Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
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Lung Pathology
Medical: I'd like to recommend that all pathologists support USCAP which, among other efforts to help us, free-for-viewing posts valuable CME handouts on-line in their Knowledge Hub14.
  • infectious:
  • noninfectious:
    1. BOOP: bronchiolitis obliterans with organizing pneumonia (BOOP) is inflammation of the small airways (bronchioles) and surrounding tissue in the lung. It can affect a small segment of the lung or the entire lung. It can be idiopathic or secondary, related to a historical insult but is not primarily infectious; spaces contain pale, "juicy" fibroplastic polyps or foci [L07-8086]; in 9/07, it was thought that the buttery-flavor, diacetyl, caused "popcorn lung" in microwave popcorn workers & the histology of that is BOOP.
    2. UIP: interstitial fibrosis that is negative for other clues to other entities.
    3. DIP: interstitial fibrosis associated with alveolar filling by pneumocytes.
    4. LIP: interstitial fibrosis Associated with a prominent lymphocytic infiltrate.
    5. tissue eosinophilia on biopsy: asthma (FA11-186, a death in asthmatic & presumed status asthmaticus), ABPA, eosinophilic pneumonia, other allergic.
    6. collagen vascular disease associtated interstitial fibrosis: broncho-alveolar lavage...BAL...may show eosinophilia.
    7. idiopathic pulmonary fibrosis.
    8. granulomatous: sarcoid (epithelioid), rheumatoid (palisaded).
  • chronic cough causes.
  • infections: CMV nuclear inclusions; AFB or fungal granulomatous (polys...caseation) (FNA elsewhere DX lung ca. but lobect. LMC had histoplasmosis, L07-4666); polys (think bacterial...but there are some non-infectious causes of polys).
  • diffuse alveolar damage (DAD): alveolar spaces lined with fibrin & may see reactive, quite atypical pneumocytes.
    1. inspired agents etiology: toxic...infectious.
    2. shock lung: shock lung without or with transfusion of blood bank products (transfusion associated lung injury...TRALI [newe acute lung injury within 6 hours of a transfusion]). TRALI5 has an incidence of 1:5000 transfusions. DDX is SOB due to fluid overlod (diuretic Rx) vs.TRALI (maybe best to not give diuretic) and has about two proposed mechanisms as of the end of 2007:
      • the antibody payhway: an uncertain anti-leukocyte (anti-WBC; anti-neutrophil) antibody in donor unit binds to an antigen site on the recipient WBCs to start a detrimental, damaging immunological TRALI cascade. Multiparous women tend to carry the highest incidence of these antibodies.
      • the two hit pathway: (1) biological response modifiers...such as cellular or molecular breakdown products or donor blood then (2) get transfused into a recipient whose WBCs are primed or activated (maybe by sepsis) an d the interaction trtiggers TRALI.
  • pulmonary hypertension: [Pulm. Hyperten. Assn.] [Heath-Edwards pulmonary hypertension vasculopathy grades].
  • Post obstructive pulmonary edema syndrome (POPE): induced by inspiration against a closed glottis (negative pressure pulmonary edema), as in drowning or post-extubation (or other events triggering bronchospasm), and can be a cause of minor problems to nearly sudden death [FA04-87].
  • benign nodules:
    • fungal nodules
    • acid fast organism nodules:
    • granulomata without organisms: sarcoid, pneumoconiosis, BCGosis (MERosis)3[T07-183; L07-8188].
  • pulmonary calcification:
  • metaplastic bone: tends to occur in lung having any kind of fibrotic process2.
    • diffuse pulmonary ossification (DPO): innumerable branching linear delicate ossifications felt as gritty, thread-like, stiff-hairbrush-like texture on cut surface [L06-3321; L07-7191] & not bronchocentric.
    • tracheobronchopathia osteoplastica: sometimes bronchoscopically visible boney accumulations in bronchial subepithelial stroma.
