Pathology 1:00 P.M. M.McIntire/B. Gill
Thursday, Nov. 16, 2000
Dr. Mamlock
Pediatric Pathology
Note from Dr. Mamlock: Lecture will only go for an hour today. She won’t “bore us to death for two hours, a Pathology joke”. If you have any questions, see her in Anatomic Pathology downstairs. Please see your notes for info covered in lecture. Also, see your Robbins textbook (Ch. 11) for pictures and better explanations. If you read the book, that’s “more than enough”. She’ll mention “key points” in lecture that you might want to read “two times, then you’ll be in very fine shape.”
I. Cystic Fibrosis (CF), pg. 257 in notes
· “Probably one of the most important genetic pediatric diseases”
· still fatal in childhood, but some can make it to maximum of 30 now
· incidence about 1:2,500 births; rare in African Americans and Asians; an autosomal recessive disease and a GENETIC disease. Thus, CFTR gene (cystic fibrosis transmembrane conductase regulator gene is mutated on chromosome 7 (typo in notes)
· REMEMBER FOR EXAMS (now and later): CF is genetic disease due to mutation on CFTR gene on chromosome 7
· What is CFTR? Slide of a diagram illustrating the CFTR (see Robbins Fig 11-7 and 11-8): CFTR gene product looks like a “pac man” sitting in the cell membrane. When a stimulus binds to “some kind of receptor” in cell membrane, you get increased cAMP, activated PKA and, as a result, phosphorylation of CFTR. Then, like a fence, the CFTR allows a gate to open so that chloride ions, together with Na+ and water, rush out of the cell. This gives viscosity to NORMAL mucus.
· What happens in CF? Something’s wrong with the CFTR gene, but there’s varying severities:
¨ Most severe scenario: totally absent CFTR. No matter what you try (more stimuli or a different stimulus), your “gate” or channel stays closed. Thus, no chloride, Na+ or water leaves. The result: very thick mucus in airways, GI tract, essentially all organs in body affected!
¨ Less severe (maybe a different mutation of CFTR gene): your gate opens, but no all the way. Thus, SOME Cl-, Na+ and water leave. Result: mildly viscous mucus (more it opens, the more viscosity, the better!) These kids might have just pulmonary problems or just pancreatic problems. Worst case scenario might have bronchiectasis (dilated bronchi), cirrhosis or a wiped-out pancreas.
· Clinical manifestations (p. 258 notes): Remember: almost ALL people with CF will have a CHRONIC pulmonary disease! CF affects the EXOCRINE portion of pancreas. The Islets are not affected. Thus, insulin secretion is o.k. and very few, will get diabetes. Complications of inspissated mucus occurs all over (see notes)
· Slides: I’ll refer to the book when I can:
· Gross cross-section of lung (Fig. 11-20): see big holes that are dilated bronchi = bronchiectasis. Almost all CF patients with chronic pulmonary disease present with this pathology
· Another gross cross section of lung with greenish-white areas that appear to fill the dilated bronchi. When mucus isn’t cleared from bronchi, a great medium for microorganisms is created (most common = Pseudomonas aeruginosa – why it’s GREEN).
· Histological slide of bronchus filled with thick, pink mucus (it’s almost totally blocked with pink mucus)
Probably still early on in the disease here and still manageable since only small amount of lung spaces are filled (still needs attention)
· Slide of progression from above slide: wait awhile and we are set up for infection; thus, bronchitis. Inflammation is limited to bronchi and you can tell by increased number of blue inflammatory cells filling the bronchi.
· Slide of even further progression: now it’s all blue inflammatory cells and alveolar septae are totally destroyed. At this point your patient has “rip-roaring” bronchopneumonia.
· Histological slide of exocrine pancreas (Fig 11-21): see ductules and pink, inspissated mucus in them. Eventually, they dilate and pancreas gets wiped out (worst case scenario above). Sometimes hard to see this in a newborn. Pathologists will use PAS stains to see mucus better in this case.
· Histological slide of wiped-out pancreas: all you see is fibrous tissue, fat and two lonely Islets of Langerhans are left intact (no effects on endocrine pancreas) . Yet, they can’t even function in a sea of fat; thus, this person had diabetes.
· Cross section of GI tract from above patient: see broad band of inspissated secretions sitting like 2 pink bricks in the GI tract. Also, the glands above the bricks are dilated and filled with similar pink material. Closer look and see the dilated glands filled with thick mucus.
