Diseases of White Cells and Lymphoid Tissue: Dr. H. Marah Ganti Siregar, Sppa

DISEASES of WHITE CELLS and
LYMPHOID TISSUE
Dr. H. MARAH GANTI SIREGAR, SpPA

Topics for Chapter 14
Leukopenia/Neutropenia
Leukocytosis
Lymphadenitis/Lymphadenopathy
(Malignant) Lymphoma
NON-Hodgkins Lymphoma
Hodgkins Lymphoma (Hodgkins Disease)
ALL/CLL (Acute/Chronic Lymphocytic Leukemia)
Multiple Myeloma
M1/M2/M3/M4/M5/M6/M7
Myeloproliferative Disorder
CML and Polycythemia Vera
Essential Thrombocytosis
Splenomegaly
Thymoma Dr. H. MARAH GANTI SIREGAR, SpPA
WBC/LYMPHOID DISORDERS
Review of Normal WBC Structure/Function
Benign Neutrophil and Lymphoid Disorders
Leukemias
Lymph Nodes
Spleen/Thymus
REVIEW

NEUTROPHILS
Normal TOTAL WBC count 6-11 K
Neutrophils usually 2/3 of total normal
Myeloblast Promyelocyte Myelocyte
Metamyelocyte Band (stab) Mature
Neutrophil (Poly, PMN, Neutrophilic Granulocyte)
Produced in red (hematopoetic) marrow, sequester
(pool) in spleen, live in peripheral blood, migrate
OUT of vascular compartment PRN, live a couple
days normally

NEUTROPHIL
Neutrophil
Polymorphonuclear Leukocyte,
PMN, PML
Leukocyte
Granulocyte, Neutrophilic
granulocyte
Poly-
Polymorph
NEUTROPHIL MATURATION
LYSOSOMAL CONSTITUENTS
PRIMARY SECONDARY
Also called Also called SPECIFIC
AZUROPHILIC, or Lactoferrin
NON-specific
Lysozyme
Myeloperoxidase
Lysozyme (Bact.) Alkaline Phosphatase
Acid Hydrolases Collagenase

FUNCTIONS
Margination
Rolling
Adhesion
Transmigration (Diapedesis)
Chemotaxis
Phagocytosis: Recognition, Engulfment,
Killing (digestion)
Equilibrium with splenic pool
PELGER-HUET ANOMALY
Genetic
Sometimes ACQUIRED (Pseudo-PELGER-HUET)
All neutrophils look like BANDS
NOT serious, mostly a cute incidental finding

CHEDIAK-HIGASHI SYNDROME
Also genetic
Abnormal LARGE irregular neutrophil granules
Impaired lysosomal digestion of bacteria
Associated with pigment and bleeding disorders
CAN be serious, especially in kids

LEUKO-penia/NEUTRO-penia
Neutropenia/Agranulocytosis
INADEQUATE PRODUCTION
INCREASED DESTRUCTION
500-1000/mm3 is the DANGER

zone!
INADEQUATE PRODUCTION
Stem cell suppression, e.g., aplastic anemias
DRUGS, esp. CHEMO, MANY antibiotics,
aminopyrene, thio-uracil, phenylbutazone
DNA suppression due to
megaloblastic/myelodysplastic states
Kostmann Syndrome (genetic, congenital)
Marrow usually shows granulocytic HYPO-
plasia, just as in RBC and PLAT decreased
production

INCREASED DESTRUCTION
Immune mediated
By itself (idiopathic), or as in SLE
After sensitization by many drugs
Splenic sequestration, hypersplenism
Increased peripheral demand, as in
overwhelming infections, esp. fungal
Marrow usually shows granulocytic
HYPER-plasia, just as in RBC and PLAT
increased destructions
Leukocytosis/Neutrophilia
Marrow and splenic pool size
Rate of release between pool and circulation
Marginating pool
Rate of WBCs (neutrophils/monocytes) leaving the
vascular compartment
NON-vascular pools FIFTY times larger than the
vascular pools
TNF/IL-1/cytokines stimulate T-cells to produce
CSF, the WBC equivalent of EPO
NEUTROPHIL INCREASES
(e.g., NEUTROPHILIA)
BACTERIA
TISSUE NECROSIS, e.g., MI
DHLE BODIES and TOXIC
GRANULES are often seen with
NEUTROPHILIA
Accompanied by a LEFT shift

EOSINOPHIL INCREASES
(i.e., EOSINOPHILIA)
ALLERGIES (esp. DRUG allergies)

