Showing papers on "Large cell published in 2006"

Large cell neuroendocrine carcinoma of prostate: a clinicopathologic summary of 7 cases of a rare manifestation of advanced prostate cancer.

Abstract: Neuroendocrine (NE) differentiation in prostate cancer is typically detected by immunohistochemistry as single cells in conventional adenocarcinoma. Prostatic NE tumors, such as carcinoid or small cell carcinoma, are rare and large cell NE carcinoma (LCNEC) is described only in case reports. We identified 7 cases of LCNEC and compiled their clinicopathologic characteristics. In 6 cases, there was a history of adenocarcinoma treated with hormone therapy for a mean of 2.4 years (range: 2 to 3 y). The remaining case was de novo LCNEC. LCNEC was incidentally diagnosed in palliative transurethral resection specimens in 5 cases. The mean patient age at diagnosis with LCNEC was 67 years (range: 43 to 81 y). LCNEC comprised solid sheets and ribbons of cells with abundant pale to amphophilic cytoplasm, large nuclei with coarse chromatin and prominent nucleoli along with brisk mitotic activity and foci of necrosis. In 6 cases, there were foci of admixed adenocarcinoma, 4 of which showed hormone therapy effects. LCNEC was strongly positive for CD56, CD57, chromogranin A, synaptophysin, and P504S/alpha methylacyl CoA racemase. There was strong bcl-2 overexpression, expression of MIB1, and p53 in >50% of nuclei, focally positive staining for prostate specific antigen and prostatic acid phosphatase and negative androgen receptor staining. Follow-up was available for 6 patients, all of who died with metastatic disease at mean of 7 months (range: 3 to 12 mo) after platinum-based chemotherapy. LCNEC of prostate is a distinct clinicopathologic entity that typically manifests after long-term hormonal therapy for prostatic adenocarcinoma and likely arises through clonal progression under the selection pressure of therapy.

Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking

Abstract: Somatically acquired mutations in the epidermal growth factor receptor (EGFR) gene in lung cancer are associated with significant clinical responses to gefitinib, a tyrosine kinase inhibitor that targets EGFR. We screened the EGFR in 469 resected tumours of patients with lung cancer, which included 322 adenocarcinomas, 102 squamous cell carcinomas, 27 large cell carcinomas, 13 small cell carcinomas, and five other cell types. PCR with a specific condition was performed to identify any deletion in exon 19, while mutant-allele-specific amplification was performed to identify a mutation in codon 858 of exon 21. EGFR mutations were found in 136 cases (42.2%) with adenocarcinoma, in one case with large cell carcinoma, and in one case with pleomorphic carcinoma. An in-frame deletion in exon 19 was found in 62 cases while an L858R mutation was found in 77 cases. In the 322 cases with adenocarcinoma, these mutations were more frequently found in women than in men (P=0.0004), in well differentiated tumours than in poorly differentiated tumours (P=0.0014), and in patients who were never smokers than in patients who were current/former smokers (P<0.0001). The mutation was more frequently observed in patients who smoked ⩽20 pack-year, and in patients who quit at least 20 years before the date of diagnosis for lung cancer. The K-ras mutations were more frequently found in smokers than in never smokers, and in high-dose smokers than in low-dose smokers. In conclusion, the mutations within the tyrosine kinase domain of EGFR were found to specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking.

Comparative genomic hybridization detects an increased number of chromosomal alterations in large cell/anaplastic medulloblastomas.

Abstract: We correlate chromosomal changes in medulloblastomas with histologic subtype, reporting the analysis of 33 medulloblastoma specimens by comparative genomic hybridization, and a subset by fluorescence in situ hybridization. Of the 33 tumors, 5 were desmoplastic/nodular, 10 were histologically classic, and 18 were large cell/anaplastic. Chromosomal gains and losses were more common in anaplastic medulloblastomas than in non-anaplastic ones. We identified 4 medulloblastomas with c-myc amplification and 5 medulloblastomas with N-myc amplification; all 9 were of the large cell/anaplastic subtype. Additional regions with high level gains included 2q14-22, 3p23, 5p14-pter, 8q24, 9p22-23, 10p12-pter, 12q24, 12p11-12, 17p11-12, and Xp11. The majority of these high level gains occurred in anaplastic cases. We also found loss of chromosome 17p in 7 large cell/anaplastic cases but no nonanaplastic medulloblastomas. Finally, we detected a significantly increased overall number of chromosomal alterations in large cell/anaplastic medulloblastomas (6.8/case) compared to non-anaplastic ones (3.3/case). These findings support an association between myc oncogene amplification, 17p loss, and large cell/anaplastic histology.

