"gastrointestinal stromal tumor" AND pathology

ls -la /home/daytona/workspace/

mkdir -p /home/daytona/workspace/gist-pathology

~/gist-pathology/gist_pathology.py

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.platypus import ListFlowable, ListItem

OUTPUT = "/home/daytona/workspace/gist-pathology/GIST_Pathology.pdf"

# ── Colour palette ─────────────────────────────────────────────────────────
DARK_BLUE   = colors.HexColor("#1A3557")
MID_BLUE    = colors.HexColor("#2E6DA4")
LIGHT_BLUE  = colors.HexColor("#D6E8FA")
ACCENT      = colors.HexColor("#E87722")
TABLE_HEAD  = colors.HexColor("#2E6DA4")
TABLE_ALT   = colors.HexColor("#EEF4FB")
WHITE       = colors.white
DARK_GRAY   = colors.HexColor("#333333")
MID_GRAY    = colors.HexColor("#666666")
LIGHT_GRAY  = colors.HexColor("#F5F5F5")

# ── Document setup ──────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=2*cm, rightMargin=2*cm,
    topMargin=2.2*cm, bottomMargin=2.2*cm,
    title="GIST – Pathology Perspective",
    author="Orris Medical Reference"
)

W = A4[0] - 4*cm   # usable width

# ── Styles ──────────────────────────────────────────────────────────────────
base = getSampleStyleSheet()

def S(name, **kw):
    s = ParagraphStyle(name, **kw)
    return s

cover_title = S("CoverTitle",
    fontSize=32, leading=40, textColor=WHITE,
    fontName="Helvetica-Bold", alignment=TA_CENTER, spaceAfter=8)

cover_sub = S("CoverSub",
    fontSize=15, leading=20, textColor=colors.HexColor("#D0E8FF"),
    fontName="Helvetica", alignment=TA_CENTER, spaceAfter=4)

cover_note = S("CoverNote",
    fontSize=10, leading=14, textColor=colors.HexColor("#B0CCEE"),
    fontName="Helvetica", alignment=TA_CENTER)

h1 = S("H1",
    fontSize=16, leading=20, textColor=WHITE,
    fontName="Helvetica-Bold", alignment=TA_LEFT,
    spaceBefore=6, spaceAfter=6, leftIndent=0)

h2 = S("H2",
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    fontName="Helvetica-Bold", alignment=TA_LEFT,
    spaceBefore=10, spaceAfter=4)

body = S("Body",
    fontSize=10, leading=15, textColor=DARK_GRAY,
    fontName="Helvetica", alignment=TA_JUSTIFY,
    spaceAfter=5)

bullet = S("Bullet",
    fontSize=10, leading=15, textColor=DARK_GRAY,
    fontName="Helvetica", alignment=TA_LEFT,
    leftIndent=14, spaceAfter=3,
    bulletIndent=4)

caption = S("Caption",
    fontSize=8, leading=11, textColor=MID_GRAY,
    fontName="Helvetica-Oblique", alignment=TA_CENTER, spaceAfter=4)

key_box = S("KeyBox",
    fontSize=10, leading=15, textColor=DARK_BLUE,
    fontName="Helvetica-Bold", alignment=TA_LEFT,
    leftIndent=10, spaceAfter=3)

source_style = S("Source",
    fontSize=8, leading=11, textColor=MID_GRAY,
    fontName="Helvetica-Oblique", alignment=TA_LEFT,
    spaceAfter=2)

# ── Helper: section header bar ───────────────────────────────────────────────
def section_header(title):
    data = [[Paragraph(title, h1)]]
    t = Table(data, colWidths=[W])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), DARK_BLUE),
        ("LEFTPADDING",  (0,0), (-1,-1), 10),
        ("RIGHTPADDING", (0,0), (-1,-1), 10),
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        ("BOTTOMPADDING",(0,0), (-1,-1), 7),
        ("ROUNDEDCORNERS", [4]),
    ]))
    return t

def sub_header(title):
    return Paragraph(title, h2)

def hr():
    return HRFlowable(width="100%", thickness=0.5, color=colors.HexColor("#C0D0E0"), spaceAfter=4)

def spacer(h=0.3):
    return Spacer(1, h*cm)

def bp(txt):
    return Paragraph(f"<bullet>&bull;</bullet> {txt}", bullet)

def source(txt):
    return Paragraph(f"<i>Source: {txt}</i>", source_style)

def info_box(lines):
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    data = [[item] for item in items]
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    t.setStyle(TableStyle([
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        ("BOTTOMPADDING",(0,0), (-1,-1), 5),
        ("BOX",          (0,0), (-1,-1), 1, MID_BLUE),
    ]))
    return t

# ── Generic table helper ─────────────────────────────────────────────────────
def make_table(headers, rows, col_widths=None):
    th_style = ParagraphStyle("TH", fontSize=9, fontName="Helvetica-Bold",
                               textColor=WHITE, alignment=TA_CENTER, leading=13)
    td_style = ParagraphStyle("TD", fontSize=9, fontName="Helvetica",
                               textColor=DARK_GRAY, alignment=TA_LEFT, leading=13)
    td_c     = ParagraphStyle("TDC", fontSize=9, fontName="Helvetica",
                               textColor=DARK_GRAY, alignment=TA_CENTER, leading=13)

    data = [[Paragraph(h, th_style) for h in headers]]
    for i, row in enumerate(rows):
        data.append([Paragraph(str(c), td_c if j > 0 else td_style)
                     for j, c in enumerate(row)])

    if col_widths is None:
        col_widths = [W / len(headers)] * len(headers)

    t = Table(data, colWidths=col_widths, repeatRows=1)
    style = [
        ("BACKGROUND",   (0,0), (-1,0),  TABLE_HEAD),
        ("TEXTCOLOR",    (0,0), (-1,0),  WHITE),
        ("GRID",         (0,0), (-1,-1), 0.4, colors.HexColor("#AACCEE")),
        ("TOPPADDING",   (0,0), (-1,-1), 5),
        ("BOTTOMPADDING",(0,0), (-1,-1), 5),
        ("LEFTPADDING",  (0,0), (-1,-1), 7),
        ("RIGHTPADDING", (0,0), (-1,-1), 7),
        ("VALIGN",       (0,0), (-1,-1), "MIDDLE"),
    ]
    for i in range(1, len(data)):
        if i % 2 == 0:
            style.append(("BACKGROUND", (0,i), (-1,i), TABLE_ALT))
    t.setStyle(TableStyle(style))
    return t

# ══════════════════════════════════════════════════════════════════════════════
# BUILD STORY
# ══════════════════════════════════════════════════════════════════════════════
story = []

# ── COVER PAGE ────────────────────────────────────────────────────────────────
cover_bg = Table(
    [[Paragraph("GASTROINTESTINAL STROMAL TUMOR", cover_title)],
     [Paragraph("GIST — A Pathology Perspective", cover_sub)],
     [spacer(0.4)],
     [Paragraph("Molecular Pathology · Histopathology · IHC · Risk Stratification · Treatment Implications", cover_note)],
     [spacer(0.6)],
     [Paragraph("Based on: Robbins &amp; Kumar Basic Pathology · Sleisenger &amp; Fordtran's GI and Liver Disease<br/>"
                "Sabiston Textbook of Surgery · Quick Compendium of Clinical Pathology 5e<br/>"
                "Fischer's Mastery of Surgery · Current Surgical Therapy 14e", cover_note)],
     [spacer(0.4)],
     [Paragraph("Prepared by Orris Medical Reference · July 2026", cover_note)],
    ],
    colWidths=[W]
)
cover_bg.setStyle(TableStyle([
    ("BACKGROUND",   (0,0), (-1,-1), DARK_BLUE),
    ("TOPPADDING",   (0,0), (-1,-1), 18),
    ("BOTTOMPADDING",(0,0), (-1,-1), 18),
    ("LEFTPADDING",  (0,0), (-1,-1), 20),
    ("RIGHTPADDING", (0,0), (-1,-1), 20),
    ("ROUNDEDCORNERS", [8]),
]))
story.append(spacer(2))
story.append(cover_bg)
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# 1. DEFINITION & HISTORY
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("1. Definition and Historical Context"))
story.append(spacer(0.3))
story.append(Paragraph(
    "Gastrointestinal stromal tumor (GIST) is the <b>most common mesenchymal neoplasm of the GI tract</b>, "
    "accounting for 1–3% of all malignant GI tumors. The term was coined by <b>Mazur and Clark in 1983</b> as "
    "a descriptive label for non-epithelial intra-abdominal tumors exhibiting mixed smooth muscle and neural "
    "histologic features.", body))
story.append(Paragraph(
    "Before 1999, GISTs were frequently misdiagnosed as <b>leiomyomas, leiomyosarcomas, plexosarcomas</b>, or "
    "'gastrointestinal autonomic nerve tumors' due to the absence of specific molecular markers. "
    "Consistent classification became possible only after the landmark 1998 discovery of near-universal "
    "<b>KIT (CD117) expression</b> and gain-of-function KIT mutations in these tumors.", body))
story.append(source("Sleisenger and Fordtran's Gastrointestinal and Liver Disease; Maingot's Abdominal Operations"))
story.append(spacer(0.2))

# ══════════════════════════════════════════════════════════════════════════════
# 2. CELL OF ORIGIN
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("2. Cell of Origin"))
story.append(spacer(0.3))
story.append(Paragraph(
    "GIST originates from the <b>interstitial cells of Cajal (ICC)</b> — the pacemaker cells of the GI "
    "muscularis propria that coordinate peristalsis by linking smooth muscle cells with the autonomic "
    "nervous system. ICC and GIST cells share:", body))
for item in [
    "Ultrastructural features combining neural and muscle phenotypes",
    "Strong expression of <b>CD117 (KIT)</b> and <b>CD34</b>",
    "Expression of <b>DOG1</b> (a calcium-activated chloride channel — also called ANO1)",
    "Potential origin from telocytes in extra-GI locations (explaining pancreatic and mesenteric GISTs)",
]:
    story.append(bp(item))
story.append(source("Robbins & Kumar Basic Pathology; Sleisenger and Fordtran's"))
story.append(spacer(0.3))

# ══════════════════════════════════════════════════════════════════════════════
# 3. ANATOMIC DISTRIBUTION
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("3. Anatomic Distribution"))
story.append(spacer(0.3))
story.append(make_table(
    ["Site", "Frequency (%)"],
    [["Stomach", "40 – 60"],
     ["Jejunum / Ileum", "24 – 30"],
     ["Colon and Rectum", "5 – 15"],
     ["Duodenum", "~5"],
     ["Esophagus / Mesentery / Other", "<5"]],
    col_widths=[W*0.6, W*0.4]
))
story.append(spacer(0.15))
story.append(Paragraph(
    "<b>Note:</b> PDGFRA-mutant GISTs are overrepresented in the stomach. "
    "Non-gastric GISTs (especially small intestinal and rectal) carry a worse prognosis than gastric GISTs "
    "of the same size and mitotic rate.", body))
story.append(source("Sabiston Textbook of Surgery; Robbins & Kumar Basic Pathology"))
story.append(spacer(0.3))

# ══════════════════════════════════════════════════════════════════════════════
# 4. GROSS PATHOLOGY
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("4. Gross Pathology"))
story.append(spacer(0.3))
for item in [
    "<b>Solitary, well-circumscribed, fleshy submucosal mass</b> — most common presentation",
    "Cut surface: tan-white to pinkish; haemorrhage, necrosis, or cystic change in larger tumors",
    "Arises from the muscularis propria; may project endoluminally, exophytically, or both (dumbbell shape)",
    "Metastases: multiple small serosal nodules or large nodules in the <b>liver</b>",
    "Peritoneal seeding is common; spread outside the abdomen is uncommon",
    "<b>Lymph node metastasis is rare</b> — unlike carcinomas (exception: SDH-deficient pediatric GISTs)",
]:
    story.append(bp(item))
story.append(source("Robbins & Kumar Basic Pathology"))
story.append(spacer(0.3))

# ══════════════════════════════════════════════════════════════════════════════
# 5. HISTOPATHOLOGY
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("5. Histopathology"))
story.append(spacer(0.3))
story.append(Paragraph("Three main morphologic patterns:", h2))
story.append(make_table(
    ["Pattern", "Frequency", "Characteristics"],
    [["Spindle cell type", "~70%",
      "Thin, elongated cells in fascicles/whorls; pale eosinophilic cytoplasm; palisading nuclei"],
     ["Epithelioid type", "~20%",
      "Plumper, rounded cells; abundant clear/eosinophilic cytoplasm; more common in stomach & PDGFRA-mutant tumors"],
     ["Mixed type", "~10%",
      "Both spindle and epithelioid components present in same tumor"]],
    col_widths=[W*0.22, W*0.15, W*0.63]
))
story.append(spacer(0.2))
story.append(Paragraph(
    "Histologic features alone are insufficient for diagnosis. The pre-1999 era saw wide variation "
    "in smooth muscle actin (SMA) and S100 expression, leading to a proposed 'one-third each' classification "
    "(myogenic / neurogenic / null phenotype) — now superseded by molecular markers.", body))
story.append(source("Sleisenger and Fordtran's Gastrointestinal and Liver Disease"))
story.append(spacer(0.3))

# ══════════════════════════════════════════════════════════════════════════════
# 6. IMMUNOHISTOCHEMISTRY
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("6. Immunohistochemistry (IHC)"))
story.append(spacer(0.3))
story.append(make_table(
    ["Marker", "Positivity", "Notes"],
    [["CD117 (KIT / c-kit)", "~95%",
      "Strong, diffuse cytoplasmic staining; spindle type > epithelioid; can be heterogeneous within tumor"],
     ["DOG1 (ANO1)", "~95%",
      "Highly specific; positive even in KIT-negative GISTs — essential second-line marker"],
     ["CD34", "~60–70%",
      "Vascular/hematopoietic marker; less specific; useful supportive evidence"],
     ["Smooth muscle actin (SMA)", "Variable (~30–40%)",
      "Can be positive; does not exclude GIST"],
     ["S100 protein", "Usually negative",
      "Useful to exclude schwannoma (S100+)"],
     ["Desmin", "Usually negative",
      "Useful to exclude leiomyosarcoma (desmin+)"],
     ["SDHB", "Negative in SDH-deficient",
      "Loss of SDHB staining identifies SDH-deficient wild-type GISTs"],
    ],
    col_widths=[W*0.28, W*0.22, W*0.50]
))
story.append(spacer(0.15))
story.append(info_box([
    "⚠  Important: CD117 expression can be heterogeneous within a single tumor.",
    "    A needle biopsy may yield CD117-negative cells purely due to sampling bias.",
    "    Always use DOG1 alongside CD117 in diagnostically challenging cases.",
]))
story.append(source("Sleisenger and Fordtran's; Sabiston Textbook of Surgery"))
story.append(spacer(0.3))

# ══════════════════════════════════════════════════════════════════════════════
# 7. MOLECULAR PATHOGENESIS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("7. Molecular Pathogenesis"))
story.append(spacer(0.3))

story.append(sub_header("7.1 KIT Mutations (75–85% of GISTs)"))
story.append(Paragraph(
    "The KIT gene (chromosome 4q12) encodes a transmembrane receptor tyrosine kinase. "
    "Its natural ligand is <b>stem cell factor (SCF)</b>; binding causes receptor homodimerization, "
    "autophosphorylation, and activation of downstream signaling: <b>RAS, RAF, MAPK, AKT, and STAT3</b>. "
    "Gain-of-function mutations cause <b>constitutive (ligand-independent) receptor activation</b>, "
    "driving uncontrolled cell proliferation.", body))
story.append(spacer(0.15))
story.append(make_table(
    ["Exon (Domain)", "Mutation Type", "Frequency", "Imatinib Response"],
    [["Exon 11 (juxtamembrane)", "Deletion, insertion, point mutation", "Most common (~70%)", "~80–90% — most sensitive"],
     ["Exon 9 (extracellular)", "Tandem duplication AY502-503", "~10–15%", "40–50% (higher dose needed)"],
     ["Exon 13 (kinase domain I)", "Point mutation (K642E)", "Rare", "40–50%"],
     ["Exon 17 (kinase domain II)", "Point mutation", "Rare", "40–50%"],
    ],
    col_widths=[W*0.27, W*0.30, W*0.20, W*0.23]
))
story.append(spacer(0.3))

story.append(sub_header("7.2 PDGFRA Mutations (~8% of GISTs)"))
for item in [
    "Platelet-derived growth factor receptor A (PDGFRA), also on chromosome 4q12",
    "Structurally similar to KIT; mutations activate the <b>same downstream signaling pathways</b>",
    "<b>KIT and PDGFRA mutations are mutually exclusive</b> (both activate the same pathways)",
    "Overrepresented in gastric and epithelioid GISTs",
    "<b>D842V substitution in exon 18</b> = most common PDGFRA mutation = <b>primary imatinib resistance</b>",
    "Other PDGFRA mutations may retain some imatinib sensitivity; avapritinib is effective against D842V",
]:
    story.append(bp(item))
story.append(spacer(0.3))

story.append(sub_header("7.3 SDH-Deficient GISTs (~5–10%; majority of pediatric GISTs)"))
for item in [
    "Negative for both KIT and PDGFRA mutations ('wild-type')",
    "Mutations in <b>SDHA, SDHB, SDHC, or SDHD</b> subunit genes of the mitochondrial succinate dehydrogenase complex",
    "Loss of SDH → ↑ reactive oxygen species, HIF activation, Warburg-type glycolysis dependency",
    "Multifocal gastric GISTs; lymph node metastases more common",
    "Associated with <b>Carney triad</b> and <b>Carney-Stratakis syndrome</b>",
    "Generally <b>imatinib-insensitive</b>; require alternative/experimental therapies",
    "<b>SDHB IHC</b>: loss of staining identifies SDH-deficient tumors",
]:
    story.append(bp(item))
story.append(spacer(0.3))

story.append(sub_header("7.4 Other Wild-Type GISTs"))
story.append(make_table(
    ["Subtype", "Molecular Feature", "Notes"],
    [["NF1-associated", "KIT overexpression; KIT/PDGFRA unmutated", "Multiple small intestinal GISTs; NF1 loss drives ICC hyperplasia"],
     ["BRAF-mutant", "BRAF V600E", "Rare; may respond to BRAF inhibitors"],
     ["KRAS-mutant", "KRAS mutation", "Very rare"],
     ["Familial GIST", "Germline KIT or PDGFRA mutation", "Multiple GISTs + diffuse ICC hyperplasia; autosomal dominant"],
    ],
    col_widths=[W*0.22, W*0.30, W*0.48]
))
story.append(source("Quick Compendium of Clinical Pathology 5e; Robbins & Kumar; Sabiston Textbook of Surgery"))
story.append(spacer(0.3))

