Bronchioloalveolar carcinoma
Synonyms and keywords: Adenocarcinoma in situ (AIS); Bronchioloalveolar carcinoma (BAC)
| Bronchioloalveolar carcinoma | |
| MeSH | D002282 |
|---|---|
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Anila Hussain, MD [2] Manpreet Kaur, MD [3]
Overview
Bronchioloalveolar carcinoma (BAC) is a rare type of lung cancer which more frequently among never-smokers, women and Asians( particularly Eastern-Asian). In the new WHO classification of lung adenocarcinoma's, changes were made as proposed by the 2011 IASLC/ATS/ERS and bronchioloalveloar carcinoma (BAC) is now classified as a subtype of lung adenoacarcinoma and the term BAC is no longer in use. It is also known as "lepidic predominant adenocarcinoma" due to its progression along the alveolar walls without invading stromal, pleural or vascular tissue. By definition, BAC is not an invasive tumor. Therefore, pathologists classify it as a form of carcinoma in situ (CIS). However, unlike other forms of CIS, its behavior is malignant, often lethal. Major surgery, either a lobectomy or a pneumonectomy, is needed to control it, and recurrences are frequent. For this reason, oncologists classify it among the other malignant tumors, which are invasive tumors.
Historical prespective
- John George Adami, MD, professor of pathology used the term lepidic in an address to the Toronto Pathological Society on January 4, 1902, for tumors that were derived from surface lining cells.[1][2]
- Bronchioloalveolar carcinoma was first discovered by Dr. Averill Liebow, in the year of 1960.
- In 1999, the World Health Organization has given the term 'Pure BAC' as a subtype of adenocarcinoma that doesn’t Invade.
- There have been recent changes in pathologic classification of lung cancer by (IASLC/ATS/ERS) as compared to previous WHO classification and bronchioloalveolar carcinoma is now described as adenocarcinoma in situ or AIS (previously known as solitary or pure BAC)
Classification
According to the current criteria, bronchioloalveolar carcinoma is defined as a sub-type of lung adenocarcinoma and the lesions are now described under categories adenocarcinoma in Situ (AIS) and minimally invasive adenocarcinoma (MIA).[3][4][5][6]
However it is distinct from other lung adenocarcinomas by different clinical features, prognosis and response to treatment.[7]
IASLC/ATS/ERS Classification of Lung Adenocarcinoma in Resection Specimens describes BAC in following subheadings:[8]
Adenocarcinoma in situ (AIS) - Previously Known as solitary BAC
- Less than or equal to 3 cm
- Can be either mucinous or serous
- No stromal, lymphatic, or pleural invasion
- No necrosis
- no other growth pattern other than along the airways (lepidic)
Minimally invasive adenocarcinoma (MIA)
- Less than or equal to 3 cm
- Less than or equal to 5 mm area of stromal invasion or another type of growth patterns (in comparison with the lepidic pattern of growth)
- Can be mucinous, non-mucinous or mixed
Invasive adenocarcinoma
- Presence of stromal invasion or patterns of growth other than lepidic
- Lepidic predominant - Type of invasive adenocarcinoma with more than 5 mm invasion (Previously known as Non-Mucinous BAC with invasion)
- Invasive mucinous adenocarcinoma - Previously known as mucinous BAC
The two different sub-types of BAC depending on the cellular cytology are described as follows[9];
Mucinous BAC:
- Less common
- More often seen in non-smokers
- Develop from bronchiolar epithelial metaplasia
- Present often as pneumonia-like infiltrate
- Frequently associated with a K-Ras mutation
Non-Mucinous BAC:
- More common
- More often seen in smokers
- Originate from the terminal respiratory cells, type II pneumocytes, and Clara cells
- Presents usually as a ground glass opacity
- Frequently associated with EFGR mutations
Pathophysiology
