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Expanded question: What is the current epidemiology of patients with hepatic cysts?

Answered on November 14, 2024
Los quistes hepáticos son estructuras delgadas revestidas por epitelio de conducto biliar y llenas de líquido isotónico, generalmente asintomáticas y descubiertas incidentalmente durante estudios de imagen. La prevalencia de quistes hepáticos varía según la población estudiada y el método de detección. Un estudio realizado en una población de chequeo de salud encontró una prevalencia del 21.9% utilizando ultrasonido, con una mayor incidencia en mujeres, personas de mayor edad y aquellos con quistes renales o pancreáticos.[1] Otro estudio que utilizó resonancia magnética encontró una frecuencia del 71% en una población general, con un promedio de 3.4 quistes por persona, siendo más comunes en mujeres y aumentando con la edad.[2]
La mayoría de los quistes hepáticos son simples y no requieren intervención a menos que presenten síntomas o características de alto riesgo, como nodularidad mural o septaciones realzadas.[3] Los quistes pueden aumentar de tamaño con el tiempo, y en algunos casos, pueden requerir tratamiento si se vuelven sintomáticos o presentan complicaciones.[4] Las complicaciones son raras, pero pueden incluir obstrucción de estructuras adyacentes, ruptura o infección.[4]
En términos de clasificación, los quistes hepáticos pueden ser congénitos, neoplásicos, infecciosos/inflamatorios, o misceláneos, con una predominancia en mujeres y una baja incidencia de malignidad.[5] La mayoría de los quistes son no neoplásicos y benignos, y los quistes neoplásicos, como los neoplasmas quísticos mucinosos, son menos comunes y generalmente se presentan en mujeres perimenopáusicas.[5]
En resumen, los quistes hepáticos son comunes, especialmente en mujeres y personas mayores, y generalmente son asintomáticos y benignos. La intervención suele ser innecesaria a menos que se presenten síntomas o características de alto riesgo.

1.
The Prevalence and Natural History of Hepatic Cysts Examined by Ultrasound: A Health Checkup Population Retrospective Cohort Study.

Tsuruya K, Nishizaki Y, Tatemichi M, et al.

Scientific Reports. 2022;12(1):12797. doi:10.1038/s41598-022-16875-z.

The prevalence of hepatic cysts in the general population and their natural history are largely unknown. This study aimed to assess the prevalence and natural history of hepatic cysts by investigating health checkup participants. Ultrasonographic data of health checkup participants (n = 38,842) were retrospectively evaluated to calculate its prevalence. In addition, we assessed the changes in the size and characteristics of hepatic cysts over 10 years (n = 7709). We found the prevalence of hepatic cysts was 21.9%. Older age, female sex, and presence of kidney cysts or pancreatic cysts were associated with the occurrence of hepatic cysts. Younger age, female sex, and the existence of multiple hepatic cysts were associated with cyst enlargement. Among 126 individuals who had hepatic cysts with a diameter of 30 mm or larger at the first visit, two (1.6%) required treatment. Remain 124 cases showed four patterns: 44 cases with enlargement, 47 stable, 11 regression after enlargement, and 22 regression. Hyperechoic fluid inside the cysts was observed in 54.5% (18 of 33), which was significantly higher than 6.6% (6 of 91) of the non-regression (OR = 17.0). The appearance of intracystic hyperechoic fluid by ultrasound may predict subsequent regression of the hepatic cyst.

2.
Long-Term Outcome of Incidental Cystic Liver Tumors in the General Population.

Blum SFU, Ittermann T, Kromrey ML, et al.

Scientific Reports. 2021;11(1):11661. doi:10.1038/s41598-021-91140-3.

Aim of this study was to investigate frequency, incidence and risk factors of liver cysts in the general population in a longitudinal survey. Cyst frequency was investigated in 607 adult volunteers (288 women, 319 men, mean age 55 years) using strong T2-weighted magnetic resonance imaging. Risk factors were investigated for occurrence, frequency and size of cystic lesions at baseline. Incidence and physiological growing of the lesions were observed in a 5-years follow-up. At baseline, 431 volunteers had 1,479 cysts (71.0%). The mean number of cysts per person was 3.4 ± 9.0. The mean size of cysts was 13.1 ± 11.7 mm. Women had a higher number of cysts than men (p = 0.026). Older and male volunteers demonstrated a higher cyst frequency (p = 0.002 and p = 0.025). Per one-year increase in age the chance for a liver cyst increased by 2%. Four-hundred seventeen volunteers had cysts in the follow-up, in 24.6% new lesions had occurred. Lesion size significantly increased in follow-up (p < 0.001). Age and male sex were associated with the occurrence of at least one liver cyst. Women had a higher average number of cysts. Cystic lesion progression is a physiological phenomenon in the long-term follow-up.

