Intermediate Grade Borderline Tumors

Slide 1 · Intermediate-Grade (Borderline) Tumors

Kaposi sarcoma • Hemangioendothelioma

Vascular tumor classification · Pathogenesis · Morphology · Clinical correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Intermediate-grade vascular neoplasms

These lesions are positioned between clearly benign vascular tumors and aggressive angiosarcoma.

The principal Robbins examples are Kaposi sarcoma and hemangioendothelioma.

Clinical context and morphologic stage can substantially alter their apparent behavior.

Slide 3 · Learning outcomes

Explain how HHV8 and altered cellular immunity cooperate in Kaposi sarcoma.

Distinguish the four clinical forms of Kaposi sarcoma.

Recognize patch, plaque and nodule-stage morphologic progression.

Contrast Kaposi sarcoma, epithelioid hemangioendothelioma and their mimics.

Slide 4 · Vascular tumor classification is a continuum

Biologic behavior (schematic continuum)

Benign

Hemangioma

Typically well-differentiated

Intermediate

Kaposi sarcoma Hemangioendothelioma

Behavior depends on entity/context

Malignant

Angiosarcoma

Invasive; Readily metastatic

Angiosarcoma illustrates frankly malignant endothelial neoplasia.

Slide 5 · Most entities arise from vascular endothelium

Endothelial examples

Hemangioma · Kaposi sarcoma · hemangioendothelioma · angiosarcoma

Supporting-cell example

Glomus tumor

Cell of origin and degree of malignant behavior are different classification axes.

Slide 6 · Borderline does not mean clinically inconsequential

Intermediate-grade lesions span persistent local disease to clinically aggressive systemic involvement.

Both host immune status and lesional morphology inform expectations.

The broad grade category is not a substitute for case-specific assessment.

Slide 7 · Tumor-like proliferations are an important mimic

Reactive/infectious

Bacillary angiomatosis — Bartonella species

Neoplastic

Kaposi sarcoma — HHV8-associated vascular tumor

The classification distinguishes reactive mimics from intermediate-grade neoplasia.

Slide 8 · Kaposi sarcoma: Causal viral association

Mechanism / clinical sequence — schematic

HHV8 infection

Altered host conditions

Vascular proliferation

Kaposi sarcoma (KS) is a vascular neoplasm caused by human herpesvirus 8 (HHV8/KSHV).

Nearly all lesions contain the virus, across the recognized clinical variants.

Slide 9 · HHV8 infection is not equivalent to HIV infection

HHV8

Direct etiologic association with KS

HIV

Immune suppression that favors epidemic KS

KS in a person with HIV is an AIDS-defining condition in the Robbins classification.

Slide 10 · Four clinicopathologic forms of Kaposi sarcoma

Classic

Older men; Distal skin Usually local

Endemic African

Often HIV negative Frequent lymph nodes

Iatrogenic

Transplant immunosuppression Mucosal / visceral spread

Epidemic

AIDS-associated Early dissemination

Slide 11 · Classic KS: Characteristic host population

The classic variant predominantly affects older men.

Geographic/ancestral associations include Mediterranean and Eastern European groups.

Classic KS does not require HIV infection.

Context

Older male; Often no HIV association Clinical clue: Persistent distal cutaneous vascular lesions

Slide 12 · Classic KS: Earliest distribution

Editable concept schematic — not a patient image or histologic specimen

Multiple red-purple cutaneous plaques or nodules commonly appear on distal lower extremities.

The lesions typically increase in number and size over time.

Distribution can extend proximally with progression.

Distal lower limbs

Slide 13 · Classic KS: Local rather than systemic disease

Mechanism / clinical sequence — schematic

Distal skin

Gradual proximal spread

Often skin-limited

The initial disease is often restricted to skin and subcutaneous tissue.

Many lesions are asymptomatic despite persistence.

Slide 14 · Classic KS: Prognosis reflects limited extent

Local skin lesions are often amenable to surgical resection.

An excellent prognosis for uncomplicated skin-limited classic disease.

Clinical extent matters more than the presence of a single lesion alone.

Slide 15 · Endemic African KS: An HIV-negative setting

Frequently develops in individuals who are HIV-seronegative.