Bronchioloalveolar carcinoma is also known as "lepidic predominant adenocarcinoma" due to its progression along the alveolar walls without invading stromal, pleural or vascular tissue. The pattern of BAC can range from slow growing indolent tumor to rapidly growing fatal tumor. The mucinous type of bronchioloalveolar cancer is frequently associated with a K-Ras mutations and develop from bronchiolar epithelial metaplasia, is often seen in non-smokers and present usually as a pneumonia-like infiltrate. Non mucinous BAC develops in the cells near the alveoli (including type II pneumocytes and Clara cells) in the terminal or outer portion of the lungs and is frequently associated with EFGR mutations.It is more common in smokers and presents as ground glass opacity on radiograph. BAC can present as a solitary nodule or as multifocal lung nodules but there is no final answer to whether multiple lung nodules are due to disseminated malignant cells from primary focus or synchronous development of independent foci[10]. Type-I cystic adenomatoid malformation (CAM) has been described as a precursor lesion for the development of mucinous AIS (adenocarcinoma in situ)recently due to its intramucinous cluster of cells resembling mucinous BAC and frequent K-Ras mutations in these lesions, but these cases are uncommon[11][12]. The pathogenesis of BAC is poorly understood and hypothesized as a part of multi step carcinogenesis from atypical adenomatous hyperplasia (AAH) through bronchioloalveolar carcinoma (BAC) to invasive adenocarcinoma (AC), but there has been no formal demonstration of this phenomena so far[13].
Microscopic Pathology
Causes
Smoking:
- Smoking has not been thought to be associated with BAC generally
- Almost 30 percent patients of BAC are never smokers as compared to adenocarcinoma's (15 percent are never smokers) and squamous cell cancers (only 5 percent are never smokers)[14]
- However some recent pooled studies have shown a two-fold increased risk of BAC in smokers as compared to never-smokers and higher risk with increasing and prolonged consumption with risk decreasing in years following the smoking cessation[15]
- Still, the magnitude of the relationship between smoking and adenocarcinoma in situ (BAC) is much smaller than other lung cancers and further studies are needed on this
Genetics:
- Mucinous BAC are frequently associated with K-Ras mutations
- Non-mucinous BAC are frequently associated with EFGR mutations
Hypothesis regarding JSRV[16]:
- Jaagsiekte Sheep Retrovirus (JSRV) is a highly infectious retrovirus in sheep that causes low grade tumors in sheep resembling BAC
- This led to the hypothesis that same virus might be responsible for the similar cancer in humans
- However, no molecular study has confirmed this hypothesis so far
Differentiating Bronchioloalveolar carcinoma (Adenocarcinoma in situ) from other Diseases
- BAC must be differentiated from other diseases that cause cough, sputum, shortness of breath, and weight loss, such as:
- Cryptogenic Organizing Pneumonia (COP)
- Pneumonia
- Sarcoidosis
- Tuberculosis
- Pulmonary edema
- Atypical adenomatous hyperplasia-can be a precursor to adenocarcinoma in situ (BAC)
Epidemiology and Demographics
- BAC is a rare form of lung cancer that comprises less than 4 percent of total cases of lung cancers
- Age adjusted Incidence rates were found to be between 1 or 2 per 100,000 in USA (1970's-1980's)[17]
- Rising incidence has been suggested by some studies in later years[18], however no marked increased in incidence rate was confirmed or reported to SEER database in the next 2 decades[19] (after 1980's)
- However, adding BAC along to mixed adenocarcinoma sub-types having a BAC component, the cummulative incidence is increased up to the 20 percent of total lung cancers[20]
Age
- BAC or AIS is thought to be more commonly seen in younger population, yet no evidence of such a pattern has been found in the studies and different studies have shown different results
- According to SEER database, mean age at diagnosis for BAC (years) is 66.99 +/- 10.66 which is very similar to other NSCLC and only 6.06 percent patients were found to be below 50 years of age[21]
Gender
- Women are more commonly affected by BAC than males.
Race
- BAC usually affects individuals of the Asians( particularly Eastern-Asian) ethnicity.