High resolution analysis of non-small cell lung cancer cell lines by whole genome tiling path array CGH

Abstract: Chromosomal regions harboring tumor suppressors and oncogenes are often deleted or amplified. Array comparative genomic hybridization detects segmental DNA copy number alterations in tumor DNA relative to a normal control. The recent development of a bacterial artificial chromosome array, which spans the human genome in a tiling path manner with >32,000 clones, has facilitated whole genome profiling at an unprecedented resolution. Using this technology, we comprehensively describe and compare the genomes of 28 commonly used non-small cell lung carcinoma (NSCLC) cell models, derived from 18 adenocarcinomas (AC), 9 squamous cell carcinomas and 1 large cell carcinoma. Analysis at such resolution not only provided a detailed genomic alteration template for each of these model cell lines, but revealed novel regions of frequent duplication and deletion. Significantly, a detailed analysis of chromosome 7 identified 6 distinct regions of alterations across this chromosome, implicating the presence of multiple novel oncogene loci on this chromosome. As well, a comparison between the squamous and AC cells revealed alterations common to both subtypes, such as the loss of 3p and gain of 5p, in addition to multiple hotspots more frequently associated with only 1 subtype. Interestingly, chromosome 3q, which is known to be amplified in both subtypes, showed 2 distinct regions of alteration, 1 frequently altered in squamous and 1 more frequently altered in AC. In summary, our data demonstrate the unique information generated by high resolution analysis of NSCLC genomes and uncover the presence of genetic alterations prevalent in the different NSCLC subtypes. © 2005 Wiley-Liss, Inc.

c-Myc Overexpression Causes Anaplasia in Medulloblastoma

Abstract: Both anaplasia and increased c-myc gene expression have been shown to be negative prognostic indicators for survival in medulloblastoma patients. myc gene amplification has been identified in many large cell/anaplastic medulloblastoma, but no causative link between c-myc and anaplastic changes has been established. To address this, we stably overexpressed c-myc in two medulloblastoma cell lines, DAOY and UW228, and examined the changes in growth characteristics. When analyzed in vitro, cell lines with increased levels of c-myc had higher rates of growth and apoptosis as well as significantly improved ability to form colonies in soft agar compared with control. When injected s.c. into nu/nu mice, flank xenograft tumors with high levels of c-myc in DAOY cell line background were 75% larger than those derived from control. Overexpression of c-myc was required for tumor formation by UW228 cells. Most remarkably, the histopathology of the Myc tumors was severely anaplastic, with large areas of necrosis/apoptosis, increased nuclear size, and macronucleoli. Indices of proliferation and apoptosis were also significantly higher in Myc xenografts. Thus, c-myc seems to play a causal role in inducing anaplasia in medulloblastoma. Because anaplastic changes are often observed in recurrent medulloblastoma, we propose that c-myc dysregulation is involved in the progression of these malignant embryonal neoplasms.

Establishment in Severe Combined Immunodeficiency Mice of Subrenal Capsule Xenografts and Transplantable Tumor Lines from a Variety of Primary Human Lung Cancers: Potential Models for Studying Tumor Progression–Related Changes