3.
ACG Clinical Guideline: Focal Liver Lesions.

Frenette C, Mendiratta-Lala M, Salgia R, et al.

The American Journal of Gastroenterology. 2024;119(7):1235-1271. doi:10.14309/ajg.0000000000002857.

New Research

Hepatic cysts are thin-walled structures lined by cuboidal bile duct epithelium and filled with isotonic fluid (202). They are the result of ductal plate malformation without communication with the biliary tree (207,208). They can be solitary or multiple and often coexist with other mass lesions. They are usually asymptomatic and incidentally found, unless they are very large, in which case they can be symptomatic. There is a female predominance, although there is no established correlation with OCP use or pregnancy and cyst prevalence increases with age (208).
Simple hepatic cysts can be diagnosed on conventional grayscale ultrasound with a sensitivity and specificity of 90% (209). Simple hepatic cysts are usually homogeneously anechoic with through transmission and smooth margins. Up to 2.5%–5% of simple cysts can have up to 2 septa within them and include congenital cysts, Caroli disease, biliary hamartomas, and polycystic liver disease (PCLD). When a simple cyst is seen on ultrasound with these characteristics, no further imaging or follow-up is required. On CT, simple cysts demonstrate no internal architecture, are hypodense with fluid attenuation (<20 Hounsfield units), and demonstrate absent postcontrast enhancement. On MRI, simple cysts are hypointense on T1-weighted images and hyperintense on T2-weighted images with no enhancement. There is decreasing intensity on higher b-value diffusion-weighted imaging (209,210) (Figure 12).
There is no indication for intervention or follow-up of simple cysts, regardless of size, unless symptoms develop or there are characteristic high-risk features such as mural nodularity or enhancing septations. Symptoms can occur when cysts enlarge, rupture, or compress key structures, leading to significant abdominal pain or pressure, shortness of breath, early satiety, epigastric fullness, or lower extremity edema because of inferior vena cava compression.

4.
Complications Arising in Simple and Polycystic Liver Cysts.

Macutkiewicz C, Plastow R, Chrispijn M, et al.

World Journal of Hepatology. 2012;4(12):406-11. doi:10.4254/wjh.v4.i12.406.

Liver cysts are common, affecting 5%-10% of the population. Most are asymptomatic, however 5% of patients develop symptoms, sometimes due to complications and will require intervention. There is no consensus on their management because complications are so uncommon. The aim of this study was to perform a collected review of how a series of complications were managed at our institutions. Six different patients presenting with rare complications of liver cysts were obtained from Hepatobiliary Units in the United Kingdom and The Netherlands. History and radiological imaging were obtained from case notes and computerised radiology. As a result, 1 patient admitted with inferior vena cava obstruction was managed by cyst aspiration and lanreotide; 1 patient with common bile duct obstruction was first managed by endoscopic retrograde cholangiopancreatography and stenting, followed by open fenestration; 1 patient with ruptured cysts and significant medical co-morbidities was managed by percutaneous drainage; 1 patient with portal vein occlusion and varices was managed by open liver resection; 1 patient with infected cysts was treated with intravenous antibiotics and is awaiting liver transplantation. The final patient with a simple liver cyst mimicking a hydatid was managed by open liver resection. In conclusion, complications of cystic liver disease are rare, and we have demonstrated in this series that both operative and non-operative strategies have defined roles in management. The mainstays of treatment are either aspiration/sclerotherapy or, alternatively laparoscopic fenestration. Medical management with somatostatin analogues is a potentially new and exciting treatment option but requires further study.

5.
Hepatic Cysts: Reappraisal of the Classification, Terminology, Differential Diagnosis, and Clinicopathologic Characteristics in 258 Cases.

