Tumours of Pancreas & related Recent advances

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Tumours of pancreas are mainly divided into 2 subtypes.   

 Endocrine Pancreas (from islet of Langerhans)

Exocrine Pancreas    ( Non isler tumours)

Endocrine pancreas tumours are divided as per the type of cell & accordingly shall be the clinical features.

Some of the tumours secrete more than 1 hormone at different stages of tumour progression.

 

 CELL                         CONTENTS MAJOR               MINOR

 

1.A cell                             Glucagon                       TRH, CCK Endorphins, PYY, Pancreastin

2.B cell                              Insulin                           TRH,CGRP,Amylin,Pancreastin, Prolactin

3.D cell                              Somatostatin                  Metaencephalon

4.D2 cell                            VIP

5.EC                                   Substance P                   Serotonin

6.G cell                              Gastrin                           ACTH related peptides

7.PP                                   Pacreatic                        Metaencephalan, PHI

                                          Polypeptides   

The above mentioned chart shows various cells of pancreas & hormones secreted by them.

 

Now let us discuss each major cell with syndrome separately.

 

(1)                Insulinoma

   

  Insulinoma usually arise from body & tail of pancreas from B cells.

     Clinical features: are due to insulin & catecholamine release.

1. Whipples Triad    Symptoms of Hypoglycemia, Blood Glucose levels of 40 mgs%, relief of

    symptoms after IV Glucose.

2. Fatigue., weakness, tremors, sweating.

3. Autonomic Hyperactivity

    Mental confusion, irritability, delirium,blurring of vision, stupor, convulsion, coma.

 10% of insulinomas are malignant, 10% are associated with MEN I Syndrome.

 

Investigations;

 

During attacks of Hypoglycemia, Serum insulin levels are > 5u/ ml.
Selective Porto-Venous Sampling for insulin levels in pancreatic venous tributaries. It has
Accuracy of 75%.

Selective Intra-arterial injection of Calcium in Gastroduodenal, Splenic, Rt, Hepatic arteries &
Obtain samples for radioimmunoassay of insulin from Rt.Hepatic vein. Here Ca stimulates release

Of insulin.


(2)                Glucagonamas

       

        Glucagonamas arise from A cells. All are malignant & arise from body & tail of pancreas.

 

      Clinical features:

Skin Rash (Necrolytic Migratory Erythema ) & unrelenting dermatitis.
Diabetes mellitus (mild).
Anaemia, weight loss , increase in Glucose levels.
 

 Investigation:

 

1.Serum levels of Glucagon  200-2000pg/ml is diagnostic.

 

 

(3)                Gastrinomas (Zollinger- Ellison Syndrome)

 

       Gastrinoma is second most common islet cell tumours. It is most symptomatic& malignant endocrine

Tumour of pancreas. Half of Gastrinomas arise from duodenum.

 

Clinical Features:

Presents as virulent peptic ulcer or Gastro esophageal reflux disease.
Absence of H. Pylori & no response to H. Pylori treatment.
Present with secretory diarrhoea which is halted by Naso Gastric Aspiration.
25% associated with MEN I Syndrome.
Pain,severe peptic ulcer symptoms, bleeding & perforation.
1/3 present as severe Gastro esophageal reflux disease.
25% present as MEN I Syndrome. Here it presents as hyperparathyroidism, Pituitary tumours.
 

Investigations.

1.Serum levels of Gastrin > 1000 pg / ml.

2. Basal acid output > 15 mEq /hr with Gastric juice pH < 2.

3.IV Secretin 2 cu / kg, Serum Gastrin levels > 200 pg / ml.

4.SRS Somatostatin Receptor Scintigram

  Inject Radiolabelled octreotide 6 mci & body images are taken at 4 & 24 hrs. It will localize gastrinoma

  It is most sensitive for primary & metastatic gastrinomas.

5.Selective porto-venous sampling of gastrin.

6.Direct Endoscopy & Transillumation used for localization of duodenal gastrinomas.

 

 

 

(4)       VIPO mas   (Verner Morrison Syndrome)

 

  It secretes VIP.

 

Clinical Features:

1.Watery Diarrhoea (3-5 litres / day)  causes hypovolemia, hypokalemia, Acidosis.

2. Achlorhydria / Hypercalcemia / Hyperglycemia

Present as flushing with rash.
 

Investigation:

Serum levels of VIP > 225 pg / ml.
 

 

 

(4)                Somatostatinomas

 

It arises in body & tail of pancreas . Also in ectopic sites like upper small bowel & duodenum.

 

Clinical Features:

1.Presest as Steatorrhoea , diabetes mellitus, hypochlorhydria , Gall stones.

 

Investigation:

Serum Levels of somatostatin 100-400 pg / ml.