Abstract: Purpose: Lung cancer is a biologically diverse disease and relevant models reflecting its diversity would facilitate the improvement of existing therapies. With a view to establishing such models, we developed and evaluated xenografts of a variety of human lung cancers. Experimental Design: Using nonobese diabetic/severe combined immunodeficiency mice, subrenal capsule xenografts were generated from primary lung cancer tissue, including moderate- ly and poorly differentiated squamous cell carcinoma, adenocarcinoma, adenosquamous carcino- ma, small cell carcinoma, large cell undifferentiated carcinoma, and carcinosarcoma. After 4 to 12 weeks, xenografts were harvested for serial transplantation and comparison with the original tissue via histologic, chromosomal, and cytogenetic analyses. Results: Xenografts were successfully established. H&Estaining showed that xenografts retained major histologic features of the original cancers. Immunohistochemistry and fluores- cence in situ hybridization confirmed the human origin of the tumor cells and development in xenografts of murine supportive stroma. Four transplantable lines were developed from rapidly growing tumors (>5 generations), i.e., a small cell lung carcinoma, large cell undiffer- entiated carcinoma, pulmonary carcinosarcoma, and squamous cell carcinoma. Analyses including spectral karyotyping, comparative genomic hybridization, and fluorescence in situ hybridization, revealed that the xenografts were genetically similar to the original tumors, showing chromosomal abnormalities consistent with karyotypic changes reported for lung cancer. Conclusions: The subrenal capsule xenograft approach essentially provides a living tumor bank derived from patient material and a means for isolating and expanding specific cell populations. The transplantable tumor lines seem to provide good models for studying various aspects of tumor progression and a platform for developing novel therapeutic regimens, with the possibility of patient-tailored therapies.

Gastric large cell neuroendocrine carcinomas: a distinct clinicopathologic entity.

Abstract: The current histologic classifications of gastric cancers define only carcinoids and small cell carcinomas in the neuroendocrine (NE) category. This study aimed to characterize the histologic and clinical features of high-grade gastric NE carcinomas of nonsmall cell type, tentatively named large cell neuroendocrine carcinoma (LCNEC). Tumors with histologic features suspicious of NE differentiation were selected by a histologic review of 2835 resected gastric cancers, and those with a NE phenotype in > 50% and 1% to approximately 50% tumor cells assessed by expressing chromogranin A and/or synaptophysin were defined as LCNEC and adenocarcinoma with neuroendocrine differentiation (ACNED), respectively. One hundred ninety-nine tumors were selected and of the 109 positive for chromogranin A and/or synaptophysin, 42 and 44 met the criteria for LCNEC and ACNED, respectively. Generally, LCNECs demonstrated less predominant NE morphology than carcinoids, and could be roughly divided into solid (30 cases), tubular (7 cases), and scirrhous (5 cases) subtypes with reference to their main growth pattern. The prognosis of LCNECs was significantly worse than that of conventional adenocarcinomas (P 20% positivity of NE markers could be enough to characterize LCNEC, as long as light microscopic NE morphology was present in the tumor.

Primary cutaneous T-cell lymphoma occurring after organ transplantation.

Abstract: Lymphoma occurring after organ transplantation has been well described. The majority of cases are B-cell lymphomas and are usually associated with Epstein-Barr virus. Only a minority of posttransplant lymphomas are of T-cell origin, and primary cutaneous T-cell lymphoma (CTCL) is extremely rare. In this article, we report a case of cutaneous peripheral T-cell lymphoma, pleomorphic CD30 + large-cell type, and review the literature relating to posttransplant primary CTCL. Of the 23 cases of posttransplant primary CTCL, 5 patients had erythrodermic disease, and 8 had primary cutaneous anaplastic large cell lymphoma. In addition, there are two cases of mycosis fungoides, one case of subcutaneous panniculitis-like T-cell lymphoma, one case of CD30 + lymphomatoid papulosis, and 6 cases of peripheral T-cell lymphoma, of which 3 were CD30 + large cell lymphomas. Seventeen cases had renal transplants and the majority received both cyclosporine and azathioprine. No consistent viral association was noted among these cases. The sex ratio was 18:5 (male/female), and the mean age at diagnosis was 53 years. Mean time from transplantation to diagnosis is 6.4 years and mean survival time from diagnosis is 14.5 months. The prognoses normally associated with particular subsets of CTCL do not apply in the posttransplant setting.

Primary large cell neuroendocrine carcinoma of the urinary bladder

Abstract: Primary large cell neuroendocrine carcinomas (LCNEC) of the urinary bladder are rare. Reported herein is a case of a primary, pure LCNEC occurring in a man. The patient was a 32-year-old man who presented with hematuria of 1 week's duration. On cystoscopic examination, a solitary mass measuring 3 cm in diameter was detected protruding from the anterosuperior wall of the urinary bladder. Two months after the primary transurethral resection, significant regrowth of the remnant mass was noted on CT, and the patient underwent a partial cystectomy. A diagnosis of LCNEC was made based upon histological and immunohistochemical findings. Tumor cells were positive for synaptophysin, chromogranin A, CD56, epithelial membrane antigen, and cytokeratin. Histologically, the tumor penetrated the deep muscle and perivesical fat. In spite of three cycles of chemotherapy, the patient developed multiple metastases in the lung and liver 10 months postoperatively. LCNEC of the urinary bladder are uncommon entities, which have a possible fatal outcome.

