Jennifer Chapman-Fredricks

Frequency and extent of CD30 expression in diffuse large B-cell lymphoma and its relation to clinical and biologic factors: a retrospective study of 167 cases

Abstract Previous studies have suggested that CD30 may be expressed in diffuse large B-cell lymphomas (DLBCLs). However, the prevalence of CD30 + DLBCLs and extent of CD30 expression within an individual tumor have not been fully evaluated. The aim of this study was to determine the frequency and extent of CD30 expression in DLBCLs, and explore possible relationships between CD30 expression and clinical and biologic variables. We retrospectively identified and analyzed 167 cases of CD30 + DLBCLs from our pathology archive. Twenty-one percent (95% confidence interval [CI]: 14.8–27.1%) of these cases expressed CD30, and in 52% of them CD30 was positive in > 80% of tumor cells. CD30 expression was more frequent in DLBCLs with non-germinal center origin phenotype, BCL2 + DLBCLs and in patients ≤ 47 years old. There was significant interaction of BCL2 expression with age and subtype of DLBCL. A multivariate analysis performed in BCL2 + DLBCLs showed a higher frequency of CD30 + cases in non-germinal center DLBCLs (odds ratio [OR]: 6.5, 95% CI: 1.1–36.5) and in patients ≤ 47 years old (OR: 6.9, 95% CI: 1.5–29.5). These associations could suggest a common biologic pathogenesis. The effectiveness of anti-CD30 drugs in other lymphomas opens the possibility for their use in patients with CD30 + DLBCLs.

Adult renal cell carcinoma with rhabdoid morphology represents a neoplastic dedifferentiation analogous to sarcomatoid carcinoma

Renal cell carcinoma (RCC) with rhabdoid morphology (RCC-RM) is a recently described variant of RCC, which has an aggressive biologic behavior and poor prognosis, akin to sarcomatoid RCC. The current World Health Organization classification of RCC does not include the rhabdoid phenotype as a distinct histologic entity. The aim of this study is to investigate whether RCC-RM represents a dedifferentiation of a classifiable-type World Health Organization RCC or a carcinosarcoma with muscle differentiation. We reviewed 168 cases of RCC obtained between 2003 and 2008. From these cases, 10 (6%) were found to have areas of classic rhabdoid morphology. Immunohistochemistry for cytokeratin, epithelial membrane antigen, desmin, CD10, and CD117 was performed in each case using the labeled streptavidin-biotin method. Rhabdoid differentiation was identified in association with conventional-type RCC (9) and with unclassifiable-type RCC with spindle cell morphology (1). In all cases, both the rhabdoid and nonrhabdoid tumoral areas were positive for cytokeratin and epithelial membrane antigen and negative for desmin. Cytokeratin positivity in the rhabdoid areas was focal. In cases associated with conventional-type RCC, CD10 was positive in both the rhabdoid and nonrhabdoid foci. CD117 was negative in these tumors. The unclassifiable-type RCC with spindle cell morphology was negative for both CD10 and CD117. The similar immunophenotype between the rhabdoid and nonrhabdoid tumoral foci supports the origin of the rhabdoid cells from the classifiable-type RCC. Areas of rhabdoid morphology do not represent muscle metaplastic differentiation. Renal cell carcinoma with rhabdoid morphology may represent a dedifferentiation of a classifiable-type RCC, similar to that of sarcomatoid differentiation. The recognition of RCC-RM is important as it allows for the inclusion of these high-grade malignancies into a category associated with poor prognosis despite lacking the spindle cell component classically identified as sarcomatoid change.

A limited immunohistochemical panel helps differentiate small cell epithelial malignancies of the sinonasal cavity and nasopharynx.

BackgroundDistinguishing small cell epithelial malignancies of the sinonasal cavity and nasopharynx is difficult due to overlapping morphologic characteristics, particularly in small biopsies. This distinction is important, however, because of the inherent differences in biology, natural history, prognosis, and treatment among these neoplasms. The aim of this study is to identify a limited immunohistochemical panel that may help to differentiate these morphologically similar small cell epithelial malignancies. DesignWe reviewed 37 cases of histologically similar small cell epithelial malignancies of the sinonasal cavity and nasopharynx: nasopharyngeal carcinoma (NPC) (16), basaloid squamous cell carcinoma (BSCC) (15), and high-grade neuroendocrine carcinoma (HGNEC) (6) obtained at Jackson Memorial Hospital/UM Sylvester Comprehensive Cancer Center between 2003 and 2007. Immunohistochemistry for pancytokeratin (CK), CK5/6, p63, and HLA-DR was performed using the labeled streptavidin-biotin method. ResultsAll cases in this study were positive for CK and p63. The CK staining pattern of HGNEC was characteristically dot-like whereas the remaining tumors stained with strong and diffuse cytoplasmic membrane positivity. Likewise, the p63 staining pattern of HGNEC was focal and weak whereas the remaining tumors stained with diffuse and strong nuclear positivity. Immunohistochemistry for HLA-DR was positive in all cases of NPC, whereas BSCC and HGNEC were uniformly negative. Cases of NPC and BSCC were positive for CK5/6 whereas cases of HGNEC were negative. ConclusionsA limited immunohistochemical panel of CK, CK5/6, p63, and HLA-DR is useful in discriminating nasopharyngeal, basaloid squamous cell, and high-grade neuroendocrine carcinomas of the sinonasal cavity and nasopharynx.