Armutlu A, Quigley B, Choi H, et al.

The American Journal of Surgical Pathology. 2022;46(9):1219-1233. doi:10.1097/PAS.0000000000001930.

The literature on liver cysts is highly conflicting, mostly owing to definitional variations. Two hundred and fifty-eight ≥1 cm cysts evaluated pathologically using updated criteria were classifiable as: I. Ductal plate malformation related (63%); that is, cystic bile duct hamartoma or not otherwise specified-type benign biliary cyst (35 with polycystic liver disease). These were female predominant (F/M=2.4), large (10 cm), often multifocal with degenerative/inflammatory changes and frequently misclassified as "hepatobiliary cystadenoma." II. Neoplastic (13%); 27 (10.5%) had ovarian-type stroma (OTS) and qualified as mucinous cystic neoplasm (MCN) per World Health Organization (WHO). These were female, solitary, mean age 52, mean size 11 cm, and 2 were associated with carcinoma (1 in situ and 1 microinvasive). There were 3 intraductal papillary neoplasms, 1 intraductal oncocytic papillary neoplasm, 1 cystic cholangiocarcinoma, and 2 cystic metastasis. III. Infectious/inflammatory (12%). These included 23 hydatid cysts (including 2 Echinococcus alveolaris both misdiagnosed preoperatively as cancer), nonspecific inflammatory cysts (abscesses, inflammatory cysts: 3.4%). IV. Congenital (7%). Mostly small (<3 cm); choledochal cyst (5%), foregut cyst (2%). V. Miscellaneous (4%). In conclusion, hepatic cysts occur predominantly in women (3/1), are mostly (90%) non-neoplastic, and seldom (<2%) malignant. Cystic bile duct hamartomas and their relative not otherwise specified-type benign biliary cysts are frequently multifocal and often misdiagnosed as "cystadenoma/carcinoma." Defined by OTS, MCNs (the true "hepatobiliary cystadenoma/carcinoma") are solitary, constitute only 10.5% of hepatic cysts, and have a significantly different profile than the impression in the literature in that essentially all are perimenopausal females, and rarely associated with carcinoma (7%). Since MCNs can only be diagnosed by demonstration of OTS through complete microscopic examination, it is advisable to avoid the term "cystadenoma/cystadenocarcinoma" solely based on radiologic examination, and the following simplified terminology would be preferable in preoperative evaluation to avoid conflicts with the final pathologic diagnosis: (1) noncomplex (favor benign), (2) complex (in 3 subsets, as favor benign, cannot rule out malignancy, or favor malignancy), (3) malignant features.

Expanded question: What is the global epidemiology of benign liver lesions such as hepatic cysts, hemangiomas, focal nodular hyperplasia, and hepatic adenomas, including data specific to Argentina?

Answered on November 14, 2024
La epidemiología global de las lesiones hepáticas benignas, como los quistes hepáticos, hemangiomas, hiperplasia nodular focal (FNH) y adenomas hepáticos, varía según la población y los métodos de detección utilizados. Un estudio que evaluó a 45,319 pacientes hospitalarios mediante ecografía encontró que las lesiones hepáticas benignas son comunes, con una prevalencia del 15.1% en la población estudiada. Los quistes hepáticos fueron la segunda lesión más común, con una prevalencia del 5.8%, seguidos por los hemangiomas hepáticos con un 3.3%. La FNH y los adenomas hepáticos fueron menos frecuentes, con prevalencias de 0.2% y 0.04%, respectivamente.[1]
La FNH es el tumor benigno no vascular más común del hígado y se encuentra típicamente en mujeres asintomáticas. Se cree que surge como una respuesta hiperplásica a un flujo sanguíneo localmente alterado. Por otro lado, los adenomas hepáticos son tumores benignos raros, principalmente en mujeres jóvenes que usan anticonceptivos que contienen estrógenos, y pueden complicarse con sangrado espontáneo o transformación maligna.[2]
En cuanto a datos específicos de Argentina, no se dispone de información detallada en la literatura médica proporcionada. Sin embargo, la prevalencia y características de estas lesiones pueden ser similares a las observadas en otras poblaciones debido a factores comunes como el uso de técnicas de imagen avanzadas y la exposición a anticonceptivos orales. Es importante considerar que la detección incidental de estas lesiones ha aumentado con el uso generalizado de modalidades de imagen de alta resolución.[2]

1.
Prevalence of Benign Focal Liver Lesions: Ultrasound Investigation of 45,319 Hospital Patients.

Kaltenbach TE, Engler P, Kratzer W, et al.