Cancer and pulmonary embolism: thrombotic embolism, tumor embolism, and tumor invasion into a large vein.

Abstract: Background The specific incidence of thrombotic pulmonary embolism (PE), tumor PE and tumor invasion into large veins according to tumor type and tumor site remains unclear. Methods and Results A total of 65,181 cancer patients were identified from 98,736 postmortem examinations. Thrombotic PE occurred in 2.32% of all cancer patients and comprised 88.6% of the total number of all PE events. The incidence of thrombotic PE was high in those with adenocarcinoma, leukemia and large cell carcinoma, and was low in those with hepatic cell carcinoma. The incidence of PE was high when tumor was present in hematogenous tissue, lungs, ovaries, pancreas and the biliary system, and was low when tumor was present in the liver. The incidence of tumor PE was high with large cell carcinoma, hepatic cell carcinoma and adenocarcinoma, and was also high when tumor was present in the lungs, ovaries, kidneys and liver. There was a significant correlation between the incidence of tumor PE and the incidence of tumor invasion into large veins. Conclusion The incidence of thrombotic PE, tumor PE and tumor invasion into large veins varies significantly according to tumor histopathology and tumor site. (Circ J 2006; 70: 744 - 749)

Recurrent childhood anaplastic large cell lymphoma: a retrospective analysis of registered cases in Japan.

Abstract: This report presents a retrospective study of 26 Japanese children with recurrent anaplastic large cell lymphoma. The first relapses were documented at a median of 10.5 months after the initial diagnosis. Twenty-four patients achieved a second remission. After a median follow-up period of 47 months, 18 patients are still alive: 15 patients are in second complete remission (CR), three patients are in third CR or later. The 5 year overall and relapse-free survival rates were 61 +/- 12% and 51 +/- 12% respectively. The patients who received allogeneic haematopoietic stem cell transplantation during second CR showed a superior outcome to other patients.

Alveolar macrophage function is altered in patients with lung cancer.

Abstract: The alveolar macrophage (AM) is believed to be of central importance in the immune response against infection and tumour. We examined patients with lung cancer in order to evaluate the immuno-stimulatory potential of AM in lung cancer. Bronchoalveolar lavage fluid samples were obtained from patients with adenocarcinoma, squamous cell carcinoma, large cell undifferentiated lung carcinoma, small cell carcinoma and control subjects. AM were isolated and phagocytic function, flow cytometry and cytokine analysis were assessed. AM from patients with small and squamous cell carcinoma had impaired uptake in vitro of 40 nm fluorescent polystyrene beads. AM from patients with small, squamous and large cell undifferentiated carcinoma showed impaired uptake of 1000 nm fluorescent polystyrene beads. Secreted levels of TNF-alpha and IL-1 from AM of patients with small, squamous, and large cell undifferentiated carcinoma were decreased compared to controls. Secreted AM IL-6 levels were decreased in small and large cell undifferentiated carcinoma. AM from adenocarcinoma patients showed similar levels of IL-10, IL-6, IL-1 and TNF-alpha compared to controls. Phenotypic analysis demonstrated that patients with small cell carcinoma were the only group that showed a decrease in MHC class II surface expression. Surface expression of ICAM-1 and CD83 was decreased on AM from patients with large, squamous and small cell carcinoma compared to controls but not adenocarcinoma. Mannose receptor levels were only decreased on AM from patients with squamous and small cell carcinoma but not adenocarcinoma and large cell undifferentiated carcinoma. We conclude that there are type-specific alterations in uptake ability, cytokine secretion and phenotype of AM from lung cancer patients, which may result in an inability to stimulate anti-tumour immunity. The observed differences between lung cancer subgroups may explain previously reported inconsistencies in descriptions of AM characteristics in lung cancer.

