Leukopoiesis

Definition

• Histology: A Text and Atlas with Correlated Cell and Molecular Biology, p. 730-731

Origin and Overview

Granulopoiesis (Myeloid White Cells)

1. Myeloblast - earliest recognizable precursor
2. Promyelocyte - large cell with primary (azurophilic) granules
3. Myelocyte - first stage to exhibit specific (secondary) granules; cell still capable of division
4. Metamyelocyte - kidney-shaped nucleus; no longer dividing
5. Band (stab) cell - horseshoe-shaped nucleus; immature neutrophil
6. Mature neutrophil (segmented) - multilobed nucleus

Monopoiesis

Lymphopoiesis

• T cells: mature in the thymus (thymus-dependent)
• B cells: mature in the bone marrow (bursa-equivalent)
• NK cells: develop from pre-NK cell precursors
• Plasma cells: terminal differentiation of activated B cells

Embryonic Leukopoiesis

• Histology: A Text and Atlas, p. 731-732

Key Regulators (Cytokines / Growth Factors)

• G-CSF (Granulocyte Colony-Stimulating Factor) - promotes neutrophil production
• M-CSF - drives monocyte differentiation
• GM-CSF - stimulates both granulocyte and monocyte lines
• IL-5 - eosinophil maturation and survival
• SCF (stem cell factor) - acts on early HSCs

Myeloid:Erythroid (M:E) Ratio

Leukocoria (Leucoria)

Definition

• The Wills Eye Manual, Section 8.1

Clinical Importance

Differential Diagnosis

• Goldman-Cecil Medicine, Table 391-5; The Wills Eye Manual, 8.1

Workup

1. Detailed fundoscopy (often under anesthesia / EUA in infants - "examination under anesthesia")
2. Ultrasound of the globe - detects calcification (suggests retinoblastoma) and assesses retinal detachment
3. MRI of orbit and brain - preferred over CT to avoid radiation; mandatory for bilateral retinoblastoma or family history
4. Serum ELISA for Toxocara (positive at 1:8 in the majority of infected patients)
5. Systemic pediatric evaluation if retinal astrocytic hamartoma, retinoblastoma, or systemic-disease-associated cataract is suspected

Caution: Anterior chamber paracentesis should be avoided if retinoblastoma is suspected - it risks tumor cell dissemination.

Treatment (by cause)

Summary Comparison

Ovarian Mass in a 17-Year-Old Female

Key Clinical Principle

• Berek & Novak's Gynecology, p. 2377; Robbins & Kumar Basic Pathology, p. 7

Differential Diagnosis

1. Germ Cell Tumors (Most Likely in This Age Group)

A. Mature Cystic Teratoma (Dermoid Cyst)

• Most common ovarian tumor in young women; vast majority are benign
• Contains derivatives of all three germ layers (teeth, hair, sebaceous material)
• Typically cystic; bilateral in ~10-15%
• AFP and hCG negative
• Complication: torsion (common due to size and mobility)

B. Dysgerminoma

• Most common malignant germ cell tumor
• Counterpart of testicular seminoma
• AFP negative, hCG negative; LDH and PLAP elevated in 95%
• May be bilateral (unique among germ cell tumors - ~10-15%)
• Associated with dysgenetic gonads (check karyotype - if 46,XY gonadal dysgenesis, both gonads must be removed)
• Highly radiosensitive and chemosensitive - excellent prognosis

C. Yolk Sac Tumor (Endodermal Sinus Tumor)

• Second most common malignant germ cell tumor
• AFP markedly elevated (key marker); hCG negative
• Aggressive; grows rapidly
• Schiller-Duval bodies on histology (pathognomonic)

D. Immature Teratoma

• Malignant; contains immature/embryonic neural tissue
• Graded 1-3 based on amount of immature neural elements
• AFP slightly elevated if hepatic/intestinal differentiation present; if markedly elevated, suggests mixed tumor
• Graded: Grade 1 (stage IA) can be managed with surgery alone

E. Embryonal Carcinoma

• Rare; AFP and hCG both positive
• Undifferentiated; precursor to other germ cell types