Affected individuals often younger than 40 years.

The course ranges from indolent to aggressive, unlike a uniform phenotype.

Host

Often HIV-seronegative Behavior: Indolent to aggressive

Slide 16 · Endemic African KS: Nodal involvement matters

Mechanism / clinical sequence — schematic

Endemic context

Frequent nodal disease

Broader clinical extent

Lymph-node involvement is more frequent than in classic KS.

Skin-focused examination may underestimate the anatomic extent.

Slide 17 · Childhood endemic KS can be fulminant

The prepubertal variant can show prominent lymph-node and visceral involvement.

Robbins characterizes this pediatric presentation as particularly severe.

Do not generalize the indolent behavior of classic KS to this subgroup.

Pediatric endemic disease ≠ indolent classic KS

Slide 18 · Classic versus endemic KS

Classic

Older men; Distal skin lesions; Usually indolent

Endemic African

Often younger / HIV-seronegative; Frequent nodes; Variable course

Endemic disease has a wider behavioral range and a stronger nodal tendency.

Slide 19 · Iatrogenic KS: T-cell suppression as a cofactor

Mechanism / clinical sequence — schematic

Transplant immunosuppression

Reduced T-cell control

HHV8-associated KS

Solid-organ transplant recipients may develop KS during T-cell immunosuppression.

Immune surveillance is an important restraint on HHV8-associated proliferation.

Slide 20 · Iatrogenic KS: Visceral disease without skin lesions

Lymph nodes, mucosa and viscera may be involved.

The skin may be free of clinically visible lesions.

Absence of a cutaneous plaque does not exclude transplant-associated KS.

Slide 21 · Reducing immunosuppression introduces a trade-off

Mechanism / clinical sequence — schematic

Lower immunosuppression

Improved control of KS

Risk of graft rejection

KS lesions may regress as T-cell immunosuppression is reduced.

Withdrawal or reduction can threaten transplanted-organ survival.

Slide 22 · Epidemic KS: Association with advanced HIV

AIDS-associated (epidemic) KS is an AIDS-defining illness.

Impaired T-cell immunity permits expansion of HHV8-associated vascular lesions.

This is a distinct clinical setting, not a distinct causal herpesvirus.

Virologic driver

HHV8/KSHV Enabling setting: HIV-associated immunodeficiency

Slide 23 · AIDS-associated KS frequently disseminates

Mechanism / clinical sequence — schematic

Cutaneous or nodal KS

Early visceral spread

Systemic burden

Lymph-node involvement is common.

Visceral dissemination can occur early in the clinical course.

Slide 24 · Antiretroviral therapy changed the KS landscape

A greater than 80% fall in AIDS-associated KS incidence after effective antiretroviral treatment became available.

Antiretroviral treatment is generally beneficial in AIDS-associated KS.

The incidence statement is a textbook historical comparison, not a current surveillance estimate.

Textbook historical effect, not a contemporary surveillance estimate

Slide 25 · Clinical variants: Compare site and host

Classic

Skin / subcutis commonly predominate

Endemic

Nodes relatively common

Iatrogenic

Nodes, mucosa and viscera; Skin may be absent

Epidemic

Nodes and early visceral dissemination

Transplant-associated and epidemic KS may involve deep organs early.

Slide 26 · Altered T-cell immunity is a central enabling factor

Mechanism / clinical sequence — schematic

HHV8

Reduced immune restraint

Proliferation / progression

HHV8 infection alone does not predict clinically evident KS.

Immune alteration can be age-related, therapy-related or HIV-associated.

Slide 27 · HHV8 transmission: Several possible routes

Mechanism / clinical sequence — schematic

Exposure

HHV8 infection

Usually asymptomatic

Sexual transmission is described in the source.

Oral-secretory and cutaneous routes are also considered possible.

Slide 28 · HHV8 has both lytic and latent programs

Complementary mechanisms — schematic

Lytic infection

VEGF + inflammatory signals

Latent infection

Cell-cycle and survival advantage

Latent infection changes cell-cycle control and cell survival.

Slide 29 · Lytic viral signaling increases VEGF

Mechanism / clinical sequence — schematic

Viral G protein

VEGF production

Endothelial proliferation

A virally encoded G protein promotes production of vascular endothelial growth factor (VEGF).