Multigene Real-time PCR Detection of Circulating Tumor Cells in Peripheral Blood of Lung Cancer Patients

Abstract: Background: CLCA2, HMGB3, L587S and ASH1 were identified in lung cancer tissues using genetic subtraction, microarray and quantitative PCR, and found to be specific and complementary for detection of non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). Materials and Methods: A real-time RT-PCR assay, simultaneously detecting four genes, was developed and tested on lung cancer specimens. Results: Twenty-two out of 24 adenocarcinomas, 18/18 squamous, 4/5 large cell, 2/2 small cell and 2/2 bronchoalveolar/ neuroendocrine cancer tissue samples tested positive. Specificity was demonstrated by evaluation of 194 other tumor and corresponding normal tissues. Circulating tumor cells in the peripheral blood of 49/108 lung cancer patient samples tested positive, and general correlations of multigene expression signals to disease status were observed. Changes in multigene expression during treatment and disease recurrence in individual patients could be detected. Conclusion: These data indicate the diagnostic and prognostic utility of a multigene real-time RT-PCR assay to detect tumor cells in the peripheral blood of lung cancer patients. Lung cancer carries the highest mortality rate of all cancers, leading to an estimated 1 million deaths annually worldwide (1, 2). The diagnosis of lung cancer is complicated by the presence of several pathologically distinct tumor types, segregated by treatment approach into two groups: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The NSCLC group includes adenocarcinoma, large cell carcinoma and squamous cell carcinoma. NSCLC comprises ~ 75% of all lung tumors, with adenocarcinoma and squamous cell carcinoma being the most prevalent forms. In most cases, the early diagnosis of NSCLC is elusive

Is EGFR expression important in non-small cell lung cancer?

Abstract: There are still many unanswered questions on the use of EGFR treatment in NSCLC Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is frequently overexpressed in non-small cell lung cancer (NSCLC). These receptors play an important role in tumour cell survival and activated phosphorylated EGFR results in the phosphorylation of downstream proteins that cause cell proliferation, invasion, metastasis, and inhibition of apoptosis. Expression appears to be dependent on histological subtypes, most frequently expressed in squamous cell carcinoma but also frequently expressed in adenocarcinomas and large cell carcinomas.1 Not surprisingly, there are many published reports attempting to correlate the relationship between EGFR protein overexpression and survival. However, the data regarding the prognostic role of EGFR expression are inconsistent and confusing, with some reports indicating that EGFR is associated with poor survival while no prognostic association was seen in other reports. In this issue of Thorax Nakamura et al carried out a meta-analysis of 18 studies (including nearly 3000 patients), reviewing whether EGFR overexpression has an impact on survival. Most of these reported studies evaluated EGFR protein expression by immunohistochemistry (IHC) and it is possible that different conclusions may reflect differences in incubation and detection methods, reagents, assay cut off points, and population studied with different stages. Nevertheless, EGFR overexpression was seen in 39% in adenocarcinoma, 58% in squamous cell carcinoma, and 38% in large cell carcinoma, and they concluded that EGFR protein overexpression using …

O6-alkylguanine-DNA alkyltransferase gene polymorphisms and the risk of primary lung cancer.

Abstract: Biomarkers of individual susceptibility: field studiesBiomarker (including alleles if genetic): AGT polymorphisms (485C>A, Leu53Leu (C>T) and Leu84Phe]Effect studied (phenotype/pathology): lung cancerMethod of analysis: PCR-RFLPStudy design: case-control Study size: 432 lung cancer patients and 432 healthy controlsImpact on outcome (including dose-response):The 485 AA genotype was associated with a significantly increased risk for overall lung cancer as compared with the 485 CC genotype and the combined 485 CCώCA genotype, respectively (adjusted OR=1.83, 95% CI=1.12- 2.99, P=0.02, and Bonferroni corrected P-value, Pc=0.04; and adjusted OR=1.67, 95% CI=1.05- 2.66, P=0.03, respectively).Quality control: performed in triplicates. KEYWORDS CLASSIFICATION: Adenocarcinoma;Adult;biomarkers of individual susceptibility: field studies;cancer epidemiology;Carcinoma,Large Cell;Carcinoma,Small Cell;Carcinoma,Squamous Cell;Case-Control Studies;DNA Damage;DNA Repair;enzymology;Female;genetics;Genetic Predisposition to Disease;Genotype;Humans;Korea;Lung Neoplasms;metabolism;Male;mechanisms of carcinogenesis;O(6)-Methylguanine-DNA Methyltransferase;pathology;Polymorphism,Genetic;Promoter Regions (Genetics);Research;Risk Factors;secondary;field studies;genetic;analysis.