# ══════════════════════════════════════════════════════════════════════════════
# 8. RISK STRATIFICATION
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("8. Risk Stratification"))
story.append(spacer(0.3))
story.append(info_box([
    "Core principle: Every GIST carries metastatic potential — there is NO truly benign GIST.",
    "Three primary prognostic variables: (1) Tumor size  (2) Mitotic rate  (3) Primary site",
]))
story.append(spacer(0.25))

story.append(sub_header("NIH (Fletcher) Consensus Risk Classification"))
story.append(make_table(
    ["Risk Category", "Size", "Mitotic Rate"],
    [["Very Low", "< 2 cm", "< 5 / 50 HPF"],
     ["Low", "2 – 5 cm", "< 5 / 50 HPF"],
     ["Intermediate", "< 5 cm  OR  5–10 cm", "6–10 / 50 HPF  OR  < 5 / 50 HPF"],
     ["High", "> 5 cm  OR  > 10 cm  OR  any", "> 5 / 50 HPF  OR  any  OR  > 10 / 50 HPF"],
    ],
    col_widths=[W*0.22, W*0.38, W*0.40]
))
story.append(spacer(0.2))
story.append(Paragraph(
    "The <b>Joensuu/Armed Forces Institute of Pathology (AFIP) system</b> and <b>AJCC staging</b> "
    "also incorporate tumor location, with separate algorithms for gastric vs. non-gastric GISTs. "
    "Non-gastric site (especially small intestine and rectum) confers higher risk at any given size "
    "and mitotic rate. Tumor rupture — spontaneous or operative — dramatically increases recurrence risk.", body))
story.append(source("Fischer's Mastery of Surgery 8e; Current Surgical Therapy 14e; Quick Compendium of Clinical Pathology 5e"))
story.append(spacer(0.3))

# ══════════════════════════════════════════════════════════════════════════════
# 9. CLINICAL FEATURES
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("9. Clinical Features"))
story.append(spacer(0.3))
story.append(make_table(
    ["Feature", "Details"],
    [["Peak incidence", "~60 years; < 10% in patients under 40"],
     ["Sex", "Slight male predominance"],
     ["Presentation", "GI bleeding, mass effect, obstruction, or incidental finding"],
     ["Metastatic sites", "Liver (most common) and peritoneum; lymph nodes rare"],
     ["Prognosis (gastric)", "Recurrence rare for < 5 cm; common for mitotically active > 10 cm"],
     ["Prognosis (non-gastric)", "More aggressive at any given size/mitotic rate"],
    ],
    col_widths=[W*0.35, W*0.65]
))
story.append(source("Robbins & Kumar Basic Pathology"))
story.append(spacer(0.3))

# ══════════════════════════════════════════════════════════════════════════════
# 10. SPECIAL SYNDROMES
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("10. GIST in Hereditary Syndromes"))
story.append(spacer(0.3))
story.append(make_table(
    ["Syndrome", "GIST Features", "Molecular Basis"],
    [["Carney Triad",
      "GIST + pulmonary chondromas + extra-adrenal paragangliomas; gastric; multifocal; young females",
      "SDH-deficient; no germline mutation in most cases (somatic/epigenetic SDHC)"],
     ["Carney-Stratakis Dyad",
      "GIST + paraganglioma; multifocal gastric GIST",
      "Germline SDH subunit mutations (SDHA/B/C/D)"],
     ["Familial GIST Syndrome",
      "Multiple GISTs; diffuse ICC hyperplasia; hyperpigmentation",
      "Germline KIT or PDGFRA mutations; autosomal dominant"],
     ["NF1 (von Recklinghausen)",
      "Multiple small intestinal GISTs; GIST often incidental; low mitotic rate",
      "NF1 loss; KIT overexpressed but unmutated"],
    ],
    col_widths=[W*0.25, W*0.38, W*0.37]
))
story.append(source("Quick Compendium of Clinical Pathology 5e; Sabiston Textbook of Surgery"))
story.append(spacer(0.3))

# ══════════════════════════════════════════════════════════════════════════════
# 11. TREATMENT IMPLICATIONS (Pathology-Relevant)
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("11. Treatment Implications from a Pathology Perspective"))
story.append(spacer(0.3))

story.append(sub_header("Surgery"))
for item in [
    "Complete surgical resection (R0) is the primary treatment for localized GIST",
    "<b>No routine lymphadenectomy</b> — lymph node spread is rare in KIT/PDGFRA-mutant GIST",
    "Avoid tumor rupture — dramatically increases peritoneal recurrence risk",
    "Margins: 1–2 cm; pseudocapsule should remain intact",
]:
    story.append(bp(item))
story.append(spacer(0.2))

story.append(sub_header("Imatinib Mesylate (Gleevec) — Tyrosine Kinase Inhibitor"))
story.append(make_table(
    ["Mutation", "Imatinib Sensitivity"],
    [["KIT exon 11", "High (~80–90%); first-line for advanced/metastatic disease"],
     ["KIT exon 9", "Moderate (40–50%); higher dose (800 mg/day) may improve response"],
     ["KIT exon 13 / 17", "Moderate; sunitinib may be preferred"],
     ["PDGFRA non-D842V", "Variable; may respond"],
     ["PDGFRA D842V", "Resistant — avapritinib is preferred"],
     ["Wild-type (SDH-deficient)", "Generally resistant; experimental therapies"],
     ["Wild-type (NF1)", "May respond; partial evidence"],
    ],
    col_widths=[W*0.42, W*0.58]
))
story.append(spacer(0.15))
story.append(Paragraph(
    "<b>Adjuvant imatinib</b>: Recommended for 3 years in high-risk resected GISTs with imatinib-sensitive mutations. "
    "<b>Neoadjuvant imatinib</b>: Used for marginally resectable disease until maximal response. "
    "<b>Lifelong therapy</b> for metastatic/unresectable GIST based on current evidence. "
    "<b>Sunitinib</b> is second-line for imatinib-resistant disease.", body))
story.append(source("Goodman & Gilman's Pharmacological Basis of Therapeutics; Schwartz's Principles of Surgery 11e"))
story.append(spacer(0.3))

# ══════════════════════════════════════════════════════════════════════════════
# 12. KEY PATHOLOGY SUMMARY TABLE
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("12. Key Pathology Summary"))
story.append(spacer(0.3))
story.append(make_table(
    ["Feature", "Key Details"],
    [["Cell of origin", "Interstitial cells of Cajal (pacemaker cells of GI muscularis propria)"],
     ["Most common site", "Stomach (40–60%)"],
     ["Histologic patterns", "Spindle cell (~70%), Epithelioid (~20%), Mixed (~10%)"],
     ["Defining IHC markers", "CD117 (KIT) and DOG1 — both ~95% sensitive"],
     ["Most common mutation", "KIT exon 11 deletion/insertion (~70% of all GISTs)"],
     ["Best imatinib predictor", "KIT exon 11 mutation"],
     ["Imatinib-resistant mutation", "PDGFRA exon 18 D842V"],
     ["Prognosis determinants", "Tumor size, mitotic rate, anatomic site (+ rupture status)"],
     ["Metastasis pattern", "Liver and peritoneum (lymph nodes spared in most cases)"],
     ["Pediatric/SDH-deficient", "Multifocal; gastric; lymph node mets possible; imatinib-resistant"],
    ],
    col_widths=[W*0.38, W*0.62]
))
story.append(spacer(0.3))

# ── FOOTER NOTE ───────────────────────────────────────────────────────────────
story.append(hr())
story.append(Paragraph(
    "Recent evidence: A 2025 systematic review (PMID 40665034) identified circulating tumor DNA (ctDNA) "
    "mutations as an emerging prognostic biomarker in GIST. An SDH-deficient GIST therapy review (PMID 40045030, 2025) "
    "summarises alternative systemic options for imatinib-resistant wild-type cases.",
    source_style))
story.append(Paragraph(
    "This document is for educational reference only. Clinical decisions should be based on current guidelines "
    "and individualised assessment.",
    source_style))

# ══════════════════════════════════════════════════════════════════════════════
# BUILD PDF
# ══════════════════════════════════════════════════════════════════════════════
doc.build(story)
print(f"PDF created: {OUTPUT}")

cd /home/daytona/workspace/gist-pathology && python gist_pathology.py

ls /home/daytona/workspace/gist-pathology/

~/gist-pathology/gist_student.py

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether, Frame, NextPageTemplate
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY, TA_RIGHT
from reportlab.platypus import BaseDocTemplate, PageTemplate
from reportlab.platypus.flowables import Flowable
import math

OUTPUT = "/home/daytona/workspace/gist-pathology/GIST_Student_Guide.pdf"

W_PAGE, H_PAGE = A4
LM = RM = 1.8*cm
TM = BM = 1.8*cm
W = W_PAGE - LM - RM

# ── COLOUR PALETTE ────────────────────────────────────────────────────────────
C_NAVY      = colors.HexColor("#0D2B55")
C_BLUE      = colors.HexColor("#1565C0")
C_BLUE_MID  = colors.HexColor("#2196F3")
C_BLUE_LITE = colors.HexColor("#BBDEFB")
C_BLUE_XLIT = colors.HexColor("#E3F2FD")
C_TEAL      = colors.HexColor("#00838F")
C_TEAL_LITE = colors.HexColor("#E0F7FA")
C_ORANGE    = colors.HexColor("#E65100")
C_ORANGE_L  = colors.HexColor("#FFF3E0")
C_GREEN     = colors.HexColor("#2E7D32")
C_GREEN_L   = colors.HexColor("#E8F5E9")
C_RED       = colors.HexColor("#C62828")
C_RED_L     = colors.HexColor("#FFEBEE")
C_PURPLE    = colors.HexColor("#6A1B9A")
C_PURPLE_L  = colors.HexColor("#F3E5F5")
C_YELLOW    = colors.HexColor("#F9A825")
C_YELLOW_L  = colors.HexColor("#FFFDE7")
C_GRAY_D    = colors.HexColor("#212121")
C_GRAY_M    = colors.HexColor("#546E7A")
C_GRAY_L    = colors.HexColor("#ECEFF1")
C_WHITE     = colors.white

# ── STYLES ────────────────────────────────────────────────────────────────────
def PS(name, **kw):
    return ParagraphStyle(name, **kw)

COVER_MAIN  = PS("CoverMain",  fontSize=38, leading=46, fontName="Helvetica-Bold",
                  textColor=C_WHITE,  alignment=TA_CENTER, spaceAfter=6)
COVER_ABBR  = PS("CoverAbbr",  fontSize=22, leading=28, fontName="Helvetica-Bold",
                  textColor=colors.HexColor("#90CAF9"), alignment=TA_CENTER, spaceAfter=4)
COVER_SUB   = PS("CoverSub",   fontSize=13, leading=18, fontName="Helvetica",
                  textColor=colors.HexColor("#BBDEFB"), alignment=TA_CENTER, spaceAfter=3)
COVER_NOTE  = PS("CoverNote",  fontSize=9,  leading=13, fontName="Helvetica",
                  textColor=colors.HexColor("#90A4AE"), alignment=TA_CENTER)

SEC_TITLE   = PS("SecTitle",   fontSize=14, leading=18, fontName="Helvetica-Bold",
                  textColor=C_WHITE, alignment=TA_LEFT)
H2_STYLE    = PS("H2",         fontSize=12, leading=16, fontName="Helvetica-Bold",
                  textColor=C_NAVY, spaceBefore=8, spaceAfter=4)
H3_STYLE    = PS("H3",         fontSize=10, leading=14, fontName="Helvetica-Bold",
                  textColor=C_BLUE, spaceBefore=6, spaceAfter=3)
BODY        = PS("Body",       fontSize=10, leading=15, fontName="Helvetica",
                  textColor=C_GRAY_D, alignment=TA_JUSTIFY, spaceAfter=4)
BODY_SML    = PS("BodySml",    fontSize=9,  leading=13, fontName="Helvetica",
                  textColor=C_GRAY_D, alignment=TA_JUSTIFY, spaceAfter=3)
BULLET      = PS("Bullet",     fontSize=10, leading=15, fontName="Helvetica",
                  textColor=C_GRAY_D, leftIndent=16, bulletIndent=4, spaceAfter=2)
BULLET_SML  = PS("BulletSml",  fontSize=9,  leading=13, fontName="Helvetica",
                  textColor=C_GRAY_D, leftIndent=16, bulletIndent=4, spaceAfter=2)
NOTE        = PS("Note",       fontSize=8,  leading=11, fontName="Helvetica-Oblique",
                  textColor=C_GRAY_M, alignment=TA_LEFT, spaceAfter=2)
MNEMONIC    = PS("Mnemonic",   fontSize=11, leading=16, fontName="Helvetica-Bold",
                  textColor=C_NAVY, alignment=TA_CENTER, spaceAfter=2)
MNEM_BODY   = PS("MnemBody",   fontSize=10, leading=15, fontName="Helvetica",
                  textColor=C_GRAY_D, alignment=TA_LEFT)
TH_S        = PS("THS",        fontSize=9,  leading=13, fontName="Helvetica-Bold",
                  textColor=C_WHITE, alignment=TA_CENTER)
TD_S        = PS("TDS",        fontSize=9,  leading=13, fontName="Helvetica",
                  textColor=C_GRAY_D, alignment=TA_LEFT)
TD_C        = PS("TDC",        fontSize=9,  leading=13, fontName="Helvetica",
                  textColor=C_GRAY_D, alignment=TA_CENTER)
EXAM_Q      = PS("ExamQ",      fontSize=10, leading=15, fontName="Helvetica-Bold",
                  textColor=C_NAVY, leftIndent=6, spaceAfter=2)
EXAM_A      = PS("ExamA",      fontSize=10, leading=15, fontName="Helvetica",
                  textColor=C_GREEN, leftIndent=20, spaceAfter=4)
KEYPOINT    = PS("KeyPoint",   fontSize=10, leading=15, fontName="Helvetica-Bold",
                  textColor=C_ORANGE, alignment=TA_LEFT, leftIndent=10)
CHAPTER_NUM = PS("ChapNum",    fontSize=48, leading=52, fontName="Helvetica-Bold",
                  textColor=colors.HexColor("#1565C020"), alignment=TA_RIGHT)