Abdominal Radiology (New York). 2016;41(1):25-32. doi:10.1007/s00261-015-0605-7.

Purpose: The aim of the study was to determine the sonographic prevalence of benign focal liver lesions on the basis of a population of hospital patients.

Methods: The ultrasound results in a population of (n = 45,319) hospital patients over a period of 10 years were examined retrospectively and evaluated for the diagnosis of benign focal liver lesions [hepatic cysts, hepatic hemangioma, focal nodular hyperplasia (FNH), hepatic adenoma, and focal fatty sparing]. Results that were incomplete or ambiguous were excluded from this study.

Results: At least one of the lesions to be investigated was diagnosed in 15.1% (n = 6839) of the patients of the total population. The most commonly recorded lesion, with a total prevalence of 6.3% (n = 2839), was focal fatty sparing, followed by hepatic cysts with 5.8% (n = 2631). The prevalence of hepatic hemangioma was 3.3% (n = 1640), while that of FNH was 0.2% (n = 81) and that of hepatic adenoma was 0.04% (n = 19). An association between the occurrence of benign focal liver lesions and age was observed.

Conclusions: The calculated prevalence of benign focal liver lesions shows that on the fortuitous discovery of space-occupying lesions of the liver, first consideration should be given to focal fatty sparing, simple hepatic cysts and hemangiomas. The finding of a FNH or an adenoma is rarely a random discovery.

2.
Focal Nodular Hyperplasia and Hepatic Adenoma: Epidemiology and Pathology.

Maillette de Buy Wenniger L, Terpstra V, Beuers U.

Digestive Surgery. 2010;27(1):24-31. doi:10.1159/000268404.

Focal nodular hyperplasia (FNH) and hepatic adenoma (HA) represent the most frequent non-vascular benign liver tumors. They are often asymptomatic. The widespread use of high-resolution imaging modalities leads to an increase of incidental detection of FNH and HA. Physicians are thus increasingly confronted with these formerly rarely recognized conditions, stressing the need for concise but adequate information on the optimal clinical strategies for these patients. FNH is the most common non-vascular benign tumor of the liver. It probably arises as a polyclonal, hyperplastic response to a locally disturbed blood flow. It is typically found in asymptomatic women. Histologically, FNH can be described as a focal form of cirrhosis. Complications of FNH are extremely rare and surgical resection is generally not advised. HA is a rare monoclonal, but benign liver tumor primarily found in young females using estrogen-containing contraceptives. Although its exact etiology is unknown, a direct link between sex steroid exposure and the uncontrolled hepatocellular growth is suspected. Complications of HA are spontaneous bleeding and malignant transformation. Withdrawal of estrogen treatment and excision of large tumors (>5 cm) are established therapeutic strategies. In conclusion, although FNH and HA are reasonably well-described clinical and histopathological entities, their epidemiology and pathophysiology need to be further unraveled.

Expanded question: What is the epidemiology of malignant liver lesions such as hepatocellular carcinoma, cholangiocarcinoma, fibrolamellar carcinoma, and metastases globally, including in Argentina?

