CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Tumor budding in rectal cancer biopsies before neoadjuvant therapy
The authors conducted a study to correlate intra-tumoral budding in pretreatment rectal cancer biopsies with pathological response to neoadjuvant chemoradiotherapy and long-term outcome. Data from a prospectively maintained database were acquired from patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy. Pretreatment rectal biopsies were retrospectively reviewed for evidence of intra-tumoral budding. Multivariate logistic regression was used to identify factors contributing to cancer-specific death, expressed as hazard ratios with 95 percent confidence intervals. Of 185 patients with locally advanced rectal cancer, 89 met the eligibility criteria, of whom 18 (20 percent) exhibited budding in a pretreatment tumor biopsy. Intra-tumoral budding predicted a poor pathological response to neoadjuvant chemoradiotherapy (higher ypT stage, P=0.032; lymph node involvement, P=0.018; lymphovascular invasion, P=0.004; and residual poorly differentiated tumors, P=0.005). No patient with intra-tumoral budding exhibited a tumor regression grade 1 or complete pathological response, providing 100 percent specificity and positive predictive value for nonresponse to neoadjuvant chemoradiotherapy. Intra-tumoral budding was associated with a lower disease-free five-year survival rate (33 versus 78 percent; P<0.001), cancer-specific five-year survival rate (61 versus 87 percent; P=0.021), and predicted cancer-specific death (hazard ratio, 3.51; 95 percent confidence interval, 1.03–11.93; P=0.040). The authors concluded that intra-tumoral budding at diagnosis of rectal cancer identifies those who will respond poorly to neoadjuvant chemoradiotherapy and those with a poor prognosis.
Rogers AC, Gibbons D, Hanly AM, et al. Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy. Mod Pathol. 2014;27:156–162.
Correspondence: K. Sheahan at k.sheahan@st-vincents.ie
Analysis of diagnostic criteria for very well-differentiated gastric carcinoma of intestinal type
Very well-differentiated gastric adenocarcinoma of intestinal type is a rare variant of gastric cancer characterized by low-grade nuclear atypia. Its diagnostic criteria and clinical behavior are not fully established. The authors presented a detailed histologic, immunohistochemical, and clinical analysis of 21 cases. Nuclear atypia was mild in all of them. Characteristic architectural features of this gastric adenocarcinoma variant were pit and glandular anastomosis, spiky glands, distended glands, discohesive cells, abortive glands, and glandular outgrowth. At least three of these features were present in all cases. Retrospective review of preoperative biopsies in 18 patients revealed that half the biopsies were originally reported as negative or indeterminate for malignancy. On the basis of immunohistochemical stains for intestinal (MUC2, CD10, and CDX-2) and gastric (MUC5AC and MUC6) markers, 11 (52 percent) cases had an intestinal immunophenotype and 10 (48 percent) cases had a mixed immunophenotype. Foci of discohesive neoplastic cells, indicating dedifferentiation toward a poorly cohesive carcinoma, were observed exclusively in neoplasms of mixed immunophenotype (n=5). All but one patient with follow-up were alive without disease at a mean of 19 months (range, 1–60 months). One individual with a pT4 tumor with associated poorly cohesive carcinoma died of disease. The authors concluded that very well-differentiated gastric adenocarcinomas are diagnostically challenging. Architectural features are critical to making the diagnosis. Cases with pure intestinal immunophenotype have not been associated with transformation into poorly cohesive carcinoma and appear to behave as biologically low grade. Those with mixed immunophenotype appear more likely to dedifferentiate and behave more aggressively.
Ushiku T, Arnason T, Ban S, et al. Very well-differentiated gastric carcinoma of intestinal type: analysis of diagnostic criteria. Mod Pathol. 2013;26:1620–1631.
Correspondence: Dr. T. Ushiku at usikut-tky@umin.ac.jp
A study of cystic hypersecretory carcinoma of the breast
Cystic hypersecretory carcinoma is an uncommon variant of ductal carcinoma in situ characterized by, among other features, the presence of luminal secretion resembling thyroidal colloid. It is thought to behave in an indolent manner but has the potential to give rise to invasive carcinoma, which is often poorly differentiated. The authors studied the immunohistochemical, clinical, and morphologic features of 10 cases of cystic hypersecretory carcinoma (CHC). All patients were women who were an average of 62.8 years old (range, 47–79 years). The clinical/radiographic presentation was a mass (five of 10), calcifications (three of 10), bloody nipple discharge (one of 10), and unknown (one of 10). The microscopic size of CHC ranged from 0.2 to 2.7 cm (mean, 0.9 cm). Micropapillary growth was present in all cases. Nuclear grade was intermediate (five of 10) or high (five of 10). One case also showed microinvasive carcinoma. All cases arose in a background of cystic hypersecretory hyperplasia or cystic hypersecretory hyperplasia with atypia, or both. CHC was ER+ in eight of 10 cases (ER+/PR+, four of 10; ER+/PR−, four of 10). Two cases were ER−/PR−, including the case with microinvasive carcinoma. All cases were HER2−. Androgen receptor was expressed in three of 10 cases. The myoepithelial stains p63, smooth muscle myosin, and CK5 showed circumferential staining in nine of 10 cases, whereas one case was negative for p63, smooth muscle myosin, and CK5 in CHC and adjacent cystic hypersecretory hyperplasia. The basal-like carcinoma markers EGFR, CK14, and CK5 were negative in all cases, with the exception of one case that was positive for EGFR. Four patients with follow-up information showed no evidence of disease (mean, 5.5 years). CHC is a distinct variant of ductal carcinoma in situ that arises in a background of cystic hypersecretory hyperplasia and is characterized by micropapillary growth, intermediate- to high-grade nuclei, and luminal colloid-like secretion. It is usually ER+ and HER2−. Negative or discontinuous reactivity with myoepithelial markers may be seen, despite its in situ nature. CHC usually behaves in a nonaggressive manner, as was seen in the authors’ patients, all of whom were free from disease at last follow-up.