  • diffuse bronchial tree cartilagenous calcification: a phenomenon of advancing age (but can see a little bit in younger age 1.
  • metastatic ca++ deposits: in general alveolar parenchyma & rarely just bronchial basement membrane zone & subepithelial fibrous stroma (renal failure and/or other chronically hypercalcemic situations).
  • malignant lung lesions: [NOTE: a new PCR-based gene expression risk stratification profile (Pervenio) has come to market in 2013 to predict pT1a cases destined to behave badly; FFPE is the sample].
    • primary vs. met.: SCC & NEC will be essentially the same, either way14a.
      • initial panel: TTF-1 (lung usually + unless SCC), ck7 (lung usually +), ck20 (lung usually -), CEA (lung usually-), PSA (lung usually -), and ER/PR (lung usually -)14a.
      • IHC DDX: calcitonin marks medullary thyroid & thyroglobulin marks thyroid; S100 & mel. proteins mark melanoma; CDX2 & ck20 mark CRC & ck7 neg.; lymphoid markers mark ALCL14a.
      • oddities: 60-90% mucinous BAC are ck20+; primary colloid mucinous adenoca. lung CDX2+, 55% ck20+, 82% ck7+, & 73% TTF-1+14a.
    • Targeted therapy molecular and H&E correlations: [DECISION TREE]
      • EGFR positivty: Second most common of 3 mutations21; more often in nonsmokers, Asians, females, grade I-II, non-mucinous BAC/AIS/lepidic17, as well as papillary14c. Cytopath of prominent intranuclear inclusions cases tend EGFR pos16. About 50% of NSCLC & various EGFR alterations are notoriously heterogeneously located within a given tumor14b.
      • ALK ISH rearrangement positivity: Least common of 3 mutations21; more often in signet ring adenoca.; younger; never/light smoker15 and solid with frequent signet cells & abundant intracytoplasmic mucin14b. ALK has many break points (break-apart) and translocation partners, most common being EML415. The IHC is poor because rearranged cases mostly have low protein expression; PCR being evaluated15. FDA approved 8/2011 the TKI, crizotinib (Xalkori) for those with ALK abnormal; some ALK-positive, nonresponsive tumors got EGFR mutations, developed ALK binding-pocket mutations, or developed an "escape" pathway19.
      • KRAS positivity: Most common of the 3 mutations21;more common in smokers & mucinous BAC14c, 17 & mucinous adenocarcinoma with bronchioloalveolar features (AWBF)18. Cytology poorly differentiated, maybe squamoid features, and necrosis tend KRAS pos16.
      • BRAF positivity: a small percentage of NSCLC are BRAF mutation positive20.
    • pT & pN stage: T2 or higher and/or lymphovascular invasion = need adjuvant treatment & no resection if mediastinal pos.
      • size & number tumors: satellite nodules in same lobe as primary are T4 and in another lobe are M1 T2 = >3CM or involves main bronchus @ 2CM or less from carina:
      • synchronous primaries: synchronous double or triple primaries (vs. intrapulmonary mets) ... synchronous primaries may have an incidence as high as 6%10 but a Chinese study11 of 4649 lung cancer cases from 1983-2004 only found 31 cases ...0.6% & cited 3 other studies suggesting between 1 & 3%). Non-BAC & defined(after 11):
        1. actually one tumor?: are they simutaneous disconnected synchronous tumors or poorly connected epicenters of a single tumor?
        2. Or, (1) H&E histology is different...or, (2) if same by H&E, they are "different" IF: absent special studies, they are in different lobes AND without N2, N3, or M1 status or if each has some original residual CIS and no cancer in lymphatics common to both (no N1 or N2). No extra-pulmonary mets at time of DX. Both should be no worse than stage I. Special studies show a clear difference: such as IHC (p53 [our T08-54]), research DNA, EM, ploidy or DNA index differences (if both aneuploid).
