium, any glandular elements on the wall of HC should be regarded as suspect for carcinoma. This study also confirms recent findings in the radiology literature that it is not the complete (diffusely calcific) porcelain gallbladder that is associated with cancer. Instead, a distinct, histopathologically defined form of cholecystitis—HC with minimal or no calcifications (incomplete porcelain gallbladder)—is associated with invasive carcinoma. Therefore, imaging protocols should focus on the correlates of HC rather than fixating on calcifications. Additional studies into the pathogenesis of this process and its mechanisms of progression to carcinoma are warranted. Patel S, Roa JC, Tapia O, et al. Hyalinizing cholecystitis and associated carcinomas: clinicopathologic analysis of a distinctive variant of cholecystitis with porcelain-like features and accompanying diagnostically challenging carcinomas. Am J Surg Pathol. 2011;35(8):1104–1113. Correspondence: Dr. Volkan Adsay at nadsay@emory.edu
Approximately 25 percent of patients with breast cancer develop cutaneous metastases. Sweat gland carcinomas (SGCs) account for about 0.05 percent of all cutaneous neoplasms. Cutaneous metastases of breast carcinoma (CMBC), especially the ductal type, can be difficult to distinguish from SGCs. Treatment and prognoses for these two types of tumors differ radically, making accurate histologic diagnosis crucial. Although a few studies attempt to differentiate these entities employing immunohistochemical (IHC) studies, the authors know of no panel of IHC stains to distinguish these entities. Therefore, the authors sought to devise a panel of IHC stains to distinguish CMBC from SGC. They retrieved from the University of Pittsburgh Medical Center archives 12 cases of ductal CMBCs (11 not otherwise specified type and one basal phenotype), 11 cases of SGCs (five eccrine carcinomas, three porocarcinomas, and three microcystic adnexal carcinomas), two benign sweat gland neoplasm cases, and two primary breast cancer cases. The authors then analyzed these cases with the following IHC panel: mammaglobin, gross cystic disease fluid protein (GCDFP) 15, p63, basal cytokeratins (CK5, CK14, and CK17), androgen receptor, and PAX5. The authors found that p63 was only weakly expressed in one of 12 CMBC cases (8.3 percent), whereas it was strongly expressed in 10 of 11 SGC cases (90.9 percent; P<.001). Basal cytokeratins demonstrated a similar immunoprofile in the SGC group, with 10 of 11 cases (90.9 percent) expressing all three markers, and a variable immunoprofile in the CMBC group, with zero (CK14; P<.001) to 16.7 percent (two of 12 cases; CK5 and CK17; P<.001) expression. Mammaglobin was expressed in eight of 12 cases (66.7 percent) of CMBC. The authors concluded that together, mammaglobin, p63, and the three basal cytokeratins combined made a panel that was 100 percent sensitive and 91 percent specific in distinguishing between CMBC and SGC. Rollins-Raval M, Chivukula M, Tseng GC, et al. An immunohistochemical panel to differentiate metastatic breast carcinoma to skin from primary sweat gland carcinomas with a review of the literature. Arch Pathol Lab Med. 2011;135:975–983. Correspondence: Dr. Marian Rollins-Raval at rollinsravalma@upmc.edu
Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous tumor that is usually low grade, except for the fibrosarcomatous variant (DFSP-FS). The authors conducted a study to compare the clinicopathological, immunohistochemical, genetic, and therapeutic features of DFSP and DFSP-FS. They reviewed the clinicopathological features for 63 DFSP and 12 DFSP-FS. Immunohistochemistry and multiplex reverse transcriptase-polymerase chain reaction were carried out using formalin-fixed, paraffin-embedded tissue using specific primers for collagen type I alpha 1 (COL1A1) and platelet-derived growth factor beta (PDGFB). The authors found that DFSP-FS was associated with tumor history longer than five years (P=.009), tumor size greater than 4 cm (P=.001), more stages of modified Mohs micrographic surgery (P=.005) than DFSP, expansive subcutaneous infiltration (P=.005), muscular invasion (P=.0001), absence of CD34 staining (P=.018), p53 positivity (P=.006), and increased proliferative activity (P=.004) compared with DFSP. The COL1A1-PDGFB fusion transcript was found in 100 percent of DFSP-FS and 72 percent of DFSP. No association was found between the various COL1A1-PDGFB fusion transcripts and the different histologic subtypes. Wide local excision (2 cm) was performed in 47 percent of cases and modified Mohs micrographic surgery in 53 percent. After a mean followup of 73 months (range, 21 to 235 months), six patients had local recurrence (five DFSP and one DFSP-FS) and one patient with DFSP-FS died of the disease. The only factor related to local recurrence was type of surgery; 17 percent had wide local excision and none had modified Mohs micrographic surgery (P=.006). The authors noted that their study was retrospective and that prospective studies are necessary to confirm their results. They concluded that their results support the contention that DFSP-FS reflects tumor progression in DFSP, with larger size, particular invasive patterns, p53 expression, and increased proliferative activity. However, as with low-grade DFSP, appropriate surgery permits a tumor-free excision. COL1A1-PDGFB is a useful tool for diagnosing DFSP and, particularly, DFSP-FS. Llombart B, Monteagudo C, Sanmartin O, et al. Dermatofibrosarcoma protuberans: a clinicopathological, immunohistochemical, genetic (COL1A1-PDGFB), and therapeutic study of low-grade versus high-grade (fibrosarcomatous) tumors. J Am Acad Dermatol. 2011;65:564–575. Correspondence: B. Llombart at llombart@uv.es
The prognostic value of molecular biomarkers, microsatellite instability, DNA ploidy, and morphometric mean shortest nuclear axis in endometrial cancer is conflicting, possibly because different studies have used mixtures of histotypes, FIGO stages, and varying nonstandardized non-automated methods. The authors conducted a study in which they evaluated the prognostic value of classical prognostic factors, molecular biomarkers, microsatellite instability, DNA ploidy, and morphometric mean shortest nuclear axis in a population-based cohort of FIGO stage I endometrial endometrioid adenocarcinomas. They reviewed curettings of 224 FIGO stage I endometrial endometrioid adenocarcinoma patients and obtained clinical information, including followup, from patients’ charts. Microsatellite instability and morphometric mean shortest nuclear axis were obtained in whole tissue sections, and molecular biomarkers in tissue microarrays. DNA ploidy was analyzed by image cytometry. Univariate (Kaplan-Meier method) and multivariate (Cox model) survival analysis was performed. With a median followup of 66 months (one to 209 months), 14 (six percent) patients developed metastases. Age, microsatellite instability, molecular biomarkers (p16, p21, p27, p53, and survivin), and morphometric mean shortest nuclear axis had prognostic value. With multivariate analysis, combined survivin, p21, and microsatellite instability overshadowed all other variables. Patients in whom any of these variables had favorable values had an excellent prognosis, in contrast to those with high survivin or low p21 values (97 percent versus 78 percent survival; P<.0001; hazard ratio, 7.8). Combined high survivin and low p21 values and high microsatellite instability identified a small subgroup with an especially poor prognosis (survival rate, 57 percent; P=.01; hazard ratio, 5.6). The authors concluded that low p21 and high survivin expression are indicators of poor prognosis in FIGO stage I endometrial endometrioid adenocarcinoma, especially when high microsatellite instability occurs. Steinbakk A, Malpica A, Slewa A, et al. Biomarkers and microsatellite instability analysis of curettings can predict the behavior of FIGO stage I endometrial endometrioid adenocarcinoma. Mod Pathol. 2011;24:1262–1271. Correspondence: Dr. J. P. Baak at jpabaak@yahoo.com Anatomic pathology abstracts editors: Michael Cibull, MD, professor and vice chair, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington; Rouzan Karabakhtsian, MD, assistant professor of pathology and laboratory medicine, University of Kentucky College of Medicine; and Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill. |