D’Alfonso TM, Ginter PS, Liu YF, et al. Cystic hypersecretory (in situ) carcinoma of the breast: a clinicopathologic and immunohistochemical characterization of 10 cases with clinical follow-up. Am J Surg Pathol. 2014;38:45–53.
Correspondence: Dr. Timothy M. D’Alfonso at tid9007@med.cornell.edu
OCT4 immunohistochemistry to evaluate retroperitoneal lymph node dissections
The authors investigated the role of OCT4 immunohistochemical staining in detecting germ cell tumor lymph node metastases. Retroperitoneal lymph node dissection is important for staging and treating testicular germ cell tumors, and OCT4 is sensitive and specific for pluripotent testicular germ cell tumors. However, micrometastases, particularly from seminoma, can be difficult to detect. The authors examined 262 lymph nodes in 45 retroperitoneal lymph node dissection specimens from germ cell tumor patients. They categorized specimens as postchemotherapy and untreated retroperitoneal lymph node dissection with or without clinical suspicion, based on lymphadenopathy or elevated serum germ cell tumor markers. Sections were stained with anti-OCT4 antibody. Twenty-one additional positive lymph nodes in 12 cases were found to harbor scattered seminoma cells, singly and in small clusters, from 256 previously considered benign in untreated retroperitoneal lymph node dissection with clinical suspicion (13 percent increase), postchemotherapy retroperitoneal lymph node dissection (seven percent), and untreated retroperitoneal lymph node dissection without suspicion (four percent). No patient with an entirely negative dissection specimen was reclassified as positive. OCT4 immunohistochemistry detected scattered seminoma cells and small clusters of seminoma cells in lymph nodes previously considered to be benign, for an overall increase of eight percent and greatest in the setting of untreated retroperitoneal lymph node dissection with clinical suspicion. Immunohistochemistry did not convert any entirely negative specimen to positive. The authors concluded that additional studies will be useful to determine whether the small volume of disease detected by immunohistochemistry has the same impact as lymph node metastases detected routinely.
Idrees MT, Williamson SR, Kieffer TW, et al. The role of OCT4 immunohistochemistry in evaluation of retroperitoneal lymph node dissections: a pilot study. Mod Pathol. 2013;26:1613–1619.
Correspondence: Dr. M. T. Idrees at midrees@iupui.edu
EGFR alterations and EML4-ALK rearrangement in primary adenocarcinoma of the urinary bladder
The identification of mutations in epidermal growth factor receptor and translocations involving anaplastic lymphoma kinase in lung adenocarcinoma has drastically changed understanding of the disease and led to the development of targeted therapies. Adenocarcinoma of the urinary bladder is rare and poorly understood at the molecular level. The authors conducted a study to determine whether epidermal growth factor receptor (EGFR) mutations, increases in EGFR copy number, or anaplastic lymphoma kinase (ALK) translocations are present in these tumors. They analyzed 28 cases of primary bladder adenocarcinoma. For EGFR mutational analysis, they analyzed PCR-amplified products on the Q24 pyrosequencer with Qiagen EGFR Pyro kits. All cases were analyzed via FISH using Vysis ALK Break Apart FISH probes for detecting ALK chromosomal translocation and Vysis dual-color probes to assess for increased gene copy number of EGFR. None of the 28 cases examined showed mutational events in EGFR or ALK rearrangements. EGFR polysomy was seen in 10 of 28 (36 percent) cases. No correlation with EGFR polysomy was seen in the tumors with respect to age, histologic subtypes, pathologic stage, or lymph node metastasis. The authors concluded that EGFR mutations and ALK rearrangements do not appear to be involved in the development of primary adenocarcinoma of the urinary bladder. However, a subgroup of cases (36 percent) demonstrated increased gene copy number of EGFR by FISH.
Alexander RE, Montironi R, Lopez-Beltran A, et al. EGFR alterations and EML4-ALK rearrangement in primary adenocarcinoma of the urinary bladder. Mod Pathol. 2014;27:107–112.
Correspondence: Dr. L. Cheng at liang_cheng@yahoo.com