 

Exocrine Pancreatic Tumors
 

Are mainly classified as Benign & Malignant .   

 

(A) Benign Exocrine Pancreatic Tumours

 

Various sub types are;

1.      Serous Cystadenomas

2.      Mucinous Tumours

3.      Intradutal papillary mucinous tumours

4.      SPEN  ( Solid Papillary Epithelial Neoplasia )

 

Clinical Features;

1. Asymptomatic.

2. Symptoms due to compression on  adjacent structures

    Jaundice , Intestinal or Gasric Outlet Obstruction.

 

Investigation:

 

FNAC : for nature of cystic fluid . To  study for glycogen & mucin content & presence of malignant
Cells.

CEA levels of cystic fluid .
 

(B)Malignant Tumours of Pancreas 

 

1.90% are adenocarcinomas.  Various sub types are Colloid Ca , Signet ring Ca ,Adeno Squamous

Ca , Anaplastic Ca .

 

2. Panreatoblastomas

 

3. Leiomyosarcoma , Liposarcoma ,Lymphymas , Plasmacytomas.

Clinical features:

1.Painless Progressive Obstructive Jaundice.

2.Pain without jaundice in patients with tumours of body & tail of  pancreas.

3.Anaemia , cachexia of malignancy .

4.Anorexia, nausea, vomiting

 

Signs:

 

1.Enlarged gall bladder

            2  Hepatomegaly,Splenomegaly (due to splenic vein thrombosis )

                  3. Icterus,Anaemia,

                  4. Enlarged lt. Supra-clavicular lymph nodes.

5. Ascites Nodules in umbilicus.

6. Peripheral edema , Thrombophlebitis (Trousseau sign ) .

 

 

Investigation

                   :

             1.Liver Funtion Tests

              In Ca Head Pancreas ^ bilirubin , ^ Serum Alk. Phosphatase

             2. Tumour Marker of Ca Pancreas are CEA , CA 19-9 levels .

             3. Protein products of over expressed gene , MIC-I , synuclein-gamma mesothelian, osteopentin.

       4. Detection of aberrantly methylated genes in serum.

       5.Proteomics, Mass spectrometry band direct analysis of unknown proteins in serum

             6.. Endoscopy for Ampullary Tumours .

             7. Biopsy  Transduodenal Biopsy of Ca Head Pancreas .

             8.  Laparoscopy diagnosis .

 
-------------------------------------------------------------------------------------------------------------------
Renal cell Carcinoma

M.G. rajamanickam, Gokul, Department of Nephrology, Kilpauk Medical College, Chennai

 

·                     Accounts for 3% of all adult malignancies

·                     Are adenocarcinomas

·                     The most lethal of all Genitourinary Malignancies

·                     Male to Female Ratio of  3:2

·                     Typically presents in 6th to 7th decades

·                     Majority are Sporadic – 4% are familial

·                     Most clear cell variants arise from proximal convoluted tubule

·                     Chromophobe, papillary & other subtypes are derived from more distal components of Nephron

·                     Only accepted environmental risk factor is tobacco use.

 

 

v                  Pathological Subtypes

·                     Traditional

1.      Clear cell

2.      Granular cell

3.      Tubulopapillary

4.      Sarcomatoid

 

·                     Kovac’s (New) Classification Scheme

 

1.      Conventional

2.      Papillary – Type 1 & Type 2

3.      Chromophobic

4.      Collecting duct

5.      Medullary cell

6.      Oncocytoma

 

§         Predilection to involve venous system seen in 10%

            Most Commonly, a contiguous tumor  thrombus is seen

§         Sporadic RCCs are

            Unilateral & Unifocal

            Bilateral in 2 to 4 % (Synchronous or asynchronous)

§         Bilaterality and multicentricity more common with familial cases

§         Inherited forms of Renal Carcinoma

 

1.      Von Hippel lindau disease – clear cell

2.      Hereditary Papillary RCC – Papillary Type 1

3.      Hereditary Leiomyomatosis  RCC – Papillary Type 2

4.      Birt Hogg Dube : Chromophobe/ Oncocytoma

5.      Familial Renal Carcinoma (FRC)

 

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Clinical Presentation

 

Owing to sequestered location of kidney within Retroperitoneum, many renal masses remain asymptomatic and non palpable until they are advanced.
More than 50% of RCCs are detected incidentally – “Radiologist’s Tumor”.
Incidental Tumors – More likely to be confined to kidney
                                 Positive impact on patient survival

 

§                     Symptoms of RCC is due to

-          Local tumor growth

-          Haemorrhage

-          Paraneoplastic syndromes

-          Metastatic disease

§                     Flank pain in RCC can be due to

-          Haemorhage

-          Clot pain

-          Locally advanced or invasive disease

§                     Classic Triad

-          Flank pain, Hematuria & palpable abdominal mass

-          “too late triad”