PARASITES

BASOPHIL INCREASES
(i.e., BASOPHILIA)
RARE. Period.
But if you want to remember
something at least, remember
myeloproliferative diseases in
which ALL cell lines are increased

MONOCYTE INCREASES
(i.e., MONOCYTOSIS)
TB
SBE
RICKETTSIAL DISEASES
MALARIA
SLE
IBD, i.e., ULCERATIVE COLITIS
LYMPHOCYTE INCREASES
(i.e., LYMPHOCYTOSIS)
TB
VIRAL
Hep-A
CMV
EBV
Pertussis (whooping cough)
MYELOPROLIFERATIVE
disorders
Also called chronic myeloproliferative disorders because
they last for years
ALL marrow cell lines are affected, splenomegaly
Proliferating cells do NOT suppress residual marrow
production, and go OUTSIDE marrow, and EXPAND
marrow to fatty appendicular marrow
Associated with EXTRA-medullary hematopoesis
Chronic Myelogenous Leukemia (CML)
P. Vera
Essential Thrombasthenia (aka, Essential Thrombocytosis)
Myelofibrosis
CML
NOT AT ALL like an acute leukemia, but can
develop into one as a condition called a blast
crisis
Age: adult, NOT kids
90% have the Philadelphia chromosome, which
are aberrations on chromosome #9 (BCR) and #22
(ABL), the BCR-ABL fusion

CML
Marrow 100% cellular, NOT 50%
ALL cell lines increased, M:E ratio massively
increased, 50K-100K neutrophils with
SIGNIFICANT left shift, but not more
than 10% blasts
SIGNIFICANT SPLENOMEGALY!!!!!
Significant breakthrough with BCR-ABL kinase
inhibitors!!! (90% remissions)
Polycythemia Vera
All cell lines increased, NOT just RBC
HIGH marrow cell turnover stimulates
increased purines which often cause gout
(10%)
BOTH thrombosis AND bleeding risks are
present because the increased platelets are
AB-normal
Do not get blast crises, BUT can progress to
myelofibrosis
ESSENTIAL THROMOCYTOSIS
Platelet count often near 1 million/mm3

Often a diagnosis of exclusion.
The RAREST of all myeloproliferative
disorders
Giant platelets usually. Why? Ans: Quicker
release from marrow (RPW/RDW)
Massively increased megakaryocytes in the
marrow

PRIMARY MYELOFIBROSIS
Rapid progressive marrow fibrosis
Oldest age group of all the MPDs, >60
Can follow other MPDs. Why?
Usually the most extensive extramedullary
hematopoesis because the marrow is NOT
the primary site of hematopoesis
LEUKOERYTHROBLASTOSIS
Like CML, 10-20% can progress to AML
WBC/LYMPHOID DISORDERS
Review of Normal WBC Structure/Function
Benign Neutrophil and Lymphoid Disorders
Leukemias
Lymph Nodes
Spleen/Thymus
REVIEW

LEUKEMIAS
MALIGNANT PROLIFERATIONS of WHITE
BLOOD CALLS
In the case of neutrophilic precursors, the
primary process is marrow and peripheral
blood, but can involve any organ or tissue
which receives blood
In the case of lymphocytes, there is an
intimate concurrence with malignant
lymphomas
Leukemias vs. Lymphomas
All leukemias of lymphocytes have lymphoma
counterparts
Primary lymphomas can have leukemic phases,
including multiple myelomas
Any myeloid leukemia can infiltrate a lymph node, or any
other site, but if/when it does it is NOT called a
lymphoma, but simply a myeloid infiltrate INTO a lymph
node
ALL lymphomas are malignant proliferations of
lymphocytes
ALL leukemias involve bone marrow changes
LYMPHOMAS
NODAL or EXTRANODAL
T or B
SMALL or LARGE CELLS
FOLLICULAR or DIFFUSE
Hodgkins or NON-Hodgkins
F.A.B. classification is currently popular
this week (FrenchAmericaBritish), for
the NON-Hodgkins lymphomas

LEUKEMIAS
Acute or Chronic
Myeloid or Lymphocytic
Childhood or Adult
All involve marrow
All ACUTE leukemias suppress normal
hematopoesis, i.e., have anemia,
thrombocytopenia
Most have chromosomal aberrations
Some can respond DRASTICALLY to chemo, most
notably ALL in children, even be cured!!!!
BLAST