      • intrapulmonary mets: if in same lobe as primary = pT4 & M0; if into another lobe, pT4 & M1. HENCE, the vital importance of distinguishing mets vs. synchronous primaries [L08-3588]!
      • pleural status:"invasion" = T2
        • when pre-op images seem to indicate malignant pleural adhesion, over 50% of the time careful histology exam proves this is wrong.
        • pleural T status: invasion does not make pT2...actual penetration makes pT24. pT1 vs. pT2: membrane invasion by direct extension (thru the visceral peripulmonary elastic layers4,8) makes pT24,7,8.
        • radiation needed? But, the pleura can be pulled down into the tumor and invasively penetrated & sealed off down in this interior space with no call for adjuvant radiation, even though it is, thereby pT2 [LMC-07-3392] & may, therefore, call for chemotherapy.
        • pT3: adhesed visceral-parietal & direct-extension penetration into parietal of chest, pericardium or mediastinum7.
        • pT47: cancer out into or onto pleural surface with intra-pleural skip foci beyond direct extension; through & out on the free pleural surface implys the set-up for an incipient [T08-54] malignant effusion (pT4) ...but is it the same (6th ed. AJCC has a "clinical" malignant effusion as cT4)? AJCC 6th not clear on this for chest7 but is clear that its pT4 for colon cancer in abdomen. But, the pleura can be pulled down into the tumor and invasively penetrated (pT2) & sealed off down in this interior closed space with no call for adjuvant radiation [LMC-07-3392] but may, therefore, call for chemotherapy.
      • bronchial margin: FS eval. of margins & resect more only if tissue is positive (not if lymphovascular positive only1,9)...T2 = >3CM or involves main bronchus @ 2CM or less from carina.
    • bronchioalveolar carcinoma (BAC): neoplastic cells along alveolar walls in lepidic growth pattern & no invasion (AIS); mucinous BAC does not respond to tyrosine kinase inhibitors6. Adenocarcinomas with at least 50% lepidic pattern and invasive foci never larger than 5mm do not go to nodes9.
    • small cell neuroendocrine carcinoma: (1) neuroendocrine granular nuclei with (2) IHC neuroendocrine positivity; & malignant features such as elevated Ki67 FNA12-573]. There are controversies as to NET/carcinoid terminology once proliferation is increased [L08-5641]...even to the point of an occassional lawsuit being filed.
    • small cell non-neuroendocrine carcinoma: (1) nuclei not neuroendocrine (2) & IHC favoring either adenoca. or SCC [here].
    • non-small cell carcinoma (NSCLC): cytopathology very strong in SCLC vs. NSCLC & also very strong in SCC vs. non-SCC21. IHC for primary NSCLC (adeno-) is TTF1 pos. and p63, K903, ck5/6 neg. while NSCLC (SCC) is the opposite21; some say no such thing as a p63 negative SCC21.
      • adenocarcinoma (responds to tyrosine kinase inhibitors6 if EGFR mutation pos. & another if ALK pos.; conventional therapy if none of 3 activating mutations or KRAS pos.).
        • NOS
        • with BAC features: if at least 50% of tumor has lepidic growth and invasive foci less than 5mm, highly associated with absence of node mets1,9.
        • papillary: has fibrovascular cores.
        • invasive micropapillary: negative for fibrovascular cores; bad (see this variant of breast cancer)!
      • squamous cell carcinoma: SCC is K903 (& ck5/6 & p63) positive (not responsive to tyrosine kinase inhibitors6); if bronchogenic & (1) pure SCC or (2) NSCLC with dominant percentage SCC component, avoid anti-endothelial chemo (e.g., Avastin) because of risk of fatal pulmonary bleed6.
      • large cell carcinoma.
      • sarcomatoid carcinoma.
    • mesothelioma: [IHC]
    • sarcoma
    • lymphoma
  • References:
    1. BWD's shared notes April 2007, highlights from USCAP 2006 meeting, Current Controversies in Diagnosis and Staging of Lung Cancer.