-          rarely found now a days

-          almost always denotes advance disease

 

§                     Indicators of advanced disease

1.      Classic triad

2.      Constitutional Symptoms – weight loss, fever, night sweats

3.      Physical examination findings

-          Palpable cervical lymphadenopathy

-          Non-reducing varicocele            Suggest venous involvement

-          Bilateral lower limb edema

4.      Symptoms of metastases

-          Bonepain

-          Persistent cough with haemoptysis

§                     Paraneoplastic  syndromes associated with RCC

-          in 20 % of patients

-          called “Internist’s tumor” due to prevalence of systemic rather than local manifestations

-          production of substances normally produced by the kidney in pathological amounts – 1,25 dihydroxy cholecalciferol and erythropoietin, Renin, prostaglandins 

-          Physiologically important  factors

-                  Parathyroid hormone like peptides

-                  Human Chorionic gonadotrophin

-                  Insulin

-                  cytokines`                               Cause Constitutional Symptoms

-                  Inflammatory mediators`

 

§                     Hypercalcemia

-          Seen in upto 13%

-          due to paraneoplastic phenomenon or osteolytic  metastasis

 

§                     Hypertension

Causes

1.      Increased  Renin production by tumor

2.      Compression or encasement of Renal A or branches leading to renal artery stenosis

3.      A V Fistula within tumor

4.      Polycythemia 

5.      Hypercalcemia

6.      Ureteral obstruction

7.      Increased intracranial tension due to cerebral metastasis

 

 

§                 Polycythemia

    due to increased erythropoietein production of tumor or adjacent parenchyma  in response to       hypoxia  induced by tumor growth

§                     Stauffers syndrome

    Non metastatic  hepatic dysfunction

    in 3% to 20% of the cases

 

Clinical features

-          All have increased serum alkaline phosphatase

-          67% show increased prothrombin and hypoalbuminemia

-          20% to 30% show increased serum bilirubin and serum transaminase

-          thrombocytopenia and neutropenia

-          Fever or Weight loss

 

            Hepatic metastasis to be excluded

            Biopsy Shows – non specific hepatitis associated with prominent lymphocytic infiltrate

            increased inter leukin 6 said to have pathogenic role 

            in 60 – 70% of cases hepatic function normalises after nephrectomy

            Persistent or recurrence of hepatic dysfunction implies presence of viable tumor & is a poor        prognostic factor

 

§     Other Systemic syndromes

-          Cushing’s  syndrome

-          hyperglycemia

-          neuromyopathy

-          clotting disorder

-          Raised ESR

 

§     Treatment of paraneoplastic syndromes needs nephrectomy or systemic immunotherapy

    - Only hypercalcemia responds to medical treatment

§                     Investigated tumor markers in RCC

1.      Tumor Specific

                      P 53

                      Bcl 2

                      Bax

                      Ki -67

2.      Non Specific

                      N – Cadherin

                      Cadherin – 6

                      Alpha – Catenin

                      sICAM ; Sv cam – 1

                      sECAM -1

                      Cyclin A & D1

                      P21

                      Tu M2 – Pk

3.      Over expressed

                      MUC -1

                      CD-44

                      PCNA

4.      Immunogenic

                      RAGE

                      Muc1

                      G 250

 

TCC Bladder

 

·             Bladder cancer behaves as a field change disease – the entire urothelium from renal pelvis to the urethra is susceptible to malignant transformation

·             TCC cells can implant  & migrate to other sites of urothelium

·             TCC bladder 2.5 times more common in men

·             Rarely found incidentally at autopsy

·             Incidence increases with age in both sexes

·             a disease of middle aged or elderly person

-          incidence increases directly with age

·             In adoloscents & in adults younger than 30 to 40 years, bladder cancer tend to express well differentiated histology and are more indolent

 

Carcinoma in situ

 

-          An aggressive form of TCC bladder &  a highly variable and unpredictable clinical course

-           first described in 1952 by Melicow

-           A frank malignancy rather than a precancerous condition

-           consists of purely differentiated TCC Confined to the epithelium

-          May be focal or diffuse

-          Symptomatic or Asymptomatic

 

·                     Clinical Features

-          Irritative bladder symptoms

-          Nocturia

-          Frequency

-          Urgency

-          Dysuria

-          Microscopic hematuria in ¾ ths

-          Reduced intercellular cohesion causes cells and clusters of cells to detach from bladder surface leading to ulcerated epithelium and high incidence of positive urine cytology -  80% -90 %

-          most commonly affects trigone,bladder floor,periureteral areas and bladder neck

-          the  initial  phase of evolution of invasive cancer

-          spontaneous regression not seen

 

 

·                 cystoscopy

-          entirely normal

-          areas of increased vascularity and erythema suggestive of inflammation

-          classic lesions

-          patchy slightly raised velvety lesions

-          ulcerations seen infrequently

 

·                 DD

1.      Inflammation

2.      Intestitial cystitis

3.      Prostatism

 

 

 

·                 Clinical Features of TCC bladder

·                 most common presenting symptom – painless hematuria- 85 %

-          all patients with cystoscopically detectable ca.bladder have at least microscopic hematuria

-          hematuria is usually intermittent.