# ── HELPER FLOWABLES ─────────────────────────────────────────────────────────
def sp(h=0.3): return Spacer(1, h*cm)
def hr(col=colors.HexColor("#CFD8DC")):
    return HRFlowable(width="100%", thickness=0.5, color=col, spaceAfter=4)

def section_bar(title, color=C_NAVY, num=""):
    inner = f"{num}  {title}" if num else title
    cell = [Paragraph(inner, SEC_TITLE)]
    t = Table([cell], colWidths=[W])
    t.setStyle(TableStyle([
        ("BACKGROUND",   (0,0),(-1,-1), color),
        ("LEFTPADDING",  (0,0),(-1,-1), 12),
        ("TOPPADDING",   (0,0),(-1,-1), 9),
        ("BOTTOMPADDING",(0,0),(-1,-1), 9),
        ("RIGHTPADDING", (0,0),(-1,-1), 12),
    ]))
    return t

def callout(lines, bg=C_BLUE_XLIT, border=C_BLUE_MID, style=None):
    st = style or BODY_SML
    rows = [[Paragraph(l, st)] for l in lines]
    t = Table(rows, colWidths=[W])
    t.setStyle(TableStyle([
        ("BACKGROUND",   (0,0),(-1,-1), bg),
        ("BOX",          (0,0),(-1,-1), 1.2, border),
        ("LEFTPADDING",  (0,0),(-1,-1), 12),
        ("RIGHTPADDING", (0,0),(-1,-1), 12),
        ("TOPPADDING",   (0,0),(-1,-1), 6),
        ("BOTTOMPADDING",(0,0),(-1,-1), 6),
    ]))
    return t

def warning_box(lines):
    return callout(["⚠  " + l for l in lines], bg=C_YELLOW_L, border=C_YELLOW,
                   style=PS("Warn", fontSize=9, leading=13, fontName="Helvetica-Bold",
                             textColor=C_GRAY_D))

def fact_box(lines):
    return callout(lines, bg=C_GREEN_L, border=C_GREEN)

def exam_box(pairs):
    """pairs = list of (question, answer)"""
    rows = []
    for q, a in pairs:
        rows.append([Paragraph(f"Q:  {q}", EXAM_Q)])
        rows.append([Paragraph(f"A:  {a}", EXAM_A)])
    t = Table(rows, colWidths=[W])
    t.setStyle(TableStyle([
        ("BACKGROUND",   (0,0),(-1,-1), C_BLUE_XLIT),
        ("BOX",          (0,0),(-1,-1), 1.2, C_BLUE),
        ("LEFTPADDING",  (0,0),(-1,-1), 10),
        ("RIGHTPADDING", (0,0),(-1,-1), 10),
        ("TOPPADDING",   (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ]))
    return t

def mnemonic_box(title, items):
    """items = list of (letter_bold, rest_of_text)"""
    rows = [[Paragraph(f"<b>{lt}</b>  —  {desc}", MNEM_BODY)] for lt, desc in items]
    header = [[Paragraph(f"🔑  MNEMONIC:  {title}", MNEMONIC)]]
    all_rows = header + rows
    t = Table(all_rows, colWidths=[W])
    t.setStyle(TableStyle([
        ("BACKGROUND",   (0,0),(0,0),  C_PURPLE_L),
        ("BACKGROUND",   (0,1),(-1,-1),C_PURPLE_L),
        ("BOX",          (0,0),(-1,-1), 1.5, C_PURPLE),
        ("LINEBELOW",    (0,0),(0,0),   1,   C_PURPLE),
        ("LEFTPADDING",  (0,0),(-1,-1), 14),
        ("RIGHTPADDING", (0,0),(-1,-1), 14),
        ("TOPPADDING",   (0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ]))
    return t

def make_table(headers, rows, col_widths=None, hdr_color=C_BLUE):
    if col_widths is None:
        col_widths = [W / len(headers)] * len(headers)
    data = [[Paragraph(h, TH_S) for h in headers]]
    for i, row in enumerate(rows):
        data.append([Paragraph(str(c), TD_C if j > 0 else TD_S) for j, c in enumerate(row)])
    t = Table(data, colWidths=col_widths, repeatRows=1)
    sty = [
        ("BACKGROUND",   (0,0),(-1,0),  hdr_color),
        ("GRID",         (0,0),(-1,-1), 0.4, colors.HexColor("#B0BEC5")),
        ("TOPPADDING",   (0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
        ("LEFTPADDING",  (0,0),(-1,-1), 7),
        ("RIGHTPADDING", (0,0),(-1,-1), 7),
        ("VALIGN",       (0,0),(-1,-1), "MIDDLE"),
    ]
    for i in range(1, len(data)):
        if i % 2 == 0:
            sty.append(("BACKGROUND", (0,i),(-1,i), C_BLUE_XLIT))
    t.setStyle(TableStyle(sty))
    return t

def bp(txt, style=BULLET):
    return Paragraph(f"<bullet>•</bullet>  {txt}", style)

def two_col(left_items, right_items, lw=None, rw=None):
    lw = lw or W*0.5 - 4
    rw = rw or W*0.5 - 4
    left_para  = [bp(x) for x in left_items]
    right_para = [bp(x) for x in right_items]
    # Pad to same length
    while len(left_para) < len(right_para):  left_para.append(sp(0.1))
    while len(right_para) < len(left_para): right_para.append(sp(0.1))
    rows = list(zip(left_para, right_para))
    t = Table(rows, colWidths=[lw, rw])
    t.setStyle(TableStyle([
        ("VALIGN",       (0,0),(-1,-1), "TOP"),
        ("LEFTPADDING",  (0,0),(-1,-1), 2),
        ("RIGHTPADDING", (0,0),(-1,-1), 2),
        ("TOPPADDING",   (0,0),(-1,-1), 1),
        ("BOTTOMPADDING",(0,0),(-1,-1), 1),
    ]))
    return t

# ══════════════════════════════════════════════════════════════════════════════
# PAGE NUMBERING
# ══════════════════════════════════════════════════════════════════════════════
def on_page(canvas, doc):
    canvas.saveState()
    # Header bar
    canvas.setFillColor(C_NAVY)
    canvas.rect(0, H_PAGE-1.1*cm, W_PAGE, 1.1*cm, fill=1, stroke=0)
    canvas.setFillColor(C_WHITE)
    canvas.setFont("Helvetica-Bold", 9)
    canvas.drawString(LM, H_PAGE-0.75*cm, "GIST — Gastrointestinal Stromal Tumor")
    canvas.setFont("Helvetica", 8)
    canvas.drawRightString(W_PAGE-RM, H_PAGE-0.75*cm, "Student Pathology Guide")
    # Footer
    canvas.setFillColor(C_NAVY)
    canvas.rect(0, 0, W_PAGE, 0.9*cm, fill=1, stroke=0)
    canvas.setFillColor(C_WHITE)
    canvas.setFont("Helvetica", 8)
    canvas.drawString(LM, 0.33*cm, "For educational use · Orris Medical Reference · 2026")
    canvas.setFont("Helvetica-Bold", 9)
    canvas.drawRightString(W_PAGE-RM, 0.33*cm, f"Page {doc.page}")
    canvas.restoreState()

def on_cover(canvas, doc):
    # Full bleed gradient background
    canvas.saveState()
    # Dark navy background
    canvas.setFillColor(C_NAVY)
    canvas.rect(0, 0, W_PAGE, H_PAGE, fill=1, stroke=0)
    # Accent stripe
    canvas.setFillColor(C_BLUE)
    canvas.rect(0, H_PAGE*0.38, W_PAGE, H_PAGE*0.26, fill=1, stroke=0)
    # Top accent line
    canvas.setFillColor(C_YELLOW)
    canvas.rect(0, H_PAGE-0.6*cm, W_PAGE, 0.6*cm, fill=1, stroke=0)
    # Bottom accent line
    canvas.setFillColor(C_TEAL)
    canvas.rect(0, 0, W_PAGE, 0.5*cm, fill=1, stroke=0)
    canvas.restoreState()

# ══════════════════════════════════════════════════════════════════════════════
# DOC SETUP
# ══════════════════════════════════════════════════════════════════════════════
doc = BaseDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=LM, rightMargin=RM,
    topMargin=TM+1.2*cm, bottomMargin=BM+1.0*cm,
    title="GIST – Student Pathology Guide",
    author="Orris Medical Reference"
)
cover_frame  = Frame(0, 0, W_PAGE, H_PAGE, id="cover",  leftPadding=2*cm, rightPadding=2*cm,
                     topPadding=3*cm, bottomPadding=2*cm)
normal_frame = Frame(LM, BM+1.0*cm, W, H_PAGE-TM-BM-2.2*cm, id="normal")
doc.addPageTemplates([
    PageTemplate(id="Cover",  frames=[cover_frame],  onPage=on_cover),
    PageTemplate(id="Normal", frames=[normal_frame], onPage=on_page),
])

# ══════════════════════════════════════════════════════════════════════════════
# STORY
# ══════════════════════════════════════════════════════════════════════════════
story = []

# ─────────────────────────────────────────────────────────────────────────────
# COVER
# ─────────────────────────────────────────────────────────────────────────────
story.append(NextPageTemplate("Cover"))
story.append(sp(3.5))
story.append(Paragraph("GASTROINTESTINAL", COVER_MAIN))
story.append(Paragraph("STROMAL TUMOR", COVER_MAIN))
story.append(sp(0.3))
story.append(Paragraph("G  ·  I  ·  S  ·  T", COVER_ABBR))
story.append(sp(0.6))
story.append(Paragraph("Complete Student Pathology Guide", COVER_SUB))
story.append(sp(0.2))
story.append(Paragraph(
    "Definition · Cell of Origin · Gross & Histopathology · IHC · Molecular Genetics<br/>"
    "Risk Stratification · Clinical Features · Hereditary Syndromes · Treatment",
    COVER_NOTE))
story.append(sp(1.5))
# decorative divider
div_data = [["  PATHOLOGY  |  ONCOLOGY  |  SURGERY  |  PHARMACOLOGY  "]]
div = Table(div_data, colWidths=[W_PAGE-4*cm])
div.setStyle(TableStyle([
    ("BACKGROUND",   (0,0),(-1,-1), C_TEAL),
    ("TEXTCOLOR",    (0,0),(-1,-1), C_WHITE),
    ("FONTNAME",     (0,0),(-1,-1), "Helvetica-Bold"),
    ("FONTSIZE",     (0,0),(-1,-1), 9),
    ("ALIGN",        (0,0),(-1,-1), "CENTER"),
    ("TOPPADDING",   (0,0),(-1,-1), 7),
    ("BOTTOMPADDING",(0,0),(-1,-1), 7),
]))
story.append(div)
story.append(sp(1.2))
story.append(Paragraph("Orris Medical Reference  ·  For Educational Use  ·  July 2026", COVER_NOTE))
story.append(PageBreak())

# ─────────────────────────────────────────────────────────────────────────────
# TABLE OF CONTENTS
# ─────────────────────────────────────────────────────────────────────────────
story.append(NextPageTemplate("Normal"))
story.append(section_bar("TABLE OF CONTENTS", color=C_TEAL))
story.append(sp(0.3))
toc_data = [
    ["01", "What is GIST? — Overview & Definition"],
    ["02", "Cell of Origin — Interstitial Cells of Cajal"],
    ["03", "Anatomic Distribution & Epidemiology"],
    ["04", "Gross Pathology"],
    ["05", "Histopathology — Microscopic Patterns"],
    ["06", "Immunohistochemistry (IHC)"],
    ["07", "Molecular Pathogenesis — Mutations & Pathways"],
    ["08", "Risk Stratification — How to Predict Behavior"],
    ["09", "Clinical Features — Presentation & Diagnosis"],
    ["10", "Hereditary Syndromes Associated with GIST"],
    ["11", "Treatment — Surgery, Imatinib & Beyond"],
    ["12", "High-Yield Exam Q&A"],
    ["13", "Key Points Summary Card"],
],
toc_num_s = PS("TOCN", fontSize=11, fontName="Helvetica-Bold", textColor=C_BLUE, alignment=TA_CENTER)
toc_txt_s = PS("TOCT", fontSize=10, fontName="Helvetica", textColor=C_GRAY_D, alignment=TA_LEFT)
for item in toc_data[0]:
    row_data = [[Paragraph(item[0], toc_num_s), Paragraph(item[1], toc_txt_s)]]
    t = Table(row_data, colWidths=[1.2*cm, W-1.2*cm])
    t.setStyle(TableStyle([
        ("VALIGN",       (0,0),(-1,-1), "MIDDLE"),
        ("TOPPADDING",   (0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
        ("LEFTPADDING",  (1,0),(1,0),   6),
        ("LINEBELOW",    (0,0),(-1,-1), 0.3, colors.HexColor("#CFD8DC")),
    ]))
    story.append(t)
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 01 ═══════════════════════════════════════════
story.append(section_bar("01  |  WHAT IS GIST? — OVERVIEW & DEFINITION", color=C_NAVY))
story.append(sp(0.3))

story.append(Paragraph(
    "A <b>Gastrointestinal Stromal Tumor (GIST)</b> is a mesenchymal (non-epithelial) neoplasm arising "
    "from the wall of the gastrointestinal tract. It is the <b>most common mesenchymal tumor of the GI tract</b> "
    "and makes up 1–3% of all malignant GI tumors.", BODY))
story.append(sp(0.15))

story.append(callout([
    "📌  GIST = Most common mesenchymal tumor of the GI tract",
    "📌  Every GIST has metastatic potential — NO truly benign GIST exists",
    "📌  Driven by gain-of-function mutations in KIT (~80%) or PDGFRA (~8%)",
    "📌  Highly responsive to imatinib (Gleevec) — a landmark targeted therapy",
], bg=C_BLUE_XLIT, border=C_BLUE))
story.append(sp(0.3))

story.append(Paragraph("Historical Milestones", H2_STYLE))
story.append(make_table(
    ["Year", "Milestone"],
    [["1983", "Term 'GIST' coined by Mazur & Clark for non-epithelial GI mesenchymal tumors"],
     ["Early 1990s", "CD34 explored as marker — insufficient sensitivity & specificity"],
     ["1998", "Hirota et al.: near-universal KIT (CD117) expression + gain-of-function KIT mutations discovered"],
     ["1999+", "DOG1 identified; molecular classification replaces histology-only diagnosis"],
     ["2001", "Imatinib mesylate first used in GIST — revolutionary targeted therapy"],
     ["2006+", "PDGFRA, SDH-deficient, and wild-type subtypes characterised"],
    ],
    col_widths=[W*0.15, W*0.85]
))
story.append(sp(0.2))
story.append(Paragraph(
    "Before 1998, GISTs were frequently misclassified as leiomyomas, leiomyosarcomas, "
    "'plexosarcomas,' or 'gastrointestinal autonomic nerve tumors' — leading to incorrect treatment.", NOTE))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 02 ═══════════════════════════════════════════
story.append(section_bar("02  |  CELL OF ORIGIN — INTERSTITIAL CELLS OF CAJAL", color=C_TEAL))
story.append(sp(0.3))

story.append(Paragraph(
    "GIST arises from <b>Interstitial Cells of Cajal (ICC)</b> — the pacemaker cells of the "
    "GI tract. These cells are located in the <b>myenteric plexus</b> (Auerbach's plexus) "
    "within the muscularis propria.", BODY))
story.append(sp(0.2))

story.append(Paragraph("What do ICCs normally do?", H2_STYLE))
for item in [
    "Act as <b>electrical pacemakers</b> — generate slow waves that drive peristalsis",
    "Link <b>smooth muscle cells</b> of the bowel wall with the <b>autonomic nervous system</b>",
    "Coordinate timing and direction of intestinal contractions",
    "Express <b>KIT (CD117)</b>, <b>CD34</b>, and <b>DOG1</b> constitutively",
]:
    story.append(bp(item))
story.append(sp(0.2))

story.append(Paragraph("Why do ICCs give rise to GIST?", H2_STYLE))
story.append(Paragraph(
    "ICCs depend on KIT signalling for their normal development and survival. "
    "A gain-of-function mutation in KIT causes <b>constitutive (always-on) KIT activation</b>, "
    "driving ICC descendants into uncontrolled proliferation — producing GIST.", BODY))
story.append(sp(0.15))

story.append(callout([
    "🧬  ICC  →  Gain-of-function KIT mutation  →  Constitutive kinase activation  →  GIST",
    "Extra-GI 'telocytes' (ICC-like cells in other tissues) may explain rare pancreatic/mesenteric GISTs",
], bg=C_TEAL_LITE, border=C_TEAL))
story.append(sp(0.3))

story.append(Paragraph("Shared Markers: ICC vs. GIST Cell", H2_STYLE))
story.append(make_table(
    ["Marker", "ICC (Normal)", "GIST Cell", "Significance"],
    [["CD117 (KIT)", "✓  Positive", "✓  ~95% Positive", "Defining diagnostic marker"],
     ["DOG1 (ANO1)", "✓  Positive", "✓  ~95% Positive", "Best confirmatory IHC marker"],
     ["CD34", "✓  Positive", "✓  ~60–70% Positive", "Supportive marker"],
     ["Smooth muscle actin", "Variable", "Variable (~30%)", "Not specific"],
     ["S100", "Negative", "Usually negative", "Helps exclude schwannoma"],
    ],
    col_widths=[W*0.26, W*0.16, W*0.22, W*0.36], hdr_color=C_TEAL
))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 03 ═══════════════════════════════════════════
story.append(section_bar("03  |  ANATOMIC DISTRIBUTION & EPIDEMIOLOGY", color=C_NAVY))
story.append(sp(0.3))

story.append(Paragraph("Where Does GIST Occur?", H2_STYLE))
story.append(make_table(
    ["Site", "Frequency", "Special Notes"],
    [["Stomach",            "40–60%", "Most common; PDGFRA mutations overrepresented here; best prognosis"],
     ["Jejunum / Ileum",    "24–30%", "Second most common; worse prognosis than gastric at same size/mitotic rate"],
     ["Colorectum",         "5–15%",  "Rectal GISTs: poor prognosis; limited surgical access"],
     ["Duodenum",           "~5%",    "Uncommon; surgical challenge near ampulla"],
     ["Esophagus",          "<1%",    "Very rare"],
     ["Extra-GI (mesentery, omentum)", "<5%", "Called 'extra-gastrointestinal stromal tumors' — same biology"],
    ],
    col_widths=[W*0.28, W*0.16, W*0.56]
))
story.append(sp(0.2))
story.append(warning_box([
    "Non-gastric GIST = worse prognosis than gastric GIST at the same size and mitotic rate.",
    "Small intestinal and rectal GISTs are classified into higher risk categories."
]))
story.append(sp(0.3))

story.append(Paragraph("Epidemiology", H2_STYLE))
story.append(make_table(
    ["Variable", "Data"],
    [["Incidence",       "10–15 per million per year (GI tract); underdiagnosed historically"],
     ["Peak age",        "~60 years (median); < 10% under age 40"],
     ["Sex",             "Slight male predominance (~55% male)"],
     ["Pediatric GIST",  "Rare; usually SDH-deficient; gastric; multifocal; female predominance"],
     ["Race",            "No significant racial predisposition in sporadic GISTs"],
    ],
    col_widths=[W*0.3, W*0.7]
))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 04 ═══════════════════════════════════════════
story.append(section_bar("04  |  GROSS PATHOLOGY", color=C_BLUE))
story.append(sp(0.3))

story.append(Paragraph("Macroscopic Features", H2_STYLE))
story.append(Paragraph(
    "Most GISTs present as <b>solitary, well-circumscribed, fleshy submucosal masses</b> arising from "
    "the muscularis propria. The overlying mucosa may be intact, thinned, or ulcerated.", BODY))
story.append(sp(0.15))