Answered on November 14, 2024
La epidemiología de las lesiones hepáticas malignas, como el carcinoma hepatocelular (HCC), el colangiocarcinoma, el carcinoma fibrolamelar y las metástasis hepáticas, presenta variaciones significativas a nivel mundial y en Argentina.
El carcinoma hepatocelular (HCC) es el tipo más común de cáncer de hígado primario, representando entre el 75% y el 85% de los casos de cáncer hepático primario. A nivel mundial, se estima que hubo aproximadamente 725,000 nuevos casos de HCC en 2020, con una alta incidencia en regiones como Asia-Pacífico, donde la infección por el virus de la hepatitis B (HBV) es un factor de riesgo predominante.[1] En América del Sur, incluyendo Argentina, el HCC es también una preocupación significativa, con la hepatitis C (HCV) y la cirrosis alcohólica como factores de riesgo principales.[2]
El colangiocarcinoma intrahepático (iCCA) es el segundo tipo más común de cáncer hepático primario, con una incidencia global estimada de 123,000 casos en 2018. Las tasas más altas de iCCA se observan en el sudeste asiático, debido a factores como la infestación por parásitos hepáticos.[3-4] En Argentina, aunque los datos específicos son limitados, se espera que las tendencias sean similares a las de otras regiones con factores de riesgo compartidos.
El carcinoma fibrolamelar es una forma rara de HCC que afecta principalmente a jóvenes sin enfermedad hepática subyacente. Su incidencia es baja y no se dispone de datos específicos para Argentina en la literatura médica revisada.
Las metástasis hepáticas son más comunes que los tumores hepáticos primarios y suelen originarse de cánceres gastrointestinales, de mama, pulmón y páncreas. La incidencia de metástasis hepáticas refleja la carga global de estos cánceres primarios y su capacidad para diseminarse al hígado.
En resumen, el HCC y el iCCA son los tipos más comunes de cáncer hepático primario a nivel mundial, con variaciones regionales en la incidencia y los factores de riesgo. En Argentina, el HCC es prevalente, impulsado principalmente por la hepatitis C y el consumo de alcohol, mientras que los datos sobre el iCCA y el carcinoma fibrolamelar son más limitados. Las metástasis hepáticas son frecuentes y reflejan la diseminación de otros cánceres primarios.

1.
Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update.

Gordan JD, Kennedy EB, Abou-Alfa GK, et al.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2024;42(15):1830-1850. doi:10.1200/JCO.23.02745.

Leading Journal
New Research

There were approximately 725,000 new cases and 664,000 deaths worldwide due to hepatocellular carcinoma (HCC) in 2020. HCC comprises 75%-85% of primary liver cancer cases and is the fourth-leading cause of annual cancer deaths worldwide. In the United States, it is estimated that liver cancer will account for approximately 41,210 new cases and about 29,380 deaths in 2023. Risk factors vary by geographic region and include chronic viral hepatitis (hepatitis B virus [HBV] infection, hepatitis C virus [HCV] infection); alcohol-related liver disease; environmental exposures, specifically aflatoxin-contaminated foods; and steatotic liver disease. Three-quarters of cases occur in the Asia-Pacific region, where the main risk factor outside of Japan is HBV. HCC is two to three times as common in men as in women. Incidence of HCC is currently on the rise in the United States, related in part to a rise in the incidence of obesity, type II diabetes, and metabolic syndrome over the past several decades. Decreases in incidence rates among Asian-Pacific Islanders and younger cohorts may contribute to an overall reduction in cases of HCC in future years.
Effective treatment options, such as resection, liver transplantation, and ablation, exist for early-stage HCC, and patients with locally advanced disease may be candidates for liver-directed therapies, including transarterial therapies chemoembolization (TACE), bland embolization, and radioembolization, and external-beam radiation therapy. Historically, the majority of HCC cases were diagnosed at an advanced, incurable stage and had a poor prognosis due to the palliative nature of currently available local and systemic therapies. Trials of systemic therapy for advanced HCC failed to show improved outcomes until the advent of the tyrosine kinase inhibitor sorafenib, followed by randomized controlled trials (RCTs) published in 2008 and 2009 demonstrating a survival benefit with sorafenib versus placebo., Following the availability of sorafenib, no further effective systemic therapy options were identified for almost a decade.

2.
Hepatocellular Carcinoma in South America: Evaluation of Risk Factors, Demographics and Therapy.

Debes JD, Chan AJ, Balderramo D, et al.

Liver International : Official Journal of the International Association for the Study of the Liver. 2018;38(1):136-143. doi:10.1111/liv.13502.

BACKGROUND &

Aims: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Most studies addressing the epidemiology of HCC originate from developed countries. This study reports the preliminary findings of a multinational approach to characterize HCC in South America.

Methods: We evaluated 1336 HCC patients seen at 14 centres in six South American countries using a retrospective study design with participating centres completing a template chart of patient characteristics. The diagnosis of HCC was made radiographically or histologically for all cases according to institutional standards. Methodology of surveillance for each centre was following AASLD or EASL recommendations.