WHITE CELL NEOPLASMS Leuk/Lymph
Many have chromosomal translocations
Can arise in inherited and/or genetic diseases:
Downs Syndrome (Trisomy 21)
Fanconis anemia (hereditary aplastic anemia)
Ataxia telangiectasia
May have a STRONG viral relationship:
HTLV-1 (lymphoid tumors)
EBV (Burkitt Lymphoma)
Human Herpesvirus-8 (B-Cell Lymphomas)

WHITE CELL NEOPLASMS Leuk/Lymph
Can be caused by H. Pylori (gastric B-Cell
lymphomas)
Can follow celiac disease (gluten
sensitive enteropathy T-Cell
lymphomas)
Are common in HIV, T-Cell lymphomas,
CNS lymphomas

A.L.L./LYMPHOMAS*
SUDDEN ONSET
ANEMIA, BLEEDING, FEVER
Bone pain, adenopathy, hepatosplenomegaly
CNS: headaches, vomiting, nerve palsies
*
( NB: These are pretty much the symptoms of
A.M.L. too and vice versa)
A.L.L./LYMPHOMAS
Lymphoblasts which can give rise either to T or B cells
are the cells of malignant proliferation
All lymphocytic leukemias CANNOT be classified
independently of lymphomas because they all have
lymphoma counterparts
A.L.L. mostly in children
Most have chromosomal changes, hyperploidy,
Philadelphia chromosome, translocations
SIGNIFICANT response to chemo: 90% remission, 75%
CURE!!!

A.L.L.

C.L.L.
Unexplained sustained (months) lymph count of >
4000/mm3 is CLL, usually picked up on CBC
M>F
Lymphs look normal and are NOT blasts
No need for marrow exam for dx, but progressive
involvement of marrow, nodes, and other organs is the
usual biologic behavior
Liver can be involved portally or sinusoidally
Translocations RARE, but trisomies and deletions
common
C.L.L.

C.L.L.
HYPO-gammaglobulinemia
15% have antibodies against RBCs
or PLATS
CANNOT be classified as separate
from lymphomas

MULTIPLE MYELOMA
DEFINED AS A MALIGNANT PROLIFERATION OF
PLASMA CELLS
Can have a leukemic phase, but the BONE
MARROW is the usual primary site of origin
Usually have MONOCLONAL GAMMOPATHIES
Secrete Heavy and Light chains, and Light chains
in the urine is known as Bence-Jones protein
Usually have elevated IL-6 (bad prognosis)

PLASMA CELL classic features
OVAL cytoplasm, ROUND
nucleus off to side
Cartwheel/Clockface
chromatin
Prominent Golgi or Hoff

MONOCLONAL SPIKE on SPE

MULTIPLE MYELOMA
BONE DESTRUCTION
Various deletions and translocations
Plasma cells usually 1-3% of marrow, but >20% or plasma
cells in SHEETS is diagnostic
Plasma cells usually look normal
IgG >> IgA, other immunoglobulins are rare
Staph, Strep, E. coli infections
Bleeding
Amyloidosis
RENAL FAILURE

Multiple Myeloma: Skull X-ray

Solitary Plasmacytoma
Progression to MM is inevitable,
with time, perhaps 10-20 years even

M.G.U.S.
Monoclonal Gammopathy of Unknown
Significance, i.e., no plasma cell
proliferation is found
Age related
1% of 50-year olds, 3% of 70-year olds, etc.
Same chromosomal aberrations as MM, but
generally follow a BENIGN course

Other GAMMOPATHIES
Waldenstroms MACROglobulinemia
(associated with lymphomas)
Heavy Chain Disease (associated with
lymphomas)
AMYLOID, follows MM and/or
chronic granulomatous diseases

A.M.L.
GENETIC ABERRATIONS INHIBIT DIFFERENTIATION
Many have various TRANSLOCATIONS
F.A.B. classifies them as M0 M7
MORE than 20% of BLASTS are needed in the
marrow for a diagnosis of acute leukemia!!! (i.e.,
ANY kind of BLAST
NORMALLY, a marrow should have only about 1-2
% blasts
M0
A.M.L.
Minimally differentiated
M1 AUER rods rare (COMMON)
M2 AUER rods common (COMMON)
M3 Acute PRO-myelocytic leukemia
M4 AMML (myelo-Mono cytic) (COMMON)
M5 Monocytic
M6 ErythroLeukemia
M7 Acute Megakaryocytic leukemia
NOTE: Diagnosis is CONFIRMED by special markers, not just
visual identification