story.append(make_table(
    ["Feature", "Description"],
    [["Shape",        "Round to oval; well-circumscribed; pseudocapsule (NOT a true capsule)"],
     ["Size",         "Range: <1 cm (incidental) to >30 cm; most symptomatic GISTs are >5 cm"],
     ["Cut surface",  "Tan-white to pinkish, fleshy; soft to firm texture"],
     ["Haemorrhage",  "Common in larger tumors — areas of red/brown discolouration"],
     ["Necrosis",     "Present in large/high-grade tumors — yellow-grey areas"],
     ["Cystic change","Occurs in larger tumors — fluid-filled spaces"],
     ["Growth pattern","Endoluminal, exophytic, or dumbbell-shaped (both directions)"],
     ["Origin layer", "Muscularis propria — NOT mucosa or submucosa primarily"],
    ],
    col_widths=[W*0.28, W*0.72]
))
story.append(sp(0.2))

story.append(Paragraph("Metastatic Pattern (Gross)", H2_STYLE))
for item in [
    "<b>Liver</b> — most common site of distant metastasis (multiple nodules)",
    "<b>Peritoneum</b> — seeding via intraperitoneal spread",
    "<b>Lymph nodes</b> — RARE in sporadic KIT/PDGFRA-mutant GIST (unlike carcinomas)",
    "<b>Exception</b>: SDH-deficient/pediatric GISTs DO metastasize to lymph nodes",
    "Distant spread outside the abdomen (lung, bone) is uncommon",
]:
    story.append(bp(item))
story.append(sp(0.15))
story.append(warning_box([
    "GIST has a pseudocapsule, NOT a true capsule. Rupture (surgical or spontaneous) dramatically",
    "increases peritoneal recurrence risk — treat ruptured GIST as already metastatic."
]))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 05 ═══════════════════════════════════════════
story.append(section_bar("05  |  HISTOPATHOLOGY — MICROSCOPIC PATTERNS", color=C_NAVY))
story.append(sp(0.3))

story.append(Paragraph(
    "Three main histologic patterns exist. However, <b>histology alone cannot diagnose GIST</b> — "
    "IHC and molecular testing are required.", BODY))
story.append(sp(0.2))

story.append(make_table(
    ["Pattern", "Frequency", "Microscopic Features", "When to Suspect"],
    [["Spindle cell", "~70%",
      "Thin, elongated cells; pale eosinophilic cytoplasm; nuclear palisading; fascicular or storiform arrangement",
      "Most common; gastric & small intestinal GISTs"],
     ["Epithelioid", "~20%",
      "Plumper, rounded cells; abundant pale/clear cytoplasm; nesting pattern; perinuclear vacuoles",
      "Stomach; PDGFRA-mutant tumors; check PDGFRA D842V if IHC equivocal"],
     ["Mixed", "~10%",
      "Both spindle and epithelioid components in the same tumor",
      "Any site; requires full IHC panel"],
    ],
    col_widths=[W*0.18, W*0.12, W*0.42, W*0.28]
))
story.append(sp(0.2))

story.append(Paragraph("Key Microscopic Details", H2_STYLE))
for item in [
    "Mitotic figures are counted per <b>50 high-power fields (HPF)</b> — critical for risk stratification",
    "Nuclear atypia is usually <b>mild to moderate</b>; severe pleomorphism is uncommon",
    "Necrosis correlates with high-grade behavior and large tumor size",
    "<b>Skeinoid fibres</b> (eosinophilic extracellular globules) — classically seen in small intestinal spindle-cell GISTs",
    "Submucosal location with intact overlying mucosa — typical but not universal",
]:
    story.append(bp(item))
story.append(sp(0.2))

story.append(Paragraph("Historical Classification (Pre-1999) — Now Obsolete", H2_STYLE))
story.append(callout([
    "Before molecular markers, GISTs were (incorrectly) divided into thirds:",
    "• 1/3  Myogenic — expressed smooth muscle actin (thought to be leiomyosarcomas)",
    "• 1/3  Neurogenic — expressed S100 (thought to be schwannomas)",
    "• 1/3  Null phenotype — no lineage-specific markers",
    "This caused widespread misdiagnosis and inappropriate treatment."
], bg=C_ORANGE_L, border=C_ORANGE))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 06 ═══════════════════════════════════════════
story.append(section_bar("06  |  IMMUNOHISTOCHEMISTRY (IHC)", color=C_TEAL))
story.append(sp(0.3))

story.append(Paragraph(
    "IHC is the backbone of GIST diagnosis. The <b>two most important markers</b> are "
    "<b>CD117 (KIT)</b> and <b>DOG1</b>, each positive in ~95% of GISTs.", BODY))
story.append(sp(0.2))

story.append(make_table(
    ["Marker", "Sensitivity", "Specificity", "Staining Pattern", "Clinical Relevance"],
    [["CD117 (KIT, c-kit)", "~95%", "Moderate", "Strong diffuse cytoplasmic (spindle); dot-like / focal (epithelioid)", "Primary diagnostic marker; cornerstone of GIST diagnosis"],
     ["DOG1 (ANO1)", "~95%", "High", "Membranous ± cytoplasmic", "ESSENTIAL in KIT-negative GISTs; more specific than CD117"],
     ["CD34", "~60–70%", "Low", "Cytoplasmic", "Supportive only; also in vascular tumors"],
     ["PDGFRA (IHC)", "~70–80% of PDGFRA-mutant", "Moderate", "Cytoplasmic", "Helps identify PDGFRA-mutant subtype when KIT negative"],
     ["SDHB (IHC)", "N/A", "High (for SDH loss)", "Normal: granular; Loss: diffuse", "Loss of SDHB staining = SDH-deficient GIST"],
     ["Smooth muscle actin", "~30%", "Low", "Cytoplasmic", "Variable; does NOT exclude GIST"],
     ["Desmin", "~5%", "Low", "Cytoplasmic", "Usually negative; helps exclude leiomyosarcoma"],
     ["S100 protein", "<5%", "Low", "Nuclear + cytoplasmic", "Usually negative; helps exclude schwannoma"],
    ],
    col_widths=[W*0.20, W*0.12, W*0.12, W*0.28, W*0.28], hdr_color=C_TEAL
))
story.append(sp(0.2))

story.append(Paragraph("IHC Diagnostic Algorithm", H2_STYLE))
story.append(callout([
    "Step 1:  Suspicious spindle/epithelioid GI mesenchymal tumor",
    "Step 2:  Stain for CD117 (KIT)  +  DOG1",
    "Step 3a: CD117+ / DOG1+ → GIST confirmed → proceed to molecular testing",
    "Step 3b: CD117– / DOG1+ → Still likely GIST → test for PDGFRA mutation",
    "Step 3c: CD117– / DOG1– → Consider: leiomyosarcoma (desmin+/SMA+), schwannoma (S100+), desmoid (β-catenin+)",
    "Step 4:  SDHB IHC on all GISTs → loss = SDH-deficient subtype (impacts treatment)",
], bg=C_BLUE_XLIT, border=C_BLUE))
story.append(sp(0.15))

story.append(warning_box([
    "CD117 can be HETEROGENEOUS within a single tumor.",
    "A needle biopsy may yield CD117-negative cells due to sampling bias alone.",
    "Always use DOG1 alongside CD117 — they are complementary, not interchangeable."
]))
story.append(sp(0.2))

story.append(mnemonic_box("CD-KIT = C-DOGS",
    [("C", "CD117 (KIT) — primary marker (~95%)"),
     ("D", "DOG1 — best specificity; positive even in KIT-negative GISTs"),
     ("O", "Only together = reliable diagnosis"),
     ("G", "Genotype (molecular testing) follows IHC to guide treatment"),
     ("S", "SDHB loss = SDH-deficient subtype — check in all wild-type GISTs"),
    ]))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 07 ═══════════════════════════════════════════
story.append(section_bar("07  |  MOLECULAR PATHOGENESIS — MUTATIONS & PATHWAYS", color=C_NAVY))
story.append(sp(0.3))

story.append(Paragraph("The KIT Signalling Pathway (Normal vs. Mutant)", H2_STYLE))
story.append(Paragraph(
    "<b>Normal:</b>  SCF (stem cell factor) binds KIT receptor → homodimerization → "
    "autophosphorylation → activation of RAS/MAPK, PI3K/AKT, JAK/STAT3 → cell growth (regulated).<br/><br/>"
    "<b>Mutant GIST:</b>  Gain-of-function KIT mutation → receptor is <b>always active</b> "
    "(ligand-independent) → constitutive downstream signalling → uncontrolled cell proliferation → GIST.",
    BODY))
story.append(sp(0.2))

story.append(Paragraph("Mutation Landscape Overview", H2_STYLE))
story.append(make_table(
    ["Mutation Type", "Frequency", "Imatinib Response", "Key Notes"],
    [["KIT exon 11 (juxtamembrane)", "~65–70%", "HIGH (~80–90%)", "Most sensitive; deletions more common than point mutations"],
     ["KIT exon 9 (extracellular)", "~10–15%",  "MODERATE (40–50%)", "Needs higher dose (800 mg/day); small intestinal predilection"],
     ["KIT exon 13 (kinase I)",      "~1–2%",   "MODERATE",          "K642E most common"],
     ["KIT exon 17 (kinase II)",     "~1%",     "MODERATE",          "D820 mutations; sunitinib may be better"],
     ["PDGFRA exon 18 D842V",        "~5–6%",   "RESISTANT",         "Avapritinib is preferred; imatinib inactive"],
     ["PDGFRA other exons",          "~1–2%",   "Variable",          "May respond to imatinib"],
     ["SDH-deficient (wild-type)",   "~5–10%",  "RESISTANT",         "Pediatric/Carney triad; SDHB IHC loss"],
     ["NF1-associated (wild-type)",  "~1%",     "Uncertain",         "Multiple small intestinal GISTs"],
     ["BRAF V600E (wild-type)",      "<1%",     "Resistant",         "May respond to vemurafenib"],
    ],
    col_widths=[W*0.30, W*0.14, W*0.18, W*0.38]
))
story.append(sp(0.2))

story.append(Paragraph("KIT vs. PDGFRA — Key Comparison", H2_STYLE))
story.append(make_table(
    ["Feature", "KIT-mutant GIST", "PDGFRA-mutant GIST"],
    [["Chromosome",    "4q12",       "4q12 (same locus — adjacent genes)"],
     ["Frequency",     "~75–85%",    "~8–10%"],
     ["Common site",   "Any GI site","Stomach (overrepresented); omentum"],
     ["Histology",     "Spindle cell predominant", "Epithelioid predominant"],
     ["IHC CD117",     "~95% positive", "Often weak/negative"],
     ["Imatinib",      "Mostly sensitive", "D842V = resistant; others variable"],
     ["Mutual exclusivity", "—",     "KIT and PDGFRA mutations NEVER coexist"],
    ],
    col_widths=[W*0.27, W*0.36, W*0.37]
))
story.append(sp(0.2))

story.append(Paragraph("SDH-Deficient GIST — Special Subtype", H2_STYLE))
story.append(callout([
    "Mutation: SDHA, SDHB, SDHC, or SDHD genes (succinate dehydrogenase complex — mitochondria)",
    "Effect: SDH dysfunction → ↑ succinate accumulation → pseudohypoxia (HIF activation) → tumour growth",
    "Profile: KIT negative, PDGFRA negative, SDHB IHC loss",
    "Clinical: Young patients; female predominance; multifocal gastric; lymph node spread possible",
    "Syndromes: Carney Triad, Carney-Stratakis Dyad",
    "Treatment: Imatinib-resistant — temozolomide, sunitinib, or clinical trials",
], bg=C_PURPLE_L, border=C_PURPLE))
story.append(sp(0.3))

story.append(mnemonic_box("KIT Exon Mutations — 'Eleven Is First'",
    [("11", "Exon 11 = Most common + Best imatinib response (juxtamembrane domain)"),
     ("9",  "Exon 9 = Second + Needs Higher dose + Small intestine"),
     ("13", "Exon 13 = Kinase I domain, rare"),
     ("17", "Exon 17 = Kinase II domain, rare"),
    ]))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 08 ═══════════════════════════════════════════
story.append(section_bar("08  |  RISK STRATIFICATION — HOW TO PREDICT BEHAVIOUR", color=C_BLUE))
story.append(sp(0.3))

story.append(callout([
    "🔑  Core Concept: Every GIST has metastatic potential — risk stratification tells us HOW MUCH risk.",
    "🔑  The 3 pillars: (1) Tumor SIZE  (2) MITOTIC RATE  (3) PRIMARY SITE",
    "🔑  A 4th factor: Tumor RUPTURE — dramatically worsens prognosis (treat as metastatic)",
], bg=C_YELLOW_L, border=C_YELLOW))
story.append(sp(0.2))

story.append(Paragraph("NIH (Fletcher) Consensus Classification — Most Used in Practice", H2_STYLE))
story.append(make_table(
    ["Risk Category", "Size", "Mitotic Rate (per 50 HPF)"],
    [["Very Low Risk",    "< 2 cm",     "< 5"],
     ["Low Risk",         "2–5 cm",     "< 5"],
     ["Intermediate Risk","< 5 cm  OR  5–10 cm", "6–10  OR  < 5"],
     ["High Risk",        "> 5 cm  OR  > 10 cm  OR  ANY size", "> 5  OR  ANY  OR  > 10"],
    ],
    col_widths=[W*0.25, W*0.35, W*0.40]
))
story.append(sp(0.15))
story.append(Paragraph(
    "Note: This system does NOT account for site. The <b>Joensuu/AFIP system</b> adds site as a variable "
    "and shows that non-gastric GISTs behave more aggressively.", NOTE))
story.append(sp(0.2))

story.append(Paragraph("Effect of Tumor Site on Prognosis (Joensuu system)", H2_STYLE))
story.append(make_table(
    ["Size + Mitotic Rate", "Gastric GIST", "Non-Gastric GIST"],
    [["≤ 2 cm / ≤ 5 mit",      "Negligible risk",  "Negligible risk"],
     ["2–5 cm / ≤ 5 mit",      "Very low risk",    "Low risk"],
     ["5–10 cm / ≤ 5 mit",     "Low risk",         "Moderate risk"],
     ["> 10 cm / ≤ 5 mit",     "Moderate risk",    "HIGH risk"],
     ["Any / > 5 mit",         "Moderate–High",    "HIGH risk"],
     ["Ruptured tumor",        "HIGH risk",        "HIGH risk"],
    ],
    col_widths=[W*0.35, W*0.32, W*0.33]
))
story.append(sp(0.2))

story.append(Paragraph("AJCC Staging (8th Ed)", H2_STYLE))
story.append(Paragraph(
    "Uses T (size: T1 ≤2 cm, T2 2–5 cm, T3 5–10 cm, T4 >10 cm), N (nodes — rare), "
    "M (distant metastasis), and <b>mitotic rate</b>. Separate staging tables exist for "
    "<b>gastric/omental</b> vs. <b>small intestinal/esophageal/colorectal/mesenteric</b> GISTs.", BODY))
story.append(sp(0.3))

story.append(mnemonic_box("Risk = SiMS + Location",
    [("Si", "SIZE — bigger = worse"),
     ("M",  "MITOTIC rate — more mitoses/50 HPF = worse"),
     ("S",  "SITE — non-gastric = worse than gastric at same size/mitotic rate"),
     ("+",  "RUPTURE — treat as already metastatic regardless of size/mitotic rate"),
    ]))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 09 ═══════════════════════════════════════════
story.append(section_bar("09  |  CLINICAL FEATURES — PRESENTATION & DIAGNOSIS", color=C_NAVY))
story.append(sp(0.3))

story.append(Paragraph("Symptoms and Presentation", H2_STYLE))
story.append(make_table(
    ["Presentation", "Details / Notes"],
    [["GI bleeding",          "Haematemesis, melaena, or occult blood loss — due to mucosal ulceration"],
     ["Abdominal pain/mass",  "Dull, vague pain; palpable mass in large tumors"],
     ["Obstruction",          "Gastric outlet obstruction or small bowel obstruction"],
     ["Dysphagia",            "Esophageal or gastric cardiac GISTs"],
     ["Incidental finding",   "Common! Found on imaging/endoscopy for other reasons — typically < 2 cm"],
     ["Acute abdomen",        "Tumor rupture → haemoperitoneum — surgical emergency"],
    ],
    col_widths=[W*0.30, W*0.70]
))
story.append(sp(0.2))

story.append(Paragraph("Diagnostic Work-Up", H2_STYLE))
for item in [
    "<b>CT scan with contrast</b> — imaging modality of choice; characterises tumor, extent, and metastases",
    "<b>Endoscopy/EUS (endoscopic ultrasound)</b> — EUS-guided FNA for biopsy when resection planned; assesses submucosal lesion layers",
    "<b>Biopsy</b> — needed for unresectable/metastatic disease before imatinib; avoid for resectable lesions (risk of rupture/seeding)",
    "<b>PET scan</b> — detects early imatinib response (metabolic response precedes size change); useful for monitoring",
    "<b>Molecular testing</b> (KIT/PDGFRA exon sequencing) — mandatory before starting targeted therapy",
    "<b>SDHB IHC</b> — on all GISTs to identify SDH-deficient subtype",
]:
    story.append(bp(item))
story.append(sp(0.2))