- White individuals are less likely to develop BAC or AIS.
Risk Factors
- Risk factors for development of BAC are poorly understood due to rarity of the type of cancer and recent change in WHO definition and classification
- Some common risk factors that can be considered in the development of BAC are smoking (not a confirmed risk factor) and genetic supectibility in certain ethnicities.
- Some single nucleotide polymorphism's (SNPs) are thought to be associated with adenocarcinoma in situ in certain ethnicities[22] (asian) and non smokers for example TERT-CLPMT1L region on Chr5p15 was found to be linked with adenocarcinoma risk in non-smoking asian women[23], however no study showed particular relation of genetic supceptibility to BAC.
Natural History, Complications and Prognosis
- The patients with BAC may remain asymptomatic for years
- Once symptomatic, patients deteriorate rapidly
- Common clinical features include cough, sputum and shortness of breath.
- If left untreated, diffuse disease usually leads to death within the 3 years
- Prognosis is generally good, especially in case of localized disease in early stages[24]
- One study showed a 5 year prognosis of 100 percent after surgery in patients with tumors 3 cm or less[25]
- However, the prognosis vary according to stage of disease at the time of diagnosis
Prognostic Subgroups[26]
- Low grade
- 100 percent 5 year disease free survival
- Includes adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA)
- Intermediate grade
- High grade
- Invasive mucinous adenocarcinoma - 75 percent 5-year disease-free survival
- Colloid predominant - 71 percent 5-year disease-free survival
- Solid predominant - 70 percent 5-year disease-free survival
- Micropapillary predominant - 67 percent 5-year disease-free survival
Diagnosis
Diagnostic Criteria
Symptoms
- Most patients are asymptomatic and BAC is discovered upon biopsy of an incidentally found solitary pulmonary nodule
- Others may presents with symptoms raging from cough, sputum, shortness of breath, hemoptysis, fever to bronchorrea which may lead to electrolyte imbalance[27]
- Below are the percentage of symptoms seen in different patients:
| Symptom | Percentage of Patients with the symptom |
|---|---|
| Cough | 35 |
| Sputum | 24 |
| Shortness of Breath | 15 |
| Weight loss | 13 |
| Hemoptysis | 11 |
| Fever | 8 |
| Bronchorrhea
(whitish mucoid or watery expectoration) |
5 |
Physical Examination
- Patients with BAC usually appear normal in early stages of the disease.
- Physical examination is usually normal for all systems including lungs in most cases
- However exam may be remarkable for:
- Fever
- Lung findings consistent with consolidation ( dullness on percussion, increased vocal fremitus and increased vocal resonance) may be seen although not present in all cases
Laboratory Findings
- There are no specific laboratory findings associated with BAC.
Imaging Findings
- CT scan is the imaging modality of choice for BAC.
- X-Ray findings can range anywhere from single or multiple ground glass opacities ( with or without solid components) to consolidation and nodules[29]
- CT scan may demonstrate ground glass opacities with or without consolidation often along with a bubble like low attenuation areas and open bronchus sign, air bronchograms or bronchiolograms, irregular or ill-defined margins and pleural tails[30]
Other Diagnostic Studies
- FDG-PET may also be used for diagnosis however it is less reliable in BAC as compared to the diagnosis of other NSCLC (Non small cell lung cancer).
- CT guided needle aspiration biopsy is very useful to confirm the diagnosis and for histological grading of the tumor
Treatment
Medical Therapy
- Treatment for BAC is primarily surgical in localized cases along with the fact that BAC is believed to be less responsive to chemotherapy as compared to other non small cell lung cancers
- However, in case of a large number of nodules or foci are found in lungs, chemotherapy is generally considered
- Initial treatment may be with standard cytotoxic platinum doublet chemotherapeutic regimen containing cisplatin or carboplatin
- Epidermal growth factor receptor tyrosine kinase inhibitors (EFGR-TKIs) like Gefitinib and Afanitib are currently used in treatment of advanced or recurrent disease with failed response to cytotoxic chemotherapy[31]
- Some studies advocate the use of bortezomib as a therapeutic method especially those who progressed with an EFGR-TKIs treatment[32] but more data is needed on that
Surgery
- Surgery is the mainstay of therapy for localized bronchioloalveolar cancer.