M0M2

M3

M4-M5
Normal classic monocyte
AMML Dr. H. MARAH GANTI SIREGAR, SpPA

M6-M7

Anemia
A.M.L.
Thrombocytopenia (bleeding)
Petechiae
Ecchymoses
Fever
Fatigue
Lymphadenopathy
60% respond, BUT only 20 % are free of remission
after 5 years, WORSE than A.L.L.
MYELO-DYSPLASTIC SYNDROMES
Increased risk of acute leukemias
But, UNLIKE the myeloPROLIFERATIVE syndromes, NOT
a hypercellular marrow
Spontaneous or drug related (even > 5 yrs!)
Has marrow ABERRATIONS
REFRACTORY ANEMIAS
RINGED SIDEROBLASTS (Fe in mitochondria)
Nuclear BUDDING
EXCESS BLASTS, but LESS than 20%
About, say 25% develop into acute leukemias
Ring Sideroblasts and BUDS

LYMPH NODES
Normal Structure, Function
Benign enlargement/Benign disease
Acute
Chronic (follicular vs. sinus histiocytosis)
Lymphomas/Malignant Lymphomas
Adjectives of various classifications
Features
STAGING
Metastatic disease TO lymph nodes

CORTEX
---SUB-capsular Sinus
---Follicles (Pri? Or second.?)
Blood flow? ---PARA-follicular zone
Lymph flow? MEDULLA
Definition of TERMS
Lymphadenopathy
Lymphadenitis
Dermatopathic
Normal size?
Palpation
What to do if a lymph node is enlarged?
Diffuse/Follicular
T/B/NK, Small/Large, Cleaved/Non-cleaved
Precursor/Peripheral
HD/Non-HD
BENIGN ENLARGEMENT
Also called LYMPHADENITIS, and HYPERPLASIA
Can be ACUTE (tender), or CHRONIC (non-tender)
Usually SUBSIDE in, say, less than 6 weeks
FOLLICULAR HYPERPLASIA is enlargement of the cortical
secondary follicles and increase in number of the cortical
secondary follicles
SINUS HISTIOCYTOSIS is prominence in medullary sinuses
(also called reticular hyperplasia)

(MALIGNANT) LYMPHOMAS
Terms in historic classifications:
Diffuse/Follicular, Small/Large, Cleaved/Non-cleaved
Hodgkins (REED-STERNBERG CELL) /NON-Hodgkins
Lukes, Rappaport, etc.
Working Formulation, WHO, NIH, FAB, Intl., etc.
B
T
PRECURSOR (less mature looking)
PERIPHERAL (more mature looking)
DIFFUSE LYMPHOMA

FOLLICULAR LYMPHOMA

LARGE CELL LYMPHOMA

SMALL CELL LYMPHOMA

CLEAVED CELL LYMPHOMA

Hairy Lymphocyte

FEATURES of LYMPHOMAS
The Antigen receptor genes re-arrangement PRECEDES
malignant transformation, so the cells are
MONOCLONAL, NOT the usual POLYCLONAL
85% B-cell, 15% T-Cell
The tumor cells congregate wherever T and B cell
congregate normally however
DISRUPTED or EFFACED normal architecture,
obliterated subcapsular sinus
HD/Non-HD staging CRUCIALLY IMPORTANT, esp. HD.
Why? HD grows more linearly

LATEST CLASSIFICATION
NON-HODGKIN
PRECURSOR B
PERIPHERAL B
PRECURSOR T
PERIPHERAL T
HODGKINS DISEASE (i.e., HODGKINS
LYMPHOMA)
PRECURSOR B
Precursor B LYMPHOBLASTIC
LEUKEMIA/LYMPHOMA

PERIPHERAL B
CHRONIC LYMPHOCYTIC LEUKEMIA/LYMPHOMA
B-Cell PRO-lymphocytic LEUKEMIA
Lymphoplasmacytic
Splenic and Nodal Marginal Zone
EXTRA-nodal Marginal Zone
Mantle Cell
Follicular
Marginal Zone
Hairy Cell Leukemia
Plasmacytoma/Multiple Myeloma
Diffuse B Cell
BURKITT LYMPHOMA (Starry Sky)
PRECURSOR T
Precursor T LYMPHOBLASTIC
LEUKEMIA/LYMPHOMA