p53 protein expression in cutaneous T‐cell lymphomas

Abstract: Summary p53 is an oncosuppressor gene located on chromosome 17p. Point mutations of the p53 gene are seen frequently in human malignancies, and are closely associated with malignant transformation under in vitro conditions. Mutated p53 protein shows a slow cell turnover rate, and accumulates in cells at the nuclear and/or cytoplasmic level. As a result, mutated p53 protein can be detected more readily by immunohistology than the wild-type protein. In this study, we used a monoclonal anti-p53 antibody (clone D07) to examine the expression of p53 protein in 25 cutaneous T-cell lymphomas (CTCL) of low- and high-grade malignancy, i.e. mycosis fungoides (n = 6), Sezary's syndrome (n = 2), and large cell lymphomas of pleomorphic (n = 14) or anaplastic (n= 3) subtype. The results showed that easily detectable p53 protein was present in many of the neoplastic cells in half of the high-grade lymphomas. In contrast, in the low-grade lymphomas no, or only very few, p53-positive neoplastic cells could be detected. These findings suggest that molecular and/or genetic alterations of p53 may be implicated in the pathogenesis of high-grade CTCL, but are unlikely to be of critical importance in low-grade CTCL.

Blastoid and common variants of mantle cell lymphoma exhibit distinct immunophenotypic and interphase FISH features

Abstract: Aims : The recognition of blastoid variant (BV) of mantle cell lymphoma (MCL) is based on morphological criteria. Our aim was to analyse 18 MCL cases including four BV-MCL for their clinicopathological features, proliferation index, cyclin D1 and CDK4 expression and interphase fluorescence in-situ hybridization (FISH) pattern. Methods and results : BV-MCL versus common MCL was characterized by a shorter overall duration of response after first-line therapy (11 months versus 28 months) and shorter overall survival (20 months versus 42 months). Interphase FISH showed a t(11;14) fusion pattern in all MCL tested cases. However, the four blastoid cases were characterized by extra copies of CCND1 signals. Using additional probes of chromosomes 11, 18, 21, these signals were shown to be the result of hypotetraploidy and not of a specific amplification of the normal or the translocated CCND1 allele. Moreover, the BV-MCL cases were characterized by a combined high percentage of cells expressing cyclin D1 and/or CDK4 with a proliferation (MIB-1–Ki67) index above 50%. Such features allowed the recognition of areas of large cell transformation in the case of secondary BV-MCL. Conclusions : Since distinction between BV and common MCL is of clinical relevance, our data underline the need to add phenotypic and cytogenetic criteria to cytomorphology for a better recognition of BV-MCL.

ALK-positive anaplastic large cell lymphoma with primary bone involvement in children.

Abstract: We describe the clinical, radiologic, and pathologic features of primary bone anaplastic large cell lymphoma (ALCL) in 3 boys. Radiologic imaging showed lytic lesions involving sacrum, femur, or rib. Bone was the only site of disease in 2 cases; an associated partial lymph node was involved in case 3. Differential diagnoses included osteomyelitis and small round cell tumors of childhood, particularly Ewing sarcoma. Preoperatively, ALCL was not a diagnostic consideration in any case. Two cases showed classic large pleomorphic cells; 1 showed a composite pattern with a distinct small cell component and the more typical large cell type. Neoplastic cells in all cases showed strong CD30 and anaplastic lymphoma kinase expression with relatively weak epithelial membrane antigen positivity. Cytotoxic granule protein was expressed in 2 cases. All cases showed unusually strong expression of neuron-specific enolase (NSE). Two patients were disease-free at last follow-up (15 months and 11 years); 1 patient died of disseminated disease within a year of diagnosis. ALCL should be considered a diagnostic possibility when evaluating neoplastic bone lesions in children. Although expression of NSE in ALCL has not been emphasized in the literature, it is worth noting because it may pose a diagnostic pitfall.