- Lobectomy in conjunction with mediastinal lymph node dissection is the most common approach to the treatment of localized BAC
- Pneumonic form of BAC ( rare variant with lobar consolidation and filling of alveoli with mucinous adenocarcinoma) has a very poor prognosis despite surgical resection[33]
Prevention
- There are no primary preventive measures available for BAC. Role of smoking as a causative factor for BAC is controversial, however, smoking cessation helps in decreasing risk of most of the lung cancers in general
- Follow-up of solitary pulmonary nodules or ground glass opacities discovered incidentally on X-ray may lead to early identification of the disease
- Once diagnosed and successfully treated, patients with early stage BAC have high disease free survival rates as compared to similar stage adenocarcinoma[34]
- Follow-up testing includes X-ray or HR-CT scan
References
- ↑ Jones, Kirk D. (2013). "WhenceLepidic?: The History of a Canadian Neologism". Archives of Pathology & Laboratory Medicine. 137 (12): 1822–1824. doi:10.5858/arpa.2013-0144-HP. ISSN 0003-9985.
- ↑ Raz, DJ (Mar 2006). "Bronchioloalveolar carcinoma: a review". Clinical Lung Cancer. Cancer Information Group. 7 (5): 313–322. Unknown parameter
|coauthors=ignored (help) - ↑ Lantuejoul S, Rouquette I, Brambilla E, Travis WD (2016). "[New WHO classification of lung adenocarcinoma and preneoplasia]". Ann Pathol. 36 (1): 5–14. doi:10.1016/j.annpat.2015.11.010. PMID 26791238.
- ↑ Butt YM, Allen TC (2015). "The Demise of the Term Bronchioloalveolar Carcinoma". Arch Pathol Lab Med. 139 (8): 981–3. doi:10.5858/arpa.2013-0385-RA. PMID 26230592.
- ↑ Travis, William D.; Brambilla, Elisabeth; Nicholson, Andrew G.; Yatabe, Yasushi; Austin, John H.M.; Beasley, Mary Beth; Chirieac, Lucian. R.; Dacic, Sanja; Duhig, Edwina; Flieder, Douglas B.; Geisinger, Kim; Hirsch, Fred R.; Ishikawa, Yuichi; Kerr, Keith M.; Noguchi, Masayuki; Pelosi, Giuseppe; Powell, Charles A.; Tsao, Ming Sound; Wistuba, Ignacio (2015). "The 2015 World Health Organization Classification of Lung Tumors". Journal of Thoracic Oncology. 10 (9): 1243–1260. doi:10.1097/JTO.0000000000000630. ISSN 1556-0864.
- ↑ Garfield DH, Cadranel J, West HL (2008). "Bronchioloalveolar carcinoma: the case for two diseases". Clin Lung Cancer. 9 (1): 24–9. doi:10.3816/CLC.2008.n.004. PMID 18282354.
- ↑ Lee, KS (Nov–Dec 1997). "Bronchioloalveolar carcinoma: clinical, histopathologic, and radiologic findings" (PDF). RadioGraphics. 17 (6): 1345–1357. PMID 9397450. Retrieved 2007-12-03. Unknown parameter
|coauthors=ignored (help) - ↑ New Pathologic Classification of Lung Cancer: Relevance for Clinical Practice and Clinical Trials William D. Travis, Elisabeth Brambilla, and Gregory J. Riely Journal of Clinical Oncology 2013 31:8, 992-1001
- ↑ Garfield DH, Cadranel J, West HL (2008). "Bronchioloalveolar carcinoma: the case for two diseases". Clin Lung Cancer. 9 (1): 24–9. doi:10.3816/CLC.2008.n.004. PMID 18282354.