F. Nongestational Choriocarcinoma

• Very rare in pure form; hCG markedly elevated
• Isosexual precocious puberty due to hCG

G. Mixed Germ Cell Tumor

• Contains ≥2 germ cell elements
• Most common component: dysgerminoma (80%), then yolk sac tumor (70%), immature teratoma (53%)

2. Functional/Physiologic Cysts

• Follicular cyst: Most common; usually <8 cm; resolves spontaneously within 1-3 menstrual cycles; no intervention needed unless persistent or symptomatic
• Corpus luteum cyst: May rupture causing acute pain and hemoperitoneum
• Theca-lutein cyst: Associated with high hCG states

3. Sex Cord-Stromal Tumors (Less Common in Adolescents)

• Granulosa cell tumor (juvenile type): Produces estrogen → isosexual precocious puberty, irregular periods; inhibin B is the marker
• Sertoli-Leydig cell tumor: Produces androgens → virilization, amenorrhea, clitoromegaly
• Fibroma: Solid; associated with Meigs syndrome (ascites + pleural effusion)

4. Epithelial Tumors (Uncommon in This Age Group)

• Serous, mucinous, endometrioid - rare under 20; more common >40 years
• If present at this age, often borderline (low malignant potential)

5. Non-Neoplastic / Other

• Endometrioma ("chocolate cyst"): Endometriosis; associated with dysmenorrhea and dyspareunia
• Tubo-ovarian abscess (TOA): Pelvic inflammatory disease; fever, leukocytosis, cervical motion tenderness
• Paraovarian cyst: Adjacent to ovary, from Wolffian duct remnants
• Ectopic pregnancy: Must always be excluded - obtain serum beta-hCG

Immediate Complication to Rule Out: Ovarian Torsion

• Torsion is more common at menarche and during adolescence
• In pre/peri-menarchal girls, torsion can occur even without an underlying mass (normal ovary, longer utero-ovarian ligament)
• Presents with sudden-onset severe unilateral pelvic pain, nausea/vomiting (70%)
• 50% of patients are initially misdiagnosed
• Nearly 70% of torsions occur on the right side

• Transvaginal/transabdominal US with Doppler - primary modality
• Ovary >4 cm is the most common US finding
• Absent venous Doppler flow may be earliest sign (arterial flow can persist until late)
• Normal Doppler does NOT exclude torsion
• Tintinalli's Emergency Medicine, p. 670-672

Workup

History

• Menstrual history (LMP, cycle regularity)
• Sexual activity (exclude ectopic pregnancy)
• Pain: onset, character, radiation
• Symptoms: precocious puberty, virilization, menstrual irregularity
• Family history of ovarian/BRCA-related cancer

Physical Examination

• Abdominal/pelvic exam (mass characteristics: unilateral/bilateral, mobile/fixed, cystic/solid)
• Signs of virilization or feminization
• Ascites, lymphadenopathy

Investigations

Adnexal masses ≥2 cm in premenarchal girls or ≥8 cm in other premenopausal patients generally require surgical exploration.

Surgical Management Principles

Fertility Preservation (Critical in Adolescents)

• Unilateral salpingo-oophorectomy is the standard approach for presumed malignant germ cell tumors - the contralateral ovary and uterus are preserved whenever possible
• Routine wedge biopsy of a normal-appearing contralateral ovary is not indicated (increases adhesion risk and may impair fertility)
• Exception: if karyotype reveals 46,XY, both gonads must be removed (malignant transformation risk)

By Tumor Type

Chemotherapy: BEP Regimen

• 3 cycles for completely resected disease / adjuvant setting
• 4 cycles for macroscopic residual disease
• Must begin within 7-10 days of surgery (tumors can progress rapidly)
• BEP is superior to EP (bleomycin inclusion significantly improves relapse-free survival: 84% vs 69%)
• Cisplatin superior to carboplatin in metastatic GCT