story.append(Paragraph("Radiologic Features (CT)", H2_STYLE))
story.append(make_table(
    ["Feature", "GIST Finding"],
    [["Enhancement",     "Heterogeneous, often hypervascular; may have necrotic/haemorrhagic areas"],
     ["Margins",         "Well-defined, smooth; pseudocapsule visible"],
     ["Response to Rx",  "Choi criteria (not RECIST): decrease in density (Hounsfield units) precedes size change"],
     ["Metastasis",      "Liver: multiple hypervascular nodules; peritoneal nodules"],
    ],
    col_widths=[W*0.3, W*0.7]
))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 10 ═══════════════════════════════════════════
story.append(section_bar("10  |  HEREDITARY SYNDROMES ASSOCIATED WITH GIST", color=C_TEAL))
story.append(sp(0.3))

story.append(make_table(
    ["Syndrome", "GIST Features", "Other Tumors", "Molecular Basis"],
    [["Carney Triad\n(NOT autosomal dominant)",
      "Gastric GIST; multifocal; young females; SDH-deficient",
      "Pulmonary chondromas + extra-adrenal paragangliomas",
      "SDHC promoter hypermethylation (somatic/epigenetic); no germline SDH mutation in most"],
     ["Carney-Stratakis Dyad\n(Autosomal dominant)",
      "Gastric GIST; multifocal; SDH-deficient",
      "Paraganglioma (no pulmonary chondroma)",
      "Germline SDHA/B/C/D mutations; autosomal dominant"],
     ["Familial GIST Syndrome\n(Autosomal dominant)",
      "Multiple GISTs at any GI site; early onset; diffuse ICC hyperplasia; cutaneous hyperpigmentation",
      "None specific",
      "Germline KIT (most common) or PDGFRA mutations"],
     ["NF1 (von Recklinghausen)\n(Autosomal dominant)",
      "Multiple small intestinal GISTs; usually small, low mitotic rate; often incidental",
      "Neurofibromas, astrocytomas, learning disability, café-au-lait spots",
      "NF1 loss (not KIT/PDGFRA mutations); KIT overexpressed but not mutated"],
    ],
    col_widths=[W*0.22, W*0.26, W*0.26, W*0.26], hdr_color=C_TEAL
))
story.append(sp(0.2))

story.append(callout([
    "Memory aid for Carney Triad:  G-P-P",
    "  G = Gastric GIST",
    "  P = Pulmonary chondroma",
    "  P = Paraganglioma (extra-adrenal)",
    "Carney-Stratakis Dyad = G + P (no pulmonary chondroma) + germline SDH mutation",
], bg=C_PURPLE_L, border=C_PURPLE))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 11 ═══════════════════════════════════════════
story.append(section_bar("11  |  TREATMENT — SURGERY, IMATINIB & BEYOND", color=C_NAVY))
story.append(sp(0.3))

story.append(Paragraph("A. Surgery", H2_STYLE))
story.append(make_table(
    ["Principle", "Details"],
    [["Goal",             "Complete resection with negative margins (R0) — primary curative treatment"],
     ["Margins",          "1–2 cm recommended; pseudocapsule must remain INTACT"],
     ["Lymphadenectomy",  "NOT routine — lymph node spread is rare in KIT/PDGFRA-mutant GIST"],
     ["Laparoscopic",     "Acceptable for gastric GISTs ≤ 5 cm with appropriate technique"],
     ["Tumor rupture",    "AVOID — treat ruptured GIST as disseminated disease regardless of other features"],
    ],
    col_widths=[W*0.28, W*0.72]
))
story.append(sp(0.2))

story.append(Paragraph("B. Imatinib Mesylate (Gleevec) — The Targeted Therapy Revolution", H2_STYLE))
story.append(Paragraph(
    "Imatinib is a <b>tyrosine kinase inhibitor (TKI)</b> that competitively inhibits KIT, PDGFRA, "
    "BCR-ABL, and PDGFRB. It transformed GIST from a chemotherapy-resistant disease into a manageable "
    "chronic condition for many patients.", BODY))
story.append(sp(0.15))

story.append(make_table(
    ["Setting", "Indication", "Duration"],
    [["Adjuvant (post-op)",   "High-risk resected GIST with imatinib-sensitive mutation", "3 years (standard); ongoing trials for longer"],
     ["Neoadjuvant (pre-op)", "Marginally resectable; large/complex tumors", "Until maximal response (typically 6–12 months)"],
     ["Metastatic/Unresectable", "All imatinib-sensitive GIST", "Lifelong — stopping leads to rapid progression"],
    ],
    col_widths=[W*0.27, W*0.44, W*0.29]
))
story.append(sp(0.15))

story.append(make_table(
    ["Mutation", "Standard Dose", "Response"],
    [["KIT exon 11",        "400 mg/day", "~80–90% — best response"],
     ["KIT exon 9",         "800 mg/day", "~40–50% (higher dose required)"],
     ["PDGFRA non-D842V",   "400 mg/day", "Variable"],
     ["PDGFRA D842V",       "Imatinib NOT used", "RESISTANT — use avapritinib"],
     ["Wild-type / SDH",    "Not recommended", "Generally resistant"],
    ],
    col_widths=[W*0.30, W*0.22, W*0.48]
))
story.append(sp(0.2))

story.append(Paragraph("C. Second-Line and Beyond", H2_STYLE))
story.append(make_table(
    ["Drug", "Line", "Mechanism", "Notes"],
    [["Sunitinib",    "2nd line", "Multi-TKI (KIT, PDGFR, VEGFR)", "Used when imatinib fails/intolerable; specific KIT mutations guide response"],
     ["Regorafenib",  "3rd line", "Multi-TKI", "After sunitinib failure"],
     ["Ripretinib",   "4th line", "Switch-control KIT/PDGFRA inhibitor", "Broad inhibition of KIT resistance mutations"],
     ["Avapritinib",  "1st line for D842V", "PDGFRA-selective TKI", "FDA approved for PDGFRA exon 18 D842V mutant GIST"],
    ],
    col_widths=[W*0.18, W*0.13, W*0.29, W*0.40]
))
story.append(sp(0.15))

story.append(callout([
    "⚡  Secondary resistance to imatinib: Develops in ~2 years in metastatic GIST via secondary KIT kinase domain mutations.",
    "    Same mechanism as imatinib resistance in CML (BCR-ABL secondary mutations).",
    "    PET scan shows single progressing lesion ('clonal progression') while others remain controlled.",
], bg=C_ORANGE_L, border=C_ORANGE))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 12 ═══════════════════════════════════════════
story.append(section_bar("12  |  HIGH-YIELD EXAM Q&A", color=C_BLUE))
story.append(sp(0.3))

story.append(exam_box([
    ("What is the cell of origin of GIST?",
     "Interstitial cells of Cajal (ICC) — pacemaker cells of the GI muscularis propria."),
    ("What are the two most important IHC markers for GIST?",
     "CD117 (KIT) and DOG1 — each positive in ~95% of GISTs."),
    ("Which GIST mutation is most common and has the best imatinib response?",
     "KIT exon 11 mutation (~65–70% of GISTs; ~80–90% response to imatinib 400 mg/day)."),
    ("Which mutation is RESISTANT to imatinib?",
     "PDGFRA exon 18 D842V mutation — use avapritinib instead."),
    ("What are the 3 pillars of GIST risk stratification?",
     "Tumor SIZE + MITOTIC RATE (per 50 HPF) + PRIMARY SITE (non-gastric = worse)."),
    ("What is 'every GIST' rule?",
     "Every GIST has metastatic potential — there is NO truly benign GIST."),
    ("What is the lymph node spread pattern in GIST?",
     "RARE in KIT/PDGFRA-mutant GISTs (unlike carcinomas). Exception: SDH-deficient/pediatric GISTs."),
    ("What is Carney Triad?",
     "Gastric GIST + Pulmonary chondroma + Extra-adrenal paraganglioma (SDH-deficient; young females)."),
    ("What happens if a GIST ruptures?",
     "Treat as already metastatic — tumor rupture dramatically increases peritoneal recurrence risk."),
    ("What IHC stain identifies SDH-deficient GIST?",
     "Loss of SDHB staining on IHC (granular pattern lost → diffuse/absent)."),
    ("Why is KIT exon 9 mutant GIST treated with higher dose imatinib?",
     "Exon 9 mutations confer lower imatinib sensitivity; 800 mg/day improves response rates."),
    ("What criteria are used to assess imatinib response on CT?",
     "Choi criteria — decrease in CT density (Hounsfield units) precedes size reduction (not RECIST)."),
]))
story.append(sp(0.3))
story.append(PageBreak())

# ═══════════════════════ CHAPTER 13 ═══════════════════════════════════════════
story.append(section_bar("13  |  KEY POINTS SUMMARY CARD", color=C_NAVY))
story.append(sp(0.3))

story.append(make_table(
    ["Topic", "Key Point"],
    [["Definition",       "Most common GI mesenchymal tumor; 1–3% of all GI malignancies"],
     ["Cell of origin",   "Interstitial cells of Cajal (ICCs) in the muscularis propria"],
     ["Most common site", "Stomach (40–60%) → Small intestine → Colorectum"],
     ["IHC markers",      "CD117 + DOG1 (~95% each); SDHB loss = SDH-deficient"],
     ["Main mutation",    "KIT exon 11 (~65–70%) — best imatinib response"],
     ["Imatinib-resistant","PDGFRA D842V — use avapritinib"],
     ["Risk pillars",     "Size + Mitotic rate (per 50 HPF) + Site (non-gastric worse)"],
     ["Lymph nodes",      "Rarely involved in sporadic GIST (exception: SDH-deficient)"],
     ["Metastasis sites", "Liver (most common) + Peritoneum"],
     ["Surgery rule",     "R0 resection; no lymphadenectomy; avoid rupture"],
     ["Adjuvant therapy", "Imatinib 3 years for high-risk resected GIST (sensitive mutations)"],
     ["Pediatric GIST",   "SDH-deficient; gastric; multifocal; lymph node spread possible; imatinib-resistant"],
     ["Carney Triad",     "GIST + Pulmonary chondroma + Paraganglioma (SDH-deficient)"],
     ["Resistance mechanism","Secondary KIT kinase mutations (like CML/BCR-ABL)"],
     ["ctDNA (emerging)", "Circulating tumour DNA — emerging prognostic biomarker (2025 meta-analysis)"],
    ],
    col_widths=[W*0.30, W*0.70]
))
story.append(sp(0.3))

story.append(hr(C_NAVY))
story.append(Paragraph(
    "Sources: Robbins &amp; Kumar Basic Pathology · Sleisenger &amp; Fordtran's GI and Liver Disease · "
    "Sabiston Textbook of Surgery · Quick Compendium of Clinical Pathology 5e · "
    "Fischer's Mastery of Surgery 8e · Current Surgical Therapy 14e · "
    "Goodman &amp; Gilman's Pharmacological Basis of Therapeutics · "
    "Schwartz's Principles of Surgery 11e",
    NOTE))
story.append(Paragraph(
    "Recent PubMed: PMID 40665034 (ctDNA meta-analysis 2025) · PMID 40045030 (SDH-deficient GIST therapies 2025) · "
    "PMID 40140195 (neoadjuvant imatinib meta-analysis 2025)",
    NOTE))
story.append(sp(0.2))
story.append(Paragraph(
    "This guide is for educational use only. Always defer to current clinical guidelines for patient care.",
    NOTE))

# ══════════════════════════════════════════════════════════════════════════════
# BUILD
# ══════════════════════════════════════════════════════════════════════════════
doc.build(story)
print(f"✅  PDF created: {OUTPUT}")

cd /home/daytona/workspace/gist-pathology && python gist_student.py 2>&1

~/gist-pathology/gist_long_answer.py

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import ParagraphStyle
from reportlab.lib.units import cm
from reportlab.platypus import (
    BaseDocTemplate, PageTemplate, Frame, SimpleDocTemplate,
    Paragraph, Spacer, Table, TableStyle, HRFlowable, PageBreak,
    KeepTogether, NextPageTemplate
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY, TA_RIGHT

OUTPUT = "/home/daytona/workspace/gist-pathology/GIST_Long_Answer.pdf"

W_PAGE, H_PAGE = A4
LM = RM = 2.0*cm
TM = BM = 1.8*cm
W = W_PAGE - LM - RM

# ── COLOURS ───────────────────────────────────────────────────────────────────
NAVY        = colors.HexColor("#0B2545")
BLUE        = colors.HexColor("#1565C0")
BLUE_MID    = colors.HexColor("#1976D2")
BLUE_LITE   = colors.HexColor("#BBDEFB")
BLUE_XLIT   = colors.HexColor("#E3F2FD")
TEAL        = colors.HexColor("#00695C")
TEAL_LITE   = colors.HexColor("#E0F2F1")
ORANGE      = colors.HexColor("#E65100")
ORANGE_L    = colors.HexColor("#FFF3E0")
GREEN       = colors.HexColor("#1B5E20")
GREEN_L     = colors.HexColor("#E8F5E9")
RED         = colors.HexColor("#B71C1C")
RED_L       = colors.HexColor("#FFEBEE")
PURPLE      = colors.HexColor("#4A148C")
PURPLE_L    = colors.HexColor("#F3E5F5")
YELLOW      = colors.HexColor("#F57F17")
YELLOW_L    = colors.HexColor("#FFFDE7")
GRAY_D      = colors.HexColor("#212121")
GRAY_M      = colors.HexColor("#546E7A")
GRAY_L      = colors.HexColor("#ECEFF1")
WHITE       = colors.white

# ── STYLES ────────────────────────────────────────────────────────────────────
def PS(name, **kw):
    return ParagraphStyle(name, **kw)

MAIN_TITLE  = PS("MainTitle", fontSize=28, leading=34, fontName="Helvetica-Bold",
                  textColor=WHITE, alignment=TA_CENTER)
SUBTITLE    = PS("Subtitle",  fontSize=14, leading=20, fontName="Helvetica",
                  textColor=colors.HexColor("#BBDEFB"), alignment=TA_CENTER)
QUESTION    = PS("Question",  fontSize=13, leading=18, fontName="Helvetica-Bold",
                  textColor=ORANGE, alignment=TA_LEFT, spaceBefore=2, spaceAfter=6)
H1          = PS("H1",        fontSize=14, leading=18, fontName="Helvetica-Bold",
                  textColor=WHITE, alignment=TA_LEFT)
H2          = PS("H2",        fontSize=12, leading=16, fontName="Helvetica-Bold",
                  textColor=NAVY, spaceBefore=8, spaceAfter=4)
H3          = PS("H3",        fontSize=10.5, leading=14, fontName="Helvetica-Bold",
                  textColor=BLUE, spaceBefore=6, spaceAfter=3)
BODY        = PS("Body",      fontSize=10.5, leading=16.5, fontName="Helvetica",
                  textColor=GRAY_D, alignment=TA_JUSTIFY, spaceAfter=5)
BODY_IND    = PS("BodyInd",   fontSize=10.5, leading=16.5, fontName="Helvetica",
                  textColor=GRAY_D, alignment=TA_JUSTIFY, leftIndent=14, spaceAfter=4)
BULLET      = PS("Bullet",    fontSize=10.5, leading=16, fontName="Helvetica",
                  textColor=GRAY_D, leftIndent=18, bulletIndent=4, spaceAfter=2)
BULLET2     = PS("Bullet2",   fontSize=10, leading=14, fontName="Helvetica",
                  textColor=GRAY_D, leftIndent=34, bulletIndent=18, spaceAfter=2)
NOTE        = PS("Note",      fontSize=8.5, leading=12, fontName="Helvetica-Oblique",
                  textColor=GRAY_M, spaceAfter=2)
TH_S        = PS("THS",       fontSize=9,  leading=13, fontName="Helvetica-Bold",
                  textColor=WHITE, alignment=TA_CENTER)
TD_S        = PS("TDS",       fontSize=9,  leading=13, fontName="Helvetica",
                  textColor=GRAY_D, alignment=TA_LEFT)
TD_C        = PS("TDC",       fontSize=9,  leading=13, fontName="Helvetica",
                  textColor=GRAY_D, alignment=TA_CENTER)
HIGHLIGHT   = PS("Highlight", fontSize=10.5, leading=16, fontName="Helvetica-Bold",
                  textColor=NAVY, leftIndent=10)
FOOTER_S    = PS("Footer",    fontSize=8,  leading=11, fontName="Helvetica",
                  textColor=WHITE, alignment=TA_LEFT)
FOOTER_R    = PS("FooterR",   fontSize=8.5, leading=11, fontName="Helvetica-Bold",
                  textColor=WHITE, alignment=TA_RIGHT)

# ── PAGE CALLBACKS ────────────────────────────────────────────────────────────
def on_cover(canvas, doc):
    canvas.saveState()
    canvas.setFillColor(NAVY)
    canvas.rect(0, 0, W_PAGE, H_PAGE, fill=1, stroke=0)
    canvas.setFillColor(BLUE)
    canvas.rect(0, H_PAGE*0.35, W_PAGE, H_PAGE*0.30, fill=1, stroke=0)
    canvas.setFillColor(YELLOW)
    canvas.rect(0, H_PAGE - 0.6*cm, W_PAGE, 0.6*cm, fill=1, stroke=0)
    canvas.setFillColor(TEAL)
    canvas.rect(0, 0, W_PAGE, 0.5*cm, fill=1, stroke=0)
    canvas.restoreState()

def on_page(canvas, doc):
    canvas.saveState()
    # Header
    canvas.setFillColor(NAVY)
    canvas.rect(0, H_PAGE - 1.0*cm, W_PAGE, 1.0*cm, fill=1, stroke=0)
    canvas.setFillColor(WHITE)
    canvas.setFont("Helvetica-Bold", 8.5)
    canvas.drawString(LM, H_PAGE - 0.68*cm, "GASTROINTESTINAL STROMAL TUMOR (GIST) — Long Answer")
    canvas.setFont("Helvetica", 8)
    canvas.drawRightString(W_PAGE - RM, H_PAGE - 0.68*cm, "Pathology Essay")
    # Footer
    canvas.setFillColor(NAVY)
    canvas.rect(0, 0, W_PAGE, 0.85*cm, fill=1, stroke=0)
    canvas.setFillColor(WHITE)
    canvas.setFont("Helvetica", 7.5)
    canvas.drawString(LM, 0.28*cm, "Orris Medical Reference  ·  Educational Use Only  ·  2026")
    canvas.setFont("Helvetica-Bold", 9)
    canvas.drawRightString(W_PAGE - RM, 0.28*cm, f"{doc.page}")
    canvas.restoreState()