· Picture of a newborn with a rectal prolapse–know this is an early sign of CF and indication for screening! Thick material sitting in gut makes it hard to defecate. They strain until a rectal prolapse occurs.
· Gross liver and spleen with pancreas lying in-between the two. The pancreas looks all yellow because it’s wiped-out and replaced by fat (histological of this above). Bile duct is dilated and filled with mucus (looks grayish) and is nodular. Patient had biliary cirrhosis and you can see compensatory splenic hypertrophy.
· Histo of vas deferens: in about 95% of boys, gets narrowed or becomes absent. Most are infertile. Girls can have problems too because ciliary action in fallopian tubes messed up by CFTR mucus problems.
· Histo of nasal polyps: HUGE pink blobs of mucus. Common in CF
· Histo of skin: again, pink mucus filling sweat glands. The CFTR in the sweat glands prevents Cl- from re-entering cells. Thus, these kids have salty skin. Mom brings them in because they taste like a potato chip when she kisses them. DO A SWEAT TEST in this case! In notes, but just know it’s not 100% accurate.
II. Hirschprung’s Disease (p. 258 notes) “the bread and butter of pediatric pathology”
· CONGENITAL absence of ganglion cells (never too many or too few – Hirschprung’s is just plain ABSENCE of the guys), not genetic! It’s a developmental problem. Innervation of gut (neural crest cells) starts at top and migrates to the anus. Don’t know the cause, but , if the cells are arrested along the way, you get Hirschprung’s.
· Important: FUNCTIONAL DILATION PROXIMAL AND DISTAL NARROWING at the site of arrested ganglion cells. Ganglion cells innervate the GI tract and push our stuff along. If these suddenly disappear, our stuff just builds up and you get dilation proximal and narrowing distal (she really harped on this – “ a wonderful exam question”). Looks like a “funnel”.
· Absence of ganglion cells in submucosal (Meissner’s) and myenteric (Auerbach’s) plexus. For some reason, the nonmelinated nerve fibers hypertrophy and become prominent (helpful to the pathologist).
· Common problem: incidence 1:5,000 – 8,000 births. Some think it’s non-existent in pre-term infants, but it’s rare in low birth rate infants. Frequent in Down’s syndrome. She read the slide word for word (p. 259) Older kids get constipation and that’s why they are brought to the doctor. Worst case scenario: kid gets very distended abdomen.
· Student question about is colon constrictive and functional. Answer: it’s narrowed and normally developed. It just lacks ganglion cells.
· Risk can occur at any level (see pg. 260): Rectosigmoid and only need to resect short segment of bowel and bring normal segment down to anus and kid is fine. If it involves entire colon or small bowel, you must resect, put in a colostomy and, hopefully, connect the normal segment to the anus. Although, it will take about 2-3 years to teach the small bowel to behave like the colon.
· Histo of cross section: looks normal (muscularis, submucosa and mucosa), but you are missing the submucosal ganglion and myenteric plexus. You can see a ball of purple cells that’s almost “squiggly”. This is your hypertrophied plexus. This good indication to go further and look for similar results for a diagnosis. Student question about why they are hypertrophied. Answer: we don’t know!
· Histo of frozen and stained section: see “pinworm” like purple cells at low power. These are gangilon cells and a good sign for no Hirschprung’s. Higher power: see large pink cells with prominent nucleus and bright pink dot of nucleolus in it. See this and “your in heaven”. NO Hirschprung’s!
· Some pathologists do acetylcholine esterase staining, but she doesn’t believe in it (just wanted us to be aware of it).
Now we will discuss two MALIGNANT NEOPLASMS:
III. Neuroblastoma - NB -(p. 260) “most common childhood extracranial solid tumor”
· See slide pg. 260. She read each point almost word for word. I’ll add what she said.
· About half affect abdomen and about 35% affect adrenal gland, but they can occur anywhere along the sympathetic chain. The second most common (that’s all she said) occurs in the paravertebral body, but can also occur in the mediastinum, the thorax and pelvis.
· Most common in young children is the large abdominal mass. Parents feel mass when bathing the kid and go to the doctor. Read the rest of slide word for word.
· Pg. 261- Just like Hirschprung’s, NB derived from primitive neural crest cells
· Homer-Wright pseudorosettes – seen histologically and called this because true rosettes have a little lumen and these don’t. These may undergo spontaneous involution or start differentiating on themselves.