PERIPHERAL T and NK
T-Cell PRO-Lymphocytic Leukemia
Large Granular
Mycossis fungoides/Sezary Cell syndrome (skin)
Peripheral T-Cell
Anaplastic large cell
Angioimmunoblastic T-Cell
Enteropathy-associated T-Cell
Panniculitis-like
Hepatosplenic gamma-delta
Adult T-Cell
NK/T Cell nasal
NK-Cell leukemia
LYMPHOCYTE MARKERS (CD-)
i.e., LYMPHOCYTE ANTIGENS
T-Cell: 1,3,4,5,8
B-Cell: 10 (CALLA), 19,20,21,23,79a
Mono/Mac: 11c, 13, 14, 15, 33, 34
STEM: 34
RS: 15, 30
All: 45 (Leukocyte Common Antigen)
NK: (16, 56)
HODGKINS DISEASE
NEED R-S (Reed-Sternberg, or Sternberg-Reed)
cells for correct diagnosis
NODULAR SCLEROSIS (Young Women), the
R-S cells may be called LACUNAR cells
MIXED CELLULARITY
Lymphocyte RICH
Lymphocyte POOR
Lymphocyte PREDOMINANCE

STERNBERG-REED CELL

STAGING, HD & NHD
I ONE NODE or NODE GROUP
II MORE than ONE, but on ONE side of diaph.
III BOTH sides of diaph., but still in nodes only
IV OUTSIDE of NODES, e.g., liver, marrow, etc.
A No systemic symptoms
B fever and/or night sweats and/or 10% weight loss

METASTATIC CARCINOMA
Perhaps the single most important staging and
prognostic feature of tumors
The metastatic cells FIRST enter into the
SUBCAPSULAR SINUS
The tumor may replace the entire node and
enlarge it
The tumor may be focal
The tumor usually looks the same as its primary
or other metastases
The tumor usually ENLARGES the node
METASTATIC SQUAMOUS CELL
CARCINOMA

METASTATIC ADENOCARCINOMA

SUBCAPSULAR SINUS

SPLEEN
150 grams POST-LUQ (just like kidney, 1/10 of liver)
Bordered by diaphragm, kidney, pancreas, splenic flexure,
stomach
SMOOTH & GLISTENING capsule
50% RED pulp, 50% WHITE pulp
ABNORMAL SPLEEN

ABNORMAL SPLEEN

SPLENIC FUNCTION
REMOVE OLD BLOOD CELLS
MAJOR SECONDARY ORGAN of the IMMUNE
SYSTEM
HEMATOPOIESIS
SEQUESTER (POOL) BLOOD CELLS
15% of bodys PHAGOCYTIC activity is in the
spleen (liver has >80)
SPLENOMEGALY
CONGESTIVE vs INFILTRATIVE
HYPERSPLENISM
Anemia
Leukopenia
Thrombocytopenia
DECISION for SPLENECTOMY

SPLENOMEGALY
INFECTIONS: TB, Mono, Malaria, Fungus
PORTAL HTN: CHF, CIRRHOSIS, PV Thromb.
LYMPHOHEMATOGENOUS: Leuk, Lymph
IMMUNE: RA, SLE
STORAGE: Gaucher, Niemann-Pick
MISC: Amyloid, mets (melanoma, lymphoma, Germ cell
tumors of testis)
LONG STANDING CONGESTION breeds FIBROSIS

INFARCT

PRIMARY TUMORS (RARE)
HEMANGIOMA
LYMPHANGIOMA
fibroma
osteoma
Chondroma
LYPHOMA Dr. H. MARAH GANTI SIREGAR, SpPA

MISC
Congenital Absence (very rare)
Accessory spleens (very
common)
RUPTURE
THYMUS
Mother of all T-Cells
Massive in newborns, virtually absent in the
elderly, bilobed
Under manubrium
1) Thymocytes
2) Epithelial Ret. Cells
3) Hassals Corpuscles

HASSALs CORPUSCLES

DISEASES
HYPOPLASIA/APLASIA
DiGeorge Syndrome
CYSTS (incidental)
THYMOMAS

THYMOMAS
ALL (most) thymomas show counterparts of
BOTH lymphoid as well as epithelial reticular
cells, hence, the classic name
LYMPHOEPITHELIOMA
Benign thymoma: (encapsulated)
Malignant Thymoma I: (locally invasive)
Malignant Thymoma II: (easily metastasizable)

THYMOMAS

TERIMA KASIH

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DISEASES of WHITE CELLS and

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

500-1000/mm3 is the DANGER

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

ALLERGIES (esp. DRUG allergies)

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Platelet count often near 1 million/mm3

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Normal classic monocyte

AMML Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

II MORE than ONE, but on ONE side of diaph.

III BOTH sides of diaph., but still in nodes only

IV OUTSIDE of NODES, e.g., liver, marrow, etc.

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA

Dr. H. MARAH GANTI SIREGAR, SpPA