VEGF stimulates endothelial proliferation.

Slide 30 · Lytic inflammation amplifies proliferation

Mechanism / clinical sequence — schematic

Lytic HHV8

Inflammatory cells

Growth-supportive cytokines

Inflammatory cells are recruited to sites of lytic viral infection.

Their cytokines support a local proliferative environment.

Slide 31 · Latent HHV8 perturbs cell-cycle regulation

Mechanism / clinical sequence — schematic

Latent HHV8

Viral cyclin-D homologue

Cell-cycle advantage

Latently infected cells express viral proteins that disrupt proliferation controls.

A viral homologue of cyclin D as one mechanism.

Slide 32 · Latent HHV8 also favors cell survival

Mechanism / clinical sequence — schematic

Latent HHV8

P53 inhibition

Reduced apoptosis

Viral products can inhibit the p53 pathway.

Dampening of apoptosis favors persistence of abnormal infected cells.

Slide 33 · Two programs converge on lesion growth

Complementary mechanisms — schematic

Extrinsic environment

VEGF · inflammatory cytokines

Intrinsic advantage

Cell-cycle activation · apoptosis inhibition

Together these mechanisms favor expansion of HHV8-positive vascular cells.

Slide 34 · Infected-cell fraction expands during progression

Mechanism / clinical sequence — schematic

Early lesion: Few infected cells

Progressive expansion

Late: Most cells infected

Early KS may contain only a minority of HHV8-infected cells.

As lesions evolve, nearly all proliferating cells can harbor HHV8.

Slide 35 · Host and tumor programs act jointly

Mechanism / clinical sequence — schematic

Viral effects + host immunity

Clonal expansion

Clinical lesion

HHV8 supplies proliferative and survival signals.

Reduced T-cell control enables viral persistence and tumor expansion.

Slide 36 · Cutaneous KS progresses through three stages

Patch

Macule

Irregular spaces; Inflammation

Plaque

Raised

Jagged channels; Spindle cells

Nodule

Mass

Spindle-cell sheets; RBC slits

Schematic — not a photograph or histologic specimen

The sequence is characteristic but is not mandatory in every clinical variant.

Slide 37 · Patch-stage KS: A flat red-purple lesion

Editable concept schematic — not a patient image or histologic specimen

Grossly the patch is a red-purple macule.

The flat appearance reflects early lesional architecture.

Clinical recognition is difficult because many benign and reactive conditions resemble this stage.

Flat macule

Surface elevation: Schematic

Slide 38 · Patch-stage KS: Endothelial-lined spaces

Editable concept schematic — not a patient image or histologic specimen

Histology demonstrates dilated, irregular endothelial-lined vascular spaces.

Lymphocytes and plasma cells are interspersed among these channels.

Macrophages may contain hemosiderin.

Channels + inflammatory cells

Slide 39 · Early KS may mimic granulation tissue

Early KS

Irregular vascular spaces + lymphocytes/plasma cells

Granulation tissue

Reactive vascular proliferation; Overlap in early KS appearance

The source specifically cautions that distinction may be difficult in early lesions.

Slide 40 · Plaque-stage KS: Progressive elevation

Editable concept schematic — not a patient image or histologic specimen

Patches enlarge and become violaceous raised plaques.

Dermal proliferative tissue makes the lesion more palpable.

The histologic transition adds conspicuous spindle cells to distorted channels.

Raised plaque

Surface elevation: Schematic

Slide 41 · Plaque stage: Jagged vascular channels

Editable concept schematic — not a patient image or histologic specimen

Dermal vascular channels become dilated and irregularly jagged.

Plump spindle cells line and surround these spaces.

Extravasated red cells and mononuclear inflammation accumulate between channels.

Jagged channels + spindle cells

Slide 42 · Nodular KS: More overt neoplasia

Editable concept schematic — not a patient image or histologic specimen

Lesions evolve into distinct raised nodules.

A mass of proliferating spindle cells becomes the dominant histologic component.

Nodules can extend through dermis into subcutaneous tissue.

Nodular mass

Surface elevation: Schematic

Slide 43 · Nodular KS: Sheets of spindle cells

Editable concept schematic — not a patient image or histologic specimen

Plump spindle cells form cellular sheets.