The genetic basis of hepatosplenic T-cell lymphoma

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets.Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR.See related commentary by Yoshida and Weinstock, p. 352This article is highlighted in the In This Issue feature, p. 339.

Biased Use of the IGHV4 Family and Evidence for Antigen Selection in Chlamydophila psittaci-Negative Ocular Adnexal Extranodal Marginal Zone Lymphomas

Extranodal marginal zone lymphomas (EMZL) are the most common lymphomas in the ocular adnexa. The etiology and potential role for antigenic stimulation in these lymphomas are still controversial. We have examined IGHV gene usage and mutations in 67 Chlamydophila psittaci-negative ocular adnexal EMZL. Clonal IGHV gene sequences were identified in 43 tumors originating from the orbit (19), conjunctivae (18) and lacrimal gland (6). Forty four potentially functional clonal IGHV gene sequences were detected with overrepresentation of the IGHV4 family and IGHV4-34 gene. All but 3 sequences were mutated with the average percent homology to the germ line of 93.5±6.1. Multinomial model and Focused binomial test demonstrated evidence for positive and/or negative antigen selection in 59% of the potentially functional IGHV genes. Intraclonal variation was detected in 8 of 11 tumor specimens. Overall our findings demonstrate that C. psittaci-negative ocular adnexal EMZL exhibit biased usage of IGHV families and genes with evidence for intraclonal heterogeneity and antigen selection in multiple tumors, implicating B-cell receptor-mediated antigen stimulation in the pathogenesis of these lymphomas.

Molecular and genomic aberrations in Chlamydophila psittaci negative ocular adnexal marginal zone lymphomas.

The etiology and pathogenesis of ocular adnexal extranodal marginal zone lymphoma (OAEMZL) are still unknown and the association with Chlamydophila psittaci (C. psittaci) has been shown in only some geographic regions. Herein, we comprehensively examined the frequency of chromosomal translocations as well as CARD11, MYD88 (L265P), and A20 mutations/deletions in 45 C. psittaci negative OAEMZLs. t(14;18)(q32;q21) IGH‐MALT1 and t(11;18)(q21;q21) API2‐MALT1 were not detected in any of the analyzed tumors while three tumors harbored IGH translocations to an unidentified partner. CARD11 mutations were not found in all analyzed tumors, while the MYD88 L265P mutation was detected in three (6.7%) tumors. A20 mutations and deletions were each detected in seven (15.6%) and six (13.3%) tumors, respectively. Therefore, the observed genetic aberrations could account for the activation of the nuclear factor (NF)‐kB signaling pathway in only a minority of the cases. Further studies are needed to identify the molecular mechanisms underlying the pathogenesis of OAEMZL. Am. J. Hematol. 88:730–735, 2013.

INTRACAVAL LIVER WITH CARDIAC EXTENSION. A NEW DEVELOPMENTAL ANOMALY

Inferior vena cava (IVC) obstruction is uncommon in children. We report a patient with liver within a IVC extending to the right atrium who underwent successful surgical resection. A 12-year-old boy with an Arnold Chiari malformation was admitted for seizures. Premature ventricular contractions prompted an echocardiogram. This revealed a pedunculated mass in the right atrium and an IVC producing turbulent flow. He underwent a mass excision that was continuous with the liver. Histology demonstrated normal liver parenchyma. Based on the embryologic intimacy between the caudate lobe and the IVC, we postulate that the ectopic hepatic nodule was due to aberrant migration of hepatocytes into the IVC during embryogenesis.