- ↑ Saintigny P, Wistuba II, Kim ES (2010). "Bronchioloalveolar carcinoma: a translational perspective". Oncology (Williston Park). 24 (10): 907–8, 914. PMID 21138171.
- ↑ Abecasis F, Gomes Ferreira M, Oliveira A, Vaz Velho H (2008). "[Bronchioloalveolar carcinoma associated with congenital pulmonary airway malformation in an asymptomatic adolescent]". Rev Port Pneumol. 14 (2): 285–90. PMID 18363023.
- ↑ Scialpi M, Cappabianca S, Rotondo A, Scalera GB, Barberini F, Cagini L; et al. (2010). "Pulmonary congenital cystic disease in adults. Spiral computed tomography findings with pathologic correlation and management". Radiol Med. 115 (4): 539–50. doi:10.1007/s11547-010-0467-6. PMID 20058095.
- ↑ Bettio D, Cariboni U, Venci A, Valente M, Spaggiari P, Alloisio M (2012). "Cytogenetic findings in lung cancer that illuminate its biological history from adenomatous hyperplasia to bronchioalveolar carcinoma to adenocarcinoma: A case report". Exp Ther Med. 4 (6): 1032–1034. doi:10.3892/etm.2012.725. PMC 3494121. PMID 23226769.
- ↑ Bracci PM, Sison J, Hansen H, Walsh KM, Quesenberry CP, Raz DJ; et al. (2012). "Cigarette smoking associated with lung adenocarcinoma in situ in a large case-control study (SFBALCS)". J Thorac Oncol. 7 (9): 1352–60. doi:10.1097/JTO.0b013e31825aba47. PMC 3421052. PMID 22814813.
- ↑ Boffetta P, Jayaprakash V, Yang P, Asomaning K, Muscat JE, Schwartz AG; et al. (2011). "Tobacco smoking as a risk factor of bronchioloalveolar carcinoma of the lung: pooled analysis of seven case-control studies in the International Lung Cancer Consortium (ILCCO)". Cancer Causes Control. 22 (1): 73–9. doi:10.1007/s10552-010-9676-5. PMC 3002160. PMID 21072579.
- ↑ Mornex JF, Thivolet F, De las Heras M, Leroux C (2003). "Pathology of human bronchioloalveolar carcinoma and its relationship to the ovine disease". Curr Top Microbiol Immunol. 275: 225–48. PMID 12596901.
- ↑ Falk RT, Pickle LW, Fontham ET, Greenberg SD, Jacobs HL, Correa P; et al. (1992). "Epidemiology of bronchioloalveolar carcinoma". Cancer Epidemiol Biomarkers Prev. 1 (5): 339–44. PMID 1339048.
- ↑ Barsky SH, Cameron R, Osann KE, Tomita D, Holmes EC (1994). "Rising incidence of bronchioloalveolar lung carcinoma and its unique clinicopathologic features". Cancer. 73 (4): 1163–70. PMID 8313318.
- ↑ Read WL, Page NC, Tierney RM, Piccirillo JF, Govindan R (2004). "The epidemiology of bronchioloalveolar carcinoma over the past two decades: analysis of the SEER database". Lung Cancer. 45 (2): 137–42. doi:10.1016/j.lungcan.2004.01.019. PMID 15246183.
- ↑ Godoy MC, Naidich DP (2009). "Subsolid pulmonary nodules and the spectrum of peripheral adenocarcinomas of the lung: recommended interim guidelines for assessment and management". Radiology. 253 (3): 606–22. doi:10.1148/radiol.2533090179. PMID 19952025.