Small vessels and slit-like channels containing erythrocytes remain present.

Mitoses can be common, reflecting active proliferation.

Spindle-cell sheets + small slits

Slide 44 · Slit-like spaces contain erythrocytes

Editable concept schematic — not a patient image or histologic specimen

Small irregular slit-like spaces interrupt the spindle-cell proliferation.

Erythrocytes within these spaces emphasize the vascular nature of the neoplasm.

This is a hallmark of the nodular architectural pattern.

Blood-containing slit-like spaces

Slide 45 · Hemorrhage and hemosiderin explain pigmentation

Mechanism / clinical sequence — schematic

Red-cell leakage

Macrophage clearance

Hemosiderin deposition

Extravasated red cells contribute to the hemorrhagic appearance.

Macrophages remove red-cell debris and may accumulate hemosiderin.

Slide 46 · Eosinophilic globules in nodular KS

Round pink cytoplasmic globules may occur within spindle-cell lesions.

Robbins interprets these as degenerating red cells within phagolysosomes.

The finding accompanies, rather than replaces, assessment of the overall vascular pattern.

Slide 47 · Nodular progression may precede systemic spread

Mechanism / clinical sequence — schematic

Nodular spindle-cell lesion

Possible nodal disease

Possible visceral disease

The nodular stage often heralds lymph-node or visceral involvement.

This association is clinical, not proof that every nodule has disseminated.

Slide 48 · Three stages: How morphology changes

Patch

Subtle vascular spaces; Inflammatory cells

Plaque

Jagged vascular channels with plump spindle cells

Nodule

Dense spindle-cell sheets with erythrocyte-containing slits

Nodular stage becomes a dense neoplasm with slit-like spaces.

Slide 49 · Microanatomy mirrors gross progression

Mechanism / clinical sequence — schematic

Vascular dilation

Spindle-cell-rich plaque

Confluent cellular nodule

A flat lesion is often architecturally subtle.

Raised plaques correlate with more abundant dermal cells and channels.

Slide 50 · Clinical behavior depends on context and extent

Local disease

Often suitable for local measures

Disseminated disease

May need systemic and immune-directed measures

Classic, iatrogenic and epidemic settings therefore require different approaches.

Slide 51 · Classic KS: Local treatment

Mechanism / clinical sequence — schematic

Skin-limited lesions

Local resection / radiation

Favorable control

Surgical resection is commonly adequate for limited classic cutaneous KS.

Radiation can be used for several lesions within a restricted region.

Slide 52 · Widespread KS often warrants systemic therapy

The source describes chemotherapy as helpful for disseminated lesions.

Nodal involvement changes the management context.

Treatment choice follows disease extent rather than visible skin color alone.

Slide 53 · Iatrogenic KS: Modify the immune environment

Mechanism / clinical sequence — schematic

Review immunosuppression

Potential KS response

Graft-rejection risk

Reducing immunosuppression may cause KS regression.

Local or systemic therapies may be adjuncts when necessary.

Slide 54 · Epidemic KS: Immune restoration is important

Mechanism / clinical sequence — schematic

Antiretroviral therapy

Improved host context

Possible KS control

Antiretroviral drugs are generally beneficial in AIDS-associated KS.

Additional therapy may be needed depending on disease burden.

Slide 55 · Management contrasts across clinical settings

Classic

Excision; Focal radiation when appropriate

Iatrogenic

Reduce immunosuppression if feasible; Graft risk

AIDS-associated

Antiretroviral drugs ± other therapy

AIDS-associated disease depends strongly on antiretroviral treatment.

Slide 56 · Hemangioendothelioma: A borderline spectrum

Hemangioendotheliomas are vascular tumors between hemangioma and angiosarcoma in biologic behavior.

The category is heterogeneous rather than a single uniform prognosis.

Epithelioid hemangioendothelioma as the named example.

Slide 57 · Epithelioid hemangioendothelioma: An adult tumor

Editable concept schematic — not a patient image or histologic specimen

Epithelioid hemangioendothelioma (EHE) occurs in adults.

Its occurrence around medium-sized and large veins.