# ── DOCUMENT SETUP ────────────────────────────────────────────────────────────
doc = BaseDocTemplate(
    OUTPUT, pagesize=A4,
    leftMargin=LM, rightMargin=RM,
    topMargin=TM + 1.1*cm, bottomMargin=BM + 0.9*cm,
    title="GIST Long Answer — Pathology Essay",
    author="Orris Medical Reference"
)
cover_f  = Frame(0, 0, W_PAGE, H_PAGE, leftPadding=2*cm, rightPadding=2*cm,
                 topPadding=2.5*cm, bottomPadding=1.5*cm, id="cover")
normal_f = Frame(LM, BM + 0.9*cm, W, H_PAGE - TM - BM - 2.0*cm, id="normal")
doc.addPageTemplates([
    PageTemplate(id="Cover",  frames=[cover_f],  onPage=on_cover),
    PageTemplate(id="Normal", frames=[normal_f], onPage=on_page),
])

# ── HELPERS ───────────────────────────────────────────────────────────────────
def sp(h=0.3): return Spacer(1, h*cm)
def hr(c=colors.HexColor("#CFD8DC")):
    return HRFlowable(width="100%", thickness=0.5, color=c, spaceAfter=4)

def sec_bar(title, color=NAVY):
    t = Table([[Paragraph(title, H1)]], colWidths=[W])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,-1), color),
        ("LEFTPADDING",   (0,0),(-1,-1), 12),
        ("RIGHTPADDING",  (0,0),(-1,-1), 12),
        ("TOPPADDING",    (0,0),(-1,-1), 8),
        ("BOTTOMPADDING", (0,0),(-1,-1), 8),
    ]))
    return t

def box(lines, bg=BLUE_XLIT, bd=BLUE_MID, st=None):
    st = st or BODY
    t = Table([[Paragraph(l, st)] for l in lines], colWidths=[W])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,-1), bg),
        ("BOX",           (0,0),(-1,-1), 1.2, bd),
        ("LEFTPADDING",   (0,0),(-1,-1), 12),
        ("RIGHTPADDING",  (0,0),(-1,-1), 12),
        ("TOPPADDING",    (0,0),(-1,-1), 6),
        ("BOTTOMPADDING", (0,0),(-1,-1), 6),
    ]))
    return t

def imp_box(lines):
    st = PS("ImpSt", fontSize=10, leading=15, fontName="Helvetica-Bold", textColor=GRAY_D,
             leftIndent=4)
    return box(["🔑  " + l for l in lines], bg=YELLOW_L, bd=YELLOW, st=st)

def make_table(headers, rows, cw=None, hc=BLUE):
    if cw is None: cw = [W/len(headers)]*len(headers)
    data = [[Paragraph(h, TH_S) for h in headers]]
    for i,row in enumerate(rows):
        data.append([Paragraph(str(c), TD_C if j>0 else TD_S) for j,c in enumerate(row)])
    t = Table(data, colWidths=cw, repeatRows=1)
    sty = [
        ("BACKGROUND",    (0,0),(-1,0),  hc),
        ("GRID",          (0,0),(-1,-1), 0.4, colors.HexColor("#B0BEC5")),
        ("TOPPADDING",    (0,0),(-1,-1), 5),
        ("BOTTOMPADDING", (0,0),(-1,-1), 5),
        ("LEFTPADDING",   (0,0),(-1,-1), 7),
        ("RIGHTPADDING",  (0,0),(-1,-1), 7),
        ("VALIGN",        (0,0),(-1,-1), "MIDDLE"),
    ]
    for i in range(1, len(data)):
        if i%2==0: sty.append(("BACKGROUND",(0,i),(-1,i),BLUE_XLIT))
    t.setStyle(TableStyle(sty))
    return t

def bp(txt, s=BULLET):  return Paragraph(f"<bullet>•</bullet>  {txt}", s)
def bp2(txt):            return Paragraph(f"<bullet>–</bullet>  {txt}", BULLET2)

# ══════════════════════════════════════════════════════════════════════════════
# STORY
# ══════════════════════════════════════════════════════════════════════════════
S = []

# ─── COVER ────────────────────────────────────────────────────────────────────
S.append(NextPageTemplate("Cover"))
S.append(sp(4))
S.append(Paragraph("GASTROINTESTINAL STROMAL TUMOR", MAIN_TITLE))
S.append(Paragraph("(GIST)", MAIN_TITLE))
S.append(sp(0.4))
S.append(Paragraph("Comprehensive Long Answer — Pathology Essay", SUBTITLE))
S.append(sp(0.3))
S.append(Paragraph("For MBBS / MD / Postgraduate Examinations", SUBTITLE))
S.append(sp(1.5))
div = Table([["  DEFINITION  ·  AETIOLOGY  ·  PATHOGENESIS  ·  MORPHOLOGY  ·  IHC  ·  MOLECULAR  ·  CLINICAL  ·  TREATMENT  "]], colWidths=[W_PAGE-4*cm])
div.setStyle(TableStyle([("BACKGROUND",(0,0),(-1,-1),TEAL),("TEXTCOLOR",(0,0),(-1,-1),WHITE),
    ("FONTNAME",(0,0),(-1,-1),"Helvetica-Bold"),("FONTSIZE",(0,0),(-1,-1),8.5),
    ("ALIGN",(0,0),(-1,-1),"CENTER"),("TOPPADDING",(0,0),(-1,-1),7),("BOTTOMPADDING",(0,0),(-1,-1),7)]))
S.append(div)
S.append(sp(1.2))
S.append(Paragraph("Orris Medical Reference  ·  Educational Use Only  ·  July 2026",
    PS("CN",fontSize=9,leading=13,fontName="Helvetica",textColor=colors.HexColor("#90A4AE"),alignment=TA_CENTER)))
S.append(PageBreak())

# ─── NORMAL PAGES ─────────────────────────────────────────────────────────────
S.append(NextPageTemplate("Normal"))

# ══ QUESTION ══════════════════════════════════════════════════════════════════
S.append(box([
    "LONG ANSWER QUESTION:",
    "Write a detailed note on Gastrointestinal Stromal Tumor (GIST) under the following headings:",
    "Definition · Epidemiology · Cell of Origin · Pathogenesis · Gross Pathology · "
    "Microscopic Pathology · Immunohistochemistry · Molecular Classification · "
    "Risk Stratification · Clinical Features · Diagnosis · Treatment · Prognosis · "
    "Hereditary Syndromes"
], bg=ORANGE_L, bd=ORANGE,
st=PS("QSt",fontSize=10.5,leading=16,fontName="Helvetica-Bold",textColor=GRAY_D,leftIndent=4)))
S.append(sp(0.3))

# ══ 1. DEFINITION ════════════════════════════════════════════════════════════
S.append(sec_bar("1.  DEFINITION", color=NAVY))
S.append(sp(0.25))
S.append(Paragraph(
    "A <b>Gastrointestinal Stromal Tumor (GIST)</b> is a <b>mesenchymal (non-epithelial) neoplasm</b> "
    "arising from the wall of the gastrointestinal tract. It is now well established as "
    "the <b>most common primary mesenchymal tumor of the GI tract and the abdomen</b>. "
    "The term was first coined by <b>Mazur and Clark in 1983</b> to describe intra-abdominal tumors "
    "that were not carcinomas but showed histologic features of both smooth muscle and neural elements. "
    "However, the true nature and molecular basis of GIST were not understood until 1998, when "
    "<b>Hirota and colleagues</b> demonstrated near-universal expression of the receptor tyrosine kinase "
    "<b>KIT (CD117)</b> and the presence of <b>gain-of-function KIT mutations</b> in these tumors, "
    "fundamentally transforming the understanding of GIST pathogenesis and treatment.", BODY))
S.append(sp(0.15))
S.append(imp_box([
    "GIST = Most common mesenchymal tumor of the GI tract",
    "Every GIST carries metastatic potential — there is NO truly benign GIST",
    "Driven by activating mutations in KIT (~80%) or PDGFRA (~8%)",
]))
S.append(sp(0.35))

# ══ 2. EPIDEMIOLOGY ══════════════════════════════════════════════════════════
S.append(sec_bar("2.  EPIDEMIOLOGY", color=NAVY))
S.append(sp(0.25))
S.append(Paragraph(
    "GIST accounts for approximately <b>1–3% of all malignant gastrointestinal tumors</b>. "
    "The estimated incidence is <b>10–15 cases per million per year</b>, though this likely "
    "underestimates the true frequency due to historical misclassification. "
    "With widespread use of molecular markers, incidence figures have increased.", BODY))
S.append(sp(0.1))
S.append(make_table(
    ["Epidemiologic Variable","Details"],
    [["Incidence",    "10–15 per million per year; up to 5,000 new cases/year in the USA"],
     ["Peak age",     "6th decade (~60 years); median age 55–65 years; <10% under age 40"],
     ["Sex",          "Slight male predominance (~55% male); equal in some series"],
     ["Pediatric GIST","Rare; median age ~12 years; female predominance; usually SDH-deficient"],
     ["Race",         "No significant racial predisposition in sporadic cases"],
     ["Sporadic vs familial","Vast majority sporadic; familial GIST syndromes are rare"],
    ], cw=[W*0.30,W*0.70]))
S.append(sp(0.35))

# ══ 3. CELL OF ORIGIN ════════════════════════════════════════════════════════
S.append(sec_bar("3.  CELL OF ORIGIN", color=TEAL))
S.append(sp(0.25))
S.append(Paragraph(
    "The cell of origin of GIST is the <b>Interstitial Cell of Cajal (ICC)</b>, "
    "or a common precursor cell shared between ICCs and smooth muscle cells. "
    "ICCs are <b>pacemaker cells of the gastrointestinal tract</b>, located within the "
    "<b>myenteric plexus (Auerbach's plexus)</b> of the muscularis propria. "
    "Their primary function is to generate <b>electrical slow waves</b> that coordinate "
    "intestinal peristalsis by linking smooth muscle cells with the autonomic nervous system.", BODY))
S.append(sp(0.15))
S.append(Paragraph("Evidence Supporting ICC Origin:", H2))
for item in [
    "ICCs and GIST cells share <b>ultrastructural features</b> combining both neural and smooth muscle phenotypes",
    "Both express <b>KIT (CD117)</b> — KIT signalling is essential for ICC development and survival",
    "Both express <b>DOG1 (ANO1)</b> — a calcium-activated chloride channel",
    "Both express <b>CD34</b> — a hematopoietic/vascular progenitor marker",
    "In NF1-associated and familial GIST, <b>diffuse ICC hyperplasia</b> precedes GIST development",
    "<b>Germline KIT mutations</b> in familial GIST syndrome cause ICC hyperplasia throughout the GI tract",
    "Extra-GI 'telocytes' (ICC-like cells) may explain rare <b>mesenteric, omental, and pancreatic GISTs</b>",
]:
    S.append(bp(item))
S.append(sp(0.35))

# ══ 4. PATHOGENESIS ══════════════════════════════════════════════════════════
S.append(sec_bar("4.  PATHOGENESIS", color=NAVY))
S.append(sp(0.25))

S.append(Paragraph("4.1  Normal KIT Signalling", H2))
S.append(Paragraph(
    "KIT is a <b>transmembrane receptor tyrosine kinase</b> encoded by the <b>KIT gene on chromosome 4q12</b>. "
    "Its natural ligand is <b>Stem Cell Factor (SCF)</b>. Upon SCF binding, KIT undergoes "
    "<b>homodimerization and autophosphorylation</b>, activating multiple downstream signalling cascades:", BODY))
for item in [
    "<b>RAS → RAF → MAPK pathway</b>: cell proliferation and survival",
    "<b>PI3K → AKT → mTOR pathway</b>: cell growth, anti-apoptosis, metabolism",
    "<b>JAK → STAT3 pathway</b>: transcription of pro-survival genes",
    "<b>PLC-γ pathway</b>: calcium mobilisation and PKC activation",
]:
    S.append(bp(item))
S.append(sp(0.15))

S.append(Paragraph("4.2  Gain-of-Function KIT Mutations (75–85% of GISTs)", H2))
S.append(Paragraph(
    "Gain-of-function mutations in the KIT gene cause <b>constitutive (ligand-independent) receptor "
    "activation</b>. The receptor is always phosphorylated and active even in the absence of SCF, "
    "leading to continuous downstream signalling, uncontrolled cell proliferation, "
    "inhibition of apoptosis, and ultimately tumour formation.", BODY))
S.append(sp(0.1))
S.append(make_table(
    ["KIT Exon","Domain","Mutation Type","% of GIST","Imatinib Response"],
    [["Exon 11","Juxtamembrane domain","Deletions (most common), insertions, point mutations","~65–70%","HIGH (~80–90%); most sensitive to standard dose 400 mg/day"],
     ["Exon 9","Extracellular domain","Tandem duplication of codons 502–503 (AY502-503)","~10–15%","MODERATE (40–50%); requires higher dose 800 mg/day; small intestinal predilection"],
     ["Exon 13","Kinase domain I","Point mutations (K642E most common)","~1–2%","Moderate; sunitinib may be preferred"],
     ["Exon 17","Kinase domain II","Point mutations (D820, N822, Y823)","~1%","Moderate; secondary resistance mutations also in exon 17"],
    ], cw=[W*0.10,W*0.20,W*0.25,W*0.12,W*0.33]))
S.append(sp(0.2))

S.append(Paragraph("4.3  PDGFRA Mutations (~8% of GISTs)", H2))
S.append(Paragraph(
    "Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) is encoded by a gene also located on "
    "<b>chromosome 4q12</b>, immediately adjacent to KIT. PDGFRA belongs to the same receptor "
    "tyrosine kinase superfamily and activates identical downstream signalling pathways. "
    "<b>KIT and PDGFRA mutations are mutually exclusive</b> — they cannot coexist because "
    "activating either gene alone is sufficient to drive tumourigenesis through the same pathway.", BODY))
S.append(sp(0.1))
for item in [
    "<b>PDGFRA exon 18 D842V substitution</b>: most common PDGFRA mutation (~70% of PDGFRA-mutant GISTs); "
    "<b>primary resistance to imatinib</b>; responds to avapritinib",
    "<b>Other PDGFRA exon 18 mutations</b>: variable imatinib sensitivity",
    "<b>PDGFRA exon 12 and 14 mutations</b>: rare; may retain imatinib sensitivity",
    "PDGFRA-mutant GISTs are overrepresented in the <b>stomach and omentum</b>, more often show "
    "<b>epithelioid morphology</b>, and are frequently CD117-negative by IHC",
]:
    S.append(bp(item))
S.append(sp(0.2))

S.append(Paragraph("4.4  SDH-Deficient GISTs (Wild-Type; ~5–10%)", H2))
S.append(Paragraph(
    "A subset of GISTs are negative for both KIT and PDGFRA mutations — termed 'wild-type' GISTs. "
    "The majority of these harbour mutations in genes encoding subunits of the "
    "<b>mitochondrial succinate dehydrogenase (SDH) complex</b> (SDHA, SDHB, SDHC, or SDHD). "
    "SDH normally catalyses the conversion of succinate to fumarate in the Krebs cycle. "
    "SDH loss leads to:", BODY))
for item in [
    "<b>Succinate accumulation</b> → inhibition of prolyl hydroxylase → stabilisation of HIF-1α",
    "<b>Pseudohypoxia</b>: HIF-1α activates VEGF and other pro-angiogenic/pro-tumourigenic genes",
    "<b>Increased reactive oxygen species (ROS)</b> → genomic instability",
    "<b>Warburg effect</b>: enhanced glycolysis as primary energy source",
]:
    S.append(bp(item))
S.append(sp(0.1))
S.append(Paragraph(
    "SDH-deficient GISTs are <b>characteristically gastric, multifocal, and occur in young patients</b> "
    "(especially females). They frequently metastasise to <b>lymph nodes</b> (unlike other GISTs) and are "
    "<b>resistant to imatinib</b>. Loss of SDHB protein by IHC is the diagnostic hallmark.", BODY))
S.append(sp(0.2))

S.append(Paragraph("4.5  Other Wild-Type GISTs", H2))
S.append(make_table(
    ["Subtype","Molecular Feature","Clinical Context"],
    [["NF1-associated","NF1 biallelic loss; KIT overexpression without mutation","Multiple small intestinal GISTs; neurofibromatosis type 1; low mitotic rate"],
     ["BRAF V600E","BRAF activating mutation","Rare; may respond to BRAF inhibitors (vemurafenib)"],
     ["KRAS-mutant","KRAS oncogenic mutation","Very rare; sporadic"],
     ["Familial GIST","Germline KIT or PDGFRA mutation","Multiple GISTs + diffuse ICC hyperplasia; autosomal dominant; early onset; cutaneous hyperpigmentation"],
    ], cw=[W*0.22,W*0.30,W*0.48]))
S.append(sp(0.35))