Results: Sixty-eight percent of individuals were male with a median age of 64 years at time of diagnosis. The most common risk factor for HCC was hepatitis C infection (HCV, 48%), followed by alcoholic cirrhosis (22%), Hepatitis B infection (HBV, 14%) and NAFLD (9%). We found that among individuals with HBV-related HCC, 38% were diagnosed before age 50. The most commonly provided therapy was transarterial chemoembolization (35% of HCCs) with few individuals being considered for liver transplant (<20%). Only 47% of HCCs were diagnosed during surveillance, and there was no difference in age of diagnosis between those diagnosed incidentally vs by surveillance. Nonetheless, being diagnosed during surveillance was associated with improved overall survival (P = .01).

Conclusions: Our study represents the largest cohort to date reporting characteristics and outcomes of HCC across South America. We found an important number of HCCs diagnosed outside of surveillance programmes, with associated increased mortality in those patients.

3.
Global, Regional and National Burden of Primary Liver Cancer by Subtype.

Rumgay H, Ferlay J, de Martel C, et al.

European Journal of Cancer (Oxford, England : 1990). 2022;161:108-118. doi:10.1016/j.ejca.2021.11.023.

Introduction: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) are the two main histological subtypes of primary liver cancer. Estimates of the burden of liver cancer by subtype are needed to facilitate development and evaluation of liver cancer control globally. We provide worldwide, regional and national estimates of HCC and iCCA incidence using high-quality data.

Methods: We used population-based cancer registry data on liver cancer cases by histological subtype from 95 countries to compute the sex- and country-specific distributions of HCC, iCCA and other specified histology. Subtype distributions were applied to estimates of total liver cancer cases for 2018 from the Global Cancer Observatory. Age-standardised incidence rates (ASRs) were calculated.

Results: There were an estimated 826,000 cases of liver cancer globally in 2018: 661,000 HCC (ASR 7.3 cases per 100,000); 123,000 iCCA (ASR 1.4) and 42,000 other specified histology (ASR 0.5). HCC contributed 80% of the world total liver cancer burden followed by iCCA (14.9%) and other specified histology (5.1%). HCC rates were highest in Eastern Asia (ASR 14.8), Northern Africa (ASR 13.2) and South-Eastern Asia (ASR 9.5). Rates of iCCA were highest in South-Eastern Asia (ASR 2.9), Eastern Asia (ASR 2.0), Northern Europe, the Caribbean and Central America and Oceania (ASR all 1.8).

Conclusion: We have shown the importance of uncovering the distinct patterns of the major subtypes of liver cancer. The use of these estimates is critical to further develop public health policy to reduce the burden of liver cancer and monitor progress in controlling HCC and iCCA globally.

4.
Liver Cancer: Descriptive Epidemiology and Risk Factors Other Than HBV and HCV Infection.

Chuang SC, La Vecchia C, Boffetta P.

Cancer Letters. 2009;286(1):9-14. doi:10.1016/j.canlet.2008.10.040.

Leading Journal

The incidence of liver cancer is high in all low-resource regions of the world, with the exception of Northern Africa and Western Asia. The estimated worldwide number of new cases of liver cancer in 2002 is 600,000, of which 82% are from developing countries. Given the poor survival from this disease, the estimated number of deaths is similar to that of new cases. Hepatocellular carcinoma (HCC) is the main form of liver cancer. A part from chronic infections with Hepatitis B and Hepatitis C viruses, which are the main causes of HCC, contamination of foodstuff with aflatoxins, a group of mycotoxins produced by the fungi Aspergillus flavus and Aspergillus parasiticus, is an important contributor to HCC burden in many low-income country. Alcoholic cirrhosis is an important risk factor for HCC in populations with low prevalence of HBV and HCV infection, and the association between tobacco smoking and HCC is now established. Diabetes is also related to an excess risk of HCC and the increased prevalence of overweight and obesity likely contributes to it. The second most important type of liver cancer is cholangiocarcinoma, whose main known cause is infestation with the liver flukes, Opistorchis viverrini and Clonorchis sinensis, which is frequent in some areas in South-East Asia. Angiosarcoma is a rare form of liver cancer whose occurence is linked to occupational exposure to vinyl chloride.