Its relation to veins is an anatomic clue to its vascular origin.

Vein-associated epithelioid cells

Slide 58 · EHE: Epithelioid cells obscure the vascular nature

Tumor cell shape

Plump · cuboidal · epithelioid

Vascular lumina

May be difficult to identify

The name “epithelioid” describes cytomorphology, not epithelial origin.

Slide 59 · EHE: Outcome is variable

Many EHE cases are cured by excision.

A clinically important subset behaves aggressively.

Approximately 25% five-year mortality; This is a textbook estimate, not individual risk prediction.

Some EHE behaves aggressively despite frequent excision cure

Slide 60 · Why EHE remains an intermediate-grade category

Mechanism / clinical sequence — schematic

Often excision-curable

Variable outcome

Some serious mortality

Frequent curability by excision argues against universal high-grade malignancy.

The reported five-year mortality argues against a uniformly benign label.

Slide 61 · Kaposi sarcoma versus EHE

Kaposi sarcoma

HHV8-related; Patch → plaque → spindle-cell nodule

Epithelioid hemangioendothelioma

Adult tumor near veins; Cuboidal cells; Obscure channels

Shared intermediate-grade placement does not imply common etiology or appearance.

Slide 62 · Intermediate-grade versus angiosarcoma

Intermediate-grade

Kaposi sarcoma; Hemangioendothelioma — behavior varies

Malignant

Angiosarcoma — invasive with metastatic potential

EHE and KS should not automatically inherit the same prognosis or treatment as angiosarcoma.

Slide 63 · KS versus bacillary angiomatosis

Kaposi sarcoma

HHV8; Spindle-cell-rich vascular lesion

Bacillary angiomatosis

Bartonella; Vascular proliferation + neutrophils; Antibiotics clear infection

It is a treatable infection; KS is HHV8-associated neoplasia.

Slide 64 · Case: Indolent distal cutaneous lesions

An older man develops multiple slowly increasing violaceous plaques on the lower legs.

Pathology interpretation

The lesions are otherwise asymptomatic and remain skin-predominant. Most consistent Robbins clinical form: Classic Kaposi sarcoma.

Slide 65 · Case: Systemic lesions after transplantation

A transplant recipient on T-cell suppression develops lymph-node and mucosal KS.

Pathology interpretation

There may be no characteristic cutaneous plaque. This setting demonstrates iatrogenic KS and the graft-versus-tumor management conflict.

Slide 66 · Case: HIV-associated disseminated KS

A patient with AIDS presents with vascular lesions and early visceral spread.

Pathology interpretation

The neoplasm is driven by HHV8, in a permissive immunodeficient host. Antiretroviral therapy is a core treatment consideration.

Slide 67 · Case: Epithelioid vascular tumor near a vein

An adult has a vascular neoplasm centered near a large vein.

Pathology interpretation

Cells are plump and cuboidal; Recognizable vascular lumina are sparse. This pattern is compatible with epithelioid hemangioendothelioma in the Robbins framework.

Slide 68 · Mechanism check: Why can HHV8 drive growth?

Complementary mechanisms — schematic

Lytic

VEGF + cytokines

Latent

Cell cycle + survival

Both mechanisms increase the expansion advantage of infected vascular cells.

Slide 69 · Morphology check: Which stage is this?

Patch

Macule

Irregular spaces; Inflammation

Plaque

Raised

Jagged channels; Spindle cells

Nodule

Mass

Spindle-cell sheets; RBC slits

Schematic — not a photograph or histologic specimen

Spindle-cell sheets with blood-containing slits: Nodule.

Slide 70 · Integrated clinicopathologic synthesis

Begin with the vascular-tumor classification and exclude reactive mimics.

For KS, integrate HHV8 biology with immune setting and morphologic stage.

For EHE, recognize epithelioid cells, venous association and variable behavior.

Always distinguish local cutaneous disease from nodal/visceral involvement.

Slide 71 · Principal reference and scope

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Vascular tumors: intermediate-grade (borderline) neoplasms and immediate comparator entities.

Course material derives from the supplied textbook extraction; no external updates or unsourced diagnostic assays have been added.

Morphology schematics are conceptual teaching drawings, not textbook images or histology specimens.