 

·                 Second most common presentation

-          Symptom complex of bladder irritability and urinary frequency, urgency and dysuria.

-          usually associated with CIS/ invasive Ca. bladder

 

·                 Others

-          Flank pain – ureteral obstruction

-          Pelvic mass

-          lower extremity oedema

·                 Signs of advanced disease

-          Weight loss

-          pain   -   Abdominal  or bone

 

Urine Cytology

 

·                     Malignant urothelial cells be observed on microscopic examination of urinary sediment or bladder washings

·                     tumor cells have large nuclei with irregular, coarsely textured chromatin; increased nuclear cytoplasmic ratio, eccentric nuclear position,prominent nucleoli,mitotic figures,lack of cytoplasmic vacuolation

·                     is more sensitive in patients with high grade tumor or CIS

·                     Limitations

1.      Cytologically normal appearance of cells from well differentiated tumors

2.      Cells of well differentiated cancer are more cohesive & are not readily shed into urine

 

·                     False positive cytology

 

-          1% to 12%

-          Urothelial atypia

-          Inflammation

-          Post RT

-          Post Surgery

-          Post Chemotherapy

-          Stone disease

 

·                     The preferred specimen is clean catch voided urine

-          catheterisation can be used to obtain bladder washing when a high suspicion of bladder malignancy exists

-          improves   -Cellular yield

                        -extent of area sampled

                        -Eliminates contamination from non bladder epithelium

-     Specimens to the placed on ice or refrigerated to prevent degeneration and bacterial growth and processed within a few hours

-           if delay is anticipated, it should be immediately fixed with an equal volume of 50% ethanol

-           slides are prepared by direct smears of a centrifuged sediment or subsequent to cytocentrifugation or membrane filtration

-           slides are stained by papanicolaou method.

 

·                     Flowcytometry

                    measures the DNA content of cells whose nuclei have been stained with a DNA binding fluorescent dye.

                    Aneuploidy is a common feature of high grade tumors, hence flowcytometry is especially accurate in patients  with CIS or high grade malignancies

 

·                     HA-HAase test

 

                    Hyaluronic acid – a bladder glycosaminoglycan seen beneath the superficial layer of cells and HAase – an HA degrading enzyme - have potential roles in angiogenesis & bladder tumor progression.

                    Both HA and HAase can be measured in urine and can assist in detection of Ca bladder

                   An elevated urinary HA level (> 500 ng/ml) indicates a positive HA test and suggests the presence of bladder cancer regardless of tumor grade.

                   The urine HAase levels correlate with the malignant potential of bladder cancer and are elevated (> 10 mu/ml) in patients with G2 and G3 bladder cancer.

                  Both can be combined (the HA-HAase test) and that increases the sensitivity to detect bladder Ca and to monitor tumor recurrence.

 

·                     BTA – TRAK Test

 

-          A quantitative sandwich format enzyme immunoassay.

-          Assay of hcFHrp -  similar to human complement factor H.

 

·                     BTA – STAT Test

-          a qualitative test based on hcFHrp antigen pair

 

·                     Nuclear Matrix Protein

-          Are part of internal structural framework of the nucleus

-          The NMP testing kit MMP 22 measures a nuclear mitotic apparatus protein, a specific class of nuclear matrix protein

-          Better sensitivity in detecting TCC than urine cytology

-          Advantage of being useful in presence of gross or microscopic hematuria

-          There is no universally accepted cutoff value

 

·                     Cystoscopy

                         All patients suspected of having Ca bladder should have careful cystocopy and bi manual examination under anaesthesia, abnormal areas should be biopsied

                        Selected site mucosal biopsies from areas adjacent to tumor and from opposite bladder wall, bladder dome, trigone, and prostatic  urethra to be done

                         Such biopsies give prognostic information  about the likelihood of tumor recurrence

                         30% to 70% of muscle invasive bladder cancers  are associated with CIS elsewhere in bladder

                         The propensity of tumors to retain flourescing porphyrin derivatives can be used. 5 ALA can be administered intravesically in conjunction with fluorescent cystoscopy using blue light at 375 to 440 nm to enable detection of lesions invisible with white light cystoscopy.