Prognosis

Summary Algorithm

17-year-old with ovarian mass
         ↓
1. Is she pregnant? (beta-hCG)
2. Is this torsion? (acute pain → urgent US Doppler → surgical emergency)
         ↓
Tumor markers: AFP, beta-hCG, LDH, Inhibin B
Imaging: Pelvic US → MRI ± CT chest
         ↓
Predominantly CYSTIC       Predominantly SOLID/MIXED
     ↓                              ↓
Functional cyst?          Likely neoplasm
Mature teratoma?          Germ cell tumor most likely
Endometrioma?             Send karyotype
         ↓
   Surgical staging + Fertility-sparing surgery
         ↓
   Histology → Adjuvant BEP if indicated

Neoplastic Ovarian Mass in a 17-Year-Old: Full Oncologic Approach

Why This Age Changes Everything

• Berek & Novak's Gynecology, p. 2377

Likely Neoplasm Types (Ranked by Probability at Age 17)

Germ Cell Tumors (Most Likely)

Sex Cord-Stromal Tumors (Less Common)

Epithelial Tumors (Rare at 17, but consider)

• Borderline (low malignant potential) serous or mucinous tumor - more likely than frankly invasive at this age
• CA-125 useful but non-specific
• If invasive epithelial cancer found, refer urgently to gynecologic oncologist

Macroscopic / Imaging Clues to Type

Pre-operative Workup

Mandatory Blood Tests

Karyotype

• Mandatory in all premenopausal girls with a suspected malignancy, especially dysgerminoma
• If 46,XY gonadal dysgenesis (Swyer syndrome): malignant transformation risk in both gonads → both gonads must be removed (uterus may be preserved for future embryo transfer)

Imaging

• Pelvic MRI: best soft-tissue characterization; preferred over CT (no radiation in a young patient)
• CT chest: germ cell tumors metastasize to lungs and mediastinum
• CT abdomen/pelvis: assess retroperitoneal lymphadenopathy (dysgerminomas spread to para-aortic nodes around the renal vessels), liver metastases, ascites

FIGO Staging (Used at Surgery)

Surgical Management: Fertility-Sparing is the Default

Intra-operative Principles

1. Unilateral salpingo-oophorectomy (USO) of the affected side - standard for germ cell and stromal tumors in young patients; uterus and contralateral ovary preserved
2. Comprehensive staging at the same operation:
   • Peritoneal washings / ascites for cytology
   • Inspection and palpation of all peritoneal surfaces
   • Biopsy of any suspicious lesion
   • Unilateral pelvic lymphadenectomy + biopsy/palpation of para-aortic nodes (especially for dysgerminoma)
   • Omental biopsy
3. Do NOT do routine wedge biopsy of the contralateral ovary - increases adhesion risk and impairs fertility
4. Exception: if contralateral ovary looks abnormal, excisional biopsy of the suspicious area is appropriate (dysgerminoma is the only GCT that tends to be bilateral)
5. For immature teratomas: contralateral involvement is rare; do not resect a normal-appearing contralateral ovary

"Surgery should be fertility-sparing in the setting of a young patient with a germ cell tumor or low-grade epithelial tumor." - Sabiston Textbook of Surgery, p. 2804

Adjuvant Treatment by Tumor Type

BEP Regimen Details

• Bleomycin + Etoposide + Platinum (cisplatin)
• International standard of care for malignant ovarian GCTs
• Start within 7-10 days of surgery (these tumors grow rapidly)
• 3 cycles for completely resected / adjuvant; 4 cycles for macroscopic residual disease
• Cisplatin is superior to carboplatin in metastatic GCT
• Bleomycin inclusion is important for non-dysgerminomatous tumors (BEP 84% RFS vs EP 69%)
• Second-line for relapse post-BEP: TIP (paclitaxel + ifosfamide + cisplatin) or VIP (vinblastine + ifosfamide + cisplatin)

Surveillance After Surgery

• Regular clinical review + physical examination
• Tumor markers (AFP, hCG, LDH) - most frequent early on, as most relapses occur within 2 years (all relapses within 13 months in Charing Cross data)
• Interval pelvic/abdominal imaging
• Overall disease-specific survival with this approach: 94% (Charing Cross series)
• 75% of dysgerminoma recurrences occur within the first year; salvage with BEP is highly successful