# ══ 5. GROSS PATHOLOGY ═══════════════════════════════════════════════════════
S.append(sec_bar("5.  GROSS PATHOLOGY", color=BLUE))
S.append(sp(0.25))

S.append(Paragraph("Location:", H2))
S.append(Paragraph(
    "GISTs arise from the <b>muscularis propria</b> of the GI tract wall. The most common sites are "
    "the <b>stomach (40–60%)</b>, followed by the small intestine — particularly the "
    "<b>jejunum and ileum (24–30%)</b>. The colorectum accounts for 5–15%, the duodenum ~5%, "
    "and the esophagus less than 1%. Rare extra-GI stromal tumors arise in the mesentery, "
    "omentum, and retroperitoneum.", BODY))
S.append(sp(0.15))

S.append(Paragraph("Macroscopic Features:", H2))
for item in [
    "<b>Solitary, well-circumscribed, fleshy mass</b> — the typical presentation of a primary GIST",
    "Covered by a <b>pseudocapsule</b> (NOT a true capsule) — the tumour compresses surrounding tissue but is not truly encapsulated",
    "<b>Growth pattern</b>: endoluminal (projecting into lumen), exophytic (projecting outward), or dumbbell-shaped (both directions simultaneously)",
    "<b>Cut surface</b>: tan-white to pinkish; firm to soft; fleshy consistency resembling fish-flesh",
    "<b>Haemorrhage</b>: common, especially in larger tumors — areas of dark red-brown discolouration",
    "<b>Necrosis</b>: yellow-grey areas; correlates with high-grade biology and large size",
    "<b>Cystic degeneration</b>: fluid-filled spaces within the tumour; common in large GISTs",
    "<b>Mucosal ulceration</b>: overlying mucosa may ulcerate due to pressure necrosis — accounts for GI bleeding",
    "<b>Size range</b>: from &lt;1 cm (incidental microGIST) to &gt;30 cm (giant GIST)",
]:
    S.append(bp(item))
S.append(sp(0.15))

S.append(Paragraph("Metastatic Gross Features:", H2))
for item in [
    "<b>Liver metastases</b>: multiple hypervascular nodules, largest organs affected; may be solitary large mass",
    "<b>Peritoneal seeding</b>: scattered serosal nodules of varying sizes",
    "<b>Omental caking</b>: diffuse peritoneal infiltration in advanced cases",
    "<b>Lymph node involvement</b>: RARE in KIT/PDGFRA-mutant GIST; more common in SDH-deficient subtype",
    "<b>Extra-abdominal metastasis</b>: lungs, bones — uncommon and indicates late disease",
]:
    S.append(bp(item))
S.append(sp(0.15))
S.append(box([
    "⚠  CRITICAL: GIST has a pseudocapsule — NOT a true capsule.",
    "    Rupture (spontaneous or iatrogenic/surgical) dramatically increases peritoneal recurrence risk.",
    "    A ruptured GIST must be managed as already disseminated/metastatic disease."
], bg=RED_L, bd=RED,
st=PS("WSt",fontSize=10,leading=15,fontName="Helvetica-Bold",textColor=GRAY_D,leftIndent=4)))
S.append(sp(0.35))

# ══ 6. MICROSCOPIC PATHOLOGY ═════════════════════════════════════════════════
S.append(sec_bar("6.  MICROSCOPIC (HISTOLOGICAL) PATHOLOGY", color=NAVY))
S.append(sp(0.25))

S.append(Paragraph(
    "Histology alone is <b>insufficient</b> for a definitive GIST diagnosis — IHC and molecular "
    "studies are mandatory. Three main histological patterns are recognised:", BODY))
S.append(sp(0.1))

S.append(Paragraph("6.1  Spindle Cell Type (~70%)", H3))
S.append(Paragraph(
    "The most common pattern. Tumour cells are <b>thin, elongated, uniform, and spindle-shaped</b> "
    "with pale, eosinophilic, fibrillary cytoplasm. The nuclei are oval, vesicular, "
    "with inconspicuous nucleoli. Cells are arranged in:", BODY_IND))
for item in [
    "<b>Short fascicles</b> or interlacing bundles",
    "<b>Storiform (cartwheel) pattern</b> — cells radiating from a central point",
    "<b>Whorling or palisading</b> of nuclei (reminiscent of schwannoma)",
    "Sheet-like growth in solid areas",
]:
    S.append(bp2(item))
S.append(sp(0.1))
S.append(Paragraph(
    "A characteristic finding in <b>small intestinal spindle-cell GISTs</b> is the presence of "
    "<b>skeinoid fibres</b> — eosinophilic, PAS-positive, extracellular globular deposits of "
    "collagen-like material in the stroma. These are highly specific for small intestinal GIST.", BODY_IND))
S.append(sp(0.1))

S.append(Paragraph("6.2  Epithelioid Type (~20%)", H3))
S.append(Paragraph(
    "Tumour cells are <b>plumper and rounder</b> with abundant clear or eosinophilic cytoplasm, "
    "giving an epithelial appearance. Characteristic features include:", BODY_IND))
for item in [
    "<b>Perinuclear cytoplasmic vacuoles</b> — highly characteristic of epithelioid GIST",
    "<b>Nesting or sheet-like</b> arrangement of cells",
    "Clear cell change due to glycogen accumulation",
    "May mimic carcinoma, melanoma, or paraganglioma",
    "More commonly seen in <b>gastric GISTs</b> and <b>PDGFRA-mutant tumors</b>",
]:
    S.append(bp2(item))
S.append(sp(0.1))

S.append(Paragraph("6.3  Mixed Type (~10%)", H3))
S.append(Paragraph(
    "Both spindle and epithelioid components are present in varying proportions within the same tumour. "
    "This pattern can occur at any GI site.", BODY_IND))
S.append(sp(0.15))

S.append(Paragraph("6.4  Additional Microscopic Features", H2))
S.append(make_table(
    ["Feature","Significance"],
    [["Mitotic figures (per 50 HPF)","Most critical prognostic variable after size; counted carefully under high power"],
     ["Nuclear atypia","Usually mild to moderate; severe pleomorphism is uncommon and suggests high grade"],
     ["Tumour necrosis","Correlates with high-grade behaviour; indicates rapid growth outpacing blood supply"],
     ["Skeinoid fibres","Eosinophilic extracellular globules; seen in small intestinal GISTs; PAS-positive"],
     ["Haemorrhage","Common in larger tumours; disrupts architecture"],
     ["Myxoid change","Occasional finding; may mimic other stromal tumours"],
     ["Perivascular condensation","Cells condense around blood vessels in some cases"],
    ], cw=[W*0.35,W*0.65]))
S.append(sp(0.2))

S.append(Paragraph("6.5  What Histology CANNOT Tell You", H2))
S.append(Paragraph(
    "The pre-1999 classification divided GI mesenchymal tumors into leiomyoma, leiomyosarcoma, "
    "schwannoma, or 'null phenotype' based purely on histomorphology and rudimentary IHC. "
    "This led to systematic misdiagnosis. <b>Morphology alone cannot reliably distinguish GIST "
    "from leiomyosarcoma, schwannoma, or desmoid tumour</b> — hence the absolute requirement for "
    "IHC markers (CD117, DOG1) and molecular testing in all suspected cases.", BODY))
S.append(sp(0.35))

# ══ 7. IMMUNOHISTOCHEMISTRY ═══════════════════════════════════════════════════
S.append(sec_bar("7.  IMMUNOHISTOCHEMISTRY (IHC)", color=TEAL))
S.append(sp(0.25))
S.append(Paragraph(
    "IHC is the cornerstone of GIST diagnosis. The two most critical markers — <b>CD117 (KIT)</b> and "
    "<b>DOG1</b> — are each positive in approximately 95% of GISTs and should always be used together.", BODY))
S.append(sp(0.15))

S.append(make_table(
    ["Marker","Sensitivity","Staining Pattern","Key Points"],
    [["CD117 (KIT/c-kit)","~95%","Strong diffuse cytoplasmic (spindle); focal/dot-like (epithelioid); perinuclear",
      "Primary diagnostic marker; cornerstone; can be heterogeneous within tumour — sampling bias possible"],
     ["DOG1 (ANO1)","~95%","Membranous and/or cytoplasmic",
      "More specific than CD117; ESSENTIAL for diagnosing KIT-negative GISTs; complements CD117"],
     ["CD34","~60–70%","Diffuse cytoplasmic",
      "Supportive marker; expressed by vascular endothelium too — not specific; lower sensitivity than CD117/DOG1"],
     ["PDGFRA (IHC)","~70–80% of PDGFRA-mutant","Cytoplasmic",
      "Helps identify PDGFRA-mutant subtype when CD117 is negative; not routinely available everywhere"],
     ["SDHB (IHC)","N/A (loss marker)","Normal: granular cytoplasmic; SDH-deficient: diffuse/absent",
      "Loss of granular SDHB staining = SDH-deficient GIST; perform on ALL wild-type GISTs"],
     ["Smooth muscle actin (SMA)","~30–40%","Cytoplasmic",
      "Variably positive; does NOT exclude GIST; helps exclude leiomyosarcoma if strongly positive with desmin"],
     ["Desmin","~5–10%","Cytoplasmic",
      "Usually negative in GIST; strongly positive in leiomyosarcoma — useful in differential diagnosis"],
     ["S100 protein","<5%","Nuclear + cytoplasmic",
      "Usually negative in GIST; strongly positive in schwannoma — key differential marker"],
     ["Beta-catenin","Negative (nuclear)","Cytoplasmic only normally",
      "Nuclear positivity in desmoid tumour — helps exclude aggressive fibromatosis"],
    ], cw=[W*0.20,W*0.12,W*0.26,W*0.42], hc=TEAL))
S.append(sp(0.2))

S.append(Paragraph("IHC Diagnostic Algorithm in Practice:", H2))
S.append(make_table(
    ["Step","Action","Interpretation"],
    [["1","Stain with CD117 + DOG1 on all suspected GI mesenchymal tumours","—"],
     ["2","CD117 (+) and/or DOG1 (+)","Likely GIST → confirm with molecular testing"],
     ["3","CD117 (–), DOG1 (+)","Still GIST — likely PDGFRA-mutant; proceed to PDGFRA sequencing"],
     ["4","Both CD117 (–) and DOG1 (–)","Consider: leiomyosarcoma (desmin/SMA+), schwannoma (S100+), desmoid (β-catenin nuclear+), metastatic carcinoma (cytokeratin+)"],
     ["5","On all confirmed GISTs: stain SDHB","Loss of SDHB = SDH-deficient — critical for syndrome screening and treatment planning"],
    ], cw=[W*0.06,W*0.37,W*0.57]))
S.append(sp(0.2))
S.append(imp_box([
    "Never diagnose GIST on histology alone.",
    "Always use CD117 AND DOG1 together — they are complementary, not interchangeable.",
    "CD117 can be heterogeneous (sampling bias) — DOG1 may be positive where CD117 is negative.",
]))
S.append(sp(0.35))

# ══ 8. MOLECULAR CLASSIFICATION ══════════════════════════════════════════════
S.append(sec_bar("8.  MOLECULAR CLASSIFICATION", color=NAVY))
S.append(sp(0.25))
S.append(Paragraph(
    "Molecular classification of GIST is <b>essential for prognostication and treatment selection</b>. "
    "It is based on sequencing of KIT exons 9, 11, 13, 17 and PDGFRA exons 12, 14, 18, "
    "followed by SDH subunit gene sequencing and SDHB IHC in wild-type cases.", BODY))
S.append(sp(0.1))
S.append(make_table(
    ["Molecular Subtype","Frequency","Key Mutation","Imatinib Sensitivity","Special Features"],
    [["KIT exon 11","~65–70%","Deletions > insertions > point mutations","HIGH (~80–90%)","Best overall prognosis on imatinib; deletions in codons 557–558 associated with worse prognosis"],
     ["KIT exon 9","~10–15%","AY502-503 duplication","MODERATE (40–50%)","Needs 800 mg/day; predominantly small intestinal; worse prognosis than exon 11"],
     ["KIT exon 13","~1–2%","K642E point mutation","MODERATE","Kinase domain I; secondary resistance mutation too"],
     ["KIT exon 17","~1%","D820/N822/Y823 mutations","MODERATE","Kinase domain II; often secondary resistance mutations"],
     ["PDGFRA D842V","~5–6%","D842V substitution exon 18","RESISTANT","Use avapritinib; gastric/epithelioid; CD117-negative"],
     ["PDGFRA other","~1–2%","Various exon 12/14/18","Variable","May respond to imatinib"],
     ["SDH-deficient","~5–10%","SDHA/B/C/D mutations","RESISTANT","Young; female; gastric; multifocal; lymph node mets; Carney triad"],
     ["NF1-associated","~1%","NF1 biallelic loss","Uncertain","Multiple small bowel GISTs; wild-type KIT/PDGFRA"],
     ["BRAF-mutant","<1%","BRAF V600E","Resistant","May respond to BRAF inhibitors"],
    ], cw=[W*0.20,W*0.10,W*0.20,W*0.14,W*0.36]))
S.append(sp(0.35))

# ══ 9. RISK STRATIFICATION ═══════════════════════════════════════════════════
S.append(sec_bar("9.  RISK STRATIFICATION", color=BLUE))
S.append(sp(0.25))
S.append(Paragraph(
    "Since every GIST has metastatic potential, <b>risk stratification</b> is critical for "
    "determining prognosis and the need for adjuvant therapy. Three primary variables determine risk:", BODY))
for item in [
    "<b>Tumour size</b> — the larger the tumour, the higher the risk",
    "<b>Mitotic rate</b> — counted per 50 high-power fields (HPF); reflects proliferative activity",
    "<b>Primary site</b> — non-gastric GISTs (especially small intestinal and rectal) are more aggressive",
]:
    S.append(bp(item))
S.append(sp(0.15))
S.append(Paragraph("A fourth critical factor:  <b>Tumour Rupture</b> (spontaneous or operative) — "
    "automatically places the patient in the highest risk category regardless of size or mitotic rate.", BODY))
S.append(sp(0.2))

S.append(Paragraph("9.1  NIH (Fletcher) Consensus Classification — Widely Used", H2))
S.append(make_table(
    ["Risk Category","Tumour Size","Mitotic Rate (per 50 HPF)"],
    [["Very Low Risk","< 2 cm","< 5"],
     ["Low Risk","2–5 cm","< 5"],
     ["Intermediate Risk","< 5 cm   OR   5–10 cm","6–10   OR   < 5"],
     ["High Risk","> 5 cm   OR   > 10 cm   OR   Any size","Any   OR   Any   OR   > 10"],
    ], cw=[W*0.25,W*0.35,W*0.40]))
S.append(sp(0.15))
S.append(Paragraph(
    "<i>Limitation: NIH system does NOT incorporate tumour site — it treats all GISTs equally regardless of location.</i>", NOTE))
S.append(sp(0.15))

S.append(Paragraph("9.2  Joensuu / AFIP Modified Criteria — Site-Specific Risk", H2))
S.append(make_table(
    ["Size","Mitotic Rate","Gastric GIST Risk","Non-Gastric GIST Risk"],
    [["≤ 2 cm","≤ 5 / 50 HPF","Negligible","Negligible"],
     ["2–5 cm","≤ 5 / 50 HPF","Very Low","Low"],
     ["5–10 cm","≤ 5 / 50 HPF","Low","Moderate"],
     ["> 10 cm","≤ 5 / 50 HPF","Moderate","HIGH"],
     ["Any","6–10 / 50 HPF","Moderate","HIGH"],
     ["Any","> 10 / 50 HPF","HIGH","HIGH"],
     ["Any (ruptured)","Any","HIGH","HIGH"],
    ], cw=[W*0.18,W*0.22,W*0.30,W*0.30]))
S.append(sp(0.15))

S.append(Paragraph("9.3  AJCC Staging (8th Edition)", H2))
S.append(Paragraph(
    "Uses standard TNM staging supplemented by mitotic rate. Separate stage groupings exist for "
    "<b>gastric and omental GISTs</b> versus <b>small intestinal, esophageal, colorectal, mesenteric, "
    "and peritoneal GISTs</b>, reflecting their different biologic behaviour. "
    "T stages: T1 (≤2 cm), T2 (2–5 cm), T3 (5–10 cm), T4 (>10 cm). "
    "Nodal disease (N1) is uncommon and indicates high-risk/SDH-deficient subtype.", BODY))
S.append(sp(0.35))

# ══ 10. CLINICAL FEATURES ════════════════════════════════════════════════════
S.append(sec_bar("10.  CLINICAL FEATURES", color=NAVY))
S.append(sp(0.25))

S.append(Paragraph("Symptoms and Presentation:", H2))
S.append(make_table(
    ["Presentation","Mechanism","Notes"],
    [["Gastrointestinal bleeding","Mucosal ulceration from endoluminal pressure; necrosis; haemorrhage into lumen","Most common presenting symptom; haematemesis, melaena, or occult blood"],
     ["Abdominal pain / discomfort","Mass effect, stretching of serosa, or partial obstruction","Dull, vague, intermittent; often chronic before diagnosis"],
     ["Palpable abdominal mass","Large exophytic tumour","Felt in left upper quadrant (gastric) or central abdomen (small bowel)"],
     ["Obstruction symptoms","Intraluminal growth causing narrowing","Nausea, vomiting, dysphagia (esophageal GIST), constipation (rectal GIST)"],
     ["Incidental finding","Small tumour with no symptoms","Common on endoscopy/imaging for unrelated indications; typically < 2 cm"],
     ["Acute abdomen","Spontaneous tumour rupture → haemoperitoneum","Surgical emergency; treat as disseminated disease"],
     ["Weight loss and anorexia","Large tumours; metastatic disease","Late features suggesting advanced or metastatic GIST"],
    ], cw=[W*0.22,W*0.30,W*0.48]))
S.append(sp(0.35))