    2. Leslie KO & Wick MR, Practical Pulmonary Pathology, 813 pages, 2005.
    3. Hill CA, "Thoracic Tuberculosis, Mycobacteriosis, MERosis, and BCGosis in a Cancer Treatment Center", Radiology 153(2):311-316, November 1984.
    4. Butnor KJ, et. al., "Interobserver Agreement on What Constitutes Visceral Pleural Invasion by Non-small Cell Internet-based Assessment of International Current Practices", AJCP 128:638-647, October 2007.
    5. lead article CAP Today October 2007.
    6. article CAP Today November 2007, pages 93-94.
    7. AJCC Manual, 6th Edition (2002).
    8. Butnor KJ, et. al., "Interobserver Agreement on What Constitutes Visceral Pleural Invasion by Non-small Cell Lung Carcinoma", AJCP 128(4):638-647, October 2007.
    9. Farver CF, "Current Controversies in Diagnosis and Staging of Lung Cancer"...Medscape CME, Highlights of 2006 USCAP meeting.
    10. Rosai J, Rosai and Ackerman's Surgical Pathology, 2 vol. text 2977 pages, 2004.
    11. Feng FY, Zhang DC, Liu XY, Wang YG, Mao YS, "Surgical treatment and prognosis of synchronous double primary lung cancer: a report of 31 cases", Ai Zheng [Chinese Journal of Cancer] ;24(2):215-8, Feb. 2005 [author e-mailed an English translation to EBS 5/08].
    12. Kamiya K, et. al, "Histopathological features and prognostic significance of the micropapillary pattern in lung adwnocarcinoma", Mdern Pat. 21(8):992-1001, August 2008.
    13. about neuroendocrine tumors: Oberg K, " Expert Rev Anticancer Ther.", 2003; 3(6): 863-877.
    14. USCAP outstanding, freely viewable on-line Knowledge Hub handouts collection, lung TOC is HERE.
      1. Primary vs. Met. lung lesion
      2. Molecular Diagnosis of Lung Cancer, probably 2009 meeting, Lucian R. Chirieac, M.D. Assistant Professor of Pathology Harvard Medical School Staff Pathologist, Department of Pathology Brigham and Women's Hospital, Boston.
      3. “Recent advances in the molecular pathology of lung cancer: role of EGFR and KRAS mutation testing in treatment selection", from ASIP 2009 USCAP Companion Meeting, Marc Ladanyi, M.D., Memorial Sloan-Kettering Cancer Center New York, NY
    15. Gasparini R (Neogenomics chief scientific officer), PSA teleconference 29 Sept. 2011 with 23 page "handout".
    16. Marotti JD, et. al., "Cytomorphologic features of advanced lung adenocarcinomas tested for EGFR and KRAS mutations: A retrospective review of 50 cases", Daignostic Cytopathology, 16 June 2011. [HERE]
    17. Sakuma Y, et. al. "Distinctive evaluation of nonmucinous and mucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses for Japanese lung adenocarcinomas: confirmation of the correlations with histologic subtypes and gene mutations", AJCP 128(1):100-8, July 2007. [HERE]
    18. Finberg KE, et. al., "Mucinous Differentiation Correlates with Absence of EGFR Mutation and Presence of KRAS Mutation in Lung Adenocarcinomas with Bronchioloalveolar Features", J Mol Diagn, 9(3):320-326, Jul 2007. [HERE]
    19. Lung cancer targeted therapy lead article, CAP Today, November 2011 [HERE].
    20. Next generation sequencing lead article, CAP Today, November 2011 [HERE].
    21. Zakowski, Maureen F (attending pathologist, cytopathology, MSKCC), Modern Approaches to Lung Cytology, ASCP Teleconference #TC3279, 12/8/2011.
    (posted 25 November 2002; latest addition 11 November 2013)
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