Prognosis

Immediate Next Steps (Summary)

Neoplastic ovarian mass, 17-year-old
            ↓
1. Tumour markers: AFP, beta-hCG, LDH, PLAP, Inhibin B, Testosterone
2. Karyotype (mandatory)
3. MRI pelvis + CT chest + CT abdomen/pelvis
4. Refer to gynaecologic oncologist
            ↓
5. Fertility-sparing staging laparotomy / laparoscopy:
   - Unilateral salpingo-oophorectomy
   - Full surgical staging
   - Frozen section if needed
            ↓
6. Histology result → adjuvant BEP if indicated
   (start within 7-10 days of surgery)
            ↓
7. Surveillance with markers + imaging

• Berek & Novak's Gynecology, pp. 2375-2400; Sabiston Textbook of Surgery, p. 2804; Washington Manual of Medical Therapeutics, p. 857

Tubular Carcinoma and Secretory Carcinoma of the Breast

Overview: Special-Type Breast Carcinomas

Part 1: Tubular Carcinoma

Definition and Epidemiology

• Schwartz's Principles of Surgery, p. 593-594; Robbins & Kumar Basic Pathology, p. 1286

Morphology

• Macroscopic: small, irregular, spiculated mass (almost always detected by mammography rather than palpation)
• Microscopic: haphazard array of small, randomly arranged, well-formed tubules infiltrating a desmoplastic stroma
• Tubules have open lumens lined by a single layer of epithelial cells
• Cells have low-grade nuclei - bland, uniform, similar to normal epithelium
• No myoepithelial cell layer (distinguishes from benign sclerosing adenosis - a key diagnostic pitfall)
• Sometimes mistaken for a benign sclerosing lesion on low power - hence >90% tubule formation requirement for the pure diagnosis

Molecular Subtype

• ER positive: 94% (SEER database)
• PR positive in the majority
• HER2 negative
• Low proliferation index (Ki-67 low)
• Genomic profile: quiet genome, 1q+, 16q- (typical luminal A)

Behavior and Prognosis

"Distant metastases are rare in tubular carcinoma and invasive cribriform carcinoma. Long-term survival approaches 100%." - Schwartz's Principles of Surgery, p. 594

Closely Related Tumor: Invasive Cribriform Carcinoma

Treatment Implications

• Due to its excellent prognosis, adjuvant systemic therapy may often be omitted or de-escalated
• Hormone receptor positivity means endocrine therapy (tamoxifen/aromatase inhibitor) is appropriate
• No role for HER2-directed therapy
• Sentinel lymph node biopsy is still standard for staging

Part 2: Secretory Carcinoma

Definition and Historical Context

Molecular Hallmark: ETV6-NTRK3 Fusion

• Present in virtually all cases of secretory carcinoma
• The same translocation found in congenital fibrosarcoma and congenital mesoblastic nephroma (identical fusion gene, different tumor)
• Pathognomonic - its detection aids diagnosis
• Leads to constitutive activation of the TrkC tyrosine kinase → downstream PI3K and RAS/MAPK signaling

Molecular Subtype

• Triple-negative (ER-, PR-, HER2-) in most cases - technically classified as TNBC
• However, this is a molecular exception within TNBC - they do NOT behave like typical high-grade TNBC
• Listed alongside adenoid cystic carcinoma as "rare TNBCs of special histologic type with a more favorable prognosis"

"Other rare special histologic types of TNBC with a relatively favorable prognosis are adenoid cystic carcinoma, mucoepidermoid carcinoma, and secretory carcinoma; these are collectively referred to as salivary gland-like carcinoma because they are identical to their more common counterparts in the salivary glands." - Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 979

Morphology

• Cells have abundant pale, vacuolated or granular cytoplasm with intracellular secretory vacuoles (Panel H in the image above)
• Extracellular secretory material in gland lumens (PAS-positive, diastase-resistant)
• Low-grade nuclei in most cases
• Resembles lactational changes (but occurs outside of pregnancy/lactation)
• Solid, microcystic, or tubular growth patterns