# ══ 11. DIAGNOSIS ════════════════════════════════════════════════════════════
S.append(sec_bar("11.  DIAGNOSIS", color=TEAL))
S.append(sp(0.25))

S.append(Paragraph("11.1  Imaging", H2))
for item in [
    "<b>CT scan with IV contrast (MDCT)</b>: imaging modality of choice. Shows well-circumscribed, "
    "heterogeneous, hypervascular mass; evaluates size, location, local invasion, liver metastases, "
    "and peritoneal disease",
    "<b>Endoscopic Ultrasound (EUS)</b>: defines tumour layer of origin (muscularis propria); "
    "guides fine-needle aspiration (FNA) biopsy in accessible lesions; essential for small gastric lesions",
    "<b>MRI</b>: preferred for rectal and pelvic GISTs; superior soft-tissue contrast",
    "<b>PET-CT (18F-FDG)</b>: detects early metabolic response to imatinib (hours to days before size change); "
    "used for treatment monitoring, not initial diagnosis",
    "<b>Choi criteria for CT response assessment</b>: a ≥10% decrease in size OR ≥15% decrease in "
    "Hounsfield unit (HU) density = partial response — more sensitive than RECIST for GIST on imatinib",
]:
    S.append(bp(item))
S.append(sp(0.15))

S.append(Paragraph("11.2  Biopsy", H2))
for item in [
    "<b>Resectable GIST</b>: biopsy is generally NOT recommended — risk of tumour rupture, haemorrhage, "
    "and peritoneal seeding; proceed directly to surgery",
    "<b>Unresectable or metastatic GIST</b>: biopsy is mandatory before initiating imatinib therapy "
    "to confirm diagnosis and determine mutation status",
    "<b>EUS-guided FNA</b>: preferred biopsy route for gastric GISTs — avoids peritoneal seeding by "
    "traversing the stomach wall",
    "<b>Core needle biopsy</b>: preferred over FNA for adequate tissue for IHC and molecular testing",
]:
    S.append(bp(item))
S.append(sp(0.15))

S.append(Paragraph("11.3  Pathological Workup (Mandatory Steps)", H2))
for item in [
    "<b>Histomorphology</b>: document cell type (spindle/epithelioid/mixed), mitotic rate (per 50 HPF), necrosis",
    "<b>IHC panel</b>: CD117, DOG1, CD34 (core); SMA, desmin, S100 (differential diagnosis)",
    "<b>SDHB IHC</b>: on all GISTs to screen for SDH-deficient subtype",
    "<b>Mutation analysis</b>: KIT exons 9, 11, 13, 17 and PDGFRA exons 12, 14, 18 — mandatory before targeted therapy",
    "<b>SDH subunit gene sequencing</b>: in wild-type (KIT/PDGFRA-negative) GISTs",
    "<b>Tumour size and margin status</b>: document in resection specimens",
]:
    S.append(bp(item))
S.append(sp(0.35))

# ══ 12. TREATMENT ════════════════════════════════════════════════════════════
S.append(sec_bar("12.  TREATMENT", color=NAVY))
S.append(sp(0.25))

S.append(Paragraph("12.1  Surgery — Primary Treatment for Localised GIST", H2))
S.append(make_table(
    ["Principle","Details"],
    [["Goal","Complete (R0) resection with negative margins — only potentially curative modality"],
     ["Margin width","1–2 cm recommended; the pseudocapsule must remain intact and not be violated"],
     ["Lymphadenectomy","NOT routinely performed — lymph node involvement is rare in KIT/PDGFRA-mutant GIST; exception: SDH-deficient"],
     ["Laparoscopic surgery","Acceptable for gastric GISTs ≤ 5 cm; meticulous technique required to avoid rupture"],
     ["Multivisceral resection","When tumour invades adjacent organs; required to achieve R0 margins"],
     ["Rectal GIST","Preoperative imatinib often used to downsize and allow sphincter-sparing resection"],
     ["Avoid rupture","Paramount — increases peritoneal recurrence risk dramatically; changed intent to palliative"],
    ], cw=[W*0.28,W*0.72]))
S.append(sp(0.2))

S.append(Paragraph("12.2  Imatinib Mesylate (Gleevec) — Targeted Therapy", H2))
S.append(Paragraph(
    "Imatinib is a <b>selective tyrosine kinase inhibitor (TKI)</b> that competitively inhibits "
    "<b>KIT, PDGFRA, BCR-ABL, and PDGFRB</b> by occupying the ATP-binding pocket of the kinase domain. "
    "Its introduction in 2001 transformed GIST from a chemotherapy-resistant malignancy into a "
    "manageable disease. The landmark B2222 trial demonstrated response rates of ~54% in metastatic GIST, "
    "with disease control in >80% of patients.", BODY))
S.append(sp(0.1))
S.append(make_table(
    ["Clinical Setting","Indication","Dose","Duration"],
    [["Adjuvant (post-resection)","High-risk resected GIST with imatinib-sensitive mutation (KIT exon 11 primarily)","400 mg/day","3 years (standard); trials evaluating 5+ years"],
     ["Neoadjuvant (pre-surgery)","Marginally resectable; large tumour requiring downsizing; rectal GIST (sphincter preservation)","400 mg/day","Until maximal response (~6–12 months); re-assess with CT/PET"],
     ["Metastatic / unresectable","Systemic therapy for disseminated disease","400 mg/day (KIT exon 11); 800 mg/day (KIT exon 9)","Lifelong — discontinuation leads to rapid progression in >80%"],
     ["PDGFRA D842V","NOT indicated","—","Resistant — use avapritinib"],
    ], cw=[W*0.22,W*0.33,W*0.18,W*0.27]))
S.append(sp(0.15))

S.append(Paragraph("12.3  Mechanisms of Imatinib Resistance", H2))
for item in [
    "<b>Primary resistance</b>: present from the outset; PDGFRA D842V mutation; SDH-deficient wild-type; "
    "some KIT exon 9 mutations",
    "<b>Secondary (acquired) resistance</b>: develops after initial response (median ~24 months); "
    "caused by <b>secondary kinase domain mutations in KIT exons 13, 14, 17, or 18</b>",
    "Secondary resistance often shows <b>clonal progression</b> (one or few nodules progressing while "
    "others remain controlled) — detectable on PET-CT",
    "Management: <b>switch to sunitinib</b> (2nd line); <b>regorafenib</b> (3rd line); <b>ripretinib</b> (4th line)",
]:
    S.append(bp(item))
S.append(sp(0.2))

S.append(Paragraph("12.4  Second-, Third-, and Fourth-Line Therapies", H2))
S.append(make_table(
    ["Drug","Line","Mechanism","Key Indication"],
    [["Sunitinib","2nd line","Multi-TKI: KIT + PDGFRA + VEGFR1–3 + FLT3","Imatinib-resistant/intolerant GIST; specific secondary KIT mutations guide response"],
     ["Regorafenib","3rd line","Multi-TKI: KIT + PDGFRA + VEGFR + RAF","After sunitinib failure; GRID trial demonstrated benefit"],
     ["Ripretinib","4th line","Switch-control inhibitor: broad KIT/PDGFRA inhibition","Designed to overcome resistance mutations; INTRIGUE trial"],
     ["Avapritinib","1st line (D842V)","Potent PDGFRA/KIT inhibitor","FDA-approved for PDGFRA exon 18 D842V mutant unresectable/metastatic GIST; NAVIGATOR trial"],
    ], cw=[W*0.18,W*0.12,W*0.32,W*0.38]))
S.append(sp(0.15))

S.append(Paragraph("12.5  Chemotherapy and Radiation", H2))
S.append(Paragraph(
    "Conventional cytotoxic chemotherapy is <b>largely ineffective</b> in GIST — response rates "
    "with doxorubicin or ifosfamide are below 5%. This is due to overexpression of the "
    "<b>MDR1/P-glycoprotein drug efflux pump</b> in GIST cells. "
    "Radiotherapy has limited application — palliative role for bone metastases or local control "
    "in selected unresectable cases. "
    "Immunotherapy (checkpoint inhibitors) shows limited activity in KIT/PDGFRA-mutant GIST "
    "due to low tumour mutational burden, but may have a role in SDH-deficient subtype "
    "(high inflammatory microenvironment).", BODY))
S.append(sp(0.35))

# ══ 13. PROGNOSIS ════════════════════════════════════════════════════════════
S.append(sec_bar("13.  PROGNOSIS", color=BLUE))
S.append(sp(0.25))
S.append(Paragraph(
    "Prognosis in GIST depends on a combination of tumour-related, treatment-related, "
    "and molecular factors.", BODY))
S.append(sp(0.1))
S.append(make_table(
    ["Favourable Prognostic Factors","Unfavourable Prognostic Factors"],
    [["Gastric location","Non-gastric location (small intestine, rectum, esophagus)"],
     ["Small tumour size (< 2 cm)","Large tumour size (> 5 cm or > 10 cm)"],
     ["Low mitotic rate (< 5/50 HPF)","High mitotic rate (> 5/50 HPF)"],
     ["KIT exon 11 mutation","KIT exon 9 mutation; wild-type"],
     ["Complete R0 surgical resection","Positive surgical margins (R1/R2); rupture"],
     ["No metastases at presentation","Liver or peritoneal metastases"],
     ["Response to imatinib","Primary or secondary imatinib resistance"],
     ["Low risk by NIH/Joensuu criteria","High-risk classification"],
    ], cw=[W*0.50,W*0.50]))
S.append(sp(0.15))
S.append(Paragraph(
    "Recurrence or metastasis is <b>rare for gastric GISTs &lt; 5 cm</b> with low mitotic rate "
    "but is <b>common for mitotically active tumours &gt; 10 cm</b>. "
    "Patients with metastatic imatinib-sensitive GIST now achieve <b>median overall survival of "
    "5+ years</b> with targeted therapy, compared to &lt;18 months before imatinib. "
    "The <b>10-year overall survival for resected low-risk GIST approaches 90%</b> with appropriate management.", BODY))
S.append(sp(0.35))

# ══ 14. HEREDITARY SYNDROMES ═════════════════════════════════════════════════
S.append(sec_bar("14.  HEREDITARY SYNDROMES ASSOCIATED WITH GIST", color=NAVY))
S.append(sp(0.25))
S.append(make_table(
    ["Syndrome","GIST Features","Associated Tumours","Genetic Basis","Inheritance"],
    [["Carney Triad",
      "Gastric GIST; multifocal; SDH-deficient; young females (median ~20 yrs); lymph node mets",
      "Pulmonary chondromas + Extra-adrenal paragangliomas",
      "SDHC promoter hypermethylation (epigenetic); no germline SDH mutation in most",
      "Not clearly heritable; sporadic (most)"],
     ["Carney-Stratakis Dyad",
      "Gastric GIST; multifocal; SDH-deficient; similar to Carney Triad GIST",
      "Paraganglioma only (no pulmonary chondroma)",
      "Germline mutations in SDHA, SDHB, SDHC, or SDHD",
      "Autosomal dominant"],
     ["Familial GIST Syndrome",
      "Multiple GISTs any GI site; diffuse ICC hyperplasia; early onset (3rd–4th decade); cutaneous hyperpigmentation; urticaria pigmentosa",
      "None specific; mast cell tumours occasionally",
      "Germline KIT gain-of-function (most common) or PDGFRA mutations",
      "Autosomal dominant; high penetrance"],
     ["NF1 (von Recklinghausen)",
      "Multiple small intestinal GISTs; usually small; low mitotic rate; often incidental; KIT overexpressed but NOT mutated",
      "Neurofibromas, gliomas, phaeochromocytoma, learning difficulties, café-au-lait macules",
      "NF1 biallelic loss (tumour suppressor); KIT/PDGFRA unmutated; distinct biology",
      "Autosomal dominant; NF1 germline mutation"],
    ], cw=[W*0.18,W*0.26,W*0.22,W*0.22,W*0.12], hc=NAVY))
S.append(sp(0.15))
S.append(imp_box([
    "Carney Triad mnemonic:  G.P.P.  =  Gastric GIST  +  Pulmonary chondroma  +  Paraganglioma",
    "Carney-Stratakis Dyad = G.P. only (no pulmonary chondroma) + germline SDH mutation",
    "Familial GIST: suspect when multiple GISTs, young patient, family history, or ICC hyperplasia on biopsy",
]))
S.append(sp(0.35))

# ══ 15. DIFFERENTIAL DIAGNOSIS ═══════════════════════════════════════════════
S.append(sec_bar("15.  DIFFERENTIAL DIAGNOSIS", color=TEAL))
S.append(sp(0.25))
S.append(make_table(
    ["Tumour","Key Distinguishing Features","Helpful IHC"],
    [["Leiomyosarcoma","Smooth muscle differentiation; coagulative necrosis; cytological atypia; rare in stomach","SMA+, Desmin+, CD117–, DOG1–"],
     ["Leiomyoma","Benign; well-differentiated smooth muscle; rare in stomach (common in oesophagus/colorectum)","SMA+, Desmin+, CD117–, DOG1–"],
     ["Schwannoma","Neural differentiation; peripheral lymphocyte cuffing; no CD117; female preponderance","S100+ (strong diffuse), CD117–, DOG1–"],
     ["Desmoid tumour","Aggressive fibromatosis; deep soft tissue; FAP association; no atypia","Beta-catenin nuclear+, CD117–, DOG1–, SMA+"],
     ["Solitary fibrous tumour","STAT6 nuclear+; CD34+; branching haemangiopericytoma-like vessels","STAT6+, CD34+, CD117–"],
     ["Metastatic melanoma","History; S100+, HMB-45+, Melan-A+; CD117+ (but clinical context clear)","S100+, SOX10+, HMB-45+"],
     ["Inflammatory fibrosarcoma","ALK translocation; inflammatory infiltrate; mesenteric origin","ALK+ (IHC or FISH), CD117–"],
    ], cw=[W*0.20,W*0.45,W*0.35], hc=TEAL))
S.append(sp(0.35))

# ══ 16. SUMMARY ══════════════════════════════════════════════════════════════
S.append(sec_bar("16.  SUMMARY — HIGH-YIELD POINTS", color=NAVY))
S.append(sp(0.25))
S.append(make_table(
    ["Topic","High-Yield Fact"],
    [["Definition","Most common GI mesenchymal tumour; 1–3% of all GI malignancies; every GIST has metastatic potential"],
     ["Cell of origin","Interstitial cells of Cajal (ICC) — pacemaker cells of the myenteric plexus"],
     ["Most common site","Stomach (40–60%) → Small intestine (24–30%) → Colorectum (5–15%)"],
     ["Histology","Spindle (~70%), Epithelioid (~20%), Mixed (~10%); skeinoid fibres in small intestinal GIST"],
     ["Key IHC","CD117 + DOG1 (~95% each); SDHB loss = SDH-deficient subtype"],
     ["Main mutation","KIT exon 11 (~65–70%) — BEST imatinib response (~80–90%)"],
     ["Worst mutation (Rx)","PDGFRA exon 18 D842V — RESISTANT to imatinib; use avapritinib"],
     ["Risk pillars","Size + Mitotic rate (per 50 HPF) + Site + Rupture status"],
     ["Lymph node spread","RARE in KIT/PDGFRA-mutant; common in SDH-deficient pediatric GIST"],
     ["Surgery rule","R0 resection; NO routine lymphadenectomy; never rupture the pseudocapsule"],
     ["Adjuvant therapy","Imatinib 3 years for high-risk resected GIST (KIT-sensitive mutations)"],
     ["Chemo/Radiotherapy","Largely ineffective — MDR1/P-glycoprotein overexpression; TKIs are the backbone"],
     ["Carney Triad","Gastric GIST + Pulmonary chondroma + Extra-adrenal paraganglioma"],
     ["Resistance mechanism","Secondary KIT kinase domain mutations (analogous to BCR-ABL in CML)"],
     ["Prognosis (metastatic)","Median OS > 5 years with imatinib; vs < 18 months pre-imatinib era"],
    ], cw=[W*0.30,W*0.70]))
S.append(sp(0.25))
S.append(hr(NAVY))
S.append(Paragraph(
    "References: Robbins &amp; Kumar Basic Pathology · Sleisenger &amp; Fordtran's GI and Liver Disease · "
    "Sabiston Textbook of Surgery · Quick Compendium of Clinical Pathology 5e · "
    "Fischer's Mastery of Surgery 8e · Current Surgical Therapy 14e · Schwartz's Principles of Surgery 11e · "
    "Goodman &amp; Gilman's Pharmacological Basis of Therapeutics · Maingot's Abdominal Operations",
    NOTE))
S.append(Paragraph(
    "PubMed (2025): PMID 40665034 (ctDNA meta-analysis) · PMID 40045030 (SDH-deficient GIST systemic therapies) · "
    "PMID 40140195 (neoadjuvant imatinib meta-analysis)",
    NOTE))
S.append(Paragraph("This document is for educational purposes only. Clinical decisions require current guidelines and individualised assessment.", NOTE))

# ── BUILD ─────────────────────────────────────────────────────────────────────
doc.build(S)
print(f"✅  PDF created: {OUTPUT}")

cd /home/daytona/workspace/gist-pathology && python gist_long_answer.py 2>&1