Distinction of high-grade neuroendocrine carcinoma/small cell carcinoma from conventional urothelial carcinoma of urinary bladder: An immunohistochemical approach

Context High-grade neuroendocrine carcinomas and small cell carcinomas (HGNEC/SmCC) of the urinary bladder are uncommon but aggressive neoplasms. Differentiation of HGNEC/SmCC from high-grade urothelial carcinoma (UC) is based on histomorphologic features, but can be difficult in small biopsies and cases with mixed morphology. Objective We attempt to identify a limited immunohistochemical panel that aids in this distinction. Design We selected 39 cases of bladder carcinoma with small cell morphology: 7 HGNEC/SmCC, 21 high-grade UC with neuroendocrine-like pattern, and 11 mixed neoplasms. Immunohistochemistry for pan-cytokeratin, synaptophysin, chromogranin, p63, and thyroid transcription factor-1 was performed. Results Pan-cytokeratin was positive in 6 of 7 cases (86%) of the HGNEC/SmCC group. All 7 tumors were positive for synaptophysin, 6 of them were negative for p63 and chromogranin, and 1 was positive for p63 and chromogranin. All 21 high-grade UC with neuroendocrine-like pattern of growth showed positive staining for pan-cytokeratin, and were all negative for synaptophysin and chromogranin. Sixteen (76%) of high-grade UC were also positive for p63. All 11 mixed tumors were positive for pan-cytokeratin. In 10 of the 11 mixed tumors (91%), synaptophysin was positive in the neuroendocrine differentiated areas and it was negative in the urothelial component. In 2 of the 11 mixed tumors (18%) chromogranin was also positive. Three (27%) of the 11 mixed cases were positive for p63 in the UC foci. Chromogranin was negative in 6 of the pure HGNEC/SmCC and in 8 of the mixed tumors. None of the 39 samples were reactive for thyroid transcription factor-1. Conclusions A limited immunohistochemical panel including pan-cytokeratin, synaptophysin, and p63 discriminates HGNEC/SmCC from high-grade UC.

P16 expression in squamous cell carcinomas of cervix and bladder

Context/Objectivep16 is a widely used immunohistochemical marker in gynecologic pathology. Strong and diffuse cytoplasmic and nuclear expression of p16 in squamous cell carcinomas (SCC) of the female genital tract is strongly associated with high-risk human papilloma virus infection and neoplasms of cervical origin. However, p16 can be expressed in other neoplasms and in several normal human tissues. Occasionally, SCCs may involve both uterine cervix and urinary bladder. Accurate identification of the site of origin in such cases has therapeutic and prognostic implications. We investigate the potential value of p16 expression in this distinction. DesignWe reviewed 74 SCCs, 38 (51%) from urinary bladder and 36 (49%) from uterine cervix obtained between 2003 and 2008. Of the 38 cases of bladder carcinoma, 21 occurred in females and 17 in males. Immunohistochemical analysis for p16 (DAKO M7247, clone 484, dilution of 1:50) expression was done in all cases using the labeled streptavidin-biotin method. ResultStrong and diffuse nuclear and cytoplasmic p16 positivity was observed in 45 cases (61%). Of the 38 SCCs of urinary bladder, 14 (37%) expressed p16 (8 males, 6 females). Of the 36 SCCs of uterine cervix, 31 (86%) were positive for p16. Conclusions(1) The majority of SCCs of uterine cervix express p16. (2) More than a third of urinary bladder SCCs express p16. (3) SCCs of urinary bladder express p16 independent of gender. (4) p16 immunohistochemical expression alone cannot be used to discriminate between SCCs arising from uterine cervix versus urinary bladder.

Biased immunoglobulin light chain use in the Chlamydophila psittaci negative ocular adnexal marginal zone lymphomas.

Ocular adnexal mucosa associated lymphoid tissue lymphomas (OAMALTL) are the most common lymphomas of the eye. The potential roles for specific antigens in these lymphomas are still controversial. Previously we examined IGHV usage and mutations in Chlamydophila (C) psittaci‐negative OAMALTL, demonstrating biased use of the IGHV4 family and IGHV4–34 gene and evidence for antigen selection. Herein, we examined the IGKV/IGLV gene usage and mutations in 34 C. psittaci‐negative OAMALTL originating from the orbit (15), conjunctivae (14), and lacrimal gland (5). Clonal potentially functional IGKV/IGLV gene sequences were identified in 30 tumors (18 kappa and 12 lambda). An overrepresentation of the IGKV4 family (P < 0.01) was observed. The IGKV3–20*01 allele was used at a greater frequency than in normal peripheral blood B‐lymphocytes (P = 0.02) and commonly paired with the IGHV4–34 allele. Twenty‐seven of the 30 unique light chain sequences displayed mutations from germline and evidence for antigen selection. Overall our findings demonstrate that in C. psittaci‐negative OAMALTL there is a biased usage of IGKV families and genes, which harbor somatic mutations. These findings and the specific paring between the IGKV3–20*01 and IGHV4–34 alleles suggest that specific antigens could play an important role in the pathogenesis of these lymphomas. Am. J. Hematol. 88:379–384, 2013.