Behavior and Prognosis

• Generally favorable - indolent behavior, especially in younger/pediatric patients
• Low risk of nodal metastasis in pure low-grade cases
• However, some adult cases can behave more aggressively with nodal and even distant metastases
• Overall better prognosis than typical triple-negative breast cancer

Therapeutic Relevance: NTRK Inhibitors

Comparison Table

Grading Note

• Tubular: high tubule score (3 points) + low nuclear score (1) + low mitotic score (1) = grade 1 (Nottingham score 5/9)
• Secretory: low nuclear grade in most cases

Role of PCV (Packed Cell Volume / Hematocrit) in Dengue

Why PCV Matters: The Pathophysiology

• Blood becomes concentrated (haemoconcentration)
• PCV rises as the ratio of RBCs to total blood volume increases
• This rise is proportional to the degree of plasma leakage

Key PCV Thresholds

A haematocrit rise of ≥20% or more is a core criterion for DHF Grades I-IV (WHO classification).

• Park's Textbook of Preventive and Social Medicine, p. 295

WHO Classification: PCV as a Diagnostic Criterion

When and How to Monitor PCV

Baseline PCV (Febrile Phase)

• A full blood count including hematocrit at the first visit establishes the patient's own baseline
• This is essential because the ≥20% rise must be calculated relative to the individual's baseline, not a population average
• If baseline is unavailable, age-specific population hematocrit values can be used as a surrogate

Serial PCV Monitoring

• Daily from the 3rd day of illness until temperature has been normal for 1-2 days
• The critical period is the transition from febrile to afebrile phase (usually day 3-5 of illness)
• A rapidly falling platelet count in parallel with a rising hematocrit is the earliest warning of progression to the critical/plasma leakage phase
• If hematocrit measurement is unavailable, haemoglobin determination may be done as an alternative
• Patients in DHF should be monitored every hour for vital signs and urine output

PCV as a Guide to IV Fluid Therapy

Indicator for Initiating IV Therapy

• Hct rise ≥20% = initiate IV therapy
• Start: 6 ml/kg/h crystalloid (normal saline or Ringer's lactate) for 1-2 hours

Indicator of Response to Treatment

• Improvement = Hct falls + pulse rate stable + BP stable + urine output rises → reduce IV rate step-wise (6 → 3 → 1.5 ml/kg/h) → discontinue after 24-48 hours
• No improvement = Hct continues to rise → escalate IV fluids to 10 ml/kg/h

The Critical PCV Decision: Rising vs. Falling in Shock

"In cases of persistent shock when haematocrit continues to decline, internal bleeding should be suspected." - Park's Textbook of Preventive and Social Medicine, p. 296

Volume Replacement Algorithms (WHO / Park's)

For DHF Grade I & II (Moderate - Haemorrhagic tendencies + Hct rise ≥20%):

For DHF Grade III (Compensated shock - pulse pressure ≤20 mmHg, Hct >20% rise):

PCV and Blood / Platelet Transfusion Decisions

Red Cell Transfusion Indications (PCV-guided)

1. Overt blood loss ≥10% of total blood volume
2. Refractory shock with declining hematocrit (despite adequate fluids)
3. Replacement: 10 ml/kg whole blood OR 5 ml/kg packed RBC at a time
4. If fluid overload is present → packed cells preferred over whole blood

Platelet Transfusion

• PCV is NOT used to guide platelet transfusion - platelet count drives this decision
• No prophylactic platelet transfusion even at platelet count <20,000/cu.mm in general
• Give at <10,000/cu.mm, or in prolonged shock with coagulopathy, or systemic massive bleeding

Criteria for Discharge: PCV Stability Required

1. Afebrile for ≥24 hours without antipyretics
2. PCV/hematocrit is stable (no further rise or decline)
3. Adequate urine output
4. Improvement in clinical status (appetite returns, abdominal pain resolves)