· Metastases by any of three listed on p. 261 can occur (remember this is a malignant disease)
· Staging of Neuroblastoma – IF ANYTHING, LEARN THIS! You’ll see this in your clinicals (p. 261)
¨ Stage 1 – Tumor stays in organ/structure origin
¨ Stage 2 – Tumor extends in CONTINUITY beyond origin, but doesn’t cross midline (starts in left adrenal, it stays in left adrenal, may go into peri-adrenal fat, but doesn’t cross midline). Also, lymph nodes on side of tumor may or may not be involved.
¨ Stage 3 – Tumor extends across midline. Both sides of lymph nodes may or may not be involved.
¨ Stage 4 - Crosses midline and get distant metastases
¨ Stage 4S (sub) – Tumor like Stage 1 or 2 (stays on origin side), but have distant metastases. This stage has very good prognosis for young children.
¨ Age and stage correlate very well with prognosis: e.g. child less than 1 yr old presents with Stage 1, 2, or 4S. These have about 80% survival in 5 years. Also, child older than one is in Stage 3 or 4 and has about a 10% 5 year survival. Summary: the younger you get NB, THE BETTER!
¨ Illustration of child and the stages 1 – 4. You can see how 1 and 2 stay on the same side and 3 and 4 cross. Also, you can see how 2, 3, and 4 can extend beyond the tumor of origin.
¨ Histo slide of fetal adrenal gland: pink cells are adrenal cortex cells while blue are neuroblasts in the adrenal medulla. Some pathologists would call this an in-situ neurblastoma (like a stage 1 thing). These are NOT! This is a normal developmental phenomenon. Fetuses have neuroblasts in their adrenal medulla.
¨ Gross adrenal gland with NB: see a big ball that appears to have fleshy, friable mass or lesion on it and see white areas of calcification on it.
¨ Histo of above: see a “sheets” (see p. 261) or a sea of small, round blue cells that all look the same. Another slide of higher mag. shows similar blue neoplastic cells scattered throughout the frame with all having “peppery” or granular looking chromatin. Not really seeing mitotic figures in nucleus.
¨ EM showing small, totally black granules. A GIVEAWAY! These are neurosecretory granules. A cell is next to these and it’s huge compared to these granules.
¨ Histo of Homer-Wright pseudorosette: small round blue cells surround a lumen with delicate, brownish fibrillar material filling the lumen.
¨ EM of pseudorosette: projections toward center.
¨ Histo of NB in bone: see bony trabeculae (pink) and bone marrow overrun by our little blue cells
¨ Remember, some tumors will involute or differentiate. As child gets older, tumors may mature. When you remove these (gross picture of tumor cut in half and looking at inside), you see that the tumor looks firmer and there’s chalky white areas of calcification in the middle. Compare to gross adrenal slide above.
¨ Histo slide of ganglion cells: just like in the gut, neuroblasts will mature to ganglion cells. Remember NB can have spontaneous maturation of its neural crest cells from which it is derived. Thus, we can have varying numbers of ganglion cells in NB. Looks just like the normal ganglion cells described in Hirschprung’s above : large pink cell, pink nucleus and prominent nucleolus. Also, you still see the little blue neuroblasts all over the place. This is called a “ganglioneuroblastoma”.
¨ Histo slide showing NB maturing to all ganglion cells: called a “ganglioneruroma”
¨ Histo slide showing clusters of gangilon cells, all having a fibrillary background. These ganglion cells have lots of cytoplasm, a big nucleus prominent nucleolus and clumped material around the out side of the cell. This is Nissl substance.
¨ Neuroblastoma biologic features (p. 262) – chromosome tests have shown 1p deletion (short arm of chrom. 1) – she said she didn’t think she would ask anything about this, but it’s good to know. See the oncogene, n-myc, amplification.
¨ Karyotype shown: see double minutes (small, little pieces of chromosome) mixed in with normal chromosomes. The more double minutes you have, the worse the prognosis. These are minute (small) chromosomes showing amplification.
¨ Remember age and stage correlate with prognosis (young age + low stage = good) and so does amplification of n-myc and double minutes (little amplification = good)
IV. Wilm’s Tumor (p. 263) “most common pediatric renal tumor”
· Usually seen at age 2-4 and rare in infancy or over 10 yrs. – start thinking other tumors if above 10