- ↑ <ref name="RazJablons2006">Raz, Dan J.; Jablons, David M. (2006). "Bronchioloalveolar Carcinoma Is Not Associated with Younger Age at Diagnosis: An Analysis of the SEER Database". Journal of Thoracic Oncology. 1 (4): 339–343. doi:10.1016/S1556-0864(15)31592-6. ISSN 1556-0864.</r
- ↑ Jin G, Xu L, Shu Y, Tian T, Liang J, Xu Y; et al. (2009). "Common genetic variants on 5p15.33 contribute to risk of lung adenocarcinoma in a Chinese population". Carcinogenesis. 30 (6): 987–90. doi:10.1093/carcin/bgp090. PMID 19369581.
- ↑ Hsiung CA, Lan Q, Hong YC, Chen CJ, Hosgood HD, Chang IS; et al. (2010). "The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia". PLoS Genet. 6 (8). doi:10.1371/journal.pgen.1001051. PMC 2916850. PMID 20700438.
- ↑ Liu YY, Chen YM, Huang MH, Perng RP (2000). "Prognosis and recurrent patterns in bronchioloalveolar carcinoma". Chest. 118 (4): 940–7. PMID 11035660.
- ↑ Sakurai H, Dobashi Y, Mizutani E, Matsubara H, Suzuki S, Takano K; et al. (2004). "Bronchioloalveolar carcinoma of the lung 3 centimeters or less in diameter: a prognostic assessment". Ann Thorac Surg. 78 (5): 1728–33. doi:10.1016/j.athoracsur.2004.05.017. PMID 15511463.
- ↑ Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG; et al. (2011). "Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases". Mod Pathol. 24 (5): 653–64. doi:10.1038/modpathol.2010.232. PMID 21252858.
- ↑ Lee KS, Kim Y, Han J, Ko EJ, Park CK, Primack SL (1997). "Bronchioloalveolar carcinoma: clinical, histopathologic, and radiologic findings". Radiographics. 17 (6): 1345–57. doi:10.1148/radiographics.17.6.9397450. PMID 9397450.
- ↑ Lee, K S; Kim, Y; Han, J; Ko, E J; Park, C K; Primack, S L (1997). "Bronchioloalveolar carcinoma: clinical, histopathologic, and radiologic findings". RadioGraphics. 17 (6): 1345–1357. doi:10.1148/radiographics.17.6.9397450. ISSN 0271-5333.
- ↑ Gandara DR, Aberle D, Lau D, Jett J, Akhurst T, Heelan R; et al. (2006). "Radiographic imaging of bronchioloalveolar carcinoma: screening, patterns of presentation and response assessment". J Thorac Oncol. 1 (9 Suppl): S20–6. PMID 17409997.
- ↑ https://www.vcuthoracicimaging.com/historyanswer.aspx?qid=47&fid=1
- ↑ Raz DJ, Kim JY, Jablons DM (2007). "Diagnosis and treatment of bronchioloalveolar carcinoma". Curr Opin Pulm Med. 13 (4): 290–6. doi:10.1097/MCP.0b013e32816ebc62. PMID 17534175.
- ↑ Ramalingam SS, Davies AM, Longmate J, Edelman MJ, Lara PN, Vokes EE; et al. (2011). "Bortezomib for patients with advanced-stage bronchioloalveolar carcinoma: a California Cancer Consortium Phase II study (NCI 7003)". J Thorac Oncol. 6 (10): 1741–5. doi:10.1097/JTO.0b013e318225924c. PMC 3220078. PMID 21716143.
- ↑ Rusch VW, Tsuchiya R, Tsuboi M, Pass HI, Grunenwald D, Goldstraw P (2006). "Surgery for bronchioloalveolar carcinoma and "very early" adenocarcinoma: an evolving standard of care?". J Thorac Oncol. 1 (9 Suppl): S27–31. PMID 17409998.
- ↑ Rena, O (2003). "Stage I pure bronchioloalveolar carcinoma: recurrences, survival and comparison with adenocarcinoma of the lung". European Journal of Cardio-Thoracic Surgery. 23 (3): 409–414. doi:10.1016/s1010-7940(02)00830-8. ISSN 1010-7940.
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