Summary: PCV Roles at a Glance

Peritoneal Fluid Cytology - Microscopic Interpretation

Two Slides - Two Different Stains

Cellular Findings (Both Slides)

1. Mesothelial Cells ✓

• Image 1: Present as both single cells and a cohesive 3D cluster with characteristic intercellular "windows" (gaps between adjacent cells) - the hallmark of reactive mesothelial cells
• Image 2: Medium-large round-to-oval single cells; some show a characteristic lighter "halo/fringe" at the outer border (another mesothelial feature)
• Nuclei: Round to oval, smooth nuclear membranes, evenly distributed benign chromatin, no significant atypia or hyperchromasia
• Cytoplasm: Moderate, pink-lavender (Pap) or pale blue-grey (Romanowsky)
• Assessment: Reactive/benign mesothelial cells - no malignant features

2. Macrophages / Histiocytes ✓

• Scattered individually throughout both smears
• Larger than lymphocytes; eccentric, kidney-shaped (reniform) or folded nuclei
• Abundant pale, vacuolated (foamy) cytoplasm containing phagocytosed debris
• Image 2: Some show large clear cytoplasmic vacuoles compressing the nucleus peripherally (vacuolated macrophages / "signet-ring-like" histiocytes - a benign reactive finding)

3. Lymphocytes ✓

• Small, mature mononuclear cells scattered individually
• High nuclear-to-cytoplasmic ratio
• Dense, dark chromatin; scant cytoplasm

4. Occasional Neutrophils ✓

• Segmented/multilobed nuclei
• Scattered, not dominant

5. Squamous Contaminant (Image 1 only)

• A single large, flat, polygonal superficial squamous epithelial cell in the upper-left quadrant
• Brightly eosinophilic cytoplasm with pyknotic nucleus
• Benign contaminant from skin or lower genital tract introduced during paracentesis - not clinically significant

Most Striking Feature: The Background

1. Mucinous ascites / Pseudomyxoma peritonei (PMP) - most important consideration
2. Ruptured or leaking mucinous ovarian cyst
3. Pancreatitis with lipid-rich exudate
4. Highly proteinaceous reactive effusion

Overall Cytological Interpretation

Benign/Reactive Peritoneal Fluid with Prominent Mucinous/Proteinaceous Background

Showing: reactive mesothelial cells, macrophages, lymphocytes, and occasional neutrophils in a rich vacuolated mucinous background, with no malignant cells identified.

• Malignant cells (no nuclear enlargement, hyperchromasia, prominent nucleoli, irregular nuclear membranes, high N:C ratio, or atypical mitoses)
• Carcinoma cells
• Lymphoma cells
• Malignant mesothelioma cells

The Critical Question: What Is Causing the Mucinous Background?

Most Important - Pseudomyxoma Peritonei (PMP)

• A syndrome of mucinous ascites caused by accumulation of mucin in the peritoneal cavity
• Primarily arises from appendiceal mucinous neoplasms (low-grade: LAMN; high-grade: HAMN; mucinous adenocarcinoma)
• Can also arise from mucinous ovarian, pancreatic, colorectal, or gastric tumors
• Cytology typically shows acellular or paucicellular mucin with scattered bland epithelial cells or histiocytes - matching this appearance
• Clinical presentation: painless abdominal distention, "jelly belly"
• Definitive diagnosis: gelatinous material at laparotomy/laparoscopy
• Treatment: Cytoreductive surgery (CRS) + HIPEC (Hyperthermic Intraperitoneal Chemotherapy)

"Pseudomyxoma peritonei is a syndrome of mucinous ascites... primarily associated with appendiceal epithelial neoplasms... Presenting symptoms are usually painless abdominal distention." - Sleisenger and Fordtran's GI and Liver Disease, p. 645

Other Differentials

• Ruptured mucinous ovarian cyst/cystadenoma: mucin released into peritoneum; benign source
• Chronic inflammatory exudate: protein-rich but usually more cellular
• Pancreatitis: lipase-rich fluid may look vacuolated; clinical context distinguishes

Recommended